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Notes: Abstract: The incidence of breast cancer and mortality from this disease remain high in countries with limited resources such as the Ukraine. Because of a lack of mammography equipment and formal screening programs, as well as educational and other factors, breast cancer is usually diagnosed in late stages in such countries. We report the experience of the PATH Breast Cancer Assistance Program in introducing a pilot breast cancer screening program in one territory of the Ukraine, the Chernihiv oblast. The program entailed educating the public, training health care providers in clinical breast examination (CBE) and mammography, opening a dedicated mammography facility, designating a center for breast cancer care, building diagnostic capacity, and fostering the formation of support groups. From 1998 to 2002, 18,000 women underwent screening with CBE and 8778 women underwent screening with mammography. When implementing the program we encountered various cultural, economic, and logistic difficulties, such as reservations about showing bare breasts in educational materials, the lack of an established system for collecting screening data, and barriers to follow-up in women with positive screening results. Screening mammography proved to be more effective in detecting small and nonpalpable lesions; 8.7% of cancers detected in the mammography group were in situ, compared with 0% in the CBE group. However, introduction of CBE as a screening modality required fewer financial resources compared with mammography and was recommended as a transitional method before the introduction of mammography screening programs in countries with limited resources. The introduction of screening was associated with favorable changes in indicators of breast cancer care, including an increase in the percentage of breast-preserving operations and new legislation to provide funding for breast cancer services. We conclude that this successful pilot program of breast cancer screening in a limited-resource setting can serve as an example for other similar programs. 

Notes: Abstract: Mammography is the most sensitive available means for early detection of breast cancer, but both clinical breast examination (CBE) and breast self-examination (BSE) have the potential to advance the diagnosis of breast cancer without the expense of a mammography facility. CBE detects about 60% of cancers detected by mammography, as well as some cancers not detected by mammography. There have been no randomized trials comparing breast cancer mortality between women offered and not offered CBE. However, indirect evidence comes from a Canadian study in which women were randomly assigned to CBE alone or CBE plus mammography. Women in the two groups had similar rates of nodal involvement at diagnosis and of breast cancer mortality. Thus if receipt of mammography averts some deaths from breast cancer, the results of this study suggest that CBE has the potential to do so as well. Most studies have found that breast cancers detected by BSE are smaller than those detected without screening and are more likely to be confined to the breast; furthermore, survival after a diagnosis of breast cancer tends to be longer among women who practice BSE than among women who do not. However, neither observational nor randomized studies of BSE provide evidence that this screening modality reduces breast cancer mortality. A recent randomized study in Shanghai, China, found that women assigned to extensive BSE instruction and women assigned to another health intervention had similar distributions of cancer size and stage at diagnosis and similar breast cancer mortality rates. In summary, CBE appears to be a promising means of averting some deaths from breast cancer, whereas BSE appears to have little or no impact on breast cancer mortality. 

Notes: Abstract: Minimally invasive breast biopsy techniques, such as core needle biopsy (CNB) and fine-needle aspiration biopsy (FNAB), offer several advantages over surgical biopsy. Patients in whom minimally invasive biopsy techniques are used may undergo biopsy more quickly, are more likely to have only one surgery for treatment of the breast tumor and axillary staging, and are less likely to need reoperation after breast-conserving surgery because of positive margins. Knowledge of a diagnosis of cancer before surgery allows patients to participate in treatment decisions, and compared with surgical biopsy, minimally invasive biopsy has lower costs, produces less scarring, has nearly equivalent diagnostic accuracy, and does not require general anesthesia or sedation. Minimally invasive biopsy can permit accurate diagnosis and prompt intervention in a cost-effective manner, particularly in countries with limited resources, where patients often present with advanced-stage breast cancer. Several events characterize the implementation of a successful program in minimally invasive breast biopsy: public education about the less invasive nature of these techniques, which may encourage women to seek care at earlier stages; a change in the philosophy of medical personnel that favors involving patients in treatment decisions and acceptance of less extensive but accurate methods of diagnosis; education of medical personnel in the selection of patients for minimally invasive biopsy, performance of the biopsy, and interpretation of histologic and/or cytologic samples; quality assessment and use of the triple test (i.e., correlation of clinical, radiologic, and pathologic findings); and economical use of resources, which results from the lower costs of minimally invasive procedures and the avoidance of unnecessary surgery for benign conditions. 

Notes: Abstract: Genomic instability is one of the earliest features of cancer cell behavior and can lead to gene mutation, amplification, or deletion. Rarely one of these genomic events can give the cell a growth advantage or some other characteristic that contributes to carcinogenesis and also leads to clonal expansion. Solid tumors contain numerous genetic abnormalities and these vary among individuals. New techniques from the laboratory allow unprecedented levels of detail in cancer genetic analysis of human tumors. One technique called comparative genomic hybridization (CGH) can pinpoint areas of the genome that are amplified or deleted. These changes that occur at a high frequency are likely to represent genes that are important in cancer development and progression. How can this be translated into new biologic therapy as well as a better understanding of factors that predict responses to standard chemotherapy to allow better individualized tailoring of treatment? Through the linkage of CGH data on human tumors to their clinical outcomes, specific questions can be asked about the relationship of specific genes to clinical variables. For example, genes that are gained in patients who are resistant to anti-HER-2 antibody (Herceptin) might help select patients for such therapy or identify genes that could be pharmacologically targeted to overcome Herceptin resistance. Prospects for better treatment and recent advances in genomic research may lead to an increased understanding of the basic mechanisms resulting in initiation and progression of breast cancer. 

Notes: Abstract:  Trastuzumab is a humanized monoclonal antibody against the epidermal growth factor family oncogene, Her-2/neu. It has revolutionized therapy for the 15–20% of patients with metastatic breast cancer whose tumors have gene amplification for Her-2/neu. Results of clinical trials with single agent trastuzumab and in combination with paclitaxel, docetaxel, vinorelbine, gemcitabine and platinum salts have been encouraging. Durable remissions in excess of 5 years have occasionally been reported. Subjectively the side effect profile of this novel, targeted therapy, has been mild. Cardiac toxicity, while reported in combination regimens with anthracyclines tend to be easily manageable and not absolute contradictions to continuation of trastuzumab. Outside of clinical trials, however, anthracycline/trastuzumab combinations should be avoided. Preliminary results of trials with various combinations of chemotherapeutic agents have been promising while combinations with hormonal and other biologic therapy are ongoing. Trastuzumab is an exciting new monoclonal antibody with interesting anti-tumor activity in patients with Her-2/neu gene amplified breast cancer. We look forward to ongoing clinical trials combining trastuzumab with a broad array of other chemotherapeutic, hormonal and biological agents.

Notes: Background. Dyspepsia is a very common problem in Thailand. Etiology of gastritis, incidence of Helicobacter pylori and mode of transmission of Helicobacter pylori infection in the country was proposed.Methods. A nation-wide study of gastric biopsy in 3776 dyspeptic patients from six different geographic regions for incidence of gastritis, type of gastritis, incidence of H. pylori infection, gastric atrophic change and intestinal metaplasia in three age-groups of each region was done.Results. 58.7% of dyspeptic patients had histological gastritis. Pangastritis was the most common type (77.3%) with mostly mild active inflammation (60.6%) and was found most commonly in the age group 31–60 years. Incidence of gastritis was slightly lower in the coastal and peninsular community compared with the mountain, jungle, semiarid plateau and fertile plain communities. Geographic factor, socioeconomic status and dietary habit were proposed to be important factors in inducing gastritis. H. pylori infection was found in 48.2% of dyspeptic patients with high incidence in the age-group 31–60 years (63.7%) and 98.2% of H. pylori infection was found to be associated with gastritis. Semi-arid plateau, mountain, jungle and fertile plain communities had high incidences of H. pylori infection varying from 54.0 to 67.1% while the coastal and peninsular communities had low incidences of 32%. Oral to oral spread is proposed to be the mode of bacterial transmission. Incidences of gastric atrophic change and intestinal metaplasia were low in this country and were found in 11.6% and 8.2% of subjects, respectively, with no significantly different distribution in geographic regions. Type I or intestinal type was found to be the most common type of intestinal metaplasia.

Notes: Background. Helicobacter pylori CagA is injected into the host cell and tyrosine-phosphorylated. We examined tyrosine-phosphorylation sites of CagA, as well as the function of CagA proteins in vivo and in vitro.Methods. After proteolytic digestion of CagA with lysyl endopeptidase, CagA tyrosine-phosphorylation sites were determined using quadropolar time-of-flight (Q-TOF) mass spectrometry analysis. Specific anti-pY CagA polyclonal and anti-CagA monoclonal antibodies were used to examine gastric mucosal biopsy specimens from H. pylori infected patients.Results. Mass spectrometry identified five crucial tyrosine-phosphorylation sites of CagA at Tyr893, Tyr912, Tyr965, Tyr999, and Tyr1033 within the five repeated EPIYA sequences of H. pylori (NCTC11637)-infected AGS cells. CagA protein also had an immuno-receptor tyrosine-based activation motif (ITAM)-like amino acid sequences in the 3′ region of the cagA, EPIYATIx27EIYATI, which closely resembled the ITAM. CagA proteins: (i) were localized to the 1% TritonX-100 resistant membrane fraction (lipid rafts); (ii) formed a cluster of phosphorylated CagA protein complexes; (iii) associated with tyrosine-phosphorylated GIT1/Cat1 (G protein-coupled receptor kinase-interactor 1/Cool-associated tyrosine-phosphorylated 1), substrate molecules of receptor type protein-tyrosine phosphatase (RPTPζ/β), which is the receptor of VacA; and (iv) were involved in a delay and negative regulation of VacA-induced signal. Furthermore, immunohistochemical staining of gastric mucosal biopsy specimens provided strong evidence that tyrosine-phosphorylated CagA is found together with CagA at the luminal surface of gastric foveola in vivo.Conclusion. These findings suggest an important role for CagA containing ITAM-like sequences in the pathogenesis of H. pylori-related disease.

Notes: Background & Aims. The acid inhibitory effect of proton pump inhibitors is reported to be greater in the presence than in the absence of an H. pylori infection. This study was undertaken to test the hypothesis that the acid inhibitory effect of omeprazole given twice a day is greater in H. pylori infected healthy volunteers than in the same individuals following eradication because of differences in the pharmacodynamics of omeprazole, greater duodenogastric reflux, the effects of ammonia produced by the H. pylori, or lower gastric juice concentrations of selected cytokines, which may inhibit gastric acid secretion.Materials and Methods. We undertook 24-hour pH-metry in 12 H. pylori-positive healthy volunteers: (1) when on no omeprazole; (2) when on omeprazole 20 mg bid for 8 days; (3) 2 months after eradication of H. pylori and when on no omeprazole; and (4) after eradication of H. pylori and when on omeprazole 20 mg twice a day.Results. In subjects given omeprazole, eradication of H. pylori reduced pH and percentage pH ≥ 3, as well as increasing the area under the H+ concentration-time curve. These differences were not due to alterations in (1) gastric juice concentrations of IL-1α, IL-8, IL-13, epidermal growth factor, or bile acids; (2) serum gastrin concentrations; or (3) the pharmacokinetics of omeprazole. There was no change in the difference in the H+ concentration-time curve ‘without omeprazole’ minus ‘with omeprazole’, when comparing ‘after’ versus ‘before’ eradication of H. pylori.Conclusions. Eradication of H. pylori was not associated with an alteration in the acid inhibitory potency when comparing the difference in gastric acidity ‘with’ versus ‘without’ omeprazole. When the results were expressed by simply taking into account the acid measurements while on omeprazole before versus after eradication of H. pylori, the acid inhibition with omeprazole was greater in the presence than in the absence of a H. pylori infection. The clinical significance of the small difference is not clear.

Notes: Abstract: Sentinel lymph node biopsy (SLNB) is widely employed to detect axillary lymph node metastases in breast cancer patients with clinically negative (N0) axillae. One of the few reported contraindications to SLNB is prior treatment with systemic chemotherapy (neoadjuvant/induction chemotherapy). Previous investigators reported difficulty identifying the sentinel node and an unacceptable false-negative rate in this patient cohort. We present one experienced surgeon's experience with SLNB following induction chemotherapy (n = 21). Following treatment with Adriamycin and Cytoxan (AC)-based cyclic chemotherapy, patients underwent SLNB, followed by levels I and II axillary lymph node dissection (ALND). At least one sentinel node was identified in all patients (100%). With respect to metastatic disease, the status of the sentinel node(s) accurately reflected the status of the axilla in 20 of 21 patients (95%). Eleven patients (52%) had axillary metastases identified by ALND. Of this group, SLNB failed to identify metastatic disease in one patient (9%). Previous treatment with induction chemotherapy should not be considered an absolute contraindication to SLNB. An experienced surgeon may utilize the technique in these patients, sparing them the added morbidity of axillary dissection. 

Notes: Abstract: Standard practice in surgical pathology dictates that random sections from the four quadrants of the breast be taken in mastectomy specimens. These sections are obtained in addition to sampling of any grossly visible lesions within the breast specimen. While tradition dictates the submission of these sections, we are unaware of any study supporting their efficacy. We have investigated the utility and significance of these random sections in a series of 78 mastectomy specimens. This retrospective study identified mastectomy specimens from pathology files of Magee Woman's Hospital, the University of Pittsburgh, and the University of Utah School of Medicine between 1997 and 2000. Clinical data (palpable versus nonpalpable), radiographic features (mammographic diagnosis, presence of mass density and/or calcification), and pathologic features (size, histopathologic type, etc.) were studied. The histologic sections of the cases were reviewed and the random sections were specifically studied for pathologic findings. Diagnosis and clinically significant features obtained from examining these random sections, but not demonstrable in grossly selected sections, were tabulated. A total of 78 mastectomy specimens were analyzed. Diagnoses rendered were infiltrating ductal carcinoma (23), infiltrating ductal carcinoma with ductal carcinoma in situ (DCIS) (16), DCIS (25), infiltrating lobular carcinoma (4), biopsy cavity with no residual malignancy (4), infiltrating lobular carcinoma with lobular carcinoma in situ (3), invasive ductal and lobular carcinoma (1), adenoid cystic carcinoma (1), and atypical ductal hyperplasia (1). The number of random sections ranged from 2 to 17 (mean 9). Random sections provided additional information in 21 of 78 mastectomies (27%). The multifocal/multicentric nature of the lesion was diagnosed in 20 cases: DCIS (6), lobular carcinoma in situ and invasive (2), invasive ductal carcinoma (6), invasive and in situ ductal carcinoma (5), invasive lobular carcinoma (1), invasive ductal and lobular carcinoma (1). Additional findings include lymphovascular invasion (2 cases), atypical ductal hyperplasia (1), DCIS at the operative margin (1), DCIS within less than 1 mm of an operative margin (1), and atypical lobular hyperplasia (1). In the remaining 57 cases, random sections did not provide any additional information. Histologic examination of random sections from breast quadrants yielded important information about the presence of multifocality, multicentricity, vascular invasion, and margin involvement by carcinoma in only a minority of cases, many of which had a lobular morphology. 

Notes: Abstract: Nodular fasciitis is a soft tissue lesion that in rare instances occurs in the breast. It can clinically and radiologically mimic malignant tumor. We describe a case of nodular fasciitis of the breast in a young woman that was misdiagnosed as phyllodes tumor. The histologic features and a review of the literature are presented. Awareness of such an entity in the breast obviates the need for unnecessary surgical intervention.

Notes: Abstract:  This study examines proliferative activity in tumor cells of patients with histologically documented invasive breast carcinoma treated with magnetic resonance-guided interstitial laser photocoagulation (MR-GILP). Immunohistochemical marker for proliferating cell nuclear antigen (PCNA), a nuclear protein abundant in actively proliferating cells, is used. The study demonstrates the effectiveness of MR-GILP in ablating tumor cells of infiltrating breast cancer. The diagnosis of infiltrating breast carcinoma was confirmed by core needle biopsies. Using a specially designed magnetic resonance imaging (MRI) device, rotating delivery of excitation off-resonance (RODEO), tumors were measured ranging from 1.8 to 4.0 cm in greatest dimension. Seven formalin-fixed, paraffin-embedded archival tissues from seven patients with infiltrating carcinoma, status post-MR-GILP, were analyzed. Using PCNA immunoperoxidase (Biomeda Corp.), the proliferative capability of the remaining tumor cells around the focus of laser photocoagulation was determined. The lesions were digitally acquired using a Nikon Eclipse E800 microscope with an automated stage. Images were analyzed using Cool SNAP image editing software (version 1.0). Appropriate thresholds were set for positive staining and limited concentric radial measurements of equal area between all samples were compared at radial millimeter intervals from the center of laser ablation. The integrated area occupied by PCNA-positive cells per radial millimeter from the charcoal site (the center of the laser) increased as the distance from this site increased (a mean average at each radial measurement revealed: at the 1 mm radius the positive integrated area was 0.0024 mm2; at 2 mm, 0.0145 mm2; at 3 mm, 0.0351 mm2; at 4 mm, 0.0696 mm2; at 5 mm, 0.1025 mm2; and at 6 mm, 0.1263 mm2). MR-GILP is an effective mean of ablating breast carcinoma. This treatment option may represent an alternative to lumpectomy for a single lesion ≤1 cm, or make patients with two separate lesions eligible for lumpectomy.

Notes: Abstract: The purpose of this study was to determine the frequency with which low-literacy patients in a developing country chose their treatment plan. In this study, data for 312 patients admitted to different hospitals in Egypt were reviewed regarding their disease stage, optimal management plan, and treatment. It was found that the majority of patients were primarily concerned with keeping their breasts, regardless of the disease stage. 

Notes: Abstract: Twenty-three patients with inflammatory breast cancer treated with a combined modality approach including anthracycline-based induction chemotherapy-surgery-chemotherapy-radiotherapy were reviewed. Twelve patients (52.2%) received FAC (5-fluorouracil, adriamycin, cyclophosphamide) and 11 patients (47.8%) were treated with FEC (5-fluorouracil, epirubicin, cyclophosphamide) induction chemotherapy for three cycles every 3 weeks. Surgery was followed by the initial chemotherapy or second-line chemotherapy for an additional six cycles to complete nine cycles and radiotherapy, respectively. The median overall survival (OS) time was 27 months and the median disease-free survival (DFS) was 13 months. Furthermore, patients treated with FAC induction chemotherapy have been found to have longer median OS and DFS periods compared to patients with FEC induction chemotherapy in both univariate and multivariate analysis. In conclusion, the superiority of doxorubicin-containing chemotherapy over epirubicin-containing chemotherapy should be established in larger randomized studies and more effective chemotherapeutic agents such as taxans are required for better survival rates in inflammatory breast cancer patients. 

Notes: Abstract: The management of lobular neoplasia (LN) found on percutaneous core biopsy remains a clinical dilemma. The purpose of this study was to establish guidelines for the management of LN when obtained on percutaneous core needle biopsy. A retrospective review of the Breast Imaging Tissue Sampling Database at New York Presbyterian Hospital–Columbia Comprehensive Breast Center was performed from 1998 to 2000. A total of 1460 percutaneous core breast biopsies were performed using 11- or 14-gauge needles with LN identified in 43 biopsies from 34 patients. Eleven biopsies were ultrasound guided for nonpalpable masses and 32 were stereotactically guided for mammographically detected densities (10) and microcalcifications (22). The 43 LN biopsies were divided into three groups based on additional findings associated with LN on core biopsy: group I (n = 19), LN with invasive cancer or ductal carcinoma in situ (DCIS); group II (n = 11), LN plus a second indication for open surgical biopsy, such as atypical ductal hyperplasia (ADH), radial scar, phyllodes tumor, or intraductal papilloma; and group III (n = 13), LN plus benign fibrocystic changes. In group I, 19 of 19 biopsies (100%) yielded invasive cancer or DCIS on surgical biopsy versus 3 of 11 (27%) for group II, and 1 of 13 (8%) for group III. Outcomes in group III are described as follows: three patients were lost to follow-up, three patients did not undergo surgical biopsy but demonstrated more than 1 year of mammographic stability following core biopsy. Of the remaining seven patients, two had LN and ADH on surgical biopsy (one had a contralateral cancer), one had atypical lobular hyperplasia (with a contralateral cancer), two had LN and benign fibrocystic changes, one had LN and intraductal papilloma, and one had LN and invasive ductal carcinoma (IDC) with DCIS (with a contralateral cancer). These results suggest that surgical biopsy is indicated for patients with LN when found on core biopsy and when the biopsy demonstrates invasive cancer, DCIS, or other indications for surgical biopsy such as ADH, or in the examination of a patient with a synchronous contralateral breast cancer. The diagnosis of LN alone without these indications on percutaneous biopsy may not warrant routine surgical biopsy. 

Notes: Abstract: Invasive lobular carcinoma (ILC) may be a difficult tumor to detect early by physical examination, mammography, or ultrasound. We undertook this study to describe the spectrum of gadolinium enhancement and morphologic features of ILC on magnetic resonance imaging (MRI). Nineteen patients with ILC who presented with a palpable mass, a mammographically visible abnormality, or an unknown primary underwent preoperative MRI of both breasts using a T1-weighted high-resolution gradient echo sequence (pre- and postcontrast), and an echoplanar sequence during the administration of gadolinium. Using a quantitative measure of gadolinium uptake over time, called the extraction flow (EF) product, and a normal tissue threshold EF level of 25 or less, enhancement for 15 of the 19 cancers was characterized. By consensus, three radiologists categorized the morphologic features of the lesions. For the 15 cases of ILC that had echoplanar data, analysis showed peak EFs ranging between 25 and 120, and the majority showed EFs in the 30s. A substantial portion of two tumors enhanced in a similar fashion to normal breast tissue, with EFs in the low 20s. Morphologically MRI showed a focal mass in eight cases, regional enhancement in five, segmental enhancement in one, segmental enhancement with multiple small nodules in one, a mixture of a focal mass and regional enhancement in one, diffuse enhancement in one, multiple small nodules in one, and bilateral disease in one. Of the focal masses, seven were irregular in shape and one was round; six had ill-defined margins and two had spiculated margins. All eight enhanced heterogeneously. Four cases had multifocal disease and one case had unsuspected contralateral disease discovered only on MRI. MRI using a combination of morphology and a quantitative measure of gadolinium uptake was able to detect the majority of cases of ILC. However, there was a variable morphologic appearance and contrast enhancement pattern on MRI. A few lesions were difficult to distinguish from normal tissue. This suggests that some cases of ILC may be difficult to detect on MRI. 

Notes: The mechanisms by which Helicobacter pylori escape the host immune response remains an important topic. Regulatory T cells appear to play a role in the persistence of the infection and the control of tissue damage. In the thought that the host genetic background influences the cross-talk between pathogens and hosts, the impact of cytokine polymorphisms on the outcome of H. pylori has been further delineated in the review period. On the other hand, several additional genes of H. pylori have been shown to participate in the pro-inflammatory cytokine and chemokine response to the infection. Finally, progress has been achieved in vaccine development, with new vaccine delivery systems and routes of immunization tested in animal models and human volunteers.

Notes: Numerous studies are still published on diagnostic tests for Helicobacter pylori, essentially for noninvasive tests. The urea breath test is applied in different types of patients, and there are attempts to have quicker and simpler protocols. Stool tests using monoclonal antibodies are now evaluated while serology is still a subject of interest. The progress in PCR (multiplex PCR, real-time PCR) has also stimulated the research in this area of invasive tests, in order to get insight into virulence factors, macrolide susceptibility and to detect H. pylori in nonconventional specimens.

Notes: Abstract: Breast cancer treatment and research is becoming more multidisciplinary in nature. Several modalities and areas of expertise are critical for optimal patient management. The basis for medical decisions and recommendations must reflect outcomes and clinical trial data that are designed and interpreted with broad input across different fields. Hence there has been a trend for specialization in breast disease in many large community and academic practices. Furthermore, a system of communication and standardization of data values, procedures, and protocols has begun, but needs much further development. There are many natural barriers to the process of multidisciplinary care and research in terms of logistics, finances, and education. The example of preoperative neoadjuvant therapy for early stage locally advanced breast cancer is one that involves multiple disciplines in the formulation of a treatment and in future research that will define the optimal individualized approach. This process can also shed further light on biologic principles and potential for improved treatment. Solutions for overcoming barriers to multidisciplinary care should include incentives for collaborative and coordinated clinical care across disciplines. A model of increased efficiency because of pooled resources and specialization in several fields should also be accompanied by a demonstration of increased quality of care and patient satisfaction. Any process that adds to cost or inconvenience needs to be justified in an evidence-based manner. Finally, these initiatives need to be effectively communicated to the professional and policy-making communities and to the public at large through well-conceived and unbiased educational venues. 

Notes: The healing process in acute wounds has been extensively studied and the knowledge derived from these studies has often been extrapolated to the care of chronic wounds, on the assumption that nonhealing chronic wounds were simply aberrations of the normal tissue repair process. However, this approach is less than satisfactory, as the chronic wound healing process differs in many important respects from that seen in acute wounds. In chronic wounds, the orderly sequence of events seen in acute wounds becomes disrupted or “stuck” at one or more of the different stages of wound healing. For the normal repair process to resume, the barrier to healing must be identified and removed through application of the correct techniques. It is important, therefore, to understand the molecular events that are involved in the wound healing process in order to select the most appropriate intervention. Wound bed preparation is the management of a wound in order to accelerate endogenous healing or to facilitate the effectiveness of other therapeutic measures. Experts in wound management consider that wound bed preparation is an important concept with significant potential as an educational tool in wound management.This article was developed after a meeting of wound healing experts in June 2002 and is intended to provide an overview of the current status, role, and key elements of wound bed preparation. Readers will be able to examine the following issues;• the current status of wound bed preparation;• an analysis of the acute and chronic wound environments;• how wound healing can take place in these environments;• the role of wound bed preparation in the clinic;• the clinical and cellular components of the wound bed preparation concept;• a detailed analysis of the components of wound bed preparation. (WOUND REP REG 2003;11:1–28)

Notes: Arginine is a basic amino acid that plays several pivotal roles in cellular physiology. Like any amino acid, it is involved with protein synthesis, but it is also intimately involved with cell signaling through the production of nitric oxide and cell proliferation through its metabolism to ornithine and the other polyamines. Because of these multiple functions, arginine is an essential substrate for wound healing processes. Numerous studies have shown that arginine supplementation can lead to normalization or improvement of healing. This article reviews the basic biochemistry and cell signaling within which arginine performs its functions. In particular, the requirement for this amino acid in tissue repair is highlighted. (WOUND REP REG 2003;11:419–423)

Notes: The orthodox view has been that reactive oxygen species are primarily damaging to cells. There is general agreement that while high (3%) doses of H2O2 may serve as a clinical disinfectant, its overall effect on healing is not positive. Current work shows that at very low concentrations, reactive oxygen species may regulate cellular signaling pathways by redox-dependent mechanisms. Recent discoveries show that almost all cells of the wound microenvironment contain specialized enzymes that utilize O2 to generate reactive oxygen species. Numerous aspects of wound healing are subject to redox control. An understanding of how endogenous reactive oxygen species are generated in wound-related cells may influence the healing process and could result in new redox-based therapeutic strategies. Current results with growth factor therapy of wounds have not met clinical expectations. Many of these growth factors, such as platelet-derived growth factor, rely on reactive oxygen species for functioning. Redox-based strategies may serve as effective adjuncts to jump-start healing of chronic wounds. The understanding of wound-site redox biology is also likely to provide novel insights into the fundamental mechanisms that would help to optimize conditions for oxygen therapy. While a window of therapeutic opportunity seems to exist under conditions of low concentrations of reactive oxygen species, high levels may complicate regeneration and remodeling of nascent tissue. (WOUND REP REG 2003;11:431–438)

Notes: The foot ulcer is one of most common and devastating complications of diabetes and is associated with considerable morbidity and mortality. The major causes of these ulcers are ischemia/hypoxia, neuropathy, and infection, and they often coexist. Despite conventional therapy including revascularization procedures when appropriate, three situations lead frequently to amputation: persistent critical limb ischemia, soft tissue infection, and impaired wound healing from osteomyelitis. In these conditions, hyperbaric oxygen therapy may be used as an adjunctive treatment and is associated with a better outcome. Randomized, prospective, controlled trails have shown the benefit of hyperbaric oxygen therapy in diabetic ulcers of the lower extremity. Transcutaneous oxygen measurement performed under hyperbaric oxygen therapy has a prognostic significance when used to select patients who are the most likely to benefit from therapy. Hyperbaric oxygen should be added to conventional treatment if the transcutaneous oxygen tension close to the trophic lesion in 2.5 ATA hyperbaric oxygen is over 200 mmHg. Peri-wound transcutaneous oxygen tensions over 400 mmHg in 2.5 ATA hyperbaric oxygen or over 50 mmHg in normobaric pure oxygen predict healing success with adjuncted hyperbaric oxygen therapy with high accuracy. (WOUND REP REG 2003;11:458–461)

Notes: Smad3 is involved in mediating intracellular signaling by members of the transforming growth factor-β superfamily and plays a critical role in the cellular proliferation, differentiation, migration, and elaboration of matrix pivotal to cutaneous wound healing. Cross-talk between Smad3 and hormone signaling in vitro has been suggested as an important control mechanism regulating cell activities; however, its relevance in vivo is unknown. Here we report that Smad3 plays a role in androgen-mediated inhibition of wound healing but not in the responses to estrogen modulation in vivo. Both wild-type and Smad3 null female mice exhibited delayed healing following ovariectomy, which could be reversed by estrogen replacement. By contrast, castration accelerated healing in wild-type male mice and was reversible by exogenous androgen treatment. Intriguingly, modulation of androgen levels resulted in no discernible perturbation in the healing response in the Smad3 null mice. Mutant monocytes could be lipopolysaccharide stimulated to produce specific pro-inflammatory agents (macrophage monocyte inhibitory factor) in a fashion similar to wild-type cells, but exhibited a muted response to androgen-mediated stimulation while maintaining a normal response to estrogen-induced macrophage inhibitory factor inhibition. These data suggest that Smad3 plays a role in mediating androgen signaling during the normal wound healing response and implicate Smad3 in the modulation of inflammatory cell activity by androgens. (WOUND REP REG 2003;11:468–473)

Notes: The participation of fibroblasts in wound repair is a coordinated effort requiring sequential cellular modulations to behavior including migration (entering), proliferation (increasing cell numbers), synthesis (depositing a collagen matrix), remodeling (organizing collagen), transformation into myofibroblasts, apoptosis, and elimination. Disruptions in that orderly sequence of behaviors will alter repair. Insights into controlling wound repair have focused on soluble factors such as cytokines and growth factors. Here we examine the direct communications between coupled cells through gap junctional intercellular communications. Molecules of less than 1000 MW pass directly between cells through gated gap junction channels. Sugars, amino acids, and oxygen, as well as second messengers such as cAMP, inositol phosphates, and calcium can pass directly between coupled cells. Does gap junctional intercellular communication affect fibroblast phenotype progression in granulation tissue maturation? In rats gap junctional intercellular communication uncouplers heptanol and endosulfan were injected daily into polyvinyl alcohol sponge implants. At 7 days, uncoupler-treated implants had capsules with increased fibroblast density, reduced cell penetration into the sponge, and diminished numbers of myofibroblasts. By polarized light, the uncouplers reduced the deposition and organization of collagen and thereby disrupted the coordinated phenotypic changes seen in fibroblasts during the repair process. It is proposed that gap junctional intercellular communication is critical for fibroblast progression from migratory cell to apoptosis as granulation tissue matures into scar. (WOUND REP REG 2003;11:481–489)

Notes: Work from Tom Hunt's laboratory first identified wound hypoxia as a potential regulator of the biology of cells participating in tissue repair. Current understanding of the role of oxygen in the regulation of gene expression begins to provide a mechanistic basis for the prediction that oxygen could be a fundamental regulator of wound healing made by the Hunt laboratory. The present article describes the experience of the authors' laboratory in defining the expression of two oxygen-regulated genes, those for the inducible form of nitric oxide synthase and for arginase I in experimental wounds. Observations made regarding these two genes are discussed in the context of the overall regulatory role of oxygen as a phenotypic modulator of inflammatory cells. (WOUND REP REG 2003;11:445–451)

Notes: For many years, lactate has been known to accelerate collagen deposition in cultured fibroblasts and, without detailed explanation, has been presumed to stimulate angiogenesis. Similarly, hypoxia has been linked to angiogenic effects and collagen deposition from cultured cells. Paradoxically, however, wound angiogenesis and collagen deposition are increased by breathing oxygen and decreased by hypoxia. Lactate accumulates to 4–12 mM in wounds for several reasons, only one of which is the result of hypoxia. Oxygen in wounds is usually low but can be increased by breathing oxygen (without change in lactate). We have reported that lactate elicits vascular endothelial growth factor (VECF) from macrophages, as well as collagen, some heat shock proteins, and VECF from endothelial cells, and collagen from fibroblasts, even in the presence of normal amounts of oxygen. Hypoxia exerts many of these same effects in cultured cells. In this study, we elevated extracellular lactate in wounds by implanting purified solid-state, hydrolysable polyglycolide. A steady-state 2–3 mM additional elevation of lactate resulted. With it, there was a significant short-term elevation of interleukin-1β, a long-term elevation of VECF (2×) and transforming growth factor-β1 (2–3×), a 50% elevation in collagen deposition, and a large reduction of insulin-like growth factor-1 (− 90%). We propose that lactate induces a biochemical “perception” of hypoxia and instigates several signals that activate growth factor/cytokine signals while the continued presence of molecular oxygen allows endothelial cells and fibroblasts to reproduce and deposit collagen. The data are consistent with ADP-ribosylation effects and oxidant signaling. (WOUND REP REG 2003;11:504–509)

Notes: Nearly 36 years ago Thomas K. Hunt, with Patrick Twomey, was the first to report that the level of lactate significantly increases in healing wounds. This observation convinced him that lactate, besides being the by-product of glycolysis, must have a regulatory role in the healing process. He set out to investigate this observation and found it to be so. This article is written in recognition of his foresight. It summarizes the salient findings emanating from this fundamental observation and describes the biochemical principles by which most of the lactate action may be explained. Down-regulation of the ubiquitous protein modification reaction called ADP-ribosylation turned out to be a basic signal behind the role of lactate in wound healing. (WOUND REP REG 2003;11:439–444)

Notes: Numerous reports support the concept that tissues require an adequate oxygen supply to heal well and to prevent complications of infection. Adequate oxygen supply to tissue depends on perfusion as well as arterial oxygen tension, and tissue oxygen tension, particularly in peripheral tissues, is dependent on adequate vascular volume. Therefore, potential benefits to wound healing and reduction in infection in postsurgical patients might be attained by judicious manipulation of supplemental oxygen and/or fluids in the perioperative period. This article reviews evidence that suggests such manipulations are beneficial and proposes that integrated care pathways be developed that include these interventions. (WOUND REP REG 2003;11:462–467)

Notes: Diabetic wound healing is characterized by deficiencies in both growth factor and collagen production. We have observed that expression of homeobox D3 (HoxD3), a collagen-inducing transcription factor, and expression of collagen are reduced in an established animal model of diabetic wound repair, the leptin-deficient diabetic (db/db) mouse. We sought to evaluate whether the diminished expression of collagen and HoxD3 would be maintained once fibroblasts were removed from the diabetic wound environment. Fibroblasts were isolated from both wild-type and diabetic animals and expression of HoxD3 and collagen assessed. We found that when removed from the diabetic wound environment, HoxD3 and type I collagen expression are increased in diabetic fibroblasts when compared to wild-type fibroblasts. The increase in type I collagen is not related to increased production or activation of transforming growth factor-β1. However, when the diabetic fibroblasts are cultured in a 3D collagen matrix, expression of type I collagen and HoxD3 is markedly reduced and reflects the pattern of gene expression observed in the in vivo diabetic wound environment. Thus, although diabetic fibroblasts can regain the capacity to express high levels of collagen and HoxD3 once removed from the diabetic wound environment, culturing cells in the presence of a 3D collagen matrix is sufficient to revert these fibroblasts to their previous nonsynthetic state. (WOUND REP REG 2003;11:474–480)

Notes: Although it is well recognized that pressure-induced ischemia initiates the formation of pressure ulcers, the many complex mechanisms responsible for the pathogenesis of these ulcers remain poorly understood. It has been reported that chronic ulcers contain an elevated level of proteolytic enzymes, especially neutrophil-derived matrix metalloproteinase-8 and elastase. This evidence suggests that neutrophils are a major component in the pathogenesis of chronic pressure ulcers. Therefore, this study characterized the cellular components of chronic pressure ulcers. Three-millimeter biopsies (6 mm deep) from granulation tissue in pressure ulcers were obtained from 11 patients. A total of 14 biopsies were obtained from these 11 patients for analysis. A portion of each specimen was fixed in formalin for routine histology. Other portions of biopsies were frozen for analysis of myeloperoxidase activity. In addition, cells on the surfaces of the ulcers were collected by lavage for histologic characterization. Routine histologic analysis of all 14 biopsies of the pressure ulcers showed regions near the surface of each that contained dense neutrophil infiltration associated with edema and apparent marked matrix dissociation. In the deeper regions there was an increased density of blood vessels, and many contained rounded endothelial cells surrounded by migrating neutrophils. Cells collected by lavage from the ulcer surface were prepared by Cytospin and found to be greater than 95% neutrophils with occasional large macrophages actively phagocytosing depleted neutrophils. In addition, there was a significant correlation of myeloperoxidase activity with actual neutrophil counts in the ulcer biopsies further confirming the dense presence of neutrophils. These studies directly show that there is extensive neutrophil infiltration in chronic pressure ulcer granulation tissue. Furthermore, the persistence of neutrophils and their destructive enzymes appears responsible for the extensive matrix dissociation and thus contributes to the chronicity of these ulcers. (WOUND REP REG 2003;11:490–495)

Notes: Tissue PO2 levels are known to directly modulate numerous processes involved in the reparative response to cutaneous tissue injury, including cell differentiation and migration, extracellular matrix synthesis and maturation, and effectiveness of endogenous and exogenous growth factors. Oxygen is therefore likely the critical variable determining the healing capabilities of any tissue. Significant advances in the understanding of cutaneous wound healing progressed with advances in the measurement of tissue PO2, which has advanced over the past several decades from implantable probes to now include molecular tools such as the transcription factor hypoxia inducible factor-1 (HIF-1). HIF-1 modulates the expression of genes that drive the cellular adaptive response to hypoxia and possess the HIF-1 binding sequence named hypoxia response element within their promoter sequence. Molecular biology techniques are now allowing exploitation of the HIF-1/hypoxia response element pathway to drive the expression of potential vulnerary ectopic genes. Here we show the utility of the hypoxia response element for hypoxia-driven expression of the transforming growth factor-β–signaling component Smad3 in vitro and the in vivo detection of ischemic hypoxia using luciferase. Smad3 is a positive effector of transforming growth factor-β superfamily signal transduction. Such approaches are the latest evolution of work championed by Hunt and colleagues over the past 4 decades. (WOUND REP REG 2003;11:496–503)

Notes: In previous studies, mice given a full-thickness scald injury had an influx of neutrophils into the skin that followed a local increase in a neutrophil chemoattractant. Because macrophages are known to infiltrate the wound area after neutrophils and are essential for normal wound repair, studies were designed to characterize the time course of macrophage accumulation in the wound and to identify the factor(s) responsible for this influx. A macrophage infiltrate into the wound was observed at 4 days post-injury and persisted through at least 10 days. This influx was preceded by an initial fourfold increase in dermal monocyte chemoattractant protein-1 levels at 24 hours post-injury (p 〈 0.05). This elevation in monocyte chemoattractant protein-1 was enhanced at 4 and 10 days postburn resulting in a sixfold increase over baseline (p 〈 0.01). Levels of tumor necrosis factor-α, a proinflammatory cytokine known to induce chemokine production, were elevated at 90 minutes after injury in burn- versus sham-injured groups (p 〈 0.05). Furthermore, administration of tumor necrosis factor-α neutralizing antibody in vivo reduced the dermal levels of monocyte chemoattractant protein-1 seen at 10 days postburn by 57% (p 〈 0.01); however, macrophage accumulation was not altered. Thus, elevated systemic TNF-α levels may influence the local chemokine milieu following burn injury. (WOUND REP REG 2003;11:110–119)

Notes: Impaired wound healing is characteristic of diabetic patients. Potential reasons include poor inflammatory response, granulation tissue formation, and abnormal patterns of cytokine release and response. Vascular endothelial growth factor, abnormally regulated during healing in diabetics, is the major factor stimulating angiogenesis during normal wound healing. We tested our hypothesis that topically applied vascular endothelial growth factor would improve wound closure rates in diabetic animals in a full-thickness wound model in genetically diabetic mice (C57 BL/KsJ db/db). Animals received either 1.0 µg of vascular endothelial growth factor165 or polyethylene glycol alone topically to wounds daily between days 0 and 4 postwounding. Wound area was measured at days 0, 5, 10, 15, and 21. Data were analyzed using probit analysis and expressed as length-of-time (LT) to 50, 90, and 95% wound closure. Among untreated animals, nondiabetics had an LT50 of 8.5 days (fiducial limits 8.3–8.7), while diabetics had an LT50 of 15.8 days (15.6–16.1). Vascular endothelial growth factor-treated animals had LT50 values of 7.8 (7.6–8.1) and 11.8 days (11.6–12.0) for nondiabetics and diabetics, respectively, representing a 25% improvement in time to 50% closure in treated diabetics. We conclude that topically applied vascular endothelial growth factor improves time to wound closure in the genetically diabetic mouse model. (WOUND REP REG 2003;11:127–131)

Notes: There is evidence from animal and human study that suggests clinical use of monocytes/macrophages may be of benefit in wound healing, tissue regeneration, and cancer therapy. To facilitate further study, a method was developed for sterile isolation and cryopreservation of adherent monocyte/macrophages from mononuclear cell apheresis units collected from unstimulated normal human donors. Preparations contained approximately 1 × 108 total cells and were comprised of approximately 60% monocytes, 38% lymphocytes, and 2% granulocytes. Cells could be cryopreserved for up to 8 months and subsequently thawed and stored at 1–6°C for up to 4 hours with retention of viability and adequate phagocytic function. These cells can be used in clinical trials to determine their possible therapeutic benefit, e.g., whether administration of exogenously supplied cells improves the healing of chronic wounds or promotes the regeneration of transected nerves. (WOUND REP REG 2003;11:145–149)

Notes: There is a great need to establish reproducible methods for evaluative studies of wound treatment and wound healing. Validation of the healing process through optical techniques, as well as histologic and immunohistochemical methodologies, have been improved and to some extent have become well-established assays. Data relating to biomechanical properties, e.g., evaluation of the tensile strength of scar tissue that forms in experimental wound treatment strategies, are less widely available. We chose the domestic pig as an animal model in which to examine epidermal wound healing. We implanted specially made chambers that served to isolate the wounds and prevent epidermal migration from the edges. We performed histologic and immunohistochemical analyses as well as evaluation of biomechanical qualities of scar tissue using laser tensiometry. Pig skin is well suited for wound healing studies, and wound creation, implantation of the chambers, and the regular changing of dressings could all be carried out in the operating theater. In addition to established macroscopic evaluation and microscopic documentation, the need for objective biomechanical assessment of scar tissue by measuring tensile strength has been met using laser tensiometry. By optimizing methods for measuring tensile strength, it is possible to evaluate the biomechanical quality of scar tissue formed following different courses of wound treatment, as well as histologic assessment. (WOUND REP REG 2003;11:150–157)

Notes: An altered metabolism of endothelial cell–derived nitric oxide has been implicated in the microvascular dysfunction associated with ischemia/reperfusion. The objective of this study was to examine whether S-nitroso human serum albumin, a novel nitric oxide-donor, improves flap viability and whether it influences edema formation after prolonged ischemia when administered prior to and in the initial phase of reperfusion. Denervated epigastric island skin flaps were elevated in 30 male Sprague Dawley rats, rendered ischemic for 8 hours, subsequently reperfused and further observed for either 3 hours (acute) or 7 days (chronic). In the sham rats (n = 6), skin flaps were elevated only. Starting 1 hour prior to reperfusion, S-nitroso human serum albumin (n = 12) or human serum albumin (n = 12) as placebo was infused systemically for 2 hours. In the chronic model, flap necrosis as well as viable flap size was evaluated after 7 days of reperfusion in six rats per group, comparing to sham rats. In the acute model, edema formation was evaluated after 3 hours of reperfusion in six rats per group. Administration of S-nitroso human serum albumin significantly decreased flap necrosis from 18.1 ± 15.6% in the human serum albumin group to 2.1 ± 1.5% in the S-nitroso human serum albumin group, which was similar to the sham group (2.5 ± 4.2%). Viable flap size (sham 13.4 ± 1.6 cm2) was also significantly improved in the S-nitroso human serum albumin group (10.1 ± 1 cm2) versus the human serum albumin group (7.0 ± 2.2 cm2). There was no significant difference between the groups regarding postischemic edema formation. These results show that administration of S-nitroso human serum albumin prior to and in the initial phase of reperfusion significantly improves flap viability after 7 days but does not influence early observable edema formation. These findings support the role of nitric oxide as an important mediator in the protection against skin flap ischemia/reperfusion injury. (WOUND REP REG 2003;11:3–10)

Notes: The objective of this study was to characterize fibroblasts at sequential time points during intra-oral wound healing in the rat. Experimental wounds were made at several time points in the mucoperiosteum of the palate of 35-day-old Wistar rats. Fibroblasts were cultured from the biopsies under standard conditions for the same number of passages. The expression of the integrin subunits α1, α6, and β1; and the intermediate filaments α-smooth muscle actin and vimentin were analyzed by flow cytometry. Western blot analysis was performed at 0, 8, and 60 days postwounding to confirm the expression of both intermediate filaments. The phenotypic profiles of fibroblasts cultured from subsequent stages in the wound healing process differed considerably. We conclude that distinct fibroblast phenotypes can be isolated from different stages in wound healing. These phenotypes remained stable during in vitro culturing. In addition, cryosections of the wound areas were made at identical time points and were immunohistochemically stained for the same antigens. The immunohistochemical staining correlated well to the flow-cytometric data. These results suggest the occurrence of multiple subpopulations of fibroblasts with a specialized function during wound healing. We hypothesize that undesirable consequences of wound healing might be prevented through the modulation of specific fibroblast subpopulations. (WOUND REP REG 2003;11:55–63)

Notes: Adult wound repair occurs with an initial inflammatory response, reepithelialization, and the formation of a permanent scar. Although the inflammatory phase is often considered a necessity for successful adult wound healing, fetal healing studies have shown the ability to regenerate skin and to heal wounds in a scarless manner in the absence of inflammation. The cyclooxygenase-2 (COX-2) enzyme, a known mediator of inflammation, has been shown to contribute to a variety of inflammatory conditions and to the development of cancer in many organs. To examine the role of COX-2 in the wound healing process, incisional wounds were treated topically with the anti-inflammatory COX-2 inhibitor celecoxib. Acutely, celecoxib inhibited several parameters of inflammation in the wound site. This decrease in the early inflammatory phase of wound healing had a significant effect on later events in the wound healing process, namely a reduction in scar tissue formation, without disrupting reepithelialization or decreasing tensile strength. Our data suggest that in the absence of infection, adult wound healing is able to commence with decreased inflammation and that anti-inflammatory drugs may be used to improve the outcome of the repair process in the skin by limiting scar formation. (WOUND REP REG 2003;11:25–34)

Notes: Type I collagen is a clinically approved biomaterial largely used in tissue engineering. It acts as a regenerative template in which the implanted collagen is progressively degraded and replaced by new cell-synthesized tissue. Apligraf®, a bioengineered living skin, is composed of a bovine collagen lattice containing living human fibroblasts overlaid with a fully differentiated epithelium made of human keratinocytes. To investigate its progressive remodeling, athymic mice were grafted and the cellular and the extracellular matrix components were studied from 0 to 365 days after grafting. Biopsies were analyzed using immunohistochemistry with species-specific antibodies and electron microscopy techniques. We observed that this bioengineered tissue provided living and bioactive cells to the wound site up to 1 year after grafting. The graft was rapidly incorporated within the host tissue and the bovine collagen present in the graft was progressively replaced by human and mouse collagens. A normal healing process was observed, i.e., type III collagen appeared transiently with type I collagen, the major collagen isoform present at later stages. New molecules, such as elastin, were produced by the living human cells contained within the graft. This animal model combined with species-specific immunohistochemistry tools is thus very useful for studying long-term tissue remodeling of bioengineered living tissues. (WOUND REP REG 2003;11:35–45)

Notes: Upon stimulation, mast cells release a heterogeneous group of factors that promote inflammation and influence cell proliferation. Mast cells accumulate at sites of injury, further suggesting a critical role in wound healing. To assess the importance of mast cells in tissue repair, we compared wound healing in mast cell–deficient WBB6F1/J-KitW/KitW–v (KitW/KitW–v) and wild type WBB6F1/++ (WT) mice. During the inflammatory phase, neutrophil infiltration into wounds of the KitW/KitW–v mice was significantly less than that of WT mice (84.6 ± 10.3 vs. 218 ± 26.0 cells/10 high-power fields at day 3, p 〈 0.001), while wound macrophage and T cell infiltration were similar in both strains. The decrease in neutrophils could not be explained by changes in tumor necrosis factor-α or macrophage inflammatory protein-2 levels, because the amounts of these two neutrophil chemoattractants were similar in both KitW/KitW–v and WT mice. Surprisingly, the absence of mast cells had no effect on the proliferative aspects of wound healing, including reepithelialization, collagen synthesis, and angiogenesis. Although mast cells are known to release proangiogenic mediators, vascular endothelial growth factor levels were similar in WT and KitW/KitW–v mice. Moreover, levels of fibroblast growth factor-2 were increased in KitW/KitW–v mice (4206 ± 107 vs. 1865 ± 249 pg/ml, p 〈 0.01). These results suggest that mast cells modulate the recruitment of neutrophils into sites of injury, yet indicate that mast cells are unlikely to exert a major influence on the proliferative response within healing wounds. (WOUND REP REG 2003;11:46–54)

Notes: Wounding skin generates an endogenous electric field of 100–200 mV/mm in the immediate vicinity of the wound. When keratinocytes are exposed to direct current electric fields of this magnitude, they exhibit galvanotaxis, or directional migration toward the cathode, suggesting that wound-generated electric fields provide migrational cues that contribute to wound healing. Because melanocytes must also migrate into the healing wound to repigment it, their motility in response to electric fields of physiologic magnitude was examined. Human skin–derived melanocytes, either exposed to 100 mV/mm direct current electric fields or nonexposed controls, both exhibited motility rates of 9 µm/hour, significantly (three- to five-fold) lower than the motility rates of keratinocytes under identical conditions. However, in sharp contrast to keratinocytes, melanocytes exhibited no directional migration in the electric field. Additionally, neither the number of primary dendrites per cell, nor the orientation of the dendrites with respect to the field vector, nor the average length of the dendrites was significantly different in melanocytes exposed to the electric field as compared to nonexposed controls. Thus, in marked contrast to keratinocytes, human skin–derived melanocytes do not respond to direct current electric fields of physiologic magnitude with either directional migration or reorientation of dendrites. This may account for the delay in repigmentation that often accompanies wound reepithelialization. (WOUND REP REG 2003;11:64–70)

Notes: The purpose of this study was to investigate the structure and organization of collagen during the healing of penetrating rabbit corneal wounds. Full-thickness wounds were produced in both corneas of six New Zealand White rabbits with a 2-mm trephine. After 5, 10, and 16 months, wounds were examined using transmission electron microscopy and wide-angle synchrotron X-ray diffraction, which allowed the quantification of the relative amount of collagen and fibril orientation in different parts of the cornea. The intensity of the diffraction patterns taken from the wound edge was much higher than patterns collected at the wound center, indicating a greater amount of collagen near the wound edge. This collagen was shown to have a preferred orientation, forming a circular pattern around the wound. As the wounds healed, the amount of preferentially aligned collagen decreased and lamella formation and ordered fibrillar arrangement increased as shown by electron microscopy. The orientation of collagen fibrils in healing penetrating corneal wounds is not random. Instead, fibrils tend to be circularly arranged within and without the wound, gradually becoming more normal over time. We speculate that collagen is artefactually displaced during trephination, resulting in an abnormal alignment of the fibrils surrounding the wound edge, and that this influences the wound healing process. (WOUND REP REG 2003;11:71–78)

Notes: Integrin-mediated cell adhesion and growth factor stimuli are both required for optimal control of cell proliferation. In the context of skin injury, cell-derived fibronectin and platelet-derived growth factor play important roles in the stimulation of cell proliferation and migration, activities that are crucial to the healing process. To assess the ability of exogenously supplied plasma-derived fibronectin to stimulate wound repair and to study its ability to cooperate with platelet-derived growth factor-BB during healing, we devised a novel topical delivery formulation that allows the controlled release of both molecules to a wound. Using this topical formulation and the rabbit ear model of dermal wound healing, we show that plasma fibronectin is a potent stimulator of the wound healing process. We also show that administration of fibronectin and platelet-derived growth factor-BB in combination has additive wound healing effects. Finally, we report novel findings on the ability of soluble plasma fibronectin to potentiate the mitogenic effects of platelet-derived growth factor-BB in vitro. These findings not only show that optimal concentrations of exogenous fibronectin administered using an effective delivery system stimulate wound healing; they also suggest that PDGF-BB should be administered with fibronectin to achieve optimal therapeutic stimulation of wound healing. (WOUND REP REG 2003;11:79–89)

Notes: The abundance and morphology of microdiamond in dolomite marble from Kumdy-kol in the Kokchetav Massif, are unusual; a previous study estimated the maximum content of diamonds in dolomite marble to be about 2700 carat ton−1. Microdiamond is included primarily in garnet, and occasionally in diopside and phlogopite pseudomorphs after garnet. They are classified into three types on the basis of their morphology: (1) S-type: star-shaped diamond consisting of translucent cores and transparent subhedral to euhedral very fine-grained outer parts; (2) R-type: translucent crystals with rugged surfaces; and (3) T-type: transparent, very fine-grained crystals. The S-type is the most abundant.Micro-Laue diffraction using a 1.6-µm X-ray beam-size demonstrated that the cores of the star-shaped microdiamond represent single crystals. In contrast, the most fine-grained outer parts usually have different orientations compared to the core. Laser–Raman studies indicate that the FWHM (Full Width at Half Maximum) of the Raman band of the core of the S-type diamond is slightly larger than that for the outer parts. Differences in morphology, crystal orientations, and in the FWHM of the Raman band between the core and the fine-grained outer-parts of S-type microdiamond suggest that the star-shaped microdiamond was formed discontinuously in two distinct stages.

Notes: Oscillatory zoning in low δ18O skarn garnet from the Willsboro wollastonite deposit, NE Adirondack Mts, NY, USA, preserves a record of the temporal evolution of mixing hydrothermal fluids from different sources. Garnet with oscillatory zoning are large (1–3 cm diameter) euhedral crystals that grew in formerly fluid filled cavities. They contain millimetre-scale oscillatory zoning of varying grossular–andradite composition (XAdr = 0.13–0.36). The δ18O values of the garnet zones vary from 0.80 to 6.26‰ VSMOW and correlate with XAdr. The shape, pattern and number of garnet zones varies from crystal to crystal, as does the magnitude of the correlated chemistry changes, suggesting fluid system variability, temporal and/or spatial, over the time of garnet growth. The zones of correlated Fe content and δ18O indicate that a high Fe3+/Al, high δ18O fluid mixed with a lower Fe3+/Al and δ18O fluid. The high δ18O, Fe enriched fluids were likely magmatic fluids expelled from crystallizing anorthosite. The low δ18O fluids were meteoric in origin.These are the first skarn garnet with oscillatory zoning reported from granulite facies rocks. Geochronologic, stable isotope, petrologic and field evidence indicates that the Adirondacks are a polymetamorphic terrane, where localized contact metamorphism around shallowly intruded anorthosite was followed by a regional granulite facies overprint. The growth of these garnet in equilibrium with meteoric and magmatic fluids indicates an origin in the shallow contact aureole of the anorthosite prior to regional metamorphism. The zoning was preserved due to the slow diffusion of oxygen and cations in the large garnet and protection from deformation and recrystallization in zones of low strain in thick, rigid, garnetite layers. The garnet provide new information about the hydrothermal system adjacent to the shallowly intruded massif anorthosite that predates regional metamorphism in this geologically complex, polymetamorphic terrane.

Notes: The blueschist and greenschist units on the island of Sifnos, Cyclades were affected by Eocene high-pressure (HP) metamorphism. Using conventional geothermobarometry, the HP peak metamorphic stage was determined at 550–600 °C and 20 kbar, close to the blueschist and the eclogite facies transition. The retrograde P–T paths are inferred with phase diagrams. Pseudosections based on a quantitative petrogenetic grid in the model system Na2O–CaO–FeO–MgO–Al2O3–SiO2–H2O reveal coeval decompression and cooling for both the blueschist and the greenschist unit. The conditions of the metamorphic peak and those of the retrograde stages conform to a similar metamorphic gradient of 10–12 °C km−1 for both units. The retrograde overprint can be assigned to low-pressure blueschist to HP greenschist facies conditions. This result cannot be reconciled with the (prograde) Barrovian-type event, which affected parts of the Cyclades during the Oligocene to Miocene. Instead, the retrograde overprint is interpreted in terms of exhumation, directly after the HP stage, without a separate metamorphic event. Constraints on the exhumation mechanism are given by decompression-cooling paths, which can be explained by exhumation in a fore-arc setting during on-going subduction and associated crustal shortening. Back-arc extension is only responsible for the final stage of exhumation of the HP units.

Notes: Metabasic rocks from the Adula Nappe in the Central Alps record a regional high-pressure metamorphic event during the Eocene, and display a regional variation in high-pressure mineral assemblages from barroisite, or glaucophane, bearing garnet amphibolites in the north to kyanite eclogites in the central part of the nappe. High-pressure rocks from all parts of the nappe show the same metamorphic evolution of assemblages consistent with prograde blueschist, high-pressure amphibolite or eclogite facies conditions followed by peak-pressure eclogite facies conditions and decompression to the greenschist or amphibolite facies. Average PT calculations (using thermocalc) quantitatively establish nested, clockwise P–T paths for different parts of the Adula Nappe that are displaced to higher pressure and temperature from north to south. Metamorphic conditions at peak pressure increase from about 17 kbar, 640 °C in the north to 22 kbar, 750 °C in the centre and 25 kbar, 750 °C in the south. The northern and central Adula Nappe behaved as a coherent tectonic unit at peak pressures and during decompression, and thermobarometric results are interpreted in terms of a metamorphic field gradient of 9.6 ± 2.0 °C km−1 and 0.20 ± 0.05 kbar km−1. These results constrain the peak-pressure position and orientation of the nappe to a depth of 55–75 km, dipping at an angle of approximately 45° towards the south. Results from the southern Adula Nappe are not consistent with the metamorphic field gradient determined for the northern and central parts, which suggests that the southern Adula Nappe may have been separated from central and northern parts at peak pressure.

Notes: The Priest pluton contact aureole in the Manzano Mountains, central New Mexico preserves evidence for upper amphibolite contact metamorphism and localized retrograde hydrothermal alteration associated with intrusion of the 1.42 Ga Priest pluton. Quartz–garnet and quartz–sillimanite oxygen isotope fractionations in pelitic schist document an increase in the temperatures of metamorphism from 540 °C, at a distance of 1 km from the pluton, to 690 °C at the contact with the pluton. Comparison of calculated temperature estimates with one-dimensional thermal modelling suggests that background temperatures between 300 and 350 °C existed at the time of intrusion of the Priest pluton. Fibrolite is found within 300 m of the Priest pluton in pelitic and aluminous schist metamorphosed at temperatures 〉580 °C. Coexisting fibrolite and garnet in pelitic schist are in oxygen isotope equilibrium, suggesting these minerals were stable reaction products during peak metamorphism. The fibrolite-in isograd is coincident with the staurolite-out isograd in pelitic schist, and K-feldspar is not observed with the first occurrence of fibrolite. This suggests that the breakdown of staurolite and not the second sillimanite reaction controls fibrolite growth in staurolite-bearing pelitic schist. Muscovite-rich aluminous schist locally preserves the Al2SiO5 polymorph triple-point assemblage – kyanite, andalusite and fibrolite. Andalusite and fibrolite, but not kyanite, are in isotopic equilibrium in the aluminous schist. Co-nucleation of fibrolite and andalusite at 580 °C in the presence of muscovite and absence of K-feldspar suggests that univariant growth of andalusite and fibrolite occurred. Kyanite growth occurred during an earlier regional metamorphic event at a temperature nearly 80 °C lower than andalusite and fibrolite growth. Quartz–muscovite fractionations in hydrothermally altered pelitic schist and quartzite are small or negative, suggesting that late isotopic exchange between externally derived fluids and muscovite, but not quartz, occurred after peak contact metamorphism and that hydrothermal alteration in pelitic schist and quartzite occurred below the closure temperature of oxygen self diffusion in quartz (〈500 °C).

Notes: Abstract Concordant U–Pb ages of c. 530–510 Ma and c. 470–420 Ma on titanite from calcsilicate, orthogneiss and amphibolite rocks constrain the age of high-T metamorphism in the Early Palaeozoic mobile belt at the western margin of Proterozoic Gondwana (Argentina, 26–29°S). The U–Pb ages document the time of titanite formation at high-T conditions according to the stable mineral paragenesis and occurrence of titanite in the metamorphic fabric. The presence of migmatite at all sample sites indicates temperatures were 〉 c. 650 °C. Titanite formed at similar metamorphic conditions at different times on the regional and on the outcrop scale. The titanite crystals preserved their U–Pb isotopic signatures and chemical composition under ongoing upper amphibolite to granulite facies temperatures. Different thermal peaks or deformations are only detected by the different U–Pb ages and not by changes in the mineral paragenesis or metamorphic fabric of the samples. The range of U–Pb ages, e.g. in the Ordovician and Silurian (c. 470, 460, 440, 430, 420 Ma), is interpreted as the effect polyphase deformation with deformation-enhanced recrystallization of titanite and/or different thermal peaks during a long-standing, geographically fixed, high-T regime in the mid-crust of a continental magmatic arc. A clear correlation of the different ages with distinct tectonic events, e.g. collision of terranes, is not possible based on the present knowledge of the region.

Notes: Abstract The garnet blueschists from the Ile de Groix (Armorican Massif, France) contain millimetre- to centimetre-sized pseudomorphs consisting of an aggregate of chlorite, epidote and paragonite. The pseudomorphed phase developed at a late stage of the deformation history, because it overgrows a glaucophane–epidote–titanite foliation. Garnet growth occurred earlier than the beginning of the ductile deformation, and thus garnet is also included in the pseudomorphs. Microprobe analyses show that garnet is strongly zoned, with decreasing spessartine and increasing almandine and pyrope contents from core to rim. Grossular content is higher in garnet cores (about 35 mole%) compared to garnet rims (about 30 mole%). Blue amphibole has glaucophane compositions with a low Fe3+ content and become more magnesian when inclusions in garnet (XMg = 0.62–0.65) are compared with matrix grains (XMg = 0.67–0.70). Matrix epidote has a pistacite content of about 50 mole%. On the basis of their shape and the nature of the breakdown products, the pseudomorphs are attributed to lawsonite. A numerical model (using Thermocalc) has been developed in order to understand the reactions controlling both the growth and the breakdown of lawsonite. Lawsonite growth could have taken place through the continuous hydration reaction Chl + Ep + Pg + Qtz + Vap = Gln + Lws, followed by the fluid-absent reaction Chl + Ep + Pg = Grt + Gln + Lws. Peak P–T conditions are estimated at about 18–20 kbar, 450 °C. This indicates that lawsonite growth took place at increasing P and T, hence can be used as a geobarometer in the buffering assemblage garnet–glaucophane–epidote. The final part of the history is recorded by lawsonite breakdown, after cessation of the ductile deformation, and recording the earliest stages of the exhumation.

Notes: Previous models of hydrodynamics in contact metamorphic aureoles assumed flow of aqueous fluids, whereas CO2 and other species are also common fluid components in contact metamorphic aureoles. We investigated flow of mixed CO2–H2O fluid and kinetically controlled progress of calc-silicate reactions using a two-dimensional, finite-element model constrained by the geological relations in the Notch Peak aureole, Utah. Results show that CO2 strongly affects fluid-flow patterns in contact aureoles. Infiltration of magmatic water into a homogeneous aureole containing CO2–H2O sedimentary fluid facilitates upward, thermally driven flow in the inner aureole and causes downward flow of the relatively dense CO2-poor fluid in the outer aureole. Metamorphic CO2-rich fluid tends to promote upward flow in the inner aureole and the progress of devolatilization reactions causes local fluid expulsion at reacting fronts. We also tracked the temporal evolution of P-T-XCO2conditions of calc-silicate reactions. The progress of low- to medium-grade (phlogopite- to diopside-forming) reactions is mainly driven by heat as the CO2 concentration and fluid pressure and temperature increase simultaneously. In contrast, the progress of the high-grade wollastonite-forming reaction is mainly driven by infiltration of chemically out-of-equilibrium, CO2-poor fluid during late-stage heating and early cooling of the inner aureole and thus it is significantly enhanced when magmatic water is involved. CO2-rich fluid dominates in the inner aureole during early heating, whereas CO2-poor fluid prevails at or after peak temperature is reached. Low-grade metamorphic rocks are predicted to record the presence of CO2-rich fluid, and high-grade rocks reflect the presence of CO2-poor fluid, consistent with geological observations in many calc-silicate aureoles. The distribution of mineral assemblages predicted by our model matches those observed in the Notch Peak aureole.

Notes: The Swakane Gneiss and the overlying Napeequa Complex in the North Cascade range, Washington, were metamorphosed and deformed during development of a Cretaceous-Paleogene continental arc, and are among the structurally deepest exposed rocks within the Cordilleran arcs of North America. Peak metamorphic conditions in both the Swakane Gneiss and Napeequa Complex were c. 640–750 °C, 9–12 kbar. Clockwise paths and widespread evidence for high-P metamorphism in meta-supracrustal rocks (burial to 〉40 km) document major vertical tectonic motion during arc construction and unroofing.These and other moderately high-pressure rocks in the North Cascades-Coast Mountains experienced a dramatically different tectonometamorphic history than metamorphic rocks within other Cordilleran arcs. The exhumed arc complexes of the Sierra Nevada and Peninsular Ranges are dominated by relatively low-P metamorphic and plutonic rocks (typically 〈6 kbar). There is no evidence that the northern Cordillera was thickened to a greater degree than these other belts, suggesting that the greater magnitude of vertical motion in the Cascades may have been related to exhumation mechanisms: Eocene extension in the northern Cordillera vs. erosional unroofing in the central and southern Cordillera.

Notes: High-pressure (HP) granulites and eclogitized metagabbro are exposed along an orogen-parallel high-P belt that was developed at c. 1050–1020 Ma in the NE Grenville Province. Among these rocks, mafic granulites derived from a Labradorian anorthosite suite of the Lelukuau terrane contain garnet, Al-Na diopside, and, depending on bulk composition, plagioclase and kyanite. Moreover, the distribution of phases is influenced by the original igneous texture. For instance, in high XMgO leucocratic varieties, garnet porphyroblasts nucleated together with kyanite in An-rich cores of plagioclase domains whereas in low XMgO rocks garnet occurs together with clinopyroxene within formerly igneous ferromagnesian domains and kyanite is missing. In contrast, garnet pseudomorphs after igneous plagioclase in melanocratic varieties display evidence of earlier corona development. Metamorphic textures are consistent with a two stage evolution: (a) development of garnet and Al-Na-diopside (Cpx1) under high-P metamorphic conditions, concomitant with elimination of plagioclase in the mesocratic to melanocratic varieties; and (b) partial loss of Al-Na from Cpx1 resulting in production of new andesitic plagioclase, and growth of new clinopyroxene (Cpx2) after garnet and quartz in leucocratic to mesocratic rocks consistent with decompression. Widespread equilibrium textures between garnet-Pl2-Cpx2 and/or reset Cpx1 are consistent with development at the thermal peak. Estimated P–T conditions for the presumed thermal peak fall in the range 1500–1800 MPa and 800–900 °C and are comparable to those recorded by eclogitized gabbros from other parts of the high-P belt of the NE Grenville province. Low jadeite content of clinopyroxene from the HP granulites is attributed to the low bulk Na2O/(Na2O + CaO) of these rocks relative to common basaltic compositions. Scarcity of apparent retrograde textural overprint in both the HP granulites and the eclogites suggests fast subsequent cooling, consistent with extrusion of the high-P belt towards the foreland shortly after the metamorphic peak.

Notes: The upper deck of the East Athabasca mylonite triangle (EAmt), northern Saskatchewan, Canada, contains mafic granulites that have undergone high P–T metamorphism at conditions ranging from 1.3 to 1.9 GPa, 890–960 °C. Coronitic textures in these mafic granulites indicate a near-isothermal decompression path to 0.9 GPa, 800 °C. The Godfrey granite occurs to the north adjacent to the upper deck high P–T domain. Well-preserved corona textures in the Godfrey granite constrain igneous crystallization and early metamorphism in the intermediate-pressure granulite field (Opx + Pl) at 1.0 GPa, 775 °C followed by metamorphism in the high pressure granulite field (Grt + Cpx + Pl) at 1.2 GPa, 860 °C. U–Pb geochronology of zircon in upper deck mafic granulite yields evidence for events at both c. 2.5 Ga and c. 1.9 Ga. The oldest zircon dates are interpreted to constrain a minimum age for crystallization or early metamorphism of the protolith. A population of 1.9 Ga zircon in one mafic granulite is interpreted to constrain the timing of high P–T metamorphism. Titanite from the mafic granulites yields dates ranging from 1900 to 1894 Ma, and is interpreted to have grown along the decompression path, but still above its closure temperature, indicating cooling following the high P–T metamorphism from c. 960–650 °C in 4–10 Myr. Zircon dates from the Godfrey granite indicate a minimum crystallization age of 2.61 Ga, without any evidence for 1.9 Ga overgrowths. The data indicate that an early granulite facies event occurred at c. 2.55–2.52 Ga in the lower crust (c. 1.0 GPa), but at 1.9 Ga the upper deck underwent high P–T metamorphism, then decompressed to 0.9–1.0 GPa. Juxtaposition of the upper deck and Godfrey granite would have occurred after or been related to this decompression. In this model, the high P–T rocks are exhumed quickly following the high pressure metamorphism. This type of metamorphism is typically associated with collisional orogenesis, which has important implications for the Snowbird tectonic zone as a fundamental boundary in the Canadian Shield.

Notes: Orthopyroxene-free garnet + clinopyroxene + plagioclase ± quartz-bearing mineral assemblages represent the paragenetic link between plagioclase-free eclogite facies metabasites and orthopyroxene-bearing granulite facies metabasites. Although these assemblages are most commonly developed under P–T conditions consistent with high pressure granulite facies, they sometimes occur at lower grade in the amphibolite facies. Thus, these assemblages are characteristic but not definitive of high pressure granulite facies. Compositional factors favouring their development at amphibolite grade include Fe-rich mineral compositions, Ca-rich garnet and plagioclase, and Ti-poor hornblende. The generalized reaction that accounts for the prograde development of garnet + clinopyroxene + plagioclase ± quartz from a hornblende + plagioclase + quartz-bearing (amphibolite) precursor is Hbl + Pl + Qtz=Grt + Cpx + liquid or vapour, depending on whether the reaction occurs above or below the solidus. There are significant discrepancies between experimental and natural constraints on the P–T conditions of orthopyroxene-free garnet + clinopyroxene + plagioclase ± quartz-bearing mineral assemblages and therefore on the P–T position of this reaction. Semi-quantitative thermodynamic modelling of this reaction is hampered by the lack of a melt model and gives results that are only moderately successful in rationalizing the natural and experimental data.

Notes: Schlieren are trains of platy or blocky minerals, typically the ferromagnesian minerals and accessory phases, that occur in granites and melt-rich migmatites, such as diatexites. They have been considered as: (1) unmelted residue from xenoliths or the source region; (2) mineral accumulations formed during magma flow; (3) compositional layering; and (4) sites of melt loss. In order to help identify schlieren-forming processes in the diatexites at St Malo, differences in the size, shape, orientation, distribution and composition of the biotite from schlieren and from their hosts have been investigated.Small biotite grains are much less abundant in the schlieren than in their hosts. Schlieren biotite grains are generally larger, have greater aspect ratios and have, except in hosts with low (〈 10%) biotite contents, a much stronger shape preferred orientation than host biotite. The compositional ranges of host and schlieren biotite are similar, but schlieren biotite defines tighter, sharper peaks on composition-frequency plots. Hosts show magmatic textures such as imbricated (tiled), unstrained plagioclase. Some schlieren show only magmatic textures (tiled biotite, no crystal-plastic strain features), but many have textures indicating submagmatic and subsolidus deformation (e.g. kinked grains) and these schlieren show the most extensive evidence for recrystallization.Magmas at St Malo initially contained a significant fraction of residual biotite and plagioclase crystals; smaller biotite grains were separated from the larger plagioclase crystals during magma flow. Since plagioclase was also the major, early crystallizing phase, the plagioclase-rich domains developed rapidly and reached the rigid percolation threshold first, forcing further magma flow to be concentrated into narrowing melt-rich zones where the biotite had accumulated, hence increasing shear strain and the degree of shape preferred orientation in these domains. Schlieren formed in these domains as a result of grain contacts and tiling in the grain inertia-regime. Final amalgamation of the biotite aggregates into schlieren involved volume loss as melt trapped between grains was expelled after the rigid percolation threshold was reached in the biotite-rich layers.

Notes: The eclogite type locality in the Eastern Alps (the Koralpe and Saualpe region) is the largest region in the Eastern Alps that preserves high-pressure metamorphic rocks from the Eo-Alpine orogenic event of the Cretaceous age. Thermobarometric data from the metapelitic gneisses in the region indicate that a metamorphic field gradient across the region can be divided into three parts. The northern part shows continuously increasing P–T from 10 ± 1.5 to 14 ± 1.5 kbar and 500 ± 68 to 700 ± 68 °C over a distance of 40 km. The continuous increase in P–T indicates that no major tectonic boundaries were active in this part during the Eo-Alpine orogeny. Small discontinuities in the pressure gradient of the northern part can be correlated with more localized deformation. The central part exposes amphibolite–eclogite facies rocks with 15 ± 1.5 kbar and 700 ± 68 °C over about 20 km length. The southern part shows decreasing P–T conditions from 15 ± 1.5 to 10 ± 1.5 kbar and 700 ± 68 to 600 ± 63 °C over a distance of 10 km beyond which conditions remain roughly constant for the remainder of the profile.Overall, the field gradient is characterized by: (i) an increase in age with decreasing metamorphic grade and (ii) a T/P ratio that is lower than common metamorphic geotherms. The age–grade relationship is consistent with the timing relationship along piezothermal arrays predicted by simple models for regional metamorphism. However, the T/P ratio of the field gradient is inconsistent with such an interpretation. These inconsistencies indicate that the profile is not simply an obliquely exposed crustal section. We suggest that the exhumation of the transect is best explained with a two dimensional model of an extruding wedge, as has recently been suggested as a typical scenario for other large scale compressional orogens.

Notes: A largely undocumented region of eclogite associated with a thick blueschist unit occurs in the Kotsu area of the Sanbagawa belt. The composition of coexisting garnet and omphacite suggests that the Kotsu eclogite formed at peak temperatures of around 600 °C synchronous with a penetrative deformation (D1). There are local significant differences in oxygen fugacity of the eclogite reflected in mineral chemistries. The peak pressure is constrained to lie between 14 and 25 kbar by microstructural evidence for the stability of paragonite throughout the history recorded by the eclogite, and the composition of omphacite in associated eclogite facies pelitic schist. Application of garnet-phengite-omphacite geobarometry gives metamorphic pressures around 20 kbar. Retrograde metamorphism associated with penetrative deformation (D2) is in the greenschist facies. The composition of syn-D2 amphibole in hematite-bearing basic schist and the nature of the calcium carbonate phase suggest that the retrograde P–T path was not associated with a significant increase or decrease in the ratio of P–T conditions following the peak of metamorphism. This P–T path contrasts with the open clockwise path derived from eclogite of the Besshi area. The development of distinct P–T paths in different parts of the Sanbagawa belt shows the shape of the P–T path is not primarily controlled by tectonic setting, but by internal factors such as geometry of metamorphic units and exhumation rates.

Notes: Previous studies suggest that the metamorphic evolution of the ultrahigh-pressure garnet peridotite from Alpe Arami was characterized by rapid subduction to a depth of c. 180 km with partial chemical equilibration at c. 5.9 Gpa/1180 °C and an initial stage of near-isothermal decompression followed by enhanced cooling. In this study, average cooling rates were constrained by diffusion modelling on retrograde Fe–Mg zonation profiles across garnet porphyroclasts. Considering the effects of temperature, pressure and garnet bulk composition on the Fe–Mg interdiffusion coefficient, cooling rates of 380–1600 °C Myr−1 for the interval from 1180 to 800 °C were obtained. Similar or even higher average cooling rates resulted from thermal modelling, whereby the characteristics of the calculated temperature-time path depend on the shape and size of the hot peridotite body and the boundary conditions of the cooling process. The very high cooling rates obtained from both geospeedometry and thermal modelling imply extremely fast exhumation rates of c. 15 mm yr−1 or more. These results agree with the range of exhumation rates (16–50 mm yr−1) deduced from geochronological results. It is suggested that the Alpe Arami peridotite passively returned towards the surface as part of a buoyant sliver, caused as a consequence of slab breakoff.

Notes: We report SHRIMP U–Th–Pb monazite, conventional U–Pb titanite, Sm–Nd garnet and Rb–Sr muscovite and biotite ages for metamorphic rocks from the Danba Domal Metamorphic Terrane in the eastern Songpan-Garzê Orogenic Belt (eastern Tibet Plateau). These ages are used to determine the timing of polyphase metamorphic events and the subsequent cooling history. The oldest U–Th–Pb monazite and Sm–Nd garnet ages constrain an early Barrovian metamorphism (M1) in the interval c. 204–190 Ma, coincident with extensive Indosinian granitic magmatism throughout the Songpan-Garzê Orogenic Belt. A second, higher-grade sillimanite-grade metamorphic event (M2), recorded only in the northern part of the Danba terrane, was dated at c. 168–158 Ma by a combination of U–Th–Pb monazite and titanite and Sm–Nd garnet ages. It is suggested that M1 was a thermal event that affected the entire orogenic belt while M2 may represent a local thermal perturbation. Rb–Sr muscovite ages range from c. 138–100 Ma, whereas Rb–Sr biotite ages cluster at c. 34–24 Ma. These ages document regional cooling at rates of c. 2–3 °C Myr−1 following the M1 peak for most of the terrane. However, those parts of the terrane affected by the higher-temperature M2 event (e.g. the migmatite zone) experienced initially more rapid (c. 8 °C Myr−1) cooling after peak M2 before joining the regional slow cooling path defined by the rest of the terrane at c. 138 Ma. Regional slow cooling between c. 138 and c. 30 Ma is thought to be the result of post-tectonic isostatic uplift after extensive crustal thickening caused by collision of the South and North China Blocks. The clustering of biotite Rb–Sr ages marks the onset of rapid uplift across the entire terrane commencing at c. 30–20 Ma. This cooling history is shared with many other regions of the Tibet Plateau, suggesting that uplift of the Tibet Plateau (including the Songpan-Garzê Orogenic Belt) occurred predominantly in the last c. 30 Myr as a response to the continuing northwards collision of India with Eurasia.

Notes: Recent studies have used the relative rotation axis of sigmoidal and spiral-shaped inclusion trails, known as Foliation Inflexion/Intersection Axis (FIA), to investigate geological processes such as fold mechanisms and porphyroblast growth. The geological usefulness of this method depends upon the accurate measurement of FIA orientations and correct correlation of temporally related FIAs. This paper uses new data from the Canton Schist to assess the variation in FIA orientations within and between samples, and evaluates criteria for correlating FIAs. For the first time, an entire data set of FIA measurements is published, and data are presented in a way that reflects the variation in FIA orientations within individual samples and provides an indication of the reliability of the data. Analysis of 61 FIA trends determined from the Canton Schist indicate a minimum intrasample range in FIA orientations of 30°. Three competing models are presented for correlation of these FIAs, and each of the models employ different correlation criteria. Correlation of FIAs in Model 1 is based on relative timing and textural criteria, while Model 2 uses relative timing, orientation and patterns of changing FIA orientations, and Model 3 uses relative timing and FIA orientation as correlation criteria. Importantly, the three models differ in the spread of FIA orientations within individual sets, and the number of sets distinguished in the data. Relative timing is the most reliable criterion for correlation, followed by textural criteria and patterns of changing FIA orientations from core to rim of porphyroblasts. It is proposed that within a set of temporally related FIAs, the typical spread of orientations involves clustering of data in a 60° range, but outliers occur at other orientations including near-normal to the peak distribution. Consequently, in populations of FIA data that contain a wide range of orientations, correlation on the basis of orientation is unreliable in the absence of additional criteria. The results of this study suggest that FIAs are best used as semiquantitative indicators of bulk trends rather than an exact measurement for the purpose of quantitative analyses.

Notes: Documentation of pressure–temperature (P–T) histories across an epidote-amphibolite facies culmination provides new insight into the tectono-thermal evolution of the Brooks Range collisional orogen. Thermobarometry reveals that the highest grade rocks formed at peak temperatures of 560–600 °C and at pressures of 8–9.5 kbar. The thermal culmination coincides with the apex of a structural dome defined by oppositely dipping S2 crenulation cleavages suggesting post-metamorphic doming. South of the thermal culmination, greenschist facies and lowermost epidote-amphibolite facies rocks preserve widespread evidence for an early blueschist facies metamorphism. In contrast, no evidence for an early blueschist facies metamorphism was found in similar grade rocks of the northern flank, indicating that the southern flank underwent initial deeper burial during southward underthrusting of the continental margin. Thus, while the dome shows a symmetric distribution of peak temperatures, the P–T paths followed by the two flanks must have varied. This variation suggests that final thermal re-equilibration to greenschist and epidote–amphibolite facies conditions did not result from a simple process of southward underthrusting followed by thermal re-equilibration from the bottom upward. The new data are inconsistent with a previous model that invokes such re-equilibration, along with northward thrusting of epidote–amphibolite facies rocks over lower grade rocks presently on the southern flank of the culmination, to produce an inverted metamorphic field gradient. Instead, it is suggested that following blueschist facies metamorphism, rocks of the southern and northern flanks were juxtaposed, during which time the more deeply buried south flank was partially emplaced above rocks to the north, where they escaped Albian epidote–amphibolite facies overprinting. Porphyroblast growth, which post-dates the main fabric on the north flank of the culmination may be the result of Albian thermal re-equilibration following this deformation. Post-metamorphic doming resulted from a combination of Albian-Cenomanian extension and Tertiary deformation.

Notes: Spiral inclusion trails in garnet porphyroblasts are likely to have formed due to simultaneous growth and rotation of the crystals, during syn-metamorphic deformation. Thus, they contain information on the strain rate of the rock. Strain rates may be interpreted from such inclusion trails if two functions are known: (1) The relationship between rotation rate and shear strain rate; (2) the growth rate of the crystal. We have investigated details of both functions using a garnetiferous mica schist from the eastern European Alps as an example. The rotation rate of garnet porphyroblasts was determined using finite element modelling of the geometrical arrangement of the crystals in the rock. The growth rate of the porphyroblasts was determined by using the major and trace element distributions in garnet crystals, thermodynamic pseudosections and information on the grain size distribution. For the largest porphyroblast size fraction (size L=12 mm) we constrain a growth interval between 540 and 590 °C during the prograde evolution of the rock. Assuming a reasonable heating rate and using the angular geometry of the spiral inclusion trails we are able to suggest that the mean strain rate during crystal growth was of the order of 〈inlineGraphic alt="inline image" href="urn:x-wiley:02634929:JMG441:JMG_441_mu1" location="equation/JMG_441_mu1.gif"/〉=6.6 × 10−14 s−1. These estimates are consistent with independent estimates for the strain rates during the evolution of this part of the Alpine orogen.

Notes: Mineral textures in metapelitic granulites from the northern Prince Charles Mountains, coupled with thermodynamic modelling in the K2O–FeO–MgO–Al2O3–SiO2–H2O–TiO2–Fe2O3 (KFMASHTO) model system, point to pressure increasing with increasing temperature on the prograde metamorphic path, followed by retrograde cooling (i.e. an anticlockwise P–T path). Textural evidence for the increasing temperature part of the path is given by the breakdown of garnet and biotite to form orthopyroxene and cordierite in sillimanite-absent rocks, and through the break-down of biotite and sillimanite to form spinel, cordierite and garnet in more aluminous assemblages. This is equated to the advective addition of heat from the regional emplacement of granitic and charnockitic magmas dated at c. 980 Ma. A subsequent increase in pressure, inferred from the break-down of spinel and quartz to sillimanite, cordierite and garnet in aluminous rocks, is attributed to crustal thickening related to upright folding dated at 940–910 Ma. The terrane attained peak metamorphic temperatures of c. 880 °C at pressures of c. 6.0–6.5 kbar during this event. Subsequent cooling is inferred from the localised breakdown of cordierite and garnet to form biotite and sillimanite that developed in the latter stages of the same event. The textural observations described are interpreted via the application of P–T and P–T–X pseudosections. The latter show that most rock compositions preserve only fragments of the overall P–T path; a result of different rock compositions undergoing mineral assemblage changes, or changes in mineral modal abundance, on different sections of the P–T path. The results also suggest that partial melting during granulite facies metamorphism, coupled with melt loss and dehydration, initiated a switch from pervasive ductile, to discrete ductile/brittle deformation, during retrograde cooling.

Notes: Fluid flow at greenschist facies conditions during exhumation of the western Alps occurred in several penecontemporaneous systems, including shear zones at lithological contacts, deformed contacts between serpentinite bodies and metabasalts, albite veins within metabasalts, and calcite + quartz veins within calcareous schists. Fluid flow in shear zones that juxtapose metasediments and ophiolitic rocks within the Piemonte Unit reset O and H isotope ratios. δ18O values are buffered by the wall rocks; however, calculated fluid δ2H values are similar within all the shear zones suggesting that they formed an interconnected network. The similarity of δ2H values of the sheared rocks and those of unsheared calcareous schists suggests that the fluids were derived from, or had equilibrated with, the schists that envelop the ophiolite rocks. Time-integrated fluid fluxes at the sheared contacts estimated from changes in Si in metabasalts were up to 105 m3 m−2, with the fluid flowing up temperature driven either by topography or seismic pumping. Individual shear zones were active for c. 2–3 Myr, implying average fluid fluxes of up to 10−9 m3 m−2 s−1. Rocks in shear zones within the ophiolite away from contacts with the metasediments show much less marked isotopic and geochemical changes, implying that fluid volumes decreased into the ophiolite unit, consistent with the source of fluids being the metasediments. Fluids were generated by dehydration reactions that were intersected during exhumation and, while many rocks show the affects of fluid–rock interaction, large-scale fluid flow between major units was not common.

Notes: Eclogites from the south Tianshan, NW China are grouped into two types: glaucophane and hornblende eclogites, composed, respectively, of garnet + omphacite + glaucophane + paragonite + epidote + quartz and garnet + omphacite + hornblende (sensu lato) + paragonite + epidote + quartz, plus accessory rutile and ilmenite. These eclogites are diverse both in mineral composition and texture not only between the two types but also among the different selected samples within the glaucophane eclogite. Using thermocalc 3.1 and recent models of activity–composition relation for minerals, a P–T projection and a series of P–T pseudosections for specific samples of eclogite have been calculated in the system Na2O–CaO–FeO–MgO–Al2O3–SiO2–H2O (NCFMASH) with quartz and water taken to be in excess. On the basis of these phase diagrams, the phase relations and P–T conditions are well delineated. The three selected samples of glaucophane eclogite AK05, AK11 and AK17 are estimated to have peak P–T conditions, respectively, of 540–550 °C at c. 16 kbar, c. 560 °C at 15–17 kbar and c. 580 °C at 15–19 kbar, and two samples of hornblende eclogite AK10 and AK30 of 610–630 °C and 17–18 kbar. Together with H2O-content contours in the related P–T pseudosections and textural relations, both types of eclogite are inferred to show clockwise P–T paths, with the hornblende eclogite being transformed from the glaucophane eclogite assemblage dominantly through increasing temperature.

Notes: This study uses field, petrographic and geochemical methods to estimate how much granitic melt was formed and extracted from a granulite facies terrane, and to determine what the grain- and outcrop-scale melt-flow paths were during the melt segregation process. The Ashuanipi subprovince, located in the north-eastern Superior Province of Quebec, is a large (90 000 km2) metasedimentary terrane, in which 〉 85% of the metasediments are of metagreywacke composition, that was metamorphosed at mid-crustal conditions (820–900 °C and 6–7 kbar) in a late Archean dextral, transpressive orogen. Decrease in modal biotite and quartz as orthopyroxene and plagioclase contents increase, together with preserved former melt textures indicate that anatexis was by the biotite dehydration reaction: biotite + quartz + plagioclase = melt + orthopyroxene + oxides. Using melt/orthopyroxene ratios for this reaction derived from experimental studies, the modal orthopyroxene contents indicate that the metagreywacke rocks underwent an average of 31 vol% partial melting.The metagreywackes are enriched in MgO, CaO and FeOt and depleted in SiO2, K2O, Rb, Cs, and U, have lower Rb/Sr, higher Rb/Cs and Th/U ratios and positive Eu anomalies compared to their likely protolith. These compositions are modelled by the extraction of between 20 and 40 wt %, granitic melt from typical Archean low-grade metagreywackes. A simple mass balance indicates that about 640 000 km3 of granitic melt was extracted from the depleted granulites.The distribution of relict melt at thin section- and outcrop-scales indicates that in layers without leucosomes melt extraction occurred by a pervasive grain boundary (porous) flow from the site of melting, across the layers and into bedding planes between adjacent layers. In other rocks pervasive grain boundary flow of melt occurred along the layers for a few, to tens of centimetres followed by channelled flow of melt in a network of short interconnected and structurally controlled conduits, visible as the net-like array of leucosomes in some outcrops. The leucosomes contain very little residual material (〈 5% biotite + orthopyroxene) indicating that the melt fraction was well separated from the residuum left in situ as melt-depleted granulite. Only 1–3 vol percentage melt remained in the melt-depleted granulites, hence, the extraction of melt generated by biotite dehydration melting in these granulites, was virtually complete under conditions of natural melting and strain rates in a contractional orogen.

Notes: Abstract  This article describes the development and pilot testing of the Good-Fit Measure (GFM), a measure that public health nurses and other providers involved with planning multidisciplinary violence prevention efforts can use. Themes derived from a series of focus group discussions from a larger study, including individuals (n = 83) from multiple community sectors, guided development of the measure. Participants in three follow-up focus groups (n = 32 participants) reviewed the measure, which was then pilot tested in two phases. Guided by information from the first phase, in which respondents indicated the measure was too complex, the measure was simplified and field tested in phase two. Results from both phases were similar. The GFM score was significantly higher for the program selected by the respondent before completing the measure than the nonselected program (p 〈 0.01). Participants indicated that the tool was helpful in articulating the specific factors for their decisions. Participants underscored the utility of the tool in facilitating program planning by individual providers and interdisciplinary or multidisciplinary teams. The GFM provides systematic consideration of multiple factors that motivate public health nurses and other community providers in their decision-making process when planning prevention strategies, increasing the likelihood of successful programs.

Notes: Abstract  Focus groups provide an effective means of incorporating the perspectives of “hidden” populations in assessments of community health needs and assets. A series of focus groups was conducted with specifically targeted segments of a community to develop a comprehensive picture of community health. The authors describe the focus group process, major findings, and the use of focus group results in a highly multicultural community. Despite differences in age, length of residence, and ethnicity, the focus groups were remarkably similar in the issues raised. The majority of participants viewed the multicultural nature of the community as an asset but voiced some of the difficulties of living in a multiethnic and multilanguage environment. Similar areas of concern in the community arose from all of the focus groups, including housing and other environmental issues and problems of access to health care. Focus group findings have been used to initiate activity addressing identified community problems. Focus group participation had the added benefit of increasing community members' participation in other community endeavors.

Notes: Abstract  Disparity of health outcomes has been identified as a key concern in the health of Americans. Marginalization of the African American population may be a contributing factor. Identification of health protectors may prove key in decreasing disparities. The effect of spirituality on health is discussed. A historical overview of the African American experience in the Islam faith, from the Nation of Islam to universal Islam, is presented. A systematic assessment of the Islamic faith, with emphasis on the African American Muslim, was conducted as an assessment for a Community Health Nursing class. Leininger's Sunrise Model of Culture Care Diversity and Universality, with the ethnonursing model of data collection, served as the framework for data collection and analysis. The Islamic faith was noted to offer holistic direction for a “way of life” that promotes health and harmony of the mind, body, and soul. Implications for research were discussed.

Notes: Abstract  The purpose of this study was to examine comprehensive prenatal case management programs in terms of organizational, program, and process characteristics. Data from 66 program surveys of government agencies were used. Organizational capacity was measured as extent of organizational change and extent of interagency agreements. Program data included age and size of the program, reasons for having case management, and funding diversity. Process data were eight types of interventions.The most highly rated reason for having case management was to improve client outcomes. The greatest organizational change was in the area of the organizational structure, followed by financial status and types of services provided. Contracts with other agencies were rare. Agencies with more interagency contacts reported higher levels of change in the case management department and turnover among mid-level managers. Older programs had fewer employees. Approximately 49% of client contacts were not billed to Medicaid. Larger programs had significantly less time allocated to emotional support and coaching.Data on organizational characteristics, program, and process variables provide insights into comprehensive case management. Relationships among these variables underscore the importance of studying client outcomes within the context of program and organizational idiosyncrasies. Future studies of comprehensive prenatal case management should focus on cross-level questions.