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Notes: Chorea-acanthocytosis (CHAC) is a hereditary neurodegenerative disorder with autosomal recessive transmission, in which selective degeneration of striatum has been reported in brain pathology. Clinically, CHAC shows Huntington's disease-like neuropsychiatric symptoms and red blood cell acanthocytosis. Recently, we identified the gene, CHAC, encoding a novel protein, chorein, in which a deletion mutation was found in Japanese families with CHAC. In the present study, we have identified the mouse CHAC cDNA sequence and the exon–intron structures of the gene and produced a CHAC model mouse introducing no. 60–61 exon deletion corresponding to a human disease mutation by a gene-targeting technique. The mice began to show acanthocytosis and motor disturbance in old age. In behavioral observations, locomotor activity was significantly decreased and the contact time at social interaction test was decreased significantly in the model mice. In the brain pathology, many apoptotic cells were observed in the striatum of the mutant mice. In neurochemical determinations, the dopamine metabolite, homovanillic acid, concentration decreased significantly in the portion including the midbrain of the mutant mice. These findings are consistent with the human results reported elsewhere and indicate that the CHAC model mice showed a mild phenotype with late adult onset. The CHAC model mouse therefore provides a good model system to study the human disease.

Notes: It is well known that two different photobiologic processes mainly take place when the human skin is exposed to ultraviolet (UV) light. The long waves of UVA and visible light (320–400 nm) irradiation causes skin tanning by melanocytic activation and the short waves of UVB (280–320 nm) can elicit variety of biologic action in cutaneous keratinocytes, melanocytes and other skin component cells. The sensitivity to the UV lights is generally depending on the three kinds of the skin type classified by the proposal of Pathak et al. [1]. The skin sensitivity of Japanese population, however, seems to be different from that of Caucasian's population because of the differences in genetic background and skin color, as indicated by Satoh and Kawada [2]. They tried to classify into three groups as J-I (always burn and rarely tan), J-II (moderately burn and moderately tan) and J-III (never burn and always tan) by the skin types to UV lights for the sun-tanning and sun-burning. Comparing these two criteria, a general concern indicates that J-I–III may correspond to the skin type II–IV of the Fitzpatrick's classification, respectively. Based on the Japanese skin types, the incidence of skin cancers and precancerous lesions related to the long-term exposure of sun-light was epidemiologically estimated by Araki et al. [3]. According to their results for several years (1992–1998), the overall number of skin cancers and precancerous states in Japanese was demonstrated to be small in comparison with the incidence of Caucasian's population, even though the people sets in areas of higher ambient solar radiation. However, working outdoors having J-I and/or a history of severe sunburn during childhood were found to be important risk factors, particularly among people of over 60 years of age. Regarding skin cancers and sun-exposed areas, we compared between 20 patients with skin cancers (males 13 and females seven) (average 65 years old) (〈link href="#t1-14"〉Table I) and 24 controls (males 10 and females 14), who were selected as similar ages to the patients at random, in their skin types and life environments by a questionnaire system. The skin types of the patients were J-I (15%), J-II (40%), and J-III (35%) and those of controls were J-I (4.2%), J-II (62.5%), and J-III (4.2%), respectively. The patient group tended not to protect from sun exposure and most of them were farmers. UV exposure is known to induce modulation of the skin immune system which Langerhans cells decrease in number in the epidermis, and on the other hand it is supposed that interleukin IL-10 producing macrophages (CD11b+) expand in the dermis. Not only IL-10, but also tumor necrosis factor (TNF)-α from macrophages and mast cells in the dermis seem to increase and suppress Th1 immune responses of the epidermis and Th2 immune responses might be induced by UV irradiation [4]. Recently, it has been reported, however, that in patients with polymorphous light eruption (PLE), the expression of TNF-α, IL-4, and IL-10 is reduced by UVB irradiation and that PLE appearance is related to UVB-induced immunosuppression [5].〈tabular xml:id="t1-14"〉I〈title type="main"〉 Twenty patients with skin cancers (average ages: 65 years old) (Department of Dermatology, Fukushima Medical University Hospital, 2001–2002) 〈table frame="topbot"〉〈tgroup cols="2" align="left"〉〈colspec colnum="1" colname="col1"/〉〈colspec colnum="2" colname="col2"/〉〈thead valign="bottom"〉〈row rowsep="1"〉Skin cancersNumber of patients〈tbody valign="top"〉Malignant melanoma8Squamous carcinoma4Bowen's disease4Basal cell carcinomas3Eccrine porocarcinoma1Location of skin cancersSun-exposed areas9Non-exposed areas11Then, we attempted to study UVB effects on atopic disease and chronic inflamed skin diseases in the therapeutic advantage, although it is harmful for the patients to be cutaneous carcinogenesis. The epidermal keratinocytes are capable of producing CC chemokines in the local Th2 response, as seen in atopic dermatitis, mycosis fungoides, etc. [6]. Thymus and activated-related chemokine (TARC) is one of the chemokines produced by keratinocytes which selectively activate lymphocytes of Th2 subset expressing CCR4 (receptor for TARC) [7]. Accumulating evidence has suggested that these chemokines have primary pathogenic importance in Th2 skin diseases. In order to find the effects of UVB irradiation on the production of TARC, we used a human keratinocyte HaCaT cell line. As assessed by RT-PCR and ELISA, UVB irradiation significantly decreased the expression of TARC mRNA and protein in HaCaT cells stimulated with interferon-γ (IFN-γ) and TNF-α in a dose-dependent manner. The down-regulation of TARC expression may be mediated in part by activation of the particular transcription, signal transducer and activator of transcription 1 (STAT 1), since it has shown that STAT 1 DNA-binding was down-regulated by UVB irradiation. Our results suggest that STAT 1 and other transcription factors play an important biological role in immune system of human skin irradiated by UVB and may support the results of Kolgen et al. [5].In this point of view, UVB irradiation will be a therapeutic tool for skin diseases related to Th2 type reaction, such as atopic dermatitis, mycosis fungoides, etc., although we need to optimize adequately the use of UVB in patients with J-I skin type or those of whom have the episode of severe sun-burn after UVB irradiation.〈section xml:id="abs1-1"〉〈title type="main"〉References1. Pathak, M.A., Nghiem, P. and Fitzpatrick, T.B. Acute and chronic effects on the skin. In: Fitzpatrick's Dermatology in General Medicine, 5th edn (Freedberg, I.M., Eisen, A.Z., Wolf, K., Austen, K.F., Goldsmith, L.A., Katz, S.I. and Fitzpatrick, T.B. eds), pp. 1598–1607. McGraw-Hill, New York (1999).2. Satoh, Y. and Kawada, A. Action spectrum for melanin pigmentation to ultraviolet light, and Japanese skin typing. In: Brown Melanoderma: Biology and Diseases of Epidermal Pigmentation (Fitzpatrick, T.B., Wick, M.M. and Toda, K. eds), pp. 87–95. University of Tokyo Press, Tokyo (1986).3. Araki, K., Nagano, T., Ueda, M., Washio, F., Watanabe, S., Yamaguchi, N. and Ichihashi, M. Incidence of skin cancers and precancerous lesions in Japanese- Risk factors and prevention. J. Epidemiol. 9, S14–S21 (1999).4. Teunissen, M. B., Piskin, G., Nuzzo, S. et al. Ultraviolet B radiation induces a transient appearance of IL-4+ neutrophils, which support the development of Th2 responses. J Immunol. 168, 3732–3739 (2002).5. Kolgen, W., van Meurs, M., Jongsma, M. et al. Differential expression of cytokines in UVB-exposed skin of patients with polymorphous light eruption. Arch. Dermatol. 140, 295–302 (2004).6. Kakinuma, T., Sugaya, M., Nakamura, K., Kaneko, F., Wakugawa, M., Matsushima, K. and Tamaki, K. Thymus and activation-regulated chemokine (TARC/CCL17) in mycosis fungoides: serum TARC levels reflect the disease activity of mycosis fungoides. J. Am. Acad. Dermatol. 48, 23–30 (2003).7. Imai, T., Nagira, M., Tkagi, S. et al. Selective recruitment of CCR4-binding Th2 cells toward antigen-presenting cells by the CC chemokins thymus and activation-regulated chemokine and macrophage-derived chemokine. Int. Immunol. 11, 81–88 (1999).

Notes: Aims:  Lymphomatous polyposis (LP) is considered to represent mantle cell lymphoma (MCL) of the gastrointestinal (GI) tract. However, a few reports have suggested that some are follicular lymphoma (FL) or mucosa-associated lymphoid tissue (MALT) lymphomas. In this study, we analysed 35 patients and clarified the clinicopathological features of LP.Methods and results:  Paraffin-embedded tissue samples were stained immunohistochemically and analysed by tissue-fluorescence in situ hybridization (T-FISH) for IGH/CCND1 (cyclin D1) and IGH/BCL2. The average age of the patients was 58.3 years. Over half of the cases showed gastric, duodenal, small intestinal, ileocaecal and sigmoid colonic lesions (15, 19, 15, 16 and 16 cases, respectively). Phenotypically, cases were classified into three types of MCL (cyclin D1+ CD5+ CD10–) (n = 12), FL (cyclin D1– CD5– CD10+) (n = 14) and MALT (cyclin D1– CD5– CD10–) (n = 9). T-FISH identified 11 of the 11 examined cases with MCLs to have IGH/CCND1, while seven of 10 cases with FL had IGH/BCL2, and none of the MALT cases were positive for IGH/CCND1 or IGH/BCL2. At the study endpoint, five of 12 patients with MCL were dead, two of 14 with FL and one of nine with MALT were dead of other disease. Event-free survival analysis showed significantly poorest outcome in MCL, followed by FL, while MALT was associated with a favourable outcome (P = 0.0040).Conclusions:  Our study emphasizes the importance of differentiating MCL, FL and MALT of LP in evaluating prognosis and hence the most suitable therapeutic regimen.

Notes: Fever is induced by a neuronal mechanism in the brain. Prostaglandin (PG) E2 acts as a pyrogenic mediator in the preoptic area (POA) probably through the EP3 subtype of PGE receptor expressed on GABAergic neurons, and this PGE2 action triggers neuronal pathways for sympathetic thermogenesis in peripheral effector organs including brown adipose tissue (BAT). To explore pyrogenic efferent pathways from the POA, we determined projection targets of EP3 receptor-expressing POA neurons with a special focus on rat hypothalamic regions including the dorsomedial hypothalamic nucleus (DMH), which is known as a center for autonomic responses to stress. Among injections of cholera toxin b-subunit (CTb), a retrograde tracer, into hypothalamic regions at the rostrocaudal level of the DMH, injections into the DMH, lateral hypothalamic area (LH) and dorsal hypothalamic area (DH) resulted in EP3 receptor immunolabelling in substantial populations of CTb-labeled neurons in the POA. Bilateral microinjections of muscimol, a GABAA receptor agonist, into the DMH and a ventral region of the DH, but not those into the LH, inhibited thermogenic (BAT sympathetic nerve activity, BAT temperature, core body temperature and expired CO2) and cardiovascular (arterial pressure and heart rate) responses to an intra-POA PGE2 microinjection. Further immunohistochemical observations revealed a close association of POA-derived GABAergic axon swellings with DMH neurons projecting to the medullary raphe regions where sympathetic premotor neurons for febrile and thermoregulatory responses are localized. These results suggest that a direct projection of EP3 receptor-expressing POA neurons to the DMH/DH region mediates febrile responses via a GABAergic mechanism.

Notes: [Auszug] Osteoarthritis is the most common form of human arthritis. We investigated the potential role of asporin, an extracellular matrix component expressed abundantly in the articular cartilage of individuals with osteoarthritis, in the pathogenesis of osteoarthritis. Here we report a significant ...

Notes: Objective:  There is no consensus of objective information to determine the indication for lower extremity amputation and the lowest amputation level that will heal. In this report, we studied amputation for the lower extremity ischemia.Objects and Methods:  We measured transcutaneous oxygen tension (tcPO2) in seven patients who had have ischemic disease of the lower extremity, two patients were in Buerger's disease and five patients were in arteriosclerosis obliterans (ASO). Of these patients, in regard to complications, four patients had diabetes mellitus (DM) and two patients underwent hemodialysis because of chronic renal failure. Six patients of them were men and only one patient was woman, mean age was 59 years old (25∼76 years old).Results:  Two patients who had Buerger's disease underwent primary amputation. All another five patients who had ASO underwent secondary amputation. Selections of lower extremity amputation levels were above-knee amputations in three patients, below-knee amputations in two patients and toe amputation in two patients. There were incurable infections in two patients.Conclusions:  It is generally said that if patients have had critical limb ischemia without providing hemodynamic improvement, it is necessary for them to be performed lower extremity amputations within 12 months, In concrete terms, segmental Doppler systolic blood pressures are below 50 mmHg and tcPO2 are below 30 mmHg. However in this our study, primary healing rate was 75% when the tcPO2 was above 20 mmHg.

Notes: Application of ultraviolet light irradiation to a photocrosslinkable chitosan (Az-CH-LA) aqueous solution including fibroblast growth factor-2 (FGF-2) results within 30 seconds in an insoluble, flexible hydrogel. The FGF-2 molecules retained in the chitosan hydrogel remain biologically active and are released from the chitosan hydrogel upon in vivo biodegradation of the hydrogel. To evaluate the accelerating effect on wound healing of this hydrogel, full-thickness skin incisions were made in the backs of healing-impaired diabetic (db/db) mice and their normal (db/+) littermates. The mice were later killed, and histological sections of the wound were prepared. The degree of wound healing was evaluated using several histological parameters such as the rate of contraction, epithelialization, and tissue filling. Application of the chitosan hydrogel significantly advanced the rate of contraction on Days 0 to 2 in db/db and db/+ mice. Although the addition of FGF-2 into the chitosan hydrogel in db/+ mice had little effect, application of the chitosan hydrogel–containing FGF-2 further accelerated the adjusted tissue filling rate (Days 2 to 4 and Days 4 to 8) in db/db mice. Furthermore, the chitosan hydrogel–containing FGF-2 markedly increased the number of CD-34-positive vessels in the wound areas of db/db mice on Day 4. Thus, the application of chitosan hydrogel–containing FGF-2 onto a healing-impaired wound induces significant wound contraction and accelerates wound closure and healing.

Notes: Abstract  Background: Although the off-pump technique is becoming widely used in coronary bypass surgery, there has been no experimental rat heart model of regional reversible ischemia. The aims of this study were to investigate the optimal duration of coronary occlusion for making reversible ischemia and to examine whether cerivastatin increases myocardial tolerance against prolonged coronary occlusion. Methods: Study 1—Male Sprague-Dawley rats (350 to 450 g) underwent temporary occlusion of either left anterior descending artery (LAD; for 3, 5, 7.5, 10, 12.5, 15, or 20 min) or circumflex artery (CX; for 5, 10, or 15 min). Study 2—Rats were divided into two groups, control and cerivastatin groups, which had 0.1 mg/kg cerivastatin intravenously after anesthesia. LAD was occluded for 10, 15, or 20 minutes. In the both studies, hearts were stained to determine the area at risk (AR) and infarcted (IF) area 24 hours after reperfusion. Results: In LAD occlusion, IF/AR increased in a time dependent manner: 4.5 ± 3.2%, 9.7 ± 5.2%, 17.2 ± 3.0%, 16.8 ± 2.7%, 23.9 ± 9.5% (p 〈 0.01 vs. 3 min), 62.4 ± 2.9% (p 〈 0.0001), and 63.4 ± 2.9% (p 〈 0.0001) at 3, 5, 7.5, 10, 12.5, 15, and 20 min, respectively. Also in CX, IF/AR increased with time: 14.3 ± 2.3%, 25.9 ± 2.1%, and 40.9 ± 6.2% (p 〈 0.001 vs. 5 min) at 5, 10, and 15 min, respectively. Cerivastatin significantly reduced IF/AR at 15 minutes (43.7 ± 6.2%) and at 20 minutes (44.6 ± 5.3%) compared to control (62.4 ± 2.9% and 60.6 ± 2.5%, respectively, p 〈 0.05). Conclusion: Cerivastatin increased myocardial tolerance after prolonged coronary occlusion over 10 minutes, which was considered to be the upper limit for creating a regional reversible ischemia in rats.

Notes: Abstract  Background: There are a number of strategies to restore/preserve endothelial function. We have compared the effects of Cerivastatin (CS) to those of L-arginine (L-ARG) supplementation on the endothelial function of human arterial grafts. Methods: During coronary artery bypass grafting, specimens of radial artery (RA) and left internal thoracic artery (LITA) were obtained. Specimens were divided into vascular rings, which were incubated with either 10−6 mol/L CS, 10−3 mol/L L-ARG, or vehicle (control) for 2 or 24 hours. Endothelial function was examined with acethylcholine (10−9 to 10−5 mol/L) following contraction by 3 × 10−8 mol/L endothelin-1. Results: Although no significant differences were observed in the RA at 2 hours, after 24 hours incubation, endothelium-dependent vasodilatation was significantly higher in CS group (68.4 ± 5.0%; n = 6) compared to L-ARG group (49.9 ± 5.4%; n = 7, p 〈 0.05) and control group (33.8 ± 2.9%; n = 13, p 〈 0.0001). In addition, there was a significant increase in L-ARG group compared to control (p 〈 0.01). After 2 hours incubation of the LITA, CS failed to enhance endothelium-dependent vasodilatation compared to control (44.1 ± 4.9%; n = 9, vs. 40.0 ± 5.2%; n = 16, respectively, NS), while L-ARG increased it (64.7 ± 4.9%; n = 7, p 〈 0.05 vs. CS and p 〈 0.01 vs. control). However, this increase disapeared at 24 hours although there was a higher trend of endothelium-dependent vasodilatation in CS group (30.3 ± 3.7%; n = 8 in L-ARG, 56.5 ± 8.8%; n = 9 in CS and 41.0 ± 5.5%; n = 18 in control). Conclusions: CS preserved endothelium-dependent vasodilatation of RA greater than L-ARG. These findings suggest that the use of statins may be an effective therapeutic strategy to preserve endothelial function in the RA grafts, and could have important implications in the clinical practice.

Notes: Abstract  Objective: The use of the radial artery (RA) as a conduit for coronary artery bypass grafting (CABG) is gaining in popularity worldwide and is being increasingly adopted by many cardiac surgeons. Encouraged by our satisfactory early experience with the use of the RA conduit, we have expanded its use to more than 90% of all coronary surgery patients. The aim of the present study was to review our clinical and angiographic results when the use of the RA conduit was expanded to all patients including those aged 65 years and older and diabetics with different surgical grafting techniques. Methods: The records of 600 consecutive patients who underwent isolated CABG using the RA graft at Harefield Hospital between January 1999 and August 2002 were reviewed retrospectively. Ninety-three (15.5%) patients consented and underwent angiography before discharge at the earliest on the fourth postoperative day, aiming to look at the quality of anastomoses and the patency of the RA grafts. Results: The 600 patients had 613 RA grafts to perform 652 distal RA anastomoses. The proximal ends of 515 (84%) RA grafts were anastomosed to the aorta, 98 (16%) RA grafts were constructed as Y-grafts with 49 (8%) RA off a vein graft hood, and 49 (8%) RA grafts were constructed as T- or Y-grafts off an internal thoracic artery (ITA) graft. The proximal ends of 19 (19/294 or 6.5%) vein grafts were constructed as Y-grafts off the RA grafts. Two hundred and sixty-one (43.5%) patients were above the age of 65 years and 111 (18.5%) patients were diabetics. There were four in-hospital deaths (0.6%) among the study patients. Six (1%) patients developed forearm hematoma/seroma postoperatively. The operation time, the hospital stay, and the incidence of conduit harvest site infection for the patients who had vein grafts in addition to the RA grafts were significantly higher than those of patients who had RA grafts only. On postoperative angiography, 86 out of 93 (92.5%) RA grafts were found to be patent with good quality distal anastomoses. The maximum stenosis of the coronary arteries bypassed by the patent 86 RA grafts was 82.6 ± 6.2%, while it was 56.3 ± 15.4% for the coronary arteries bypassed by the occluded seven RA grafts, p 〈 0.001. Conclusion: The use of the RA can be expanded to all patients with different surgical grafting techniques and provides satisfactory clinical and angiographic outcomes.