Levodopa dose-related fluctuations in presumed olivopontocerebellar atrophy

The parkinsonism that occurs in some patients with olivopontocerebellar atrophy (OPCA) can cause diagnostic confusion with idiopathic Parkinson's disease (IPD). The response to levodopa is usually a distinguishing feature, the OPCAs either failing to benefit or losing efficacy relatively quickly. A fluctuating response to levodopa in those OPCA patients who do benefit has not been emphasized in the literature previously. Reported here are three patients with presumed OPCA, dominated by parkinsonian features, who eventually developed typical fluctuations with morning akinesia, wearing off, and periodic lack of response related to meals. These fluctuations were a major source of disability and an important reason for diagnostic confusion with IPD. The possible mechanisms of these fluctuations are discussed.     

Regulation of the acid-labile subunit of the insulin-like growth factor ternary complex in patients with insulin-dependent diabetes mellitus and severe burns

OBJECTIVE Little information is available regarding the regulation of serum acid-labile subunit (ALS) in human disease. We have studied alterations in serum ALS of the insulin-like growth factor (IGF) ternary complex in children with untreated insulin-dependent diabetes mellitus (IDDM) and subjects with severe burns before and after insulin therapy. In addition, we have investigated the effect of insulin plus GH on serum ALS in burn patients. DESIGN Serum samples were obtained from children with newly diagnosed and untreated IDDM before the initiation of insulin therapy and 1 month thereafter. Serum samples were also obtained from adult patients with severe burns who were on a continuous infusion of a carbohydrate-rich enteral diet via nasogastric and duodenal catheters under basal conditions, after a 1-week period of continuous insulin infusion, and after an additional week of insulin plus recombinant GH. PATIENTS Twenty children and adolescents with untreated IDDM, aged 1.2–16 years, and 6 young adult patients with severe burns aged 17–28 years were studied longitudinally. Control sera were obtained from age, sex and pubertal status matched subjects (for children with IDDM) and from fed healthy adults. MEASUREMENTS Serum insulin, GH, cortisol and IGF-I were measured by radioimmunoassay, and serum ALS levels were assessed by Western immunoblot before and after treatment periods. RESULTS Serum ALS levels were lower in untreated children with IDDM (69 ± 6% of control children). Insulin therapy significantly increased serum ALS (79 ± 5%, P<0.05) in these children. Patients with severe burns also had lower serum ALS levels (79 ± 10% of control adults). After one week of insulin therapy serum ALS levels increased to 90 ± 15% of control values (P<0.05). Addition of GH to insulin therapy for another week did not significantly further increase serum ALS levels (95 ± 27%). Serum IGF-I concentrations increased nearly 2.5-fold in diabetic subjects and fourfold in burn subjects at the end of the study periods. There were no proteolytic fragments of ALS in the sera studied. The deglycosylation pattern of ALS did not differ between diabetic and control sera. CONCLUSION Serum ALS levels were diminished in children with untreated IDDM and were partially restored after the initiation of insulin therapy. Serum ALS levels were also diminished in patients with severe burn injury and restored by insulin treatment. Addition of GH to insulin therapy did not significantly increase serum ALS levels over levels obtained during insulin therapy alone. These decreases in serum ALS were smaller than the decrease in serum IGF-I concentrations in both conditions, suggesting that IGF-I is the limiting factor for the ternary complex formation in the catabolic states. Insulin may regulate circulating ALS levels in catabolic states and helps to restore the IGF system.     

外科切口感染危险因素研究

目的：研究术后切口感染危险因素，以降低切口感染率。方法：以１９９４～１９９６年外科手术病人为对象，进行病例对照研究。结果：病例组１３１例切口感染病人和对照组１００例无切口感染病人在手术持续时间、术前抗生素使用种类、免疫抑制剂应用与否以及手术后抗生素使用天数等方面有显著性差异。且随着手术时间延长，术后切口感染的相对危险度呈明显递增趋势。结论：为降低术后切口感染率，必须尽量缩短手术时间，并减少术前术后抗生素使用天数和种类     

KMT2C通过c-Myc/CDK4信号通路调控胃癌细胞的生长与增殖

摘要:目的 探究赖氨酸特异性甲基转移酶2C(lysine specific methyltransferase 2C,KMT2C)在胃癌发生发展中的 作用及机制。方法 通过 TCGA 数据库分析 KMT2C在胃癌与癌旁的表达差异。采用 Western blot检测 KMT2C在胃 癌与癌旁临床样本中的表达差异。通过 Kaplan-Meier Plotter数据库分析 KMT2C 对胃癌患者预后的影响。采用细胞 实验(克隆形成、EdU 及 CCK-8检测)及皮下瘤负荷模型检测 KMT2C 在体内外对胃癌细胞增殖能力的影响。结果 KMT2C在胃癌中高表达。胃癌患者中 KMT2C高表达组相对于 KMT2C低表达组预后较差。敲减 KMT2C在体内外 均有抑制胃癌 细 胞 增 殖 的 作 用。基 因 集 富 集 分 析 (GSEA)发 现 KMT2C 影 响 c-Myc信 号 通 路。敲 减 KMT2C 后, H3K4me1蛋白表达水平降低,同时,CDK4的 mRNA 与蛋白表达水平降低。KMT2C与c-Myc核内结合促进了c-Myc 与 CDK4的启动子区域的结合。结论 KMT2C通过影响c-Myc/CDK4信号通路促进胃癌细胞增殖。     

Comparison of clinical efficacy and toxicity of conventional and optimum biological response modifying doses of interferon alpha-2C in the treatment of hairy cell leukemia: a retrospective analysis of 39 patients

Hairy cell leukemia (HCL) has been shown to be extraordinarily sensitive to treatment with alpha-interferon (IFN). In order to define clinically effective IFN doses associated with minimal toxicity, the therapeutic efficacy and side effects of recombinant IFN-alpha-2C treatment of HCL were compared for two different dose regimens: 18 patients (group A) received conventional doses of recombinant IFN-alpha-2C (2 x 10(6)U/m2) for a median time of 35 weeks (range 26-52 weeks), and 21 patients (group B) received optimum biological response-modifying doses of IFN-alpha-2C (0.2-0.6 x 10(6)U/m2) for a median time of 31 weeks (range 12-52 weeks). Interferon was administered daily subcutaneously for 3 months and then every second or third day. Induction of neopterin excretion was chosen as the marker for definition of biological response. The smallest IFN dose causing maximum in vivo induction of biosynthesis of the GTP-degradation product neopterin was deemed "biologically optimal." Both dose regimens were effective, but the low-dose regimen was almost free of toxicity. Thus, in HCL patients alpha-IFN related toxicity can be separated from its antineoplastic activity. Low doses of alpha-IFN should be considered for treatment of HCL patients who develop toxic side effects and for primary treatment of HCL patients with severe cytopenia.     

Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis.

BACKGROUND: Calcific aortic stenosis (AS), the most frequent heart valve disorder in developed countries, leads to the calcification and fibrous thickening of the valve. While several studies have addressed the process of valvular calcification, the molecular pathomechanisms of the extensive matrix remodeling remain unclear. Because inflammation is present in stenotic valves, we hypothesized that the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) might influence cell proliferation and regulate the expression and activation of matrix metalloproteinases (MMPs)--enzymes that are thought to be involved in calcific AS. METHODS: Immunohistochemistry for leukocytes, TNFalpha, MMP-1, and the endogenous MMP inhibitor tissue inhibitor of metalloproteinase (TIMP)-1 was performed on human stenotic (n = 19) and control (n = 8) valves. Primary cultures of human aortic valve myofibroblasts were incubated with and without TNFalpha, and cell proliferation was assessed. The expression and activation of MMP-1 were detected by Western blotting and a specific MMP-1 activity assay. RESULTS: Control valves showed scattered macrophages and low expression of TNFalpha, MMP-1, and TIMP-1. In stenotic valves, leukocyte infiltration and a strong, colocalized expression of TNFalpha and MMP-1 were present, while TIMP-1 remained unchanged. Double-label immunofluorescence localized TNFalpha mainly to macrophages. In cultured human aortic valve myofibroblasts, TNFalpha stimulated proliferation and induced a time-dependent increase in MMP-1 expression and activation, while TIMP-1 remained unchanged. CONCLUSION: The results indicate that matrix remodeling in calcific AS involves the expression and activation of MMPs. Activated leukocytes, by the secretion of TNFalpha, may stimulate valvular myofibroblasts to proliferate and express MMPs, thus regulating actively the matrix remodeling in calcific AS.     

Presentation of alpha-galactosylceramide by murine CD1d to natural killer T cells is facilitated by plasma membrane glycolipid rafts

CD1 molecules are non-polymorphic major histocompatibility complex class I-related proteins that bind and present glycolipid antigens to T-cell antigen receptors (TCR) expressed by alphabeta T cells or natural killer-like T cells (NKT). Anti-metastatic properties of NKT cells reactive to the CD1d-binding antigen alpha-galactosylceramide (alpha-GalCer) are now being explored as a contributor to tumour cell killing. In this study, we tested the hypothesis that presentation of alpha-GalCer by murine CD1d (mCD1d) to mCD1d-restricted NKT cells was facilitated by plasma membrane glycolipid rafts. Confocal microscopy of mCD1d-transfected A20 B cells (A20mCD1d) demonstrated that mCD1d was raft-localized. This observation was confirmed by immunoblotting of raft fractions isolated on sucrose density gradients. Raft disruption by the cholesterol-binding agent nystatin, or short-chain ceramides, inhibited presentation of low concentrations of alpha-GalCer to NKT cells. Inhibition of antigen presentation was reversed by treatment of A20mCD1d cells with higher alpha-GalCer concentrations, or removal of raft-disrupting agents. These data indicate that partitioning of mCD1d into membrane rafts increases the capacity of antigen-presenting cells to present limiting quantities of glycolipid antigens, perhaps by stabilizing mCD1d/antigen structures on the plasma membrane and optimizing TCR engagement on NKT cells.     

Association between mutations in the CARD15 (NOD2) gene and Crohn's disease in Israeli Jewish patients

Ulcerative colitis (UC) and Crohn's disease (CD) are heterogeneous disorders characterized by chronic intestinal inflammation. Genetic predisposition is a major risk factor in both diseases. The CARD15 (NOD2) gene has been implied as a candidate gene in the pathogenesis CD. Our aim was to delineate the frequency of three missense and one frameshift variant of CARD15 in Israeli Jewish CD and UC patients. DNA was extracted from blood samples from 238 unrelated inflammatory bowel disease (IBD) patients, 68 with UC and 170 with CD. The DNA was genotyped for two missense mutations, R675W and G881R, and one frameshift mutation, 980FS981X. Mutations in CARD15 were observed with significantly greater frequency in CD patients (46/170, 27%) than in UC patients (7/68, 10%) (P = 0.005). Homozygous and compound heterozygous carriers were restricted to seven (4%) patients with CD as compared to none of the UC patients (P = 0.01). Similar rates in Ashkenazi and non-Ashkenazi Jewish patients were observed. Age-of-onset of disease was lower in Ashkenazi mutation carriers as compared to non-carriers of Ashkenazi origin (18.7 +/- 8.6 years vs. 25.8 +/- 13.4 years, respectively, P = 0.03). No other phenotypic characteristics could distinguish mutation carriers from non-carriers. We conclude that germline mutations in the CARD15 gene are more frequently found in CD than UC patients and appear to predict an earlier age-of-onset in Ashkenazi Jewish patients. No association could be demonstrated between CARD15 mutations and specific disease course or behavior.     

Einflüsse von Nahrungsaufnahme und Gewöhnung auf die Verteilung von 8-14C-Coffein bei der Ratte

Zusammenfassung 200 g schwere Ratten erhielten Lösungen von¹⁴C-Coffein entweder nüchtern oder nach vorheriger Verabreichung von Kohlenhydrat, Eiweiß und Fett. Die Nahrungszufuhr bedingte folgende Änderungen der Coffeinverteilung im Organismus gegenüber den nüchternen Tieren: die Coffeinresorption war deutlich verzögert, so daß die¹⁴C-Aktivitätswerte im Serum und Carcass nur langsam anstiegen. Im weiteren Verlauf des Versuches erreichte der Abfall der¹⁴C-Aktivität in Serum und Carcass und ihre Ausscheidung im Harn ein geringeres Ausmaß.Die Coffeinverteilung im Organismus zeigte außerdem bestimmte Änderungen bei Ratten, die im Anschluß an eine 14tägige Gewöhnunsperiode¹⁴C-Coffeinhaltigen Kaffee-Infus erhielten. Im Vergleich zu den nicht an Kaffee gewöhnten Ratten war hierbei die Coffeinresorption deutlich beschleunigt. Die¹⁴C-Aktivitätswerte im Serum stiegen anfangs schneller und höher an, zeigten anschließend aber einen rascheren Abfall. Auf Grund dieser Effekte war die¹⁴C-Ausscheidung durch die Niere erheblich beschleunigt und vermehrt.

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Summary Rats weighing 200 g obtained¹⁴C-caffeine solution either after starvation or after feeding carbohydrate, proteine or fat. The following differences in caffeine distribution in the fed rats compared with the starved ones were confirmed: caffeine absorption was clearly decreased, resulting in slow increase in¹⁴C-activity in the serum and the carcass. During the course of the experiment it was observed that the decline of¹⁴C-activity in serum and carcass was delayed and its excretion in the urine was decreased. Additionally caffeine distribution in the rat body showed certain changes which were accompanied by caffeine habituation in the animals after administration of¹⁴C-caffeine contained in coffee infusion for 14 days. In the coffee habituated animals the caffeine absorption was noticeably accelerated.¹⁴C-activity in serum increased initially quicker but finally showed a quicker decline. Governed by these effects the¹⁴C-excretion via kidney was increased and its rate was accelerated.

     

Cerebellar damage impairs automaticity of a recently practiced movement

It has been suggested that the cerebellum plays a critical role in learning to make movements more "automatic" (i.e., requiring less attention to the details of a movement). We hypothesized that cerebellar damage compromises learning of movement automaticity, resulting in increased attentional demands for movement control. The purpose of our study was to determine whether cerebellar damage disrupts the ability to make a practiced movement more automatic. We developed a dual task paradigm using two tasks that did not have overlapping sensory or motor requirements for execution. Our motor task required subjects to maintain an upright posture while performing a figure-8 movement using their arm. This motor task was chosen to simulate requirements of everyday movements (e.g., standing while reaching for objects), but it was novel enough to require practice for improvement. Our secondary task was an auditory vigilance task where subjects listened to letter sequences and were asked to identify the number of times a target letter was heard. We tested controls and people with cerebellar damage as they practiced the movement task alone and then performed it with the auditory task. We recorded 3D position data from the arm, trunk, and leg during the movement task. Errors were recorded for both the movement and the letter tasks. Our results show that cerebellar subjects can improve the movement to a very limited extent with practice. Unlike controls, the motor performance of cerebellar subjects deteriorates to prepractice levels when attention is focused away from the movement during dual task trials. Control subjects' insensitivity to dual task interference after practice was due to learned movement automaticity and was not a reflection of better dual task performance generally. Overall, our findings suggest that the cerebellum may be important for shifting movement performance from an attentionally demanding (unpracticed) state to a more automatic (practiced) state.