Split tolerance in chimeric GVH mice

Abstract The i.v. inoculation of parental spleen cells into unirradiated adult F1 hybrid mice results in a graft-versus-host reaction (GVHR). In the strain combination B10D2±(B10.BRx B10.D2) F1, this reaction is associated with thymic injury and transient but profound cellular immune deficiency. We further analysed the immune status of these mice 60 days after GVHR induction. Phenotypic studies of spleen cells showed that these mice were re-populated with parental lymphocytes resulting in a high degree of chimerism (85%). At this time, the mice looked healthy and recovered a normal cytotoxic T cell response (CTL) against allogeneic cells. GVH chimeric splenocytes were unresponsive against F 1 hybrid cells in mixed lymphocyte culture (MLC), but exhibited anti-F1 CTL reactivity. We also analysed the anti-F 1 reactivity of these mice in vivo. GVH chimeric splenocytes were unable to induce GVHR after injection into a new F1 hybrid and F1 GVH mice specifically rejected F1 bone marrow (BM) cells after lethal irradiation. Grafting a neonatal parental thymus prevented the rejection of F1 BM cells and restored CTL alloreactivity. It is concluded that the chimeric state induced by GVHR is associated with a split tolerance and that a radiosensitive thymic-dependent mechanism is involved in maintaining self-tolerance in these mice.     

Amphotericin B serum levels in pediatric bone marrow transplant recipients

We studied amphotericin B (AMB) serum levels (n = 590) in 41 pediatric patients, who underwent allogeneic (21) or autologous (20) bone marrow transplantation (BMT). All patients received AMB orally as part of a total gut decontamination; 30/41 patients (73%) had AMB i.v. either for prophylaxis or therapy of fungal infections. Rapid initial dose escalation of AMB and the infusion over 1 h only were well tolerated by the children. Serum level monitoring allowed AMB long-term treatment safely to be administered in children suffering from transplantation-related complications (veno-occlusive disease of the liver, graft-versus-host disease of the liver). An h.p.l.c. method was used for monitoring AMB serum trough levels to avoid levels exceeding 2 mg/l. One lethal fungal infection was observed in 41 pediatric BMT recipients (2.4%). Rapidly increasing doses of AMB at start of therapy and drug monitoring by h.p.l.c. might help to reduce fungal mortality and renal toxicity by a dose sparing effect in BMT recipients.     

Deep brain stimulation for Parkinson's disease dissociates mood and motor circuits: a functional MRI case study.

Behavioral disturbances have been reported with subthalamic (STN) deep brain stimulation (DBS) treatment in Parkinson's disease (PD). We report correlative functional imaging (fMRI) of mood and motor responses induced by successive right and left DBS. A 36-year-old woman with medically refractory PD and a history of clinically remitted depression underwent uncomplicated implantation of bilateral STN DBS. High-frequency stimulation of the left electrode improved motor symptoms. Unexpectedly, right DBS alone elicited several reproducible episodes of acute depressive dysphoria. Structural and functional magnetic resonance imaging (fMRI) imaging was carried out with sequential individual electrode stimulation. The electrode on the left was within the inferior STN, whereas the right electrode was marginally superior and lateral to the intended STN target within the Fields of Forel/zona incerta. fMRI image analysis (Analysis of Functional NeuroImages, AFNI) contrasting OFF versus ON stimulation identified significant lateralized blood oxygen level-dependent (BOLD) signal changes with DBS (P < 0.001). Left DBS primarily showed changes in motor regions: increases in premotor and motor cortex, ventrolateral thalamus, putamen, and cerebellum as well as decreases in sensorimotor/supplementary motor cortex. Right DBS showed similar but less extensive change in motor regions. More prominent were the unique increases in superior prefrontal cortex, anterior cingulate (Brodmann's area [BA] 24), anterior thalamus, caudate, and brainstem, and marked widespread decreases in medial prefrontal cortex (BA 9/10). The mood disturbance resolved spontaneously in 4 weeks despite identical stimulation parameters. Transient depressive mood induced by subcortical DBS stimulation was correlated with changes in mesolimbic cortical structures. This case provides new evidence supporting cortical segregation of motor and nonmotor cortico-basal ganglionic systems that may converge in close proximity at the level of the STN and the adjacent white matter tracts (Fields of Forel/zona incerta).     

Clinical response to local delivery of tetracycline in relation to overall and local periodontal conditions

Abstract The purpose of this study was to determine the clinical response to local delivery of tetracycline in relation to clinical and microbiological conditions of the other teeth. 4 deep pockets were monitored in 19 subjects with multiple deep periodontal lesions and high counts of P. gingivalis. In 9 patients (XT) only 2 of the selected lesions were treated by placement of tetracycline fibers (Actisite®). while the rest of the dentition was left untreated. In the other 10 patients, all teeth were supragingivally scaled and then treated by application of polymeric tetracycline HCl containing fibers, the whole dentition was subject to full mouth scaling and root planing, and the patients rinsed with 0.2% chlorhexidine (FT). A significant reduction in mean PPD was observed in all treated sites after two months. This reduction was maintained over the following 4 months. The magnitude of the effect was significantly greater in the FT group (1.74 mm) than in the LT group (0.88 mm). The mean attachment level changes were similar after 2 months in locally and fully treated subjects. A tendency of relapse was noted for treated sites in LT patients from month 2 to 6. A level of statistical significance was not reached for this effect. Data from measurements recorded at 6 sites around all teeth in the full mouth treated patients were analyzed using multiple linear regression. This analysis showed local changes in PPD and AL were significantly and strongly correlated with the baseline value of the respective parameter at the same site. In addition, more pocket depth reduction was noted if a site was not bleeding on probing at 6 months, if the location of a site was not approximal and if the tooth was not a second molar. Sites located on second molars showed also less AL gain than sites located on other teeth. Smokers showed significantly less reduction in PPD and significantly less AL gain. Furthermore, if subjects had a high % of pockets deeper than 4 mm at baseline they showed significantly less attachment gain.     

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.     

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。     

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.