Thermodynamic analysis of degenerate recognition by the NKG2D immunoreceptor: not induced fit but rigid adaptation

The homodimeric immunoreceptor NKG2D drives the activation of effector cells following engagement of diverse, conditionally expressed MHC class I-like protein ligands. NKG2D recognition is highly degenerate in that a single surface on receptor monomers binds pairs of distinct surfaces on each structurally divergent ligand, simultaneously accommodating multiple nonconservative ligand allelic or isoform substitutions. In contrast to TCR-pMHC and other NK receptor-ligand interactions, thermodynamic and kinetic analyses of four NKG2D-ligand pairs (MIC-A*001, MIC-B*005, ULBP1, and RAE-1beta) reported here show that the relative enthalpic and entropic terms, heat capacity, association rates, and activation energy barriers are comparable to typical, rigid protein-protein interactions. Rather than "induced-fit" binding, NKG2D degeneracy is achieved using distinct interaction mechanisms at each rigid interface.     

儿童阻塞性睡眠呼吸暂停低通气综合征的治疗

目的 探讨儿童阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea hypopneasyndrome,OSAHS)患儿的治疗方法和疗效观察。方法 经多道睡眠监测(polysomnography,PSG)确诊的4-12岁OSAHS患儿59例:扁桃体切除和(或)经口内镜(内窥镜,下同)引导下腺样体刮除54例;选择长期正压通气治疗(continue positive airway pressure,CPAP)2例;保守治疗3例。采用儿童OSAHS生活质量调查表(quality of life for children with obstructive sleep apnea 18 items,OSA-18)对患儿进行治疗前后的随访。结果 围手术期无术后出血、急性呼吸道梗阻发生。随访12-18个月,手术患儿无鼻咽闭锁、咽鼓管功能障碍、腺样体残留等并发症;OSA-18调查评分显示:治疗后76.3％(45例)的患儿生活质量总体指标,88.1％(52例)的患儿睡眠呼吸障碍,67.8％(40例)的患儿身体症状得到显著改善。长期CPAP治疗的有效治疗压力在5.6-7.8 em H2O左右。3例保守治疗者略有改善。结论 手术切除引起上气道阻塞的肥大的扁桃体和(或)腺样体是儿童OSAHS有效的治疗手段之一,纤维鼻咽镜检查、头颅侧位X线摄片有助于手术适应证的确定。经口内镜引导下腺样体刮除术具有直视下操作,视野清晰,切除彻底,可避免损伤周围重要结构的特点。     

p14ARF expression in invasive breast cancers and ductal carcinoma in situ – relationships to p53 and Hdm2

Introduction  

p14^ARF stabilises nuclear p53, with a variable expression of p14^ARF mRNA in breast cancers. In vitro, nuclear p14^ARF binds Hdm2 to block Hdm2-dependent nucleocytoplasmic shuttling of p53, which is required before cytoplasmic degradation of p53. p14^ARF is negatively regulated by p53 and through p53-independent pathways. No studies have yet examined levels of p14^ARF protein expression in breast cancer and their relationship to Hdm2/p53 immunoreactivity or subcellular localisation. Previously, immunohistochemical expression of cytoplasmic p14^ARF, p53 and Hdm2 has been described. HER-2 (c-erbB2/neu) predicts prognosis and interacts with the p14^ARF/Hdm2 pathway to inactivate p14^ARF and to influence Hdm2 activity and localisation. This study examined p14^ARF and p53/Hdm2 expression and subcellular localisation by using immunohistochemistry in a series of invasive ductal breast cancers (IDCs) with concomitant ductal carcinoma in situ (DCIS), to evaluate whether findings in vitro were related to clinicopathological parameters such as HER-2 and their effect on patient outcome.     

大肠癌并肝硬化与大肠癌不并肝硬化发生肝转移癌对照研究

目的 探讨大肠癌并肝硬化患者发生肝转移癌的规律。方法 回顾性分析我院1990年1月～2001年1月10年间诊治的大肠癌856例,均有病理组织学检查确诊。其中大肠癌并肝硬化患者(肝硬化组)74例,伴肝转移癌者2例;其余为不并肝硬化患者(非肝硬化组)782例,伴肝转移癌者168例。结果 肝硬化组肝转移癌发生率为2.7％(2/74);非肝硬化组肝转移癌发生率为21.5％(168/782,P<0.001)。结论 大肠癌不并肝硬化患者的肝转移癌发生率同大肠癌并肝硬化患者的肝转移癌发生率比较,前者肝转移癌发生率明显地高,后者很少发生肝转移癌。     

TP53 mutation and haplotype analysis of two large African American families

Two large apparently unrelated African American families with a high incidence of breast cancer and other tumors characteristic of Li‐Fraumeni breast sarcoma cancer family syndrome were studied. Mutation screening revealed that in both families the affected members carried a germline mutation of the TP53 gene at codon 133 (ATG→ ACG, M133T). In order to determine whether an ancestral haplotype was shared by these two families, polymorphic markers within and flanking the TP53 gene were studied. Haplotype analysis using five markers revealed an identical haplotype shared by the two families. Loss of heterozygosity at the TP53 locus in the probands' tumor tissues from each family was observed; in each case, the retained allele carried the common haplotype. The frequency of this haplotype in the general African American population is <0.003. This unique haplotype, combined with the rare TP53 mutation, suggests that these African American families share a common ancestry. This finding suggests that other African Americans may be carriers of this mutation and thus may be at risk of early‐onset breast cancer or other cancers characteristic of the Li‐Fraumeni breast sarcoma cancer family syndrome. The finding of recurring mutations in African Americans may facilitiate carrier screening and identification in this population. Hum Mutat 14:216–221, 1999. © 1999 Wiley‐Liss, Inc.     

Utilization of intraoperative electroneurography to understand the innervation of the trapezius muscle

The radical neck dissection is an operation for the management of lymph node metastases from primary sites involving the oral cavity, larynx, and other areas of the head and neck. In this procedure, the spinal accessory nerve is removed along with other structures. In modified neck dissection the spinal accessory nerve is preserved. Patients undergoing the modified neck dissection have had variable functional outcomes from little or no pain or disability, to significant muscle dysfunction. Our group hypothesized that patients with good functional outcomes following modified neck dissection may have had motor contributions from C2, C3, or C4 branches, while those with less favorable outcomes did not. To demonstrate the presence of motor input and its significance both from the spinal accessory nerve and the branches of the cervical plexus, we utilized intraoperative electroneurography. We find that although there is motor contribution from C2, C3, and C4 to the trapezius muscle, it was not consistent or significant. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20, 279–285, 1997.     

Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis patients with secondary hyperparathyroidism

To evaluate the response of circulating intact parathyroid hormone (iPTH) on myocardial hypertrophy in hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT), echocardiographic and neurohormonal assessments were performed over a 15-week period in 15 HD patients with SHPT before and after calcitriol treatment and 10 HD control patients with SHPT not receiving calcitriol therapy. We prospectively studied a group of 15 patients with significantly elevated iPTH levels (iPTH >450 pg/mL) receiving calcitriol (2 microg after dialysis twice weekly). Clinical assessment, medication status, and biochemical and hematological measurements were performed once a month. Throughout the study, calcium carbonate levels were modified to maintain serum phosphate levels at less than 6 mg/dL, but body weight, antihypertensive medication, and ultrafiltration dose remained constant. In patients treated with calcitriol, an adequate reduction of iPTH levels was found (1,112 +/- 694 v 741 +/- 644 pg/mL; P < 0.05) without changes in values of serum ionized calcium (iCa++), phosphate, or hematocrit. Blood pressure (BP), cardiac output (CO), and total peripheral resistance (TPR) did not significantly change. After 15 weeks of treatment with calcitriol, M-mode echocardiograms showed pronounced reductions in interventricular wall thickness (13.9 +/- 3.6 v 12.8 +/- 3.10 mm; P = 0.01), left ventricular posterior wall thickness (12.5 +/- 2.4 v 11.3 +/- 1.8 mm; P < 0.05), and left ventricle mass index (LVMi; 178 +/- 73 v 155 +/- 61 g/m2; P < 0.01). However, in control patients, these changes were not found after the treatment period. In addition, sequential measurements of neurohormonal mediator levels in patients receiving calcitriol showed that plasma renin (18.5 +/- 12.7 v 12.3 +/- 11.0 pg/mL; P = 0.007), angiotensin II (AT II; 79.7 +/- 48.6 v 47.2 +/- 45.7 pg/mL; P = 0.001), and atrial natriuretic peptide (ANP; 16.6 +/- 9.7 v 12.2 +/- 4.4 pg/mL; P = 0.03) levels significantly decreased, whereas antidiuretic hormone (ADH), epinephrine, and norepinephrine levels did not change significantly. The percent change in LVMi associated with calcitriol therapy had a strong correlation with the percent change in iPTH (r = 0.52; P < 0.05) and AT II (r = 0.47; P < 0.05) levels. We conclude that the partial correction of SHPT with intravenous calcitriol causes a regression in myocardial hypertrophy without biochemical or hemodynamic changes, such as heart rate, BP, and TPR. The changes in plasma levels of iPTH and, secondarily, plasma levels of neurohormones (especially AT II) after calcitriol therapy may have a key role in attenuating ventricular hypertrophy in SHPT.     

Familiality and co‐occurrence of clinical features of systemic lupus erythematosus

Objective

To evaluate familiality of 15 clinical and laboratory features in systemic lupus erythematosus (SLE)–affected sibpairs, and to estimate correlations with the age at SLE diagnosis in affected sibpairs and parent–offspring pairs.

Methods

Concordance rates and sibling risk ratios were used as indicators of familiality for 15 manifestations of SLE. Pearson's correlations and paired t‐tests were used to compare the age at SLE diagnosis in affected sibpairs and in parent–offspring pairs.

Results

Increased sibling risk ratios (1.9–3.9) for thrombocytopenia, discoid rash, neurologic disorder (defined as seizure or psychosis), and hemolytic anemia were observed in 159 SLE‐affected sibpairs. Among these clinical features, paired expression of hemolytic anemia plus thrombocytopenia and hemolytic anemia plus neurologic disorder appeared to be more frequent in 709 SLE patients than would be expected by chance (P < 0.00001 and P < 0.007, respectively). The ratio of the presence of both hemolytic anemia and neurologic disorder was ∼13 times higher in the younger affected sib than in the older affected sib (P < 0.02). Familiality of patient age at SLE diagnosis, as observed by relative correlations, was greater in 125 affected sibpairs (r = 0.67, P < 0.0001) than in 37 affected parent–offspring pairs (r = 0.47, P = 0.003). The median ± SD age at SLE diagnosis was significantly lower in offspring (21.5 ± 10.1 years) than in their parents (41.6 ± 15.8 years) (P < 0.0001) but was not different in sibpairs. The combined non‐Caucasian sibpairs had a younger mean age at SLE diagnosis compared with Caucasian sibpairs (P = 0.014).

Conclusion

Evidence for familiality of thrombocytopenia, discoid rash, neurologic disorder, hemolytic anemia, and co‐occurring neurologic disorder plus hemolytic anemia in SLE was observed in 159 affected sibpairs. Familiality of the age at SLE diagnosis in relative pairs suggests that shared genes and/or shared environmental exposures impact disease susceptibility. Shared immediate environmental triggers appear less compelling, because the average time between dates of diagnosis was 11 years in parent–offspring pairs and 7.5 years in affected sibpairs. The significantly earlier age at disease diagnosis in offspring compared with their parents suggests that some forms of anticipation might play a role in susceptibility to SLE. Stratifying families by subphenotypes that are familial may reduce heterogeneity and facilitate identification of genetic risk factors for SLE.

     

Influence of lead on the cariostatic effect of fluoride co-crystallized with sucrose in desalivated rats

OBJECTIVE: Results from previous studies have shown that pre- and perinatal exposure to lead enhances susceptibility of rats to development of dental carieS. A possible explanation for this phenomenon may be that lead complexes with fluoride and renders F insoluble and unable to exert its cariostatic effects. MATERIALS AND METHODS: Thus, to explore this hypothesis, 48 desalivated Sprague-Dawley rats were placed in a König-Höfer programmed feeder and received 17 meals of powdered sucrose daily, and water ad libitum as follows: group (1) plain sucrose and sterile distilled water (SDW); (2) sucrose containing 15 ppm F and SDW; (3) sucrose containing 15 ppm F and 10 ppm Pb water; (4) sucrose containing 15 ppm F and 25 ppm Pb water. RESULTS: The highest smooth-surface, sulcal surface caries and severity scores were observed in group 1.Animals that were exposed to fluoride showed reduced smooth-surface caries and severity scores.S. sobrinus counts did not differ among the groups. CONCLUSION: Lead did not interfere with the protective effect of fluoride in the conditions of the present study.