B cells in the pathophysiology of myasthenia gravis

Myasthenia gravis (MG) is an archetypal autoimmune disease. The pathology is characterized by autoantibodies to the acetylcholine receptor (AChR) in most patients or to muscle‐specific tyrosine kinase (MuSK) in others and to a growing number of other postsynaptic proteins in smaller subsets. A decrease in the number of functional AChRs or functional interruption of the AChR within the muscle end plate of the neuromuscular junction is caused by pathogenic autoantibodies. Although the molecular immunology underpinning the pathology is well understood, much remains to be learned about the cellular immunology contributing to the production of autoantibodies. This Review documents research concerning the immunopathology of MG, bringing together evidence principally from human studies with an emphasis on the role of adaptive immunity and B cells in particular. Proposed mechanisms for autoimmunity, which take into account that different types of MG may incorporate divergent immunopathology, are offered. Muscle Nerve 57 : 172–184, 2018     

Diphenylhydantoin-induced pure red cell aplasia

The pathogenesis of diphenylhydantoin-induced pure red cell aplasia was investigated in the case of a 32-year-old man who developed pure red cell aplasia while he was under treatment with diphenylhydantoin. The patient's serum IgG purified from serum drawn at the time of diagnosis suppressed normal allogeneic marrow colony-forming (CFU-E) and burst- forming (BFU-E) and autologous blood BFU-E growth in vitro only in the presence of diphenylhydantoin. This IgG-diphenylhydantoin complex had no effect on CFU-GM growth in vitro. Normal IgG or patient's IgG purified from serum drawn after the remission of red cell aplasia had no effect on erythroid colony formation in vitro in the presence of diphenylhydantoin. The IgG-diphenylhydantoin complex exerted no direct cytotoxic effect on normal marrow erythroblasts, CFU-E, and BFU-E, nor did it interfere with the action of erythropoietin on marrow erythroblasts. These studies suggest that diphenylhydantoin-induced red cell aplasia is immunologically mediated through an IgG inhibitor, which requires the presence of the drug to suppress erythroid colony formation in vitro. This inhibitor seems to exert its effect on erythroid progenitors at or beyond the stage of differentiation of CFU- E, but not on erythroblasts.     

Cerebrospinal fluid amino acid levels in newborn infants with intracranial hemorrhage

Cerebrospinal fluid (CSF) amino acid levels including excitatory amino acids (i.e. glutamate and aspartate) in 25 preterm and 18 full-term newborn infants with no serious disease except intracranial hemorrhage (ICH) were measured. ICH was detected in 13 preterm and six full-term infants on the basis of the clinical, lumbar puncture (LP) and cranial ultrasonography (CraUSG) findings. Twelve preterm and 12 full-term infants who were neurologically healthy comprised the control group. The mean concentration of CSF amino acids did not differ between preterm and full-term infants. The CSF concentrations of taurine, threonine, glycine, alanine, valine, isoleucine, leucine, tyrosine and phenylalanine in preterm infants, and threonine, aspartic acid and alanine in full-term infants were significantly elevated in infants with ICH. These abnormalities, especially in preterm infants, are probably related to cerebral hypoxia in CSF amino acid concentrations in newborn infants with ICH.     

The structural basis of cysteine aminoacylation of tRNAPro by prolyl-tRNA synthetases

Cysteinyl-tRNA synthetase is an essential enzyme required for protein synthesis. Genes encoding this protein have not been identified in Methanocaldococcus jannaschii, Methanothermobacter thermautotrophicus, or Methanopyrus kandleri. It has previously been proposed that the prolyl-tRNA synthetase (ProRS) enzymes in these organisms recognize either proline or cysteine and can aminoacylate their cognate tRNAs through a dual-specificity mechanism. We report five crystal structures at resolutions between 2.6 and 3.2 A: apo M. jannaschii ProRS, and M. thermautotrophicus ProRS in apo form and in complex with cysteinyl-sulfamoyl-, prolyl-sulfamoyl-, and alanyl-sulfamoyl-adenylates. These aminoacyl-adenylate analogues bind to a single active-site pocket and induce an identical set of conformational changes in loops around the active site when compared with the ligand-free conformation of ProRS. The cysteinyl- and prolyl-adenylate analogues have similar, nanomolar affinities for M. thermautotrophicus ProRS. Homology modeling of tRNA onto these adenylate complexes places the 3'-OH of A76 in an appropriate position for the transfer of any of the three amino acids to tRNA. Thus, these structures explain recent biochemical experiments showing that M. jannaschii ProRS misacylates tRNA(Pro) with cysteine, and argue against the proposal that these archaeal ProRS enzymes possess the dual capacity to aminoacylate both tRNA(Pro) and tRNA(Cys) with their cognate amino acids.     

Paclitaxel and carboplatin in pretreated advanced gastric cancer: a phase II study.

In the present study, the combination of paclitaxel and carboplatin was applied in the treatment of gastric carcinoma. This cytotoxic combination has been an effective regimen with acceptable toxicity in ovarian, lung and head and neck cancers. We evaluated 47 patients (37 male, 10 female), all with advanced disease and all having undergone prior chemotherapy treatment. All patients had disease progression or no response to the prior treatment. Forty-four patients had undergone a previous gastrectomy for gastric adenocarcinoma and 3 patients were inoperable at diagnosis. Paclitaxel 175 mg/m2 was administered as a three-hour infusion, followed by carboplatin 5 AUC infused for 90 min. Thirteen (27.66%) patients showed partial response with a median survival of 10 months; 3 (6.38%) patients showed minor response and 13 patients, stable disease with clinical benefit. The median survival of patients with minor response and disease stability was 6 months. Eighteen (38.29%) patients had disease progression with a median survival of 3 months. It appears that in advanced cancer patients, the paclitaxel-carboplatin combination is an effective second-line treatment, resulting in partial response and disease stability in 61% of patients as well as in a prolongation of median survival.     

Ki-67 proliferation index: correlation with prognostic parameters and outcome in multiple myeloma

The nuclear protein Ki-67 is a proliferation index, as it is expressed only by dividing cells. In this study, we investigated the clinical significance of Ki-67 determination on bone marrow biopsies of 35 patients with newly diagnosed multiple myeloma (MM). We examined the correlation of Ki-67 with other MM proliferation-related factors: interleukin-6 (IL-6), IL-10, bone marrow infiltration by plasma cells, serum lactate dehydrogenase (LDH), and beta 2 microglobulin (b2M). Ki-67 expression was also correlated with the survival rate of the patients. The results showed that Ki-67 expression increases with increasing stage of disease according to Durie-Salmon (classification stage III vs. I and II, p < 0.001). Furthermore, infiltration, IL-6, LDH, and b2M increase significantly with advancing stage of disease (p < 0.004). All parameters studied were significantly higher in patients versus controls. Ki-67 correlated with IL-6 (r: 0.422, p < 0.01), LDH (r: 0.437, p < 0.01), and b2M (r: 0.478, p < 0.004). There was a marked difference in survival between patients with MM with Ki-67 greater than 8% and patients with Ki-67 less than 8%, in favor of the latter (p < 0.07). We conclude that Ki-67 determination during routine pathological analysis of bone marrow in newly diagnosed MM could provide useful information about the proliferative activity and prognosis of the disease.     

Pegylated liposomal doxorubicin hydrochloride (PLD) and paclitaxel in recurrent or metastatic head and neck carcinoma: a phase I/II study conducted by the Hellenic Cooperative Oncology Group (HeCOG)

A phase I pharmacokinetics and dose-finding study and a phase II study of the combination of pegylated liposomal doxorubicin HCl (PLD) and paclitaxel were conducted in patients with recurrent or metastatic head and neck cancer (HNC). Sixty patients with recurrent or metastatic disease were enrolled in the study: 11 patients in the phase I study and 49 patients in the phase II study. In the phase I study, the initial dose level of PLD was 35 mg/m as a 1-h infusion with escalating increments of 5 mg/m until the maximum tolerated dose (MTD) was reached. A fixed dose of paclitaxel (175 mg/m) was administered as a 3-h infusion. The combination was administered every 28 days. Pharmacokinetic studies performed on 10 patients indicated that the sequence of drug administration did not cause clinically significant modifications in the pharmacokinetics of either drug. The MTD for PLD was 45 mg/m (dose level 3) and the dose-limiting toxicity was febrile neutropenia, occurring in three of five patients. The phase II dose of PLD was 40 mg/m (dose level 2) and a total of 214 cycles were delivered. Grade 3 or 4 neutropenia was observed in 26% patients and febrile neutropenia occurred in 16% of patients. Grade 3 palmar-plantar erythrodysesthesia (PPE) was recorded in only one patient. The overall response rate was 28% for patients with non-nasopharyngeal tumors [95% confidence interval (CI) 15-45%] and 28.6% for the study population (95% CI 17-43%). The median survival for the study population was 9.7 months; 1-year survival was 38%. We conclude that the recommended dose for the combination of PLD and paclitaxel is 40 and 175 mg/m every 28 days, without granulocyte colony stimulating factor support. The combination of paclitaxel with PLD demonstrated activity in recurrent or metastatic HNC, a favorable toxicity profile and relative ease of administration.     

Retrospective study of febrile seizures: subsequent electroencephalogram findings,unprovoked seizures and epilepsy in adolescents

A retrospective questionnaire to determine the prevalence of febrile seizures was given to adolescents (16- and 17-year-olds) in the final 2 years of secondary school at the five schools in Alexandroupolis, Greece. Parents were interviewed, and clinical and electroencephalographic examinations were performed in all adolescents with a history of febrile seizures. Of 1708 adolescents, 56 (3.3%) had experienced at least one febrile seizure. Of these, 44 (78.6%) were simple and 12 (21.4%) were complex febrile seizures. Recurrent seizures occurred in 22 cases (39.3%), and the mean age at onset was 25.1 months. There was a positive first-degree family history in eight cases (14.3%) and this increased to 27.3% in cases with recurrent seizures. Two of the adolescents (3.6%) had had one unprovoked seizure before the age of 3 years, and another two children developed epilepsy. Epileptiform electroencephalogram discharges were observed in only one case (1.8%) with generalized tonic-clonic epilepsy.     

Do eating habits differ according to alcohol consumption? Results of a study of the French cohort of the European Prospective Investigation into Cancer and Nutrition (E3N-EPIC)

BACKGROUND: The potential of dietary habits to confound the association between alcohol consumption and health needs further study. OBJECTIVE: We examined whether eating habits differed according to alcohol consumption in a large cohort of French women. DESIGN: This was a cross-sectional study of the French cohort of the European Prospective Investigation into Cancer and Nutrition (E3N-EPIC). The cohort was established in 1990 and includes 100000 women born between 1925 and 1950. Dietary data were obtained between 1993 and 1995 by using self-administered food-frequency questionnaires. About 73000 questionnaires were analyzed, and women were placed into 7 categories of alcohol consumption. RESULTS: After adjustment for energy derived from alcohol, increasing alcohol consumption was associated with a higher total energy intake, a higher percentage of energy intake as protein and lipids, and higher intakes of cholesterol, fatty acids, retinol, iron, and vitamin E. Conversely, energy provided by carbohydrates decreased with increasing alcohol consumption, as did beta-carotene intake. Increasing alcohol consumption was associated with higher consumption of animal products, cheese, potatoes, oil, bread, and breakfast cereals and with lower consumption of vegetables and dairy products. CONCLUSION: In this population of middle-aged, highly educated French women, marked differences in dietary patterns and nutrient intakes were found according to alcohol consumption. Part of the detrimental effect of alcohol on health may be due to the less healthy dietary habits of drinkers. This points to a confounding role of eating habits and nutrient intakes in the relation between alcohol and health.