C2orf37 mutational spectrum in Woodhouse–Sakati syndrome patients

Alazami AM, Schneider SA, Bonneau D, Pasquier L, Carecchio M, Kojovic M, Steindl K, de Kerdanet M, Nezarati MM, Bhatia KP, Degos B, Goh E, Alkuraya FS. C2orf37 mutational spectrum in Woodhouse–Sakati syndrome patients. Woodhouse–Sakati syndrome (WSS) is a rare autosomal recessive disorder that encompasses hypogonadism, deafness, alopecia, mental retardation, diabetes mellitus and progressive extrapyramidal defects. The syndrome is caused by mutation of the C2orf37 gene. Here we studied a cohort of seven new cases from three ethnic backgrounds, presenting with the hallmarks of WSS, in an effort to extend the mutational spectrum of this disorder. Genetic analysis revealed a novel mutation in each of the four families investigated, of which three were nonsense mutations and the fourth was a splice site ablation. We also examined a separate collection of 11 cases presenting with deafness and dystonia, two constituents of WSS, but found no pathogenic changes. This study doubles the number of known mutations for this disorder, confirms that truncating mutations in C2orf37 are the only known cause of WSS, and suggests that mutations in this gene do not contribute significantly to cases presenting with isolated elements of WSS such as deafness and dystonia. The lack of correlation between clinically expressivity of WSS and the site of the eight truncating mutations strongly supports that they are equally null, while the intrafamilial variability argues for an important role of modifiers in this disease.     

Positron emission tomography imaging of tissue P-glycoprotein activity during pregnancy in the non-human primate

Background and purpose:

Changes in tissue P-glycoprotein (P-gp) activity during pregnancy could affect the pharmacokinetics and thus the efficacy and toxicity of many drugs. Therefore, using positron emission tomography (PET) imaging, we tested whether gestational age affects tissue P-gp activity in the pregnant non-human primate, Macaca nemestrina.

Experimental approach:

Mid-gestational (day 75 ± 13, n= 7) and late-gestational (day 150 ± 10, n= 5) age macaques were imaged after administration of a prototypic P-gp substrate, ¹¹C-verapamil (13.7–75.4 MBq·kg⁻¹), before and during intravenous infusion of a P-gp inhibitor, cyclosporin A (CsA) (12 or 24 mg·kg⁻¹·h⁻¹). Accumulation of radioactivity in the fetal liver served as a reporter of placental P-gp activity. P-gp activity was expressed as CsA-induced percent change in the ratio of the area (0–9 min) under the ¹¹C-radioactivity concentration–time curve in the tissue (AUC_tissue) to that in the maternal plasma (AUC_plasma).

Key results:

The CsA-induced change in AUC_{fetal liver}/AUC_{maternalplasma} of ¹¹C-radioactivity significantly increased from mid- (35 ± 25%) to late gestation (125 ± 66%). Likewise, the CsA-induced change in AUC_{maternal brain}/AUC_plasma increased from mid- (172 ± 80%) to late gestation (337 ± 148%). The AUC ratio for the other maternal tissues was not significantly affected. Neither the CsA blood concentrations nor the level of circulating ¹¹C-verapamil metabolites were significantly affected by gestational age.

Conclusions and implications:

P-gp activity at the blood–brain barrier and the placental barrier in the macaque increased with gestational age. If replicated in humans, the exposure of the fetus and maternal brain to P-gp substrate drugs, and therefore their efficacy and toxicity, will change during pregnancy.     

三维肛管直肠超声在肛管直肠疾病中的应用

肛管直肠超声可用来诊断多种肛管直肠良、恶性疾病。近几年来．该技术取得了长足进步．其应用360度旋转高频（6．16MHZ）探头（焦距2．8～6．2cm）,无需转动探头便可获得高清晰的肛管直肠三维结构图。位于探头远端的换能晶片向近端边旋转边移动,持续55S．可获得长约6cm的图像。这个图像是将连续的0．2mm层厚轴向切面通过容积再现技术合成的高清晰的三维数字立体图像。其拥有多个视角（同时4～6个视野）．可同时观察多个解剖平面．进行低亮度、高对比度调整,可形成半透明暗腔。     

Genetic polymorphism of CYP2D6, GSTM1 and NAT2 and susceptibility to haematological neoplasias.

Xenobiotic-metabolizing enzymes constitute an important line of defence against a variety of carcinogens. Many are polymorphic, constituting the basis for the wide inter-individual variation in metabolic capacity and possibly a source of variation in the susceptibility to chemical-induced carcinogenesis. The aim of this study was to determine the existence of any association between the main genetic polymorphisms of cytochrome P450 2D6 (CYP2D6), glutathione S-transferase M1 (GSTM1) and N-acetyltransferase 2 (NAT2) and an altered risk for haematological neoplasias. A total of 160 patients and 128 controls were genotyped by means of PCR-RFLP-based assays. Mutated alleles comprising CYP2D6*4, GSTM1*0, NAT2*5A, *5B, *5C, *6 and *7 were analysed along with the wild-type alleles. The results showed a higher frequency of CYP2D6 extensive metabolizers carrying two functional alleles in the leukaemia group, when compared with controls (76.6 versus 57.0%, P = 0.008). No differences were found in the case of Hodgkin and non-Hodgkin lymphomas. Analysis of the GSTM1 and NAT2 polymorphisms failed to show an association with any of the neoplasias, although a near significant increase in fast acetylators was also found in the leukaemia group (50.0 versus 35.9%, P = 0.06). The results suggest an association of extensive metabolism with an increased risk for leukaemia, possibly by an increase in the metabolic activation of chemical carcinogens or linkage to another cancer-causing gene. Opposite findings presented in other studies may reflect geographical differences in the type of environmental carcinogens to which different populations are exposed.     

Bioactivation of the mushroom hydrazine, agaritine, to intermediates that bind covalently to proteins and induce mutations in the Ames test

The present study was undertaken to establish whether liver and kidney enzyme systems, from rat and mouse, have the potential to metabolise and bioactivate agaritine, beta-N-(gamma-L(+)glutamyl)-4- (hydroxymethyl)phenylhydrazine, the most abundant hydrazine present in the edible mushroom Agaricus bisporus. Agaritine was weakly mutagenic, in the absence of an activation system, in Salmonella typhimurium strain TA104. Rat kidney homogenates, characterised by high gamma- glutamyl transpeptidase activity, enhanced the mutagenic response. In contrast, hepatic microsomes, having very low gamma-glutamyl transpeptidase activity, did not influence the mutagenicity of agaritine. However, hepatic microsomes could further potentiate the mutagenic response induced by the kidney. Agaritine was a good substrate for purified gamma-glutamyl transpeptidase, being converted to a major metabolite, 4-(hydroxymethyl)phenylhydrazine, formed as a result of the loss of the glutamyl moiety. Kidney homogenates from the rat and mouse also catalysed this reaction, the former being the more effective. Metabolism of agaritine was suppressed by serine-borate, an inhibitor of gamma-glutamyl transpeptidase. Kidney homogenates from rat and mouse could metabolise agaritine to intermediate(s) that bound covalently to proteins, with the rat preparations being the more effective; covalent binding was inhibited by glutathione. In contrast, hepatic preparations alone were ineffective in producing such covalent binding but did further increase the covalent binding mediated by the kidney preparations. It is concluded that rat and mouse kidney homogenates catalyse the removal of the glutamyl group from agaritine to yield the reactive free hydrazine, which is further converted to the highly reactive diazonium ion by hepatic microsomes.      

Navoban (tropisetron, ICS 205-930) and dexamethasone combination in the prevention of vomiting for patients receiving preconditioning high-dose chemotherapy before marrow transplantation

The anti-emetic efficacy of a combination of tropisetron and dexamethasone was studied in 33 patients who underwent bone marrow transplantation. Another 50 patients receiving conventional anti-emetic therapies in bone marrow transplantation served as control. On the first and second days of preconditioning chemotherapy, 51% and 36% respectively of patients in the tropisetron and dexamethasone group did not experience vomiting, compared with only 12% and 10% of control group patients (P < 0.001). The mean number of episodes of vomiting in the tropisetron and dexamethasone group was also significantly lower than in the control group (0.97+/-1.65 vs 3.50+/-2.45 and 1.30+/-1.40 vs 4.44+/-2.91 respectively, both P < 0.001). Control of vomiting in the two groups was not significantly different during days 3-6. Analysis of patients receiving busulfan and cyclophosphamide as the preconditioning regimen still showed better anti-emetic control in the tropisetron and dexamethasone group than in the control group on the first two days of treatment (total control rate 33.3% vs 6.5% and 44.4% vs 12.9% respectively, P < 0.001). Patients given tropisetron and dexamethasone combination more frequently suffered from dizziness and burning sensation of the chest. However, diarrhea and extrapyramidal symptoms were the most frequent adverse effects seen after using conventional anti-emetic combination. The combination of tropisetron and dexamethasone was thus superior to conventional anti-emetic combinations in preventing vomiting during preconditioning period of bone marrow transplantation. The adverse effects of this combination were minimal and well tolerated by patients.      

Phase II study of the modified regimen of etoposide, leucovorin and 5-fluorouracil for patients with advanced gastric cancer

BACKGROUND: The efficacy of the treatment of advanced gastric cancer is not very good. The response rate to the original etoposide--leucovorin--5-fluorouracil (ELF) treatment is 53% with tolerable side effects. Whether increasing the dose intensity by prolonging the duration of infusion with 5-fluorouracil (5-FU) and leucovorin (LV) from 3 to 5 days for advanced or metastatic gastric cancer patients would enhance the efficacy but not increase side effects is still unknown. METHODS: Thirty-six advanced or metastatic gastric cancer and chemotherapy-naive patients with measurable or evaluable diseases were scheduled to receive intravenous etoposide 100 mg/m2/day on days 2-4, LV 300 mg/m2/day intravenously and 5-FU 500 mg/m2/day intravenously on days 1-5, every 4 weeks. All patients who received at least two courses of chemotherapy were evaluated for tumor response, survival and response duration and toxicity according to the WHO criteria. RESULTS: Thirteen patients showed a response, including five with complete response (CR). The overall response rate was 36% (95% confidence interval, CI, 20-52%) in the whole group and 46% (95% CI 28-66%) in the 28 patients with measurable disease. The median progression-free interval and overall median survival time were 5 and 7 months, respectively. The most frequent toxicity was alopecia (grade I/II 56.3%). The incidence of grade III or greater myelosuppression was 5.9%. No treatment-related death occurred. CONCLUSIONS: The efficacy of the modified ELF by increasing the dosages of 5-FU and LV is not superior to the results of the original regimen, yet it is a relatively safe and tolerable combination regimen for advanced gastric cancer.      

Human sperm non-nuclear progesterone receptor expression is a novel marker for fertilization outcome

In a prospective, blind study, we have examined the relationship among the expression of human sperm surface progesterone receptors, the ability to undergo a mannose-stimulated acrosome reaction and the rate of fertilization in vitro. Individual aliquots of motile spermatozoa were surface-labelled with progesterone and/or mannose-fluoresceinated ligands. Spontaneous acrosome loss and the increase in acrosome reactions following exposure of spermatozoa to mannose ligands were assessed using rhodaminated Pisum sativum agglutinin. Progesterone fluoresceinated ligand binding was observed to occur in two patterns: (i) a uniform distribution of labelling over the acrosome cap (pattern II), and (ii) labelling limited to the equatorial and postacrosomal regions of the human sperm head (pattern III). A conversion of pattern II to pattern III binding was observed and was associated with the acrosome reaction. Pattern III binding was highly correlated with both fertilization potential and the ability to undergo a mannose-stimulated acrosome reaction (P < 0.001). In contrast, normal sperm mannose receptor expression was seen in five men whose abnormal progesterone receptor expression/function and inability to acrosome react after mannose treatment were correlated with their reduced fertility in vitro. In conclusion, surface progesterone receptor aggregation enhances the mannose ligand-stimulated acrosome reaction. Such detection of defective sperm surface progesterone receptor expression/function may be useful in the evaluation and management of male infertility.      

Saccadic strategies in children with hemianopia

Multiple hypometric (undershooting) saccades are generally reported as a compensatory strategy in adults with homonymous hemianopia. However, hypermetric (overshooting) saccades have been reported to develop spontaneously as a beneficial strategy in response to predictable targets. We examined the saccades of 10 children (aged 5 to 16 years) with homonymous hemianopia to determine the type of compensatory eye-movement strategies employed 6 months to 16 years after hemianopia onset. Homonymous hemianopia was identified using perimetry and/or pattern visual evoked potentials and supported with results of neuroimaging. Eye movements were recorded using bitemporal electrooculography. Saccades were elicited to a red light source in a semipredictable paradigm. We found that hypermetria was not a consistent compensatory strategy in our patients. In spite of the predictability of our paradigm and the long follow-up period, multiple hypometric saccades into the blind field appeared to be the preferred strategy.     

Developments in esophageal surgery for adenocarcinoma: a comparison of two decades

Background  

The objective of this study was to examine outcomes in patients undergoing esophageal resection for adenocarcinoma at our institution during a 20-year period and, in particular, to address temporal trends in long-term survival.