Anthropometric and reproductive factors and risk of esophageal and gastric cancer by subtype and subsite: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Obesity has been associated with upper gastrointestinal cancers; however, there are limited prospective data on associations by subtype/subsite. Obesity can impact hormonal factors, which have been hypothesized to play a role in these cancers. We investigated anthropometric and reproductive factors in relation to esophageal and gastric cancer by subtype and subsite for 476,160 participants from the European Prospective Investigation into Cancer and Nutrition cohort. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models. During a mean follow-up of 14 years, 220 esophageal adenocarcinomas (EA), 195 esophageal squamous cell carcinomas, 243 gastric cardia (GC) and 373 gastric noncardia (GNC) cancers were diagnosed. Body mass index (BMI) was associated with EA in men (BMI ≥30 vs. 18.5–25 kg/m²: HR = 1.94, 95% CI: 1.25–3.03) and women (HR = 2.66, 95% CI: 1.15–6.19); however, adjustment for waist-to-hip ratio (WHR) attenuated these associations. After mutual adjustment for BMI and HC, respectively, WHR and waist circumference (WC) were associated with EA in men (HR = 3.47, 95% CI: 1.99–6.06 for WHR >0.96 vs. <0.91; HR = 2.67, 95% CI: 1.52–4.72 for WC >98 vs. <90 cm) and women (HR = 4.40, 95% CI: 1.35–14.33 for WHR >0.82 vs. <0.76; HR = 5.67, 95% CI: 1.76–18.26 for WC >84 vs. <74 cm). WHR was also positively associated with GC in women, and WC was positively associated with GC in men. Inverse associations were observed between parity and EA (HR = 0.38, 95% CI: 0.14–0.99; >2 vs. 0) and age at first pregnancy and GNC (HR = 0.54, 95% CI: 0.32–0.91; >26 vs. <22 years); whereas bilateral ovariectomy was positively associated with GNC (HR = 1.87, 95% CI: 1.04–3.36). These findings support a role for hormonal pathways in upper gastrointestinal cancers.     

Detergent fractionation with subsequent subtractive suppression hybridization as a tool for identifying genes coding for plasma membrane proteins

Abstract:  The identification of tumor-specific proteins located at the plasma membrane is hampered by numerous methodological pitfalls many of which are associated with the post-translational modification of such proteins. Here, we present a new combination of detergent fractionation of cells and of subtractive suppression hybridization (SSH) to gain overexpressed genes coding for membrane-associated or secreted proteins. Fractionation of subcellular components by digitonin allowed sequestering mRNA of the rough Endoplasmatic reticulum and thereby increasing the percentage of sequences coding for membrane-bound proteins. Fractionated mRNAs from the cutaneous T-cell lymphoma (CTCL) cell line HuT78 and from normal peripheral blood monocytes were used for SSH leading to the enrichment of sequences overexpressed in the tumor cells. We identified some 21 overexpressed genes, among them are GPR137B, FAM62A, NOMO1, HSP90, SLIT1, IBP2, CLIF, IRAK and ARC. mRNA expression was tested for selected genes in CTCL cell lines, skin specimens and peripheral blood samples from CTCL patients and healthy donors. Several of the detected sequences are clearly related to cancer, but have not yet been associated with CTCL. qPCR confirmed an enrichment of these mRNAs in the rough endoplasmic reticulum fraction. RT-PCR confirmed the expression of these genes in skin specimens and peripheral blood of CTCL patients. Western blotting verified protein expression of HSP90 and IBP2 in HuT78. GPR137B could be detected by immunohistology in HuT78 and in keratinocytes of dysplastic epidermis, but also in sweat glands of healthy skin. In summary, we developed a new technique, which allows identifying overexpressed genes coding preferentially for membrane-associated proteins.     

Vaccination against hepatitis B in liver transplant recipients: pilot analysis of cellular immune response shows evidence of HBsAg-specific regulatory T cells.

After liver transplantation for hepatitis-B-related diseases, patients currently receive lifelong treatment with hepatitis B immunoglobulin to prevent endogenous reinfection with hepatitis B virus (HBV). Active immunization with hepatitis B vaccine would be a preferable alternative; however, most attempts to immunize these patients with standard vaccine have failed. A recent study with a new adjuvanted hepatitis B vaccine was exceptionally successful, leading to a high-titered long-lasting antibody response in 80% of all vaccinees. To identify the immunological mechanisms behind these unexpected results, the successfully vaccinated participants were tested for hepatitis B surface antigen (HBsAg)-specific T and B cells, and their cellular responses to revaccination with conventional vaccine were studied. HBsAg-specific CD4(+) T lymphocytes could be detected in 13 of 16 patients after immunization with the new vaccine. Unexpectedly, these T cells produced almost exclusively interleukin (IL)-10 and had a CD4(+)/CD25(+) phenotype. They were functionally active, suppressing cytokine secretion in HBsAg-specific (Th1) cells, thus representing antigen-specific regulatory T cells (T(Reg)). Following a booster dose with conventional vaccine 22-31 months after completion of the initial vaccination series, the T-cell pattern in the revaccinated individuals changed substantially: 7 days after revaccination 9 of 11 individuals showed a switch to a Th1-type immune response with HBsAg-specific T cells secreting IL-2, interferon gamma and tumor necrosis factor alpha as observed in healthy controls. Four weeks after the booster, 4 patients still showed a Th1-type cytokine pattern, whereas in 5 patients only IL-10-secreting cells were detectable. After 1 year, in 3 of 4 revaccinated individuals only IL-10-secreting cells could be found, whereas the specific T cells of the fourth patient still showed a Th1-type of response. HBsAg-specific T(Reg) cells could be demonstrated in HBV-positive liver transplant recipients successfully immunized with a new adjuvanted vaccine. Revaccination led to immediate disappearance of the these cells and the appearance of HBsAg-specific T cells with a Th1-type cytokine profile, which in most cases were replaced by the IL-10-secreting regulatory cells during the following months. The specific induction of T(Reg) cells could contribute to the poor response of liver transplant recipients to conventional vaccine. In conclusion,, for successful vaccination of these patients, a vaccine with a strong inhibitory effect on T(Reg) cells would be desirable.     

Inspired Oxygen Fraction of 0.8 Does Not Attenuate Postoperative Nausea and Vomiting after Strabismus Surgery

Background: Postoperative nausea and vomiting (PONV) is a distressing problem after strabismus surgery. An inspired oxygen fraction has been reported to decrease PONV in patients after colon resection and to be more effective than ondansetron after gynecologic laparoscopy. Therefore, in a randomized, prospective, placebo-controlled study, the authors tested whether an inspired oxygen fraction of 0.8 decreases PONV in patients undergoing strabismus surgery and whether oxygen is more effective than ondansetron.

Methods: With approval of the authors' institutional review board, 210 patients were randomly assigned to receive one of three treatments: (1) 30% inspired oxygen in air plus intravenous administration of saline, (2) 80% inspired oxygen in air plus intravenous administration of saline, or (3) 30% inspired oxygen in air plus 75 [mu]g/kg ondansetron intravenously during induction. General anesthesia was standardized and included etomidate, alfentanil, and mivacurium for induction and sevoflurane for maintenance. PONV was evaluated 6 and 24 h postoperatively by an investigator unaware of treatment assignment.

Results: Overall postoperative incidence of nausea and vomiting was 41% for inspired oxygen fraction of 0.3 plus placebo, 38% for inspired oxygen fraction of 0.8 plus placebo, and 28% for inspired oxygen fraction of 0.3 plus ondansetron, respectively (P = 0.279). Therefore, there was no statistically significant difference of PONV incidence among groups.     

Lactation-induced plasticity in the supraoptic nucleus augments axodendritic and axosomatic GABAergic and glutamatergic synapses: an ultrastructural analysis using the disector method

The disector, an unbiased stereological method for evaluation of synaptic densities, was used to analyse putative GABA and glutamate innervations of the supraoptic nucleus of virgin and lactating rats. The analysis was performed on ultrathin sections labelled for either of the amino acids with a postembedding immunogold technique. Our observations showed that the volume of the nucleus increased by 40% in lactating animals, an increase due to a significant enlargment of dendritic and somatic, but not vascular, volumes. Nevertheless, values of overall synaptic densities in the whole nucleus remained as high as those in virgin rats (37–40×10⁶ synapses/mm³). About 45% of all synapses were immunoreactive for GABA and 25% for glutamate; there were twice as many GABA- and glutamate-positive synapses on dendrites as on somata. When we estimated synaptic densities in relation to the neuropil (by subtracting the proportion of sampled areas occupied by somatic profiles), we found a significant increase in synaptic density in lactating animals. This affected axodendritic as well as axosomatic synapses, immunopositive and immunonegative for GABA or glutamate. The disector also allowed us to determine that the number of synapses from terminals making contacts on several somata and/or dendrites simultaneously constituted about 9% of all synapses in virgin rats, a proportion which more than doubled in lactating rats. About 50% were immunopositive for GABA and 30% for glutamate.

Our data offer further evidence of physiologically-linked structural synaptic plasticity in the supraoptic nucleus and clearly demonstrate that it affects both inhibitory and excitatory inputs on dendrites, as well as on somata, throughout the nucleus.     

Linking the Disabilities of Arm, Shoulder, and Hand to the International Classification of Functioning, Disability, and Health.

The objective of this study was to explore whether the items from a specific outcome measure, that is, Disabilities of the Arm, Shoulder, and Hand (DASH), for quantifying limb symptoms and functions in musculoskeletal disorders fit into the framework of the International Classification of Functioning, Disability and Health (ICF). All DASH items were compared to the ICF according to eight linking rules. Two groups of researchers performed the linking independently, and the results were compared by correlation. The 30 DASH items and four items from the optional modules were linked to 63 ICF categories and 11 chapters: 15 categories belong to the ICF body functions component and 48 to the activities and participation component. There were no items coded under the components body structure or environmental factors. Kappa index showed an agreement of 0.73 (p<0.001). The results showed that the content of the DASH does link well with the ICF framework. Clinicians and researchers must attend to the fact that certain domains and categories from the ICF are not covered by the DASH. Limitations of the instrument may be overcome by simultaneously using other instruments that address the intended content.     

The Glutamatergic Innervation of Oxytocin- and Vasopressin-secreting Neurons in the Rat Supraoptic Nucleus and its Contribution to Lactation-induced Synaptic Plasticity

The present ultrastructural study analysed the distribution of glutamatergic synapses on oxytocin- and vasopressin-secreting neurons in the rat supraoptic nucleus (SON) after post-embedding immunogold labelling for glutamate and GABA, oxytocin or vasopressin. About 20% of SON axo—somatic synapses were enriched in glutamate immunoreactivity, visible over synaptic-like vesicles, mitochondria and synaptic densities. Double labelling for glutamate and GABA showed that putative glutamatergic terminals were distinct from GABAergic terminals. In ultrathin sections stained for glutamate and either oxytocin or vasopressin, the proportion of glutamatergic synapses was similar on oxytocinergic and vasopressinergic somata in virgin rats under basal conditions of peptide release as well as in lactating rats, in which oxytocin secretion is enhanced. Cross-sectional soma areas were significantly increased in lactating rats: oxytocinergic profiles were, on average, ˜40% larger than in virgin rats. However, the incidence of axo—somatic glutamatergic synapses (assessed as mean number of synapses per 100 μm of plasmalemma or proportion of somatic surface apposed to synaptic active zones) did not diminish, indicating that there was a compensatory increase of synapses during lactation. Also, we found an increase in the number of glutamatergic terminals making synaptic contact simultaneously onto two or more oxytocinergic elements in the same plane of section. Our observations therefore indicate that SON oxytocinergic and vasopressinergic neurons are innervated to a similar extent by a relatively large proportion of glutamatergic synapses. They reveal, moreover, that glutamatergic afferents participate in the lactation-induced synaptic plasticity of the oxytocinergic system.     

Classic complication of uterine revision after a late abortion: uterine synechia. Current review based on two cases]

The authors use two personal cases to review the etiological circumstances, pathology and clinical and paraclinical manifestations, stressing in particular the current value of diagnostic and therapeutic hysteroscopy. Advice is given concerning prevention and treatment.