Only Multiple Autoantibodies to Islet Cells (ICA), Insulin, GAD65, IA-2 and IA-2β Predict Immune-Mediated (Type 1) Diabetes in Relatives

We report here our prospective study of 15,224 non-diabetic, first-degree relatives of probands with immune-mediated (type 1) diabetes (IMD), of which 135 were found to eventually develop diabetes. We determined islet cell, insulin, GAD65, insulinoma-associated antigen-2 and 2βautoantibodies (ICA, IAA, GAD65A, IA-2A and IA-2βA), on the first available serum samples. The latter three autoantibodies were however assayed on subsets of the relatives with and without ICA, IAA and/or GAD65A, plus most of the relatives who developed diabetes. Of the relatives who progressed to diabetes, 94% had at least one of these autoantibodies on the first screening, while ICA proved to be the most sensitive single marker (sensitivity 74%). Risk of diabetes was however negligible when ICA was found in the absence of the others (5-year RISK=5.3%), but increased dramatically whenever two or more autoantibodies were present (5-year RISK=28.2% and 66.2%, respectively). The most predictive combination of markers was ICA plus IA-2A and/or IA-2β A. Loss of first phase insulin release to IVGTT also occurred only in those ICA-positive relatives who had one or more of the other autoantibodies. The data suggests that significant β-cell damage is seen only when the underlying autoimmunity has spread to multiple antigenic islet cell determinants. Combinations of the autoantibodies occurred most often in relatives with the highest risk HLA-DR/DQ phenotypes. These data document that only relatives positive for at least two or more of these five autoantibodies are at significant risk of diabetes themselves. Intervention trials for the prevention of type 1 diabetes could be designed based on testing for these autoantibodies alone, without the need for HLA typing and IVGTT testing.     

VIRUS-INDUCED DIABETES MELLITUS : I. HYPERGLYCEMIA AND HYPOINSULINEMIA IN MICE INFECTED WITH ENCEPHALOMYOCARDITIS VIRUS

Infection of DBA/2N male mice with encephalomyocarditis virus resulted in a diabeteslike syndrome characterized by hyperglycemia, glycosuria, hypoinsulinemia, polydipsia, and polyphagia. Blood glucose levels were elevated within 4 days after infection and reached a maximum mean level of 320 mg/100 ml within 12 days. Approximately 60–80% of the animals developed a transient hyperglycemia while 10–15% of the animals remained hyperglycemic for well over 6 mo. The remaining animals failed to become hyperglycemic but many had abnormal glucose tolerance curves. Hyperglycemia was most pronounced when animals were allowed free access to food, and the incidence of byperglycemia was related both to the strain and sex of the animals, with few females developing hyperglycemia. The amount of immunoreactive insulin in the plasma of infected hyperglycemic mice was significantly lower than in appropriate controls, and injection of exogenous insulin resulted in a rapid drop in the blood glucose levels. Despite the fact that certain animals were hyperglycemic for many months, virus could not be recovered from the pancreas after the first 10 days of the infection.     

mda-7/IL24 kills pancreatic cancer cells by inhibition of the Wnt/PI3K signaling pathways: identification of IL-20 receptor-mediated bystander activity against pancreatic cancer.

The melanoma differentiation-associated gene (mda-7; approved gene symbol IL24) is a tumor suppressor gene whose protein expression in normal cells is restricted to the immune system and to melanocytes. Recent studies have shown that mda-7 gene transfer inhibits cell growth and induces apoptosis in melanoma, lung cancer, breast cancer, and other tumor types through activation of various intracellular signaling pathways. In the current study, we demonstrate that Ad-mda7 transduction of human pancreatic cancer cells results in G2/M cell cycle arrest and cell killing. Cytotoxicity is mediated via apoptosis in a time- and dose-dependent manner. Tumor cell killing correlates with regulation of proteins involved in the Wnt and PI3K pathways: beta-catenin, APC, GSK-3, JNK, and PTEN. Additionally, we identify bystander cell killing activated by exposure of pancreatic tumor cells to secreted human MDA-7 protein. In pancreatic tumor cells, exogenous MDA-7 protein activates STAT3 and kills cells via engagement of IL-20 receptors. The specificity of bystander killing is demonstrated using neutralizing anti-MDA-7 antibodies and anti-receptor antibodies, which inhibit the apoptotic effects. In sum, we show that Ad-mda7 is able to induce growth inhibition and apoptosis in pancreatic cancer cells via inhibition of the Wnt/PI3K pathways and identify a novel bystander mechanism of MDA-7 killing in pancreatic cancer that functions via IL-20 receptors.     

CELLULAR IMMUNITY TO HERPES SIMPLEX VIRUS MEDIATED BY INTERFERON

Rabbit kidney cell monolayers infected with herpes simplex virus (HSV) were incubated with leukocytes from rabbits immunized with complete Freund's adjuvant. When the leukocytes were exposed to tuberculin purified protein derivative (PPD), viral replication and plaque formation were markedly inhibited. Similarly, when leukocytes from animals immunized with HSV were exposed to UV-inactivated HSV, viral replication was markedly inhibited. Exposure of leukocytes from unimmunized animals or animals immunized with incomplete Freund's adjuvant to UV-inactivated virus or PPD produced relatively little inhibition of viral replication. Examination of supernatant fluids from stimulated cultures revealed a soluble mediator that had the properties of interferon. Interferon production was detected within several hours after exposure of sensitized leukocytes to antigen. Supernatant fluids from as few as one sensitized leukocyte per 200 rabbit kidney cells inhibited HSV replication by over 90%. These findings support the concept that the cellular immune response to HSV consists of two phases: an immunologically specific antigen recognition phase, and a nonspecific effector phase that stops HSV spread by generating interferon.     

Clinical and local biological effects of an intratumoral injection of mda-7 (IL24; INGN 241) in patients with advanced carcinoma: a phase I study.

The melanoma differentiation-associated gene-7 (mda-7; approved gene symbol IL24) is a tumor suppressor gene whose expression induces selective apoptosis in tumor cells. To characterize the safety and biologic activity of mda-7 gene transfer, we conducted a phase I trial using intratumoral injections of an adenovirus containing the mda-7 construct (Ad-mda7; INGN 241; 2 x 10(10) to 2 x 10(12) vp) in 28 patients with resectable solid tumors. One hundred percent of injected lesions demonstrated INGN 241 vector transduction, transgenic mRNA, elevated MDA-7 protein, and apoptosis induction, with the highest levels near the injection site. Apoptosis of cells in injected tumors was consistently observed even in heavily pretreated patients. INGN 241 vector DNA and mRNA were detected more than 1 cm from the injection site, whereas MDA-7 protein and bioactivity were more widely distributed. Toxicity attributable to the injections was self-limiting and generally mild; however, one patient experienced a grade 3 SAE possibly related to the study drug. Evidence of clinical activity was found in 44% of lesions with the repeat injection schedule, including complete and partial responses in two melanoma patients. Thus intratumoral administration of INGN 241 is well tolerated, induces apoptosis in a large percentage of tumor cells, and demonstrates evidence of clinically significant activity.     

Is gender important? Victimisation and perpetration of intimate partner violence in mainland China

Establishing the prevalence of intimate partner violence (IPV) has been recommended by International Conventions and Declarations for some time beginning with the Convention on the Elimination of All Forms of Discrimination against Women (CEDAW Articles 12 and 19) in 1979. One important recommendation of such international protocols is the implementation of national population prevalence surveys to establishing IPV as a serious social issue globally, which is intended to provide data for planning effective responses within signatory countries. However, not all countries have undertaken national prevalence surveys meaning that there are gaps in our understanding of who are the perpetrators and victims of IPV in different cultural contexts. This article presents the results of a scoping review of literature examining gender differences in prevalence rates of victimisation and perpetration of IPV in mainland China (hereon China). There has been little written about the prevalence of IPV in China generally, and this scoping process located only nine peer‐reviewed articles written in both English‐ and Chinese‐language journals focusing on both gender and IPV published between 1997 and 2016. Results of this scoping review demonstrate that while both women and men perpetrate IPV in China, the prevalence rates of different types of IPV reflect gender differences in both perpetration and victimisation, suggesting that IPV is not a unitary phenomenon. The paper concludes by discussing the implications of the findings including the importance of increasing awareness of IPV in China more generally and developing gender‐specific interventions to directly address different types of IPV. Directions for future research are also canvassed.     

Intraoperative opioid dosing in children with and without cerebral palsy

Objective: To describe the differences in intraoperative opioid dosing and associated outcomes in children with and without cerebral palsy (CP). Background: Previous work on children with cognitive impairment has suggested that they receive less intraoperative opioid than children without cognitive impairment. This finding may be due to a common concern that impaired children are hypersensitive to the adverse effects of opioids. Patterns in intraoperative opioid dosing have yet to be studied in children with motor impairment (e.g. CP). Methods: We examined the medical records of pediatric patients with CP who underwent orthopedic surgery over the last decade at our institution, as well as the records of a randomly selected group of pediatric orthopedic patients without CP (non‐CP). Outcome variables were intraoperative opioid dosing, postoperative intensive care unit (ICU) admission, and postoperative oxygen desaturation. We collected demographic, surgical, and medical data for covariate analysis. A stepwise multivariate regression was used for each outcome. Results: Seventy‐one (71) CP and 77 non‐CP charts were included in the study. CP children received significantly less intraoperative opioid (3.26 ± 3.01 μg·kg^?1 fentanyl dose equivalents) than non‐CP children (4.58 ± 3.79 μg·kg^?1) (P = 0.02), and this difference was corroborated by the regression analysis, which significantly associated CP with decreased opioid dosing (P < 0.001). In addition, intraoperative opioid dosing, but not CP, predicted ICU admission (odds ratio: 1.463, 95% CI: 1.042–2.054, P = 0.03) and postoperative oxygen desaturation (odds ratio: 1.174, 95% CI: 1.031–1.338, P = 0.02). Conclusions: Similar to prior research on children with cognitive impairment, a reduction in intraoperative opioid dosing was found in children with CP. Given the discrepant doses of intraoperative opioid between groups, it is unclear whether children with CP are at any greater risk for untoward opioid‐related events.     

Hepatitis B Infection and Association with Other Sexually Transmitted Infections Among Men Who Have Sex with Men in Peru

To assess the epidemiology of hepatitis B virus (HBV) infection among men who have sex with men (MSM) in Peru, we evaluated the prevalence and associated risk factors for HBV serologic markers among participants of a HIV sentinel surveillance conducted in 2002–2003. The standardized prevalences for total antibodies to hepatitis B core antigen (anti-HBc) and hepatitis B surface antigen (HBsAg) were 20.2% and 2.8%, respectively. Individuals with human immunodeficiency virus (HIV-1) infection had significantly higher anti-HBc (44.3% versus 19.3%) and HBsAg (9.5% versus 2.3%) prevalences than uninfected men. Increasing age (adjusted odds ratio [AOR] = 1.06), versatile sexual role (AOR = 1.59), sex in exchange for money/gifts (AOR = 1.58), syphilis (AOR = 1.74), HIV-1 infection (AOR = 1.64), and herpes simplex virus type 2 (HSV-2, AOR = 2.77) infection were independently associated with anti-HBc positivity, whereas only HIV-1 infection (AOR = 3.51) and generalized lymph node enlargement (AOR = 3.72) were associated with HBsAg positivity. Pre-existing HBV infection is very common among Peruvian MSM and was correlated with sexual risk factors. MSM in Peru constitute a target population for further HBV preventive and treatment interventions.