Endogenous and diet-induced hypercholesterolemia in nonhuman primates: effects of age, adiposity, and diabetes on lipoprotein profiles

Nonhuman primates (NHPs) share with humans many features of lipid metabolism and often develop all features of the metabolic syndrome, including hypertriglyceridemia and low high-density lipoprotein cholesterol, and have been used in many studies of potential therapeutics during the preclinical phase. Here we identify for the first time in middle-aged and older rhesus the natural occurrence of hypercholesterolemia, and this hypercholesterolemia develops despite maintenance on a low-cholesterol diet. The aims of this study were to (a) define normal and hypercholesterolemia in rhesus monkeys, (b) determine the factors associated with the development of hypercholesterolemia, (c) compare the lipoprotein profiles in adult rhesus monkeys fed a low-fat/low-cholesterol diet (LFLC) with the profiles of human subjects, and (d) determine the effect of a 16-week high-fat/high-cholesterol (HFHC) diet feeding on total cholesterol and lipoprotein profiles in middle-aged and older monkeys. In our colony, maintained on a constant diet with negligible cholesterol, the mean total cholesterol level in healthy nondiabetic monkeys was 3.7 ± 0.02 mmol/L, with hypercholesterolemia identified as the 95th percentile of the normal cholesterol distribution (≥5.2 mmol/L). Severe hypercholesterolemia developed in the HFHC-fed group; however, despite the high-fat diet composition, unexpectedly, no weight gain occurred in these NHPs. The diet-induced hypercholesterolemia differed significantly in lipoprotein pattern from that of the spontaneous hypercholesterolemia. In summary, despite ingesting only a LFLC, NHPs frequently develop hypercholesterolemia, reflecting lipoprotein patterns similar to human subjects; and this lipid profile of spontaneous hypercholesterolemia differs significantly from the hypercholesterolemia induced by an HFHC diet.     

Survival of rat or mouse ventral mesencephalon neurons after cotransplantation with rat sertoli cells in the mouse striatum

Transplanting cells across species (xenotransplantation) for the treatment of Parkinson's disease has been considered an option to alleviate ethical concerns and shortage of tissues. However, using this approach leads to decreased cell survival; the xenografted cells are often rejected. Sertoli cells (SCs) are testis-derived cells that provide immunological protection to developing germ cells and can enhance survival of both allografted and xenografted cells. It is not clear whether these cells will maintain their immunosuppressive support of cografted cells if they are transplanted across species. In this study, we investigated the immune modulatory capacity of SCs and the feasibility of xenografting these cells alone or with allografted and xenografted neural tissue. Transplanting xenografts of rat SCs into the mouse striatum with either rat or mouse ventral mesencephalon prevented astrocytic infiltration of the graft site, although all transplants showed activated microglia within the core of the graft. Surviving tyrosine hydroxylase-positive neurons were observed in all conditions, but the size of the grafts was small at best. SCs were found at 1 and 2 weeks posttransplant. However, few SCs were found at 2 months posttransplant. Further investigation is under way to characterize the immune capabilities of SCs in a xenogeneic environment.     

Effect of hookah (water pipe) smoking on semen parameters

Hookah (water pipe) smoking, an old method of tobacco smoking, is regaining widespread popularity all over the world. Although the research in this field is still deficient, it has been proven for its harmful effect on human's health by increasing the risk of cardiovascular disease, infection and lung, oral and bladder cancer (Al-Numair et al., J Food Agric Environ, 5: 17, 2007; Bou Fakhreddine et al., Respir Med, 108: 1241–1253, 2014; Chaouachi, J Negat Results Biomed, 5: 17, 2006). However, no research was found to address its effect on human fertility or reproductive outcome. In this cross-sectional study, we aim to explore the effect of smoking hookah on human semen parameters among men attending In Vitro Fertilization LABs for seminal fluid analysis testing. 104 patients aged between 25 and 45, who are noncigarette smokers and have no chronic medical illness, were enrolled in the study: 50 hookah nonsmokers and 54 hookah smokers. Their semen parameters were compared. Semen volume, normal morphology and progressive motility were slightly lower in the hookah smoker (3.21 ml; 10.2%; 29.56%) versus (3.45 ml; 11.5%; 33.20%), respectively, in nonhookah smokers; however, the difference was not statistically significant. The effect of hookah smoking on semen observed in our study was not statistically significant. Further studies are needed to explore more and confirm any unfavourable effect.     

Human papillomavirus-related squamous cell carcinoma of the anal canal with papillary features

Human papillomavirus(HPV)related squamous cell carcinoma(SCC)involving the anal canal is a well-known carcinoma associated with high-risk types of HPV.HPVrelated SCC with papillary morphology(papillary SCC)has been described in the oropharynx.We describe,for the first time,a case of anal HPV-related squamous carcinoma with papillary morphology.The tumor arose from the anal mucosa.The biopsies revealed a superficially invasive SCCwith prominent papillary features and associated in situ carcinoma.The tumor cells were positive for p16 and were also positive for high-risk types of HPV using chromogenic in situ hybridization.The findings are consistent with a HPV-related SCC of the anal canal with papillary features.This tumor shows histologic features similar to a papillary HPV-related SCC of the oropharynx.Additional studies are needed to characterize these lesions.     

The role of connexins in the differentiation of NT2 cells in Sertoli-NT2 cell tissue constructs grown in the rotating wall bioreactor

Neural transplantation is developing as a successful treatment for neurodegenerative diseases such as Parkinson’s disease. The human Ntera-2/D1 (NT2) cell line is an attractive alternative to the use of human fetal neurons as a cell source for transplantation. We have explored combining NT2 cells, as a neuronal source, and Sertoli cells, which may act as a graft facilitator to enhance neuronal survival and differentiation, and ameliorate the host immune response, into a tissue construct for use in cell replacement therapy for neurodegenerative disease. This Sertoli-NT2-aggregated cell (SNAC) tissue construct is formed in the high aspect ratio vessel (HARV) bioreactor. NT2 cells differentiate to dopaminergic NT2N neurons within the SNAC tissue construct without retinoic acid. We report here that the gap junction protein connexin 43 is decreased among differentiated NT2N neurons. Inhibition of connexin 43 with 18β glycyrrhetinic acid and carbenoxolone, a glycyrrhetinic acid derivative, during formation of the SNAC tissue constructs disrupts the differentiation of NT2 cells. Therefore, connexin 43 is important in the differentiation of NT2 cells in the SNAC tissue construct.     

Effects of sertoli cell-conditioned medium on ventral midbrain neural stem cells: A preliminary report

The 796RMB cell line is a multipotent stem cell line isolated from human fetal midbrain tissues, a region from which dopamine neurons of the substantia nigra develop. It would be useful to increase the dopaminergic characteristics of this cell line to enhance its usefulness as a cell therapy for Parkinson's disease utilizing transplantation protocols. Sertoli cells and its conditioned media isolated from the testis have been previously shown to enhance tyrosine hydroxylase expression in ventral mesencephalon neurons both in vitro and in vivo. Therefore, the present preliminary study investigated the ability of Sertoli cell pre-conditioned medium to enhance differentiation of the 796MB cell line toward the domaminergic phenotype. Results showed that secretory products derived from Sertoli cell conditioned medium increased cell proliferation and enhanced dopaminergic neuronal differentiation of the 796RMB cell line. These findings may lead to alternative therapeutic cell transplantation protocols for the treatment of Parkinson's disease.     

Rapid differentiation of NT2 cells in Sertoli-NT2 cell tissue constructs grown in the rotating wall bioreactor

Cell replacement therapy is of great interest as a long-term treatment of neurodegenerative diseases such as Parkinson's disease (PD). We have previously shown that Sertoli cells (SC) provide neurotrophic support to transplants of dopaminergic fetal neurons and NT2N neurons, derived from the human clonal precursors cell line NTera2/D1 (NT2), which differentiate into dopaminergic NT2N neurons when exposed to retinoic acid. We have created SC-NT2 cell tissue constructs cultured in the high aspect ratio vessel (HARV) rotating wall bioreactor. Sertoli cells, NT2, and SC plus NT2 cells combined in starting ratios of 1:1, 1:2, 1:4 and 1:8 were cultured in the HARV in DMEM with 10% fetal bovine serum and 1% growth factor reduced Matrigel for 3 days, without retinoic acid. Conventional, non-HARV, cultures grown in the same culture medium were used as controls. The presence of tyrosine hydroxylase (TH) was assessed in all culture conditions. Sertoli-neuron-aggregated-cell (SNAC) tissue constructs grown at starting ratios of 1:1 to 1:4 contained a significant amount of TH after 3 days of culture in the HARV. No TH was detected in SC HARV cultures, or SC, NT2 or SC-NT2 conventional co-cultures. Quantitative stereology of immunolabled 1:4 SNAC revealed that approximately 9% of NT2 cells differentiate into TH-positive (TH+) NT2N neurons after 3 days of culture in the HARV, without retinoic acid. SNAC tissue constructs also released dopamine (DA) when stimulated with KCl, suggesting that TH-positive NT2N neurons in the SNAC adopted a functional dopaminergic phenotype. SNAC tissue constructs may be an important source of dopaminergic neurons for neuronal transplantation.