Regulation of glucocorticoid receptor mRNA and heat shock protein 70 mRNA in the developing sheep brain

Fetal hypothalamo-pituitary-adrenal (HPA) activity increases dramatically at term in sheep, however, little is known about the regulation of glucocorticoid feedback in the developing brain. Heat shock protein 70 (hsp70) is closely associated with glucocorticoid actions within the cell. We hypothesized that there is a decrease in glucocorticoid negative feedback in the brain, near term, resulting from changes in the expression of glucocorticoid receptors (GR) and hsp70. Brains were removed at various stages of development. GR mRNA levels in the paraventricular nucleus (PVN) and cortex, and hsp70 mRNA in the PVN were determined by in situ hybridization. In the hippocampus, GR mRNA levels were measured by Northern analysis. In the PVN, GR mRNA was present by d60. GR mRNA levels reached a peak at d100-110, but then decreased significantly with progression of gestation, and were lowest at term. Hippocampal GR mRNA levels were highest on day 130 of gestation, decreasing to low levels at term. In the cerebral cortex, GR mRNA levels were expressed at high levels in all layers of the cortex by day 110 of gestation with levels decreasing to term. Hsp70 mRNA was present in both parvocellular and magnocellular regions of the PVN, and there was no significant change in late gestation. In conclusion, (1) The high levels of GR mRNA present in the PVN, hippocampus and cerebral cortex during fetal life are likely important in development of these structures at a time when circulating glucocorticoids are low. (2) Changes in GR mRNA levels in the PVN are not associated with alterations in the expression of hsp70. (3) The decrease in GR mRNA in the hippocampus and PVN in late gestation, at a time when fetal plasma cortisol is increasing, likely facilitates maintained hypothalamic drive to the pituitary corticotroph.     

Squamous cell carcinoma of the lip: a retrospective review of the Peter MacCallum Cancer Institute experience 1979-88

BACKGROUND: Squamous cell carcinoma (SCC) of the lower lip is a common malignancy in Australia. Surgical excision and/or radiotherapy are used in treatment, and are regarded as equally effective. METHODS: A retrospective review of 323 patients treated at the Peter MacCallum Cancer Institute with either surgical excision and/or radiotherapy, evaluated disease recurrence, cause-specific mortality, and the incidence of metachronous lesions. RESULTS: Recurrence-free survival at 10 years was estimated to be 92.5%, and cause-specific survival at 10 years was estimated to be 98.0%. Equivalent rates of local control were obtained with surgery and radiotherapy. Recurrence was related to tumour stage and differentiation. A high incidence of metachronous lesions was noted, 25 patients had a lesion prior to presentation and 33 patients developed second lip lesions during the study period. CONCLUSIONS: Squamous cell carcinoma of the lower lip is well treated with surgery or radiotherapy. The preferred treatment for most patients with SCC of the lower lip in the Australian population is surgical excision. This study has shown a significant incidence of metachronous lip neoplasia, except in those patients whose whole lip had been resurfaced.     

Systematic Evidence Map for Over One Hundred and Fifty Per- and Polyfluoroalkyl Substances (PFAS)

Background: Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic (man-made) chemicals widely used in consumer products and industrial processes. Thousands of distinct PFAS exist in commerce. The 2019 U.S. Environmental Protection Agency (U.S. EPA) Per- and Polyfluoroalkyl Substances (PFAS) Action Plan outlines a multiprogram national research plan to address the challenge of PFAS. One component of this strategy involves the use of systematic evidence map (SEM) approaches to characterize the evidence base for hundreds of PFAS.Objective: SEM methods were used to summarize available epidemiological and animal bioassay evidence for a set of ∼150 PFAS that were prioritized in 2019 by the U.S. EPA’s Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing.Methods: Systematic review methods were used to identify and screen literature using manual review and machine-learning software. The Populations, Exposures, Comparators, and Outcomes (PECO) criteria were kept broad to identify mammalian animal bioassay and epidemiological studies that could inform human hazard identification. A variety of supplemental content was also tracked, including information on in vitro model systems; exposure measurement–only studies in humans; and absorption, distribution, metabolism, and excretion (ADME). Animal bioassay and epidemiology studies meeting PECO criteria were summarized with respect to study design, and health system(s) were assessed. Because animal bioassay studies with ≥21-d exposure duration (or reproductive/developmental study design) were most useful to CCTE analyses, these studies underwent study evaluation and detailed data extraction. All data extraction is publicly available online as interactive visuals with downloadable metadata.Results: More than 40,000 studies were identified from scientific databases. Screening processes identified 44 animal and 148 epidemiology studies from the peer-reviewed literature and 95 animal and 50 epidemiology studies from gray literature that met PECO criteria. Epidemiological evidence (available for 15 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Animal evidence (available for 40 PFAS) commonly assessed effects in the reproductive, developmental, urinary, immunological, and hepatic systems. Overall, 45 PFAS had evidence across animal and epidemiology data streams.Discussion: Many of the ∼150 PFAS were data poor. Epidemiological and animal evidence were lacking for most of the PFAS included in our search. By disseminating this information, we hope to facilitate additional assessment work by providing the initial scoping literature survey and identifying key research needs. Future research on data-poor PFAS will help support a more complete understanding of the potential health effects from PFAS exposures. https://doi.org/10.1289/EHP10343     

The role of prostaglandins in the immunosuppressive effects of supernatants from adherent cells of murine decidual tissue

Supernatants from short-term cultures of murine decidual tissue (DS) were assessed for their regulatory effects on T cell lymphoproliferation and cytotoxic T lymphocyte (CTL) activity. DS non-specifically suppressed antigen- and mitogen-induced lymphoproliferation, spontaneous thymocyte proliferation, the mixed lymphocyte reaction (MLR) and CTL generation, but had no effect on CTL lytic activity. The immunosuppressive activity was lost after dialysis (14 kDa cut off). Supernatants from indomethacin-treated decidual tissue cultures (indomethacin-DS) lacked suppressive activity in the MLR, mitogen and thymocyte proliferation assays. Indomethacin-DS also showed markedly reduced or no suppressive effects on CTL generation. These findings suggest that prostaglandin production by the decidual component of the placenta could play a role in materno-fetal cellular interactions by regulating T cell lymphoproliferative responses and CTL generation.     

Macular halos associated with Niemann-Pick type B disease

Macular halos describe a striking clinical finding of bilaterally elevated, doughnut-shaped, white rings around th fovea. This paper presents the third well-documented report of the association of macular halos with Niemann-Pick type B disease, demonstrated by color photographs and subtle fluorescein angiographic findings. The systemic association with Niemann-Pick type B disease was confirmed by bone marrow biopsy and enzyme assay. Of 13 family members examined, only the proposita had macular halos; 10 were found to be carriers by sphingomyelinase assay. Recognition of this pathognomonic eye finding warrants more widespread awareness as a presenting sign of Niemann-Pick type B disease.     

Combination anti-CD137 and anti-CD40 antibody therapy in murine myc-driven hematological cancers

In order to stimulate antigen presentation and T cell activity against cancer, we treated three different tumor models in mice with the monoclonal antibodies anti-CD40 plus anti-CD137 (BiMab). In a subcutaneous transplantable MC38 colon cancer model, there was significant enhancement in the survival of mice following BiMab treatment. Anti-CD40 has shown considerable success against lymphoma in previous studies by other investigators, and we also showed in this study that, in a model of Eμ-Myc lymphoma, there was a statistically significant enhancement of survival of mice following BiMab treatment. Following the success of the BiMab treatment in the previous two models, we wished to determine if it would be successful in a mouse model of multiple myeloma. Firstly, we tested a transplantable model of disease in which multiple myeloma cells derived from Vk*MYC mice were injected intravenously. A minor proportion of anti-CD137 and BiMab treated mice experienced prolongation of life beyond 250 days. Then we tested the therapy in a spontaneously occurring multiple myeloma model, in Vk*MYC transgenic mice. The majority of mice treated survived longer than control mice, although statistical significance was not demonstrated.     

Working with communities, governments and academic institutions to make pregnancy safer

The major medical causes of maternal death and the effective interventions to prevent maternal death due to these causes are known. Yet, every year, an estimated 529,000 women die during and following pregnancy and childbirth. Most of these deaths occur in developing countries where other non-medical determinants of maternal health influence the accessibility to these interventions. Improvements in maternal health can be achieved through a health systems approach. Care should be provided as a continuum throughout the life cycle and across health facilities through the health system. Communities, professional organizations and academic institutions should work actively with the government to: provide a package of service, based on population health needs, that is close to home; ensure availability of essential medicines and commodities; address financial barriers to receiving care; strengthen the health workforce; and gather and use information to improve maternal health.