Elevated glucocorticoid receptor levels in lymphocytes of children with the fetal hydantoin syndrome (FHS)

Our recent studies of the teratogenic mechanisms of phenytoin (DPH) and glucocorticoids in mice have indicated that DPH utilizes the anti-inflammatory pathway of glucocorticoids in producing congenital defects, such as cleft palate. This pathway is influenced by H-2 and H-3 histocompatibility-linked genes in the mouse, such that congenic strains have H-2 or H-3 alleles that confer susceptibility to DPH-induced congenital defects, and susceptible H-2 congenic strains have high glucocorticoid receptor levels. However, other H-2 or H-3 alleles confer resistance to these defects in their otherwise genetically identical congenic partner strains, and "resistant" H-2 alleles are associated with low levels of these receptors. To determine whether this animal work is applicable to the human, we have sought to investigate whether the level of glucocorticoid receptors in circulating lymphocytes of children with the fetal hydantoin syndrome (FHS) is as it is in the animals. We found that children with FHS had glucocorticoid receptor levels significantly elevated above those of unaffected children with similar DPH exposure in control families. The receptor level of affected children was also significantly elevated above that of fathers of children with the FHS and of fathers and mothers of control children. These findings are consistent with those documented in the animal models and suggest that an elevated level of glucocorticoid receptors in lymphocytes may be a marker for susceptibility to the FHS syndrome.     

Characterization of Virus-Responsive Plasmacytoid Dendritic Cells in the Rhesus Macaque

Plasmacytoid dendritic cells (PDC) are potent producers of alpha interferon (IFN-α) in response to enveloped viruses and provide a critical link between the innate and adaptive immune responses. Although the loss of peripheral blood PDC function and numbers has been linked to human immunodeficiency virus (HIV) progression in humans, a suitable animal model is needed to study the effects of immunodeficiency virus infection on PDC function. The rhesus macaque SIV model closely mimics human HIV infection, and recent studies have identified macaque PDC, potentially making the macaque a good model to study PDC regulation. In this study, we demonstrate that peripheral blood PDC from healthy macaques are both phenotypically and functionally similar to human PDC and that reagents used for human studies can be used to study macaque PDC. Both human and macaque PBMC expressed IFN-α in response to herpes simplex virus (HSV), the prototypical activator of PDC, as measured by using an IFN bioassay and IFN-α-specific enzyme-linked immunospot assays. Similar to human PDC, macaque PDC were identified by using flow cytometry as CD123⁺ HLA-DR⁺ lineage⁻ cells. In addition, like human PDC, macaque PDC expressed intracellular IFN-α, tumor necrosis factor alpha, macrophage inflammatory protein 1β/CCL4, and IFN-inducible protein 10/CXCL10 upon stimulation with HSV, all as determined by intracellular flow cytometry. We found that IFN regulatory factor 7, which is required for the expression of IFN-α genes, was, similar to human PDC, expressed at high levels in macaque PDC compared to monocytes and CD8⁺ T cells. These findings establish the phenotypic and functional similarity of human and macaque PDC and confirm the utility of tools developed for studying human PDC in this animal model.     

Changes in plasma volume during hypohydration and rehydration in subjects from the tropics

Summary Plasma volume (PV) at different levels of hypohydration was determined using radio-iodinated serum albumin-125 in 28 heat acclimated male volunteers in hot dry conditions in a climatic chamber. The heat acclimated subjects were hypohydrated to varying degrees i.e. 1%, 2%, 3% and 4% body mass deficit by moderate work in hot conditions in a climatic chamber maintained at 45°C dry bulb temperature and 30% relative humidity. A rehydration study was carried out in only those subjects who were hypohydrated to 3% and 4% body mass and they were brought back to a 2% level of hypohydration by giving a calculated amount of water. A significant decrease in PV was observed at 3% and 4% hypohydration only. The magnitude of the decrease was the same in both the groups and not related to the level of hypohydration. With partial rehydration in the 3% hypohydrated group PV was restored fully, while in the 4% hypohydrated group restoration was incomplete, indicating that at this hypohydration level some of the replenished water that entered in plasma may have moved to the intracellular compartment which may have contributed more at 4% hypohydration. It is suggested that with higher levels of thermal hypohydration significant reduction in the intracellular compartment may result in accentuated physiological strain during work in the heat.     

Branches of the splenic artery and splenic arterial segments

In 200 adult autopsy specimens, the arterial supply to the pancreas and spleen was studied radiologically and by manual dissection. The splenic artery divided into two or three lobar arteries, which supplied its corresponding lobe; each lobar artery subsequently divided into two to four lobular branches. Six to twelve lobular branches were observed entering the splenic substance at the hilum. Lobar arteries did not anastomose with each other, hence, the lobes of the spleen are also termed segments. The lobules, however, were not found to be independent segments and the arteries of one lobule anastomosed with those of other lobules. The branching pattern of the splenic artery varied from one specimen to another, so much so that a prevailing pattern could not be identified. Polar arteries, particularly to the superior pole, arose quite proximal to the hilum in 51% of cases and were occasionally missed. In 45% of males and 40% of females, the posterior gastric artery arose from about the middle of the splenic artery. The splenic artery was not found to be tortuous in fetuses, newborns, and young children. Tortuosity was seen in only 10% of adults; thus, the characteristic tortuosity of the splenic artery appears to develop with age.     

Upper gastrointestinal cancer pathology reporting: a regional audit to compare standards with minimum datasets

AIMS: Accurate pathological (pTNM) staging of oesophageal and gastric cancer provides important prognostic information. The aim of this study was to compare the standard of pathology reporting of oesophageal and gastric cancer resections from a cancer network with standards set by the Royal College of Pathologists. METHODS: All reports for oesophageal and gastric cancer resections from the five hospitals in the cancer network in 2001 were collected. Individual items of information were compared with minimum datasets provided by the Royal College of Pathologists. Items were classified as "complete", "partially complete", or "absent". RESULTS: One hundred and ten reports were audited (54 oesophageal and 56 gastric). Fourteen gastric and 17 oesophagectomy reports were over 75% complete. Clinically important missing data occurred most frequently for the pM component of TNM staging (pMx omitted in 87 reports) and completeness of resection expressed as a bold statement (absent in 50 reports). Twelve reports could not be classified because the specimen contained no residual tumour after neoadjuvant treatment. CONCLUSION: The use of a standard proforma for reporting upper gastrointestinal cancers based on a minimum dataset provided by the Royal College of Pathologists is recommended, with modifications to allow for specimens with no tumour after neoadjuvant treatment.     

Role of the carbohydrate domains of glycophorins as erythrocyte receptors for invasion by Plasmodium falciparum merozoites.

Solubilized preparations of purified glycophorins and specific domains of these molecules were assessed for their effects as inhibitors of Plasmodium falciparum invasion of human erythrocytes in vitro. The ability of newly invaded merozoites to continue developing and incorporating [3H]hypoxanthine during a 24-h period after their invasion was used as an assay for merozoite invasion. Glycophorins A, B, and C were found to be equally effective as inhibitors. Previous studies had shown N-acetylglucosamine, a sugar component of glycophorins A and C but not B, to be an effective inhibitor. Accordingly, molecular domains common to all of the glycophorins were further assessed. Sialic acid was shown to act almost as effectively as N-acetylglucosamine, presumably because of the structural similarities between these sugars. The inhibitory ability of sialic acid is considerably enhanced when presented to the parasite in a clustered form, as in an oligosaccharide. The acetyl group of these sugars does not appear to play an essential role in this inhibition. How the P. falciparum merozoite recognizes and interacts with the sugar domains of the glycophorin molecule remains to be determined.     

Autologous mixed lymphocyte reaction in man. XIV. Deficiency of the autologous mixed lymphocyte reaction in acquired immune deficiency syndrome (AIDS) and AIDS related complex (ARC). In vitro effect of purified interleukin-1 and interleukin-2.

Peripheral blood mononuclear cells from male homosexuals with acquired immune deficiency syndrome (AIDS) and with AIDS related complex (ARC) were examined for the autologous mixed lymphocyte reaction (AMLR) between responder T and irradiated autologous non-T cells and in vitro influence of purified human interleukin-1 (IL-1) and -2 (IL-2) on the AMLR. The AMLR was significantly (P less than 0.001) deficient in both ARC and AIDS; the deficiency of the AMLR was of the similar magnitude in two groups when compared to asymptomatic homosexuals and healthy heterosexuals. In vitro addition of IL-2 enhanced the AMLR to the baseline levels of control subjects in most patients in ARC group (P less than 0.01) and in four of 15 patients in AIDS group (P less than 0.01). Addition of IL-1 to IL-2 containing cultures resulted in no further increase in the AMLR response over those with IL-2 alone. This study demonstrates deficiency of the AMLR in patients with ARC and AIDS that is corrected by purified IL-2 in the majority of cases with ARC but only a subset of patients with AIDS. The significance of these findings is discussed.     

Redefining 'self': the role of microflora (commensals) mismatch in the development of GvHD after allogeneic stem cell transplantation and some possible remedies

The discovery of human leukocyte antigen (HLA) molecules and their role in allorecognition has facilitated the initiation of allogeneic stem cell transplantation in human beings. HLA mismatch to a large extent explains the phenomenon of graft rejection and graft versus host disease (GvHD). Incidence of GvHD even in syngeneic transplants suggests a role for extra genetic factors in the causation of GvHD. We hereby propose a hypothesis that the definition of 'self' (in the immunological sense) should be broadened to include both genetically determined molecules (e.g. HLA) and the microbial flora that colonize an individual. This hypothesis explains several observations about GvHD which can not fully be accounted for by the HLA mismatch theory and gives some clues towards circumventing GvHD.