Nuclear receptor NR2E3 gene mutations distort human retinal laminar architecture and cause an unusual degeneration

Mutations in the nuclear receptor gene, NR2E3, cause a disorder of human retinal photoreceptor development characterized by hyperfunction and excess of the minority S (short wavelength or blue) cone photoreceptor type, but near absence of function of the majority rod receptor. NR2E3 disease can also progress to blindness. How the human retina accommodates mis-specified types and numbers of neurons and advances to retinal degeneration are unknown. We studied the retinal organization in vivo of patients with NR2E3 mutations. Early human NR2E3 disease with S cone hyperfunction showed thickened retinal layers within an otherwise normally structured retina. With visual loss, however, lamination was coarse and there was a strikingly thick and bulging appearance to the retina, localized to an annulus encircling the central fovea. This pattern was not found in other retinal degenerations. The abnormal laminar retinal architecture of early NR2E3 disease may be due in part to larger cells with an S cone phenotype in place of rods that failed to differentiate. The later-stage dysplastic appearance suggests a previously unrecognized proliferative response in human retinal degeneration.     

Levels of polychlorinated biphenyls (PCBs), DDE,and mirex in waterfowl collected in New York State, 1981–1982

The PCBs, DDE, and mirex levels were measured in the subcutaneous fat and breast muscle of fifty-five waterfowl collected in New York State during 1981 and 1982. Levels were obtained by electron capture gas chromatography (EC-GC) on wet weight, dry weight, and lipid weight bases; results were confirmed by gas chromatography-mass spectrometry (GC-MS). The mean PCB levels were 6.1 (g/g in fat and 0.25 g/g in breast muscle on a wet weight basis. The mean DDE and mirex levels were 0.10 g/g and 0.28 g/g in fat and 0.01 g/g and 0.002 g/g in breast muscle on a wet weight basis, respectively.The results of the present study confirm those of the previous study (Kimet al. 1984). The detailed comparison, however, shows that the levels of PCBs and DDE in fat continued to decline while the level of mirex increased slightly.     

Aromatization of androstenedione to estrogen by benign prostatic hyperplasia,prostate cancer and expressed prostatic secretions

Summary Human prostatic tissue and expressed prostatic secretions (EPS) efrom patients with benign prostatic hyperplasia (BPH) and prostate cancer were incubated with (1 ³H) androstenedione. The extent of aromatization was determined by measuring the transfer of ³H from the 1 position into water. The amount of ³H₂O recovered corresponds to the estrogens formed. Tissue from 5 patients with BPH yielded 2.13 (±1.05) pmol/mg protein/h while the EPS from the same patients yielded 727 fmol/mg protein/h. In patients with prostate cancer the mean formation of estrogens was 388 fmol/mg protein/h (±75). 4-hydroxyandrostenedione, an aromatase inhibitor, successfully inhibited aromatization in BPH and prostate cancer 53–98%.Part of this paper was presented at the 5th Congress of the European Society for Urological Oncology and Endocrinology, 18–20 August 1986, Edinburgh, UK     

Tumor-specific genetically engineered murine/human chimeric monoclonal antibody

Murine variable and human constant region exons were fused to produce "chimeric" immunoglobulin gamma and kappa genes. These constructs were cotransfected into murine myeloma cells which then produced and secreted intact, functional antibody. Cells secreting the chimeric antibody were introduced into mice. The engineered immunoglobulin was subsequently harvested from ascites fluid and was purified by affinity chromatography. Its immunological properties were compared to those of the parental murine monoclonal (B6.2), which exhibits specificity for human breast, lung, and colon carcinoma cells. Competitive binding, immunofluorescent cell staining, and analysis of immunoprecipitated antigen gave similar results for the chimeric and murine B6.2. The biodistribution of chimeric and murine B6.2 after injection into mice bearing human tumors was found to be identical. These results suggest that murine/human chimeric antibodies may be viable clinical replacements for murine monoclonals with the potential for better immunological tolerance and pharmacological efficacy.     

R-Enantiomer of timolol: a potential selective ocular antihypertensive agent

Various studies were conducted to evaluate the effects of timolol, an S-enantiomer, relative to its R-enantiomer upon intraocular pressure and related ocular systems in the rabbit. The R-enantiomer was about one-third as potent as timolol in displacing³H-dihydroalprenolol binding to iris-ciliary body tissue, reducing aqueous humor formation, and lowering intraocular pressure of -chymotrypsin hypertensive eyes. In contrast, the R-enantiomer was 50 to 90 times less potent than timolol in antagonizing the effects of isoproterenol on pulmonary and atrial -adrenergic receptors. The data indicate that the R-enantiomer may lower intraocular pressure in man at concentrations less likely than timolol to block extraocular -adrenergic receptors. Finally, to account for the differential effect of the R-enantiomer upon ocular as opposed to extraocular -adrenergic receptors, it is tentatively suggested that this agent may also act upon a population of ocular -adrenergic receptors showing relatively poor stereoselectively.     

Redox potential in human semen: Validation and qualification of the MiOXsys assay

Seminal oxidative stress (OS) is a major contributing factor to male infertility. Semen analysis cannot identify reactive oxygen species (ROS), which can be measured using a chemiluminescence assay. Measurement of redox potential provides a more comprehensive assessment of OS, although the test has yet to be fully validated. This study aimed to validate the MiOX^sys analyser for measuring static oxidation–reduction potential (sORP). Results demonstrated that duplicate measurements must be taken, sensors must be batch tested, and sockets should be regularly changed to avoid inconsistency in measurement. Measurement of sORP using MiOX^sys exhibited good reproducibility across different operators (p = 0.469), analysers (p = 0.963) and days (p = 0.942). It is not affected by mechanical agitation (p = 0.522) or snap freezing and thawing (p = 0.823). The stability of sORP over time requires further verification, particularly in samples with high initial sORP. Measurement is temperature sensitive between 2 and 37°C, significantly increasing with increasing temperature (p = 0.0004). MiOX^sys is a more stable assay for assessing OS than chemiluminescence methods and permits greater flexibility for sample handling. MiOX^sys could be implemented to complement semen analysis as part of routine diagnostic testing for male infertility and may be useful in identifying contributing factors to idiopathic infertility.     

Anger Dimensions and Mental Health Following a Disaster: Distribution and Implications After a Major Bushfire

Anger is an important dimension of affect and a prominent feature of posttraumatic mental health, but it is commonly overlooked in postdisaster settings. We aimed to examine the distribution and implications of significant anger problems in the aftermath of a natural disaster, via analyses of Beyond Bushfires survey data from 736 residents of rural communities 5 years after the 2009 Black Saturday bushfires in Victoria, Australia. Assessments included the five‐item Dimensions of Anger Reaction (DAR‐5) scale along with measures of PTSD, depression, and significant mental illness, and indicators of life satisfaction, suicidality, hostile aggressive behavior, and violence exposure. The results indicated that approximately 10% of respondents from areas highly affected by the bushfires scored above the provisional cutoff criteria for significant anger problems on the DAR‐5, which was a more than 3‐fold increase, OR = 3.26, relative to respondents from areas of low‐to‐moderate bushfire impact. The rates were higher among women, younger participants, and those who were unemployed, and co‐occurred commonly, although not exclusively, with other postdisaster mental health problems. Anger problems were also associated with lower life satisfaction, β = ?.31, an 8‐fold increase in suicidal ideation, OR = 8.68, and a nearly 13‐fold increase in hostile aggressive behavior, OR = 12.98. There were associations with anger problems and violence exposure, which were reduced when controlling for covariates, including probable PTSD. The findings provide evidence indicating that anger is a significant issue for postdisaster mental health and should be considered routinely alongside other posttraumatic mental health issues.     

Primary hyperoxaluria diagnosed after kidney transplant: A review of the literature and case report of aggressive renal replacement therapy and lumasiran to prevent allograft loss

Primary hyperoxaluria type 1 is a rare inherited disorder caused by abnormal liver glyoxalate metabolism leading to overproduction of oxalate, progressive kidney disease, and systemic oxalosis. While the disorder typically presents with nephrocalcinosis, recurrent nephrolithiasis, and/or early chronic kidney disease, the diagnosis is occasionally missed until it recurs after kidney transplant. Allograft outcomes in these cases are typically very poor, often with early graft loss. Here we present the case of a child diagnosed with primary hyperoxaluria type 1 after kidney transplant who was able to maintain kidney function, thanks to aggressive renal replacement therapy as well as initiation of a new targeted therapy for this disease. This case highlights the importance of having a high index of suspicion for primary hyperoxaluria in patients with chronic kidney disease and nephrocalcinosis/nephrolithiasis or with end stage kidney disease of uncertain etiology, as initiating therapies early on may prevent poor outcomes.     

Sex Differences in Voyeuristic and Exhibitionistic Interests: Exploring the Mediating Roles of Sociosexuality and Sexual Compulsivity from an Evolutionary Perspective

Sociosexuality and sexual compulsivity predict sex differences in voyeuristic interest in the population. In this study, we used a sample of 1113 participants from the UK (46% men) to consider whether sociosexuality and sexual compulsivity interacted to explain these sex differences and whether this relationship extended to the related domain of exhibitionism. In doing so, we tested novel predictions derived from an evolutionary perspective which views voyeuristic and exhibitionistic interest as manifestations of a short-term mating strategy. Participants reported their levels of repulsion toward voyeurism and exhibitionism and their interest in performing such acts under different levels of risk. There were clear sex differences in voyeuristic and exhibitionistic repulsion that were partially mediated by the serial combination of sociosexuality and sexual compulsivity. Examining the sexes separately revealed qualitatively different relationships between sociosexuality and sexual compulsivity when predicting exhibitionistic, but not voyeuristic, repulsion. Combined, sociosexuality and sexual compulsivity also mediated the sex difference in willingness to commit acts of voyeurism, but not exhibitionism, which was equally low for both sexes. The results highlight the role sociosexuality plays in voyeuristic and exhibitionistic interest, which coupled with an evolutionary perspective, may have implications for how we view courtship disorders.