Genetic basis for individual variations in pain perception and the development of a chronic pain condition

Pain sensitivity varies substantially among humans. A significantpart of the human population develops chronic pain conditionsthat are characterized by heightened pain sensitivity. We identifiedthree genetic variants (haplotypes) of the gene encoding catecholamine-O-methyltransferase(COMT) that we designated as low pain sensitivity (LPS), averagepain sensitivity (APS) and high pain sensitivity (HPS). We showthat these haplotypes encompass 96% of the human population,and five combinations of these haplotypes are strongly associated(P=0.0004) with variation in the sensitivity to experimentalpain. The presence of even a single LPS haplotype diminishes,by as much as 2.3 times, the risk of developing myogenous temporomandibularjoint disorder (TMD), a common musculoskeletal pain condition.The LPS haplotype produces much higher levels of COMT enzymaticactivity when compared with the APS or HPS haplotypes. Inhibitionof COMT in the rat results in a profound increase in pain sensitivity.Thus, COMT activity substantially influences pain sensitivity,and the three major haplotypes determine COMT activity in humansthat inversely correlates with pain sensitivity and the riskof developing TMD.     

Morphological and morphometric characteristics of choroid plexus psammoma bodies during the human aging

Psammoma bodies are one of many choroid plexus aging changes which origin is still enigma for the scientists. During our investigation psammoma bodies were studied on 30 postmortem brains by light microscopy. They stained red with HE, and were PAS and AB PAS positive. The largest number of lamellas were stained blue with Mallory's connective tissue stain, except peripheral and next to the center lamella which stained red. During the aging, psammoma bodies became larger and more irregular, which was followed with group area and perimeter, single psammoma body average area and average perimeter, average diameter and contour index increase. Psammoma bodies mearged in the second and the third age group and mearging process led to larger and more irregular structures formation. The results of this investigation suggest that psammoma bodies are more frequent in choroid plexus of healthy older people and during the aging they obtain larger dimensions, more irregular contours, which is the result of their mutual mearging.     

Chromosomal evolution of Arvicolinae (Cricetidae, Rodentia). II. The genome homology of two mole voles (genus Ellobius), the field vole and golden hamster revealed by comparative chromosome painting

Using cross-species chromosome painting, we have carried out a comprehensive comparison of the karyotypes of two Ellobius species with unusual sex determination systems: the Transcaucasian mole vole, Ellobius lutescens (2n = 17, X in both sexes), and the northern mole vole, Ellobius talpinus (2n = 54, XX in both sexes). Both Ellobius species have highly rearranged karyotypes. The chromosomal paints from the field vole (Microtus agrestis) detected, in total, 34 and 32 homologous autosomal regions in E. lutescens and E. talpinus karyotypes, respectively. No difference in hybridization pattern of the X paint (as well as Y paint) probes on male and female chromosomes was discovered. The set of golden hamster (Mesocricetus auratus) chromosomal painting probes revealed 44 and 43 homologous autosomal regions in E. lutescens and E. talpinus karyotypes, respectively. A comparative chromosome map was established based on the results of cross-species chromosome painting and a hypothetical ancestral Ellobius karyotype was reconstructed. A considerable number of rearrangements were detected; 31 and 7 fusion/fission rearrangements differentiated the karyotypes of E. lutescens and E. talpinus from the ancestral Ellobius karyotype. It seems that inversions have played a minor role in the genome evolution of these Ellobius species.     

Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus

Primary ciliary dyskinesia (PCD), also known as Kartagener's syndrome, is a human syndrome that results from ciliary dysfunction. This syndrome is characterized by recurrent respiratory infections, situs inversus and infertility. In some cases, hydrocephalus is also observed. We have characterized an insertional mutation in a mouse axonemal dynein heavy chain gene (Mdnah5) that reproduces most of the classical features of PCD, including recurrent respiratory infections, situs inversus and ciliary immotility. These mice also suffer from hydrocephalus and die perinatally. Electron microscopic studies demonstrate the loss of axonemal outer arms. These results show that mutations in Mdnah5 are a primary cause of PCD and provide direct evidence that mutations in an axonemal dynein can cause hydrocephalus. Mutations in the human DNAH5 have recently been identified in PCD patients. Comparison of the mouse model and the human data suggests that the degree of ciliary dysfunction is causally related to the severity of human PCD, particularly the presence of hydrocephalus.     

Severity of Megakaryocyte-Driven Osteosclerosis in Mpig6b-Deficient Mice Is Sex-Linked

Patients with chronic myelofibrosis often suffer from osteosclerosis, which is associated with bone pain and may lead to bone marrow failure. The pathogenesis of myelofibrosis is linked to aberrant megakaryocyte development and function. Null and loss-of-function mutations in MPIG6B, which codes for the inhibitory heparan sulfate receptor G6b-B, result in severe macrothrombocytopenia, large megakaryocyte clusters, and focal primary myelofibrosis in mice and humans. We investigated the development of osteosclerosis in Mpig6b null (Mpig6b^−/−) mice. Although male and female Mpig6b^−/− mice presented with elevated bone marrow megakaryocyte number and macrothrombocytopenia, female Mpig6b^−/− mice developed progressive splenomegaly starting at 8 weeks of age. Micro–computed tomography (μCT) of femurs showed that female Mpig6b^−/− mice had increased cortical thickness and reduced bone marrow area starting at 8 weeks of age and developed occlusion of the medullary cavity by trabeculae by 16 weeks of age. In contrast, male Mpig6b^−/− mice developed only a small number of trabeculae in the medullary cavity at the proximal diaphysis and demonstrated a temporary decrease in bone volume fraction and trabecular thickness at 16 weeks. Ovariectomy of 10-week-old female Mpig6b^−/− mice prevented the development of medullary cavity osteosclerosis, whereas orchiectomy of male Mpig6b^−/− mice did not exacerbate their disease. Importantly, ovariectomized female Mpig6b^−/− mice also demonstrated improvement in spleen weight compared to sham-operated Mpig6b^−/− mice, establishing estrogen as a contributing factor to the severity of the megakaryocyte-driven osteosclerosis. © 2021 American Society for Bone and Mineral Research (ASBMR).     

The association of salvage intravesical therapy following BCG with pathologic outcomes and survival after radical cystectomy for patients with high-grade non-muscle invasive bladder cancer: A multi-institution analysis

IntroductionWhile numerous current clinical trials are testing novel salvage therapies (ST) for patients with recurrent nonmuscle invasive bladder cancer (NMIBC) after bacillus Calmette-Guérin (BCG), the natural history of this disease state has been poorly defined to date. Herein, we evaluated oncologic outcomes in patients previously treated with BCG and ST who subsequently underwent radical cystectomy (RC).MethodsWe identified 378 patients with high-grade NMIBC who received at least one complete induction course of BCG (n = 378) with (n = 62) or without (n = 316) additional ST and who then underwent RC between 2000 and 2018. Oncologic outcomes were compared using the Kaplan-Meier method and Cox proportional hazards models. Sensitivity analyses were conducted stratifying by presenting tumor stage, matched 1:3 for receipt vs. no receipt of ST.ResultsPatients receiving ST were more likely to initially present with CIS (26% vs. 17%) and less likely with T1 disease (34% vs. 50%, P = 0.06) compared to patients not treated with ST. Receipt of ST was not associated with increased risk of adverse pathology (≥pT2 or pN+) at RC (31% vs. 41%, P = 0.14). Likewise, 5-year cancer-specific survival did not significantly differ between groups on univariable Kaplan-Meier analysis (73% for ST and 74% for no ST, P = 0.7). Moreover, on multivariable analysis, receipt of ST was not significantly associated the risk of death from bladder cancer (HR 1.12; 95% CI 0.60–2.09, P = 0.7). Results were unchanged on sensitivity analysis.ConclusionsThese data suggest that, in carefully selected patients, ST following BCG for high grade NMIBC does not compromise oncologic outcomes for patients who ultimately undergo RC.     

Validation of a screening test for alcohol use,the Russian Federation

ObjectiveTo validate a Russian-language version of the World Health Organization’s Alcohol Use Disorders Identification Test (AUDIT).MethodsWe invited 2173 patients from 21 rural and urban primary health-care centres in nine Russian regions to participate in the study (143 declined and eight were excluded). In a standardized interview, patients who had consumed alcohol in the past 12 months provided information on their sociodemographic characteristics and completed the Russian AUDIT, the Kessler Psychological Distress Scale and the Composite International Diagnostic Interview to identify problem drinking and alcohol use disorders. We assessed the feasibility of administering the test, its internal consistency and its ability to predict hazardous drinking and alcohol use disorders in primary health care in the Russian Federation.FindingsOf the 2022 patients included in the study, 1497 were current drinkers with Russian AUDIT scores. The test was internally consistent with good psychometric properties (Cronbach’s α : 0.842) and accurately predicted alcohol use disorders and other outcomes (area under the curve > 75%). A three-item short form of the test correlated well with the full instrument and had similar predictive power (area under the curve > 80%). We determined sex-specific thresholds for all outcomes, as non-specific thresholds resulted in few women being identified.ConclusionWith the validated Russian AUDIT, there is no longer a barrier to introducing screening and brief interventions into primary health care in the Russian Federation to supplement successful alcohol control policies.     

p53 mutations in human aggressive and nonaggressive basal and squamous cell carcinomas.

PURPOSE: The purpose is to investigate whether aggressive basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) differ from nonaggressive BCC and SCC with respect to the p53 mutation spectrum and whether specific mutations can serve as prognostic indicators of tumor aggressiveness. EXPERIMENTAL DESIGN: We analyzed 342 tissues from patients with aggressive and nonaggressive BCCs and SCCs for p53 mutations by single-strand conformation polymorphism and nucleotide sequencing. RESULTS: p53 mutations were detected in 33 of 50 aggressive BCCs (66%), 37 of 98 nonaggressive BCCs (38%), 28 of 80 aggressive SCCs (35%), 28 of 56 nonaggressive SCCs (50%), and 3 of 29 samples of sun-exposed skin (10%). About 71% of the p53 mutations detected in aggressive and nonaggressive BCCs and SCCs were UV signature mutations. The frequency of CC to TT mutations in aggressive (36%) and nonaggressive SCCs (39%) was 2-fold higher than in aggressive (18%) and nonaggressive (14%) BCCs. In contrast, aggressive BCCs had a higher frequency (24%) of transversions than nonaggressive BCCs (8%) and aggressive (14%) and nonaggressive (11%) SCCs did. CONCLUSIONS: Our results indicate that UV radiation is responsible for the induction of p53 mutations and perhaps for the initiation of both aggressive and nonaggressive BCCs and SCCs. Although some differences in p53 mutation frequency, types of mutation, and hot spots were seen between aggressive and nonaggressive BCCs and SCCs, these factors do not constitute as clear-cut diagnostic or prognostic indicators of tumor aggressiveness. Tumor aggressiveness may be attributable to other genetic changes or events that occur during tumor progression.     

One-year recombinant growth hormone therapy does not improve hemoglobin state and morphology of erythrocytes in growth hormone deficient children

An increase in growth rates of children suffering from growth hormone deficiency (GHD) subjected to recombinant growth hormone treatment (rGHT) was shown to be accompanied by acceleration of metabolic processes that may stimulate oxygen consumption in various organs and tissues. Therefore, oxygen-transporting properties of RBC should undergo considerable changes during the rGHT. The aim of this study was to examine the effects of rGHT on erythrocyte shape and hemoglobin state in GHD children. The level of oxyhemoglobin (Oxy-Hb) in RBC was analyzed by Raman spectroscopy. The RBC count, mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV) and other parameters were calculated. The blood of eleven treatment-naive prepubertal children with GHD (aged 3–9, median 5.7 years) was examined and compared with control group (aged 5–7; median 6.0 years) at three time points: 0, 3 and 12 months of rGHT. Before rGHT, the MI in GHD children was higher (median 0.48 vs 0.14 p = 0.0018) and the RBC count was lower (median 4.20 vs 4.96 10¹² cells/L p = 0.0022) than in control group. After the treatment, cell count in GHD patients did not differ significantly from the control group, but Oxy-Hb level became higher (median 0.64 vs 0.41 p = 0.0075). During rGHT, MCV decreased (median 80.3 vs 83.2 μm³ p = 0.0231). Morphological and functional characteristics of erythrocytes in GHD children were shown to differ significantly from the healthy control group. A twelve-month rGHT partially improved some of the studied parameters but Oxy-Hb level and echinocyte count remained high.     

HIV/AIDS discourses in Kyrgyzstan’s policy arena

This article explores the major discourses on HIV/AIDS in the policy arena in Kyrgyzstan, a former Soviet country in Central Asia that has experienced a rapid rise in HIV infections since the early 2000s. Based on an analysis of policy documents and 54 semi-structured in-depth interviews with key stakeholders in the area of HIV/AIDS policies in Kyrgyzstan, we distinguish a number of key discourses, competing for legitimacy and authority. While some of these discourses have been used in other countries (such as those presenting HIV/AIDS as a biomedical, social or moral issue), others are more specific to Kyrgyzstan (such as a discourse presenting the country as a regional pioneer in HIV/AIDS prevention efforts). Our analysis shows how HIV/AIDS discourses in the policy arena overlap and complement each other and how stakeholders employ a number of tools and strategies to promote and secure their agendas and positions of power. Our findings help to better understand HIV/AIDS discourses in Kyrgyzstan and elsewhere. They highlight the importance of understanding which discourses are prevailing, who drives them and why, how they change over time, and how they can be framed to achieve policy objectives.