Steroid hormone imbalance drives macrophage infiltration and Spp1/osteopontin+ foam cell differentiation in the prostate.

Benign prostatic hyperplasia (BPH) occurs progressively with aging in men and drives deteriorating symptoms collectively known as lower urinary tract symptoms (LUTS). Age-associated changes in circulating steroid hormones, and prostate inflammation have been postulated in the etiology of BPH/LUTS. The link between hormones and inflammation in the development of BPH/LUTS is conflicting because they may occur independently or as sequential steps in disease pathogenesis. This study aimed to decipher the prostatic immune landscape in a mouse model of lower urinary tract dysfunction (LUTD). Steroid hormone imbalance was generated by the surgical implantation of testosterone (T) and estradiol (E2) pellets into male C57BL/6J mice and gene expression analysis was performed on ventral prostates (VPs). These experiments identified an increase in the expression of macrophage markers and Spp1/osteopontin (OPN). Localization studies of OPN pinpointed that OPN+ macrophages travel to the prostate lumen and transition into lipid-accumulating foam cells. We also observed a significant increase in the number of tissue macrophages in the VP which was prevented in OPN-knockout (OPN-KO) mice. In contrast, mast cells, but not macrophages, were significantly elevated in the dorsal prostate of T + E2-treated mice which was diminished in OPN-KO mice. Steroid hormone implantation progressively increased urinary frequency, which was ameliorated in OPN-KO mice. Our study underscores the role of age-associated steroid hormone imbalances as a mechanism of expanding the prostatic macrophage population, their luminal translocation, and foam cell differentiation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Transcriptional programs are activated and microRNAs are repressed within minutes after mating in the Drosophila melanogaster female reproductive tract.

BACKGROUND: The female reproductive tract is exposed directly to the male's ejaculate, making it a hotspot for mating-induced responses. In Drosophila melanogaster, changes in the reproductive tract are essential to optimize fertility. Many changes occur within minutes after mating, but such early timepoints are absent from published RNA-seq studies. We measured transcript abundances using RNA-seq and microRNA-seq of reproductive tracts of unmated and mated females collected at 10-15 min post-mating. We further investigated whether early transcriptome changes in the female reproductive tract are influenced by inhibiting BMPs in secondary cells, a condition that depletes exosomes from the male's ejaculate. RESULTS: We identified 327 differentially expressed genes. These were mostly upregulated post-mating and have roles in tissue morphogenesis, wound healing, and metabolism. Differentially abundant microRNAs were mostly downregulated post-mating. We identified 130 predicted targets of these microRNAs among the differentially expressed genes. We saw no detectable effect of BMP inhibition in secondary cells on transcript levels in the female reproductive tract. CONCLUSIONS: Our results indicate that mating induces early changes in the female reproductive tract primarily through upregulation of target genes, rather than repression. The upregulation of certain target genes might be mediated by the mating-induced downregulation of microRNAs. Male-derived exosomes and other BMP-dependent products were not uniquely essential for this process. Differentially expressed genes and microRNAs provide candidates that can be further examined for their participation in the earliest alterations of the reproductive tract microenvironment.

Deciphering mechanistic implications of antimicrobial and antioxidant potentials of certain new dibutyltin(IV) formulations as possible therapeutic options based on DFT and hybrid materials paradigm.

Mechanistic implications of antimicrobial and in vitro antioxidant potentials of a set of newly generated nonbridged mononuclear N,O-orthometallated and carboxylate bridged binuclear nonorthometallated dibutyltin(IV) formulations have been investigated. Some of these formulations were screened for their antibacterial and antifungal activities against Escherichia coli and Candida albicans, respectively whereas in vitro antioxidant potential was examined by Ferric reducing antioxidant power (FRAP) assay. Nonbridged mononuclear N,O-orthometallated dibutyltin(IV) formulations were generated by the reactions of Bu2 SnCl2 with sodium salts of 2-aminophenol/substituted 2-aminophenol and flexible N-protected amino acids in 1:1:1 molar ratio in refluxing dry THF. Plausible structures of these nonbridged mononuclear N,O-orthometallated dibutyltin(IV) formulations containing flexible N-protected amino acids have been suggested on the basis of spectroscopic and mass studies of some representative formulations. Plausible structures suggested on the basis of spectroscopic studies are corroborated by density functional theory (DFT/B3LYP method) (SPARTAN-20) investigation of a representative dibutyltin(IV) complex and the ligands involved in it. The presence of two different classes of organic ligands in this complex provides an opportunity to study optimized topologies, bonding, distortions, optimized energy, and stability of the complex.

Osteopontin Deficiency Ameliorates Prostatic Fibrosis and Inflammation.

Fibrogenic and inflammatory processes in the prostate are linked to the development of lower urinary tract symptoms (LUTS) in men. Our previous studies identified that osteopontin (OPN), a pro-fibrotic cytokine, is abundant in the prostate of men with LUTS, and its secretion is stimulated by inflammatory cytokines potentially to drive fibrosis. This study investigates whether the lack of OPN ameliorates inflammation and fibrosis in the mouse prostate. We instilled uropathogenic E. coli (UTI89) or saline (control) transurethrally to C57BL/6J (WT) or Spp1tm1Blh/J (OPN-KO) mice and collected the prostates one or 8 weeks later. We found that OPN mRNA and protein expression were significantly induced by E. coli-instillation in the dorsal prostate (DP) after one week in WT mice. Deficiency in OPN expression led to decreased inflammation and fibrosis and the prevention of urinary dysfunction after 8 weeks. RNAseq analysis identified that E. coli-instilled WT mice expressed increased levels of inflammatory and fibrotic marker RNAs compared to OPN-KO mice including Col3a1, Dpt, Lum and Mmp3 which were confirmed by RNAscope. Our results indicate that OPN is induced by inflammation and prolongs the inflammatory state; genetic blockade of OPN accelerates recovery after inflammation, including a resolution of prostate fibrosis.

Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection among Kidney Transplant Recipients: A Large Single-Center Experience.

Background: Kidney transplant recipients (KTRs) are a vulnerable immunocompromised population at risk of severe COVID-19 disease and mortality after SARS-CoV-2 infection. We sought to characterize the post-infection sequelae in KTRs at our center. Methods: We studied all adult KTRs (with a functioning allograft) who had their first episode of SARS-CoV-2 infection between 04/2020 and 04/2022. Outcomes of interest included risk factors for hospitalization, all-cause mortality, COVID-19-related mortality, and allograft failure. Results: Of 979 KTRs with SARS-CoV-2 infection, 381 (39%) were hospitalized. In the multivariate analysis, risk factors for hospitalization included advanced age/year (HR: 1.03, 95% CI: 1.02-1.04), male sex (HR: 1.29, 95% CI: 1.04-1.60), non-white race (HR: 1.48, 95% CI: 1.17-1.88), and diabetes as a cause of ESKD (HR: 1.77, 95% CI: 1.41-2.21). SARS-CoV-2 Vaccination was associated with decreased risk of hospitalization (HR: 0.73, 95% CI: 0.59-0.90), all-cause mortality (HR: 0.52, 95% CI: 0.37-0.74), and COVID-19-related mortality (HR: 0.47, 95% CI: 0.31-0.71) in the univariate and multivariate analyses. Risk factors for both all-cause and COVID-19-related mortality in the multivariate analyses included advanced age, hospitalization, and respiratory symptoms for hospital admission. Furthermore, additional risk factors for all-cause mortality in the multivariate analysis included being a non-white recipient and diabetes as a cause of ESKD, with being a recipient of a living donor as protective. Conclusions: Hospitalization due to COVID-19-associated symptoms is associated with increased mortality. Vaccination is a protective factor against hospitalization and mortality.

Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study.

BACKGROUND: Knowledge about the distribution of human papillomavirus (HPV) genotypes in invasive cervical cancer is crucial to guide the introduction of prophylactic vaccines. We aimed to provide novel and comprehensive data about the worldwide genotype distribution in patients with invasive cervical cancer. METHODS: Paraffin-embedded samples of histologically confirmed cases of invasive cervical cancer were collected from 38 countries in Europe, North America, central South America, Africa, Asia, and Oceania. Inclusion criteria were a pathological confirmation of a primary invasive cervical cancer of epithelial origin in the tissue sample selected for analysis of HPV DNA, and information about the year of diagnosis. HPV detection was done by use of PCR with SPF-10 broad-spectrum primers followed by DNA enzyme immunoassay and genotyping with a reverse hybridisation line probe assay. Sequence analysis was done to characterise HPV-positive samples with unknown HPV types. Data analyses included algorithms of multiple infections to estimate type-specific relative contributions. FINDINGS: 22,661 paraffin-embedded samples were obtained from 14,249 women. 10,575 cases of invasive cervical cancer were included in the study, and 8977 (85%) of these were positive for HPV DNA. The most common HPV types were 16, 18, 31, 33, 35, 45, 52, and 58 with a combined worldwide relative contribution of 8196 of 8977 (91%, 95% CI 90-92). HPV types 16 and 18 were detected in 6357 of 8977 of cases (71%, 70-72) of invasive cervical cancer. HPV types 16, 18, and 45 were detected in 443 of 470 cases (94%, 92-96) of cervical adenocarcinomas. Unknown HPV types that were identified with sequence analysis were 26, 30, 61, 67, 69, 82, and 91 in 103 (1%) of 8977 cases of invasive cervical cancer. Women with invasive cervical cancers related to HPV types 16, 18, or 45 presented at a younger mean age than did those with other HPV types (50·0 years [49·6-50·4], 48·2 years [47·3-49·2], 46·8 years [46·6-48·1], and 55·5 years [54·9-56·1], respectively). INTERPRETATION: To our knowledge, this study is the largest assessment of HPV genotypes to date. HPV types 16, 18, 31, 33, 35, 45, 52, and 58 should be given priority when the cross-protective effects of current vaccines are assessed, and for formulation of recommendations for the use of second-generation polyvalent HPV vaccines. Our results also suggest that type-specific high-risk HPV-DNA-based screening tests and protocols should focus on HPV types 16, 18, and 45.

HPV Involvement in Head and Neck Cancers: Comprehensive Assessment of Biomarkers in 3680 Patients.

BACKGROUND: We conducted a large international study to estimate fractions of head and neck cancers (HNCs) attributable to human papillomavirus (HPV-AFs) using six HPV-related biomarkers of viral detection, transcription, and cellular transformation. METHODS: Formalin-fixed, paraffin-embedded cancer tissues of the oral cavity (OC), pharynx, and larynx were collected from pathology archives in 29 countries. All samples were subject to histopathological evaluation, DNA quality control, and HPV-DNA detection. Samples containing HPV-DNA were further subject to HPV E6*I mRNA detection and to p16(INK4a), pRb, p53, and Cyclin D1 immunohistochemistry. Final estimates of HPV-AFs were based on HPV-DNA, HPV E6*I mRNA, and/or p16(INK4a) results. RESULTS: A total of 3680 samples yielded valid results: 1374 pharyngeal, 1264 OC, and 1042 laryngeal cancers. HPV-AF estimates based on positivity for HPV-DNA, and for either HPV E6*I mRNA or p16(INK4a), were 22.4%, 4.4%, and 3.5% for cancers of the oropharynx, OC, and larynx, respectively, and 18.5%, 3.0%, and 1.5% when requiring simultaneous positivity for all three markers. HPV16 was largely the most common type. Estimates of HPV-AF in the oropharynx were highest in South America, Central and Eastern Europe, and Northern Europe, and lowest in Southern Europe. Women showed higher HPV-AFs than men for cancers of the oropharynx in Europe and for the larynx in Central-South America. CONCLUSIONS: HPV contribution to HNCs is substantial but highly heterogeneous by cancer site, region, and sex. This study, the largest exploring HPV attribution in HNCs, confirms the important role of HPVs in oropharyngeal cancer and drastically downplays the previously reported involvement of HPVs in the other HNCs.

Patients' experiences and expectations of general practice: a questionnaire study of differences by ethnic group.

BACKGROUND: Research has highlighted variations in morbidity, mortality and health needs by ethnic group, and suggests that some ethnic groups may receive a poorer service. AIM: To explore the impact of ethnic group on patients' experiences and expectations of their general practice consultation. DESIGN OF STUDY: Cross-sectional survey. SETTING: One general practice in a multicultural area of London. METHOD: A total of 604 consecutive patients attending their general practice (response rate = 60.4%) who described their ethnic group as white British, black African, black African Caribbean or Vietnamese completed a measure relating to their experiences and their expectations of the general practice consultation in terms of treatment, communication, patients' agenda, patients' choice and doctor consistency. RESULTS: No differences were found for the black African or black African Caribbean patients. The Vietnamese patients reported better experiences of communication, more focus on their agenda and more attention to their choices than the white British patients. However, they also reported expecting lower levels of communication, less focus on their own agenda and reported wanting less GP consistency than the other ethnic groups. CONCLUSION: Vietnamese patients state that they are receiving better standards of care in general practice than other ethnic groups. However, they also state that they expect less. This may illustrate a problem with assessing experiences of primary care. Higher scores of experience may not illustrate better consultations as such, but only better when compared with a lower level of initial expectation. A lower expectation is easier to fulfil.

Higher prevalence of human papillomavirus infection in adolescent and young adult girls belonging to different Indian tribes with varied socio-sexual lifestyle.

BACKGROUND: Despite high prevalence of human papillomavirus (HPV) infection and cervical cancer in Indian women, no study has been done in tribal populations whose socio-sexual lifestyle is different. Therefore, HPV screening has been carried out in pre-adolescent, adolescent and young adult tribal girls using self-collected urine samples. METHODS: 20-35 ml self-collected midstream urine samples were obtained from a total of 2278 healthy tribal girls (9-25 years) comprising pre-adolescent, adolescent and young adults from three Indian states: Madhya Pradesh, Jharkhand and Chhattisgarh. ß-globin positive 2034 samples were employed for HPV detection and genotyping. RESULTS: The overall prevalence of HPV infection in tribal girls was 12.9% (262/2034). More than 65% (172/262) of them were infected with HR-HPV types of which HPV16 was the most predominant type (54%). Young adult girls aged 18-25 years showed a significantly higher prevalence of HPV infection (19.2%; OR = 3.36; 95% CI 2.97-6.34, P<0.001) as compared to that in adolescent (11.4%; OR = 1.82; 95% CI 1.20-2.76, P<0.01) or pre-adolescent girls (6.6%). CONCLUSION: This is a first study showing significantly a very high prevalence of HPV infection in adolescent and young adult tribal girls possibly due to different socio-sexual behavior, indicating a serious health concern for Indian tribal women.

Potential impact of a 9-valent HPV vaccine in HPV-related cervical disease in 4 emerging countries (Brazil, Mexico, India and China).

BACKGROUND: We estimated the potential impact of an investigational 9-valent human papillomavirus (HPV) vaccine (HPVs 6/11/16/18/31/33/45/52/58) in HPV-related cervical disease in Brazil, Mexico, India and China, to help to formulate recommendations on cervical cancer prevention and control. METHODS: Estimations for invasive cervical cancer (ICC) were based on an international study including 1356 HPV-positive cases for the four countries altogether, and estimations for precancerous cervical lesions were extracted from a published meta-analysis including 6 025 HPV-positive women from the four mentioned countries. Globocan 2012 and 2012 World Population Prospects were used to estimate current and future projections of new ICC cases. RESULTS: Combined proportions of the 9 HPV types in ICC were 88.6% (95%CI: 85.2-91.3) in Brazil, 85.7% (82.3-88.8) in Mexico, 92.2% (87.9-95.3) in India and 97.3% (93.9-99.1) in China. The additional HPV 31/33/45/52/58 proportions were 18.8% (15.3-22.7) in Brazil, 17.6% (14.2-21.2) in Mexico, 11.3% (7.5-16.1) in India and 11.9% (7.5-17.2) in China. HPV6 and 11 single types were not identified in any of the samples. Proportion of the individual 7 high risk HPV types included in the vaccine varied by cytological and histological grades of HPV-positive precancerous cervical lesions. HPV 16 was the dominant type in all lesions, with contributions in low grade lesions ranging from 16.6%(14.3-19.2) in Mexico to 39.8% (30.0-50.2) in India, and contributions in high grade lesions ranging from 43.8% (36.3-51.4) in Mexico to 64.1% (60.6-67.5) in Brazil. After HPV 16, variations in other majors HPV types were observed by country, with an under representation of HPV 18 and 45 compared to ICC. CONCLUSION: The addition of HPVs 31/33/45/52/58 to HPV types included in current vaccines could increase the ICC preventable fraction in a range of 12 to 19% across the four countries, accounting the 9-types altogether 90% of ICC cases. Assuming the same degree of efficacy of current vaccines, the implementation of the 9-valent HPV vaccine in Brazil, Mexico, India and China would substantially impact on the reduction of the world cervical cancer burden.

A head-to-head comparison of the postprandial effects of 3 meal replacement beverages among people with type 2 diabetes.

PURPOSE: The purpose of this study was to compare the effects of 3 meal replacement beverages on glycemic response among people with type 2 diabetes. METHODS: The study examined Glucerna Weight Loss Shake, Slim-Fast Shake, and Ensure with Fiber Shake, using a prospective, 3-way, cross-over design. Eighteen subjects with type 2 diabetes drank the beverages in random order on different weeks. The volume of each beverage was adjusted to include 50 grams of carbohydrates. Glucose was measured 0 to 180 minutes postprandial. Analyses included 2-factor analysis of variance (ANOVA) for repeated measures on both factors, calculation of area under the curve (AUC), and 1-way repeated measures ANOVA of AUC. RESULTS: The postprandial glucose profiles of the shakes differed. Glucerna had the best profile as indicated by the graph of mean postprandial glucose levels and its lower incremental AUC. Despite the superiority of Glucerna, 2-hour postprandial blood glucose values exceeded the ADA's recommended upper limit for 22% of the subjects. CONCLUSIONS: Meal replacement beverages are a popular and potentially effective option for people trying to lose or maintain weight; however, it is unknown to what degrees they affect postprandial blood glucose in people with type 2 diabetes. Because postprandial glycemic excursion is linked to cardiovascular disease, identifying a meal replacement beverage with the lowest glycemic response may mitigate some of the risks in patients with diabetes. Of the meal replacements observed in this study, Glucerna had the smallest effect on postprandial glucose. Glycemic response to meal replacements should be monitored given product and individual variability.

Assessment of Toxicity of Some Penta- and Hexacoordinated Organotin(IV) and Tetracoordinated Tin(II) Complexes of Heterocyclic beta-Diketones.

A number of penta- and hexacoordinated organotin(IV) complexes and tetracoordinated tin(II) complexes of compositions Me2SnCl[RCOC:CON(C6H5)N:CCH3] (where R = - CH(3), -p-ClC(6)H(4), and -C(6)H(5)), Me2Sn[RCOC:CON(C6H5)N:CCH3]2 (where R = -CH(3), and -C(6)H(5)), and Sn(II) [RCOC:CON(C6H5)N:CCH3]2 (where R = -p-ClC(6)H(4) and -C(6)H(5)) were screened for their toxicity against Musca domestica (house fly). In general, organotin(IV) complexes contribute more to the activity than tin(II) complexes.

Does homeopathy reduce the cost of conventional drug prescribing? A study of comparative prescribing costs in general practice.

There is little research on cost-effectiveness of homeopathy in General Practice. This study aimed to compare the costs of homeopathic prescribing with conventional drugs prescribing. Data were collected for 4 years on all patients who were treated homeopathically. Costs of homeopathic remedies and costs of conventional drugs which otherwise would be prescribed for these patients was calculated for the total duration of treatment. Savings were calculated. One hundred patients were included in the study. Average cost savings per patient was pounds 60.40. The majority of patients had improved and most did not report any side-effects. The limitations of this study are that it is based on one GP's work, with a small number of patients so definite and generalisable conclusions cannot be drawn. Moreover, calculated costs in this study are based on drugs only, it does not take into account doctor's time, special investigations and time off sick. Future work needs to be carried out to include all of these points for a comprehensive economic analysis.