Benign Uterine Neoplasm as a Cause of Prepubertal Bleeding.

BACKGROUND: Vaginal bleeding in the prepubertal child has several etiologies, including structural anomalies, endocrinologic dysfunction, infection, trauma, foreign body, and hematologic disorders. CASE: An 8-year-old premenarcheal girl presented with vaginal bleeding. On ultrasound, she was found to have an intramural hyperechogenic mass in the left uterine fundus. This was biopsied and showed smooth muscle. She was subsequently started on a GnRH agonist to suppress bleeding and has since been followed with serial ultrasounds. We have 6 years of follow-up imaging showing a presumed adenomyoma versus fibroid that has been stable in size. SUMMARY AND CONCLUSION: We present a novel case of adenomyosis presenting as prepubertal bleeding. Pelvic imaging is prudent to exclude structural etiologies as the cause of prepubertal vaginal bleeding.

Characteristics of a Diverse Cohort of Stroke Patients with SARS-CoV-2 and Outcome by Sex.

BACKGROUND AND PURPOSE: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is associated with stroke. The role of sex on stroke outcome has not been investigated. To objective of this paper is to describe the characteristics of a diverse cohort of acute stroke patients with COVID-19 disease and determine the role of sex on outcome. METHODS: This is a retrospective study of patients with acute stroke and SARS-CoV-2 infection admitted between March 15 to May 15, 2020 to one of the six participating comprehensive stroke centers. Baseline characteristics, stroke subtype, workup, treatment and outcome are presented as total number and percentage or median and interquartile range. Outcome at discharge was determined by the modified Rankin Scale Score (mRS). Variables and outcomes were compared for males and females using univariate and multivariate analysis. RESULTS: The study included 83 patients, 47% of which were Black, 28% Hispanics/Latinos, and 16% whites. Median age was 64 years. Approximately 89% had at least one preexisting vascular risk factor (VRF). The most common complications were respiratory failure (59%) and septic shock (34%). Compared with females, a higher proportion of males experienced severe SARS-CoV-2 symptoms requiring ICU hospitalization (73% vs. 49%; p = 0.04). When divided by stroke subtype, there were 77% ischemic, 19% intracerebral hemorrhage and 3% subarachnoid hemorrhage. The most common ischemic stroke etiologies were cryptogenic (39%) and cardioembolic (27%). Compared with females, males had higher mortality (38% vs. 13%; p = 0.02) and were less likely to be discharged home (12% vs. 33%; p = 0.04). After adjustment for age, race/ethnicity, and number of VRFs, mRS was higher in males than in females (OR = 1.47, 95% CI = 1.03-2.09). CONCLUSION: In this cohort of SARS-CoV-2 stroke patients, most had clinical evidence of coronavirus infection on admission and preexisting VRFs. Severe in-hospital complications and worse outcomes after ischemic strokes were higher in males, than females.

In-vitro effect of pembrolizumab on different T regulatory cell subsets.

Programmed death-1 (PD-1) and interactions with PD-ligand 1 (PD-L1) play critical roles in the tumour evasion of immune responses through different mechanisms, including inhibition of effector T cell proliferation, reducing cytotoxic activity, induction of apoptosis in tumour-infiltrating T cells and regulatory T cell (Treg ) expansion. Effective blockade of immune checkpoints can therefore potentially eliminate these detrimental effects. The aim of this study was to investigate the effect of anti-PD-1 antibody, pembrolizumab, on various Treg subpopulations. Peripheral blood mononuclear cells (PBMC) from healthy donors (HD) and primary breast cancer patients (PBC) were treated in vitro with pembrolizumab, which effectively reduced PD-1 expression in both cohorts. We found that PD-1 was expressed mainly on CD4+ CD25+ T cells and pembrolizumab had a greater effect on PD-1 expression in CD4+ CD25- T cells, compared to CD4+ CD25+ cells. In addition, pembrolizumab did not affect the expression levels of Treg -related markers, including cytotoxic T lymphocyte antigen-4 (CTLA-4), CD15s, latency-associated peptide (LAP) and Ki-67. Moreover, we report that CD15s is expressed mainly on forkhead box P3 (FoxP3)- Helios+ Treg in HD, but it is expressed on FoxP3+ Helios- Treg subset in addition to FoxP3- Helios+ Treg in PBC. Pembrolizumab did not affect the levels of FoxP3+/- Helios+/- Treg subsets in both cohorts. Taken together, our study suggests that pembrolizumab does not affect Treg or change their phenotype or function but rather blocks signalling via the PD-1/PD-L1 axis in activated T cells.

How often should shelf/Gellhorn pessaries be changed? A survey of IUGA urogynaecologists.

INTRODUCTION AND HYPOTHESIS: Gellhorn and shelf pessaries can be effective management for women with pelvic organ prolapse (POP). This study aimed to investigate the opinion of IUGA members about shelf/Gellhorn pessary use, and in particular, how often to change them in patients with POP. There are no evidence-based guidelines available on this subject. METHODS: Members of the International Urogynaecology Association (IUGA) and the British Society of Urogynaecology (BSUG) were sent a single electronic mailing of semi-structured questionnaires containing closed and open questions and free text response boxes. The internet-based survey consisted of 13 questions. Free text responses were analysed using a thematic qualitative analysis. RESULTS: A total of 322 respondents from the IUGA membership participated in the survey. Most consider shelf/Gellhorn pessaries an effective first-line treatment for their patients with POP. Self care is usually acceptable with ring pessaries, but with shelf/Gellhorn, 35 % would like to change them every 3 months, 31 % every 6 months and the rest varied. The routine use of oestrogens along with shelf/Gellhorn pessaries is a common practice. The risk of urogenital fistulae is well documented, but overall clinicians felt that shelf/Gellhorn pessaries are a safe and effective treatment for POP. CONCLUSIONS: This study highlights the wide variation in global practice of the management of shelf/Gellhorn pessaries for POP. In order to inform our practice, evidence-based guidelines are required. A randomised control trial may help to decide whether or not it is appropriate to change the shelf/Gellhorn pessaries at all.

Is anatomical failure following anterior vaginal repair associated with weak native vaginal tissues? A biomechanical and immunohistochemical study.

INTRODUCTION AND HYPOTHESIS: This study was performed to determine whether anatomical recurrence of cystocoele 1 year after anterior vaginal repair is related to biomechanical properties and/or the content of collagen in the vaginal wall and epithelial tissues. METHODS: In this prospective, observational study in a UK teaching hospital, we assessed women undergoing surgery for symptomatic anterior compartment prolapse. Outcome measures were anatomical recurrence, biomechanical strength and collagen content in vaginal tissues. In part one of the study, 42 women underwent biomechanical testing of full-thickness anterior vaginal wall tissue samples to determine the elastic moduli and yield stress. In part two, 59 women underwent immunohistochemical testing of anterior vaginal wall tissue samples to determine tissue content of procollagen I; collagen types I, III, V; and matrix metalloproteinases 1 and 2 (MMP-1 and 2). Results were then compared with anatomical outcome at 1 year postsurgery. RESULTS: Differences in yield strain in all outcome groups (optimal, satisfactory and unsatisfactory) were not statistically significant. Considerable variation was found in collagen type I in both satisfactory and unsatisfactory groups. There was no difference or correlation with procollagen, collagen types III and V, and MMP-1 and recurrence of pelvic organ prolapse (POP) between groups. There was a weak correlation between collagen type I and higher yield stress in both groups. CONCLUSIONS: Anatomical failure of anterior repair does not appear to be related to the biomechanical strength or collagen content of the anterior vaginal wall.

Expression of Id proteins is regulated by the Bcl-3 proto-oncogene in prostate cancer.

B-cell leukemia 3 (Bcl-3) is a member of the inhibitor of κB family, which regulates a wide range of biological processes by functioning as a transcriptional activator or as a repressor of target genes. As high levels of Bcl-3 expression and activation have been detected in different types of human cancer, Bcl-3 has been labeled a proto-oncogene. Our study uncovered a markedly upregulated Bcl-3 expression in human prostate cancer (PCa), where inflammatory cell infiltration was observed. Elevated Bcl-3 expression in PCa was dependent on the proinflammatory cytokine interleukin-6-mediated STAT3 activation. Microarray analyses, using Bcl-3 knockdown in PCa cells, identified the inhibitor of DNA-binding (Id) family of helix-loop-helix proteins as potential Bcl-3-regulated genes. Bcl-3 knockdown reduced the abundance of Id-1 and Id-2 proteins and boosted PCa cells to be more receptive to undergoing apoptosis following treatment with anticancer drug. Our data imply that inactivation of Bcl-3 may lead to sensitization of cancer cells to chemotherapeutic drug-induced apoptosis, thus suggesting a potential therapeutic strategy in PCa treatment.

Intraventricular hemorrhage: Anatomic relationships and clinical implications.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is frequently associated with intraventricular hemorrhage (IVH), which is an independent predictor of poor outcome. The purpose of this study was to examine the relationship between ICH volume and anatomic location to IVH, and to determine if ICH decompression into the ventricle is truly beneficial. METHODS: We retrospectively analyzed the CT scans and charts of all patients with ICH admitted to our stroke center over a 3-year period. Outcome data were collected using our prospective stroke registry. RESULTS: We identified 406 patients with ICH. A total of 45% had IVH. Thalamic and caudate locations had the highest IVH frequency (69% and 100%). ICH volume and ICH location were predictors of IVH (p < 0.001). Within each location, decompression ranges (specific volume ranges where ventricular rupture tends to occur) were established. Patients with IVH were twice as likely to have a poor outcome (discharge modified Rankin scale of 4 to 6) (OR 2.25, p = 0.001) when compared to patients without IVH. Caudate location was associated with a good outcome despite 100% incidence of IVH. Spontaneous ventricular decompression was not associated with better outcome, regardless of parenchymal volume reduction (p = 0.72). CONCLUSIONS: Intraventricular hemorrhage (IVH) occurs in nearly half of patients with spontaneous intracerebral hemorrhage (ICH) and is related to ICH volume and location. IVH is likely to occur within the "decompression ranges" that take into account both ICH location and volume. Further, spontaneous ventricular decompression does not translate to better clinical outcome. This information may prove useful for future ICH trials, and to the clinician communicating with patients and families.

Altered HIV-1 Gag protein interactions with cyclophilin A (CypA) on the acquisition of H219Q and H219P substitutions in the CypA binding loop.

HIV-1 Gag protein interaction with cyclophilin A (CypA) is critical for viral fitness. Among the amino acid substitutions identified in Gag noncleavage sites in HIV-1 variants resistant to protease inhibitors, H219Q (Gatanaga, H., Suzuki, Y., Tsang, H., Yoshimura, K., Kavlick, M. F., Nagashima, K., Gorelick, R. J., Mardy, S., Tang, C., Summers, M. F., and Mitsuya, H. (2002) J. Biol. Chem. 277, 5952-5961) and H219P substitutions in the viral CypA binding loop confer the greatest replication advantage to HIV-1. These substitutions represent polymorphic amino acid residues. We found that the replication advantage conferred by these substitutions was far greater in CypA-rich MT-2 and H9 cells than in Jurkat cells and peripheral blood mononuclear cells (PBM), both of which contained less CypA. High intracellular CypA content in H9 and MT-2 cells, resulting in excessive CypA levels in virions, limited wild-type HIV-1 (HIV-1(WT)) replication and H219Q introduction into HIV-1 (HIV-1(H219Q)), reduced CypA incorporation of HIV-1, and potentiated viral replication. H219Q introduction also restored the otherwise compromised replication of HIV-1(P222A) in PBM, although the CypA content in HIV-1(H219Q/P222A) was comparable with that in HIV-1(P222A), suggesting that H219Q affected the conformation of the CypA-binding motif, rendering HIV-1 replicative in a low CypA environment. Structural modeling analyses revealed that although hydrogen bonds are lost with H219Q and H219P substitutions, no significant distortion of the CypA binding loop of Gag occurred. The loop conformation of HIV-1(P222A) was found highly distorted, although H219Q introduction to HIV-1 restored the conformation of the loop close to that of HIV-1 (P222A). The present data suggested that the effect of CypA on HIV-1 replicative (WT) ability is bimodal (both high and low CypA content limits HIV-1 replication), that the conformation of the CypA binding region of Gag is important for viral fitness, and that the function of CypA is to maintain the conformation.

A potent human immunodeficiency virus type 1 protease inhibitor, UIC-94003 (TMC-126), and selection of a novel (A28S) mutation in the protease active site.

We identified UIC-94003, a nonpeptidic human immunodeficiency virus (HIV) protease inhibitor (PI), containing 3(R),3a(S),6a(R)-bis-tetrahydrofuranyl urethane (bis-THF) and a sulfonamide isostere, which is extremely potent against a wide spectrum of HIV (50% inhibitory concentration, 0.0003 to 0.0005 microM). UIC-94003 was also potent against multi-PI-resistant HIV-1 strains isolated from patients who had no response to any existing antiviral regimens after having received a variety of antiviral agents (50% inhibitory concentration, 0.0005 to 0.0055 microM). Upon selection of HIV-1 in the presence of UIC-94003, mutants carrying a novel active-site mutation, A28S, in the presence of L10F, M46I, I50V, A71V, and N88D appeared. Modeling analysis revealed that the close contact of UIC-94003 with the main chains of the protease active-site amino acids (Asp29 and Asp30) differed from that of other PIs and may be important for its potency and wide-spectrum activity against a variety of drug-resistant HIV-1 variants. Thus, introduction of inhibitor interactions with the main chains of key amino acids and seeking a unique inhibitor-enzyme contact profile should provide a framework for developing novel PIs for treating patients harboring multi-PI-resistant HIV-1.

Standards for growth in prepubertal primary school Kuwaiti children, a cross-sectional study.

In a cross-sectional study, anthropometric measurements were made in Kuwaiti primary school children aged six to nine years. The sample included 6765 children, of whom there were 3534 boys and 3231 girls. A minimum of 400 children were included in each of the 16 age-sex groups studied. Anthropometric data are presented as percentiles for weight-for-age, height-for-age, and weight-for-height. The results were smoothed and figures were constructed for the three growth standards. A comparison between locally constructed standards and a Western reference growth standard (Tanner et al.) revealed marked similarities in attainable growth. We think that the Western reference standards are suitable for use in Kuwait and probably in other similar developing countries, and the setting of lower targets for those countries is not recommended.