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Littoral cell angiomas are uncommon primary splenic haemangiomas with rare malignant potential. We report a case of a 76-year-old male with an incidental solitary littoral cell angioma found within an accessory spleen. We provide an overview of the literature of littoral cell angiomas and highlight the diagnostic challenge and treatment of this important differential for general surgeons caring for patients with splenic masses. This is the first case to describe primary resection of a littoral cell angioma with splenic preservation., Competing Interests: The authors declare that they have no conflicts of interest to disclose regarding the research presented in this article., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2023.)

First Nation people residing in rural and remote communities have limited primary healthcare access, which often affects chronic disease management leading to poor health outcomes. Individuals with lived experiences of chronic disease and substance use, along with health directors, advocated for improved services. Subsequently, an urban healthcare team in partnership with four First Nation communities developed an Outreach clinic to address healthcare access barriers. Established in 2016, this community-led clinic improves primary care access and chronic disease management in First Nation communities. Employing a qualitative research design, interviews were conducted with 15 clinic providers and 9 community members to explore the clinic's 1-year post-implementation impacts. Thematic data analysis indicated that engagement and approval by community leadership, support from Elders and community members and collaboration with existing community healthcare staff were crucial for establishing the Outreach clinic. Initial logistical challenges with space allocation, equipment, medical supplies, funding, staffing, medical records and appointment scheduling were resolved through community consultation and creative solutions. A nurse coordinator ensured continuity of care and was integral to ensuring clients receive seamless care. The commitment of the outreach team and the collective goal of providing client-centered care were instrumental in the clinic's success. In partnership with communities, access to healthcare in First Nation communities can be enhanced by coordinating Outreach clinics through existing community healthcare facilities., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Despite high prevalence of hepatitis C virus (HCV), linkage to care and treatment for Indigenous people is low. In an Indigenous community in Saskatchewan, Canada a retrospective review identified 200 individuals (∼12% prevalence) had HCV antibodies though majority lacked ribonucleic acid (RNA) testing, and few received treatment despite availability of an effective cure. Following Indigenous oral traditions, focus group discussions were held with key community members and leadership. Participants emphasized the need for a community-based screening and treatment programme. A team of community members, peers and healthcare professionals developed a streamlined screening pathway termed 'liver health event' (LHE) to reduce stigma, reach undiagnosed, re-engage previously diagnosed, and ensure rapid linkage to care/treatment. LHEs began December 2016. Statistics were tracked for each event. As of July 2019, there were 10 LHEs with 540 participants, 227 hepatitis C tests and 346 FibroScans completed. This represented 294 unique individuals, of which 64.3% were tested, and of those, 40.8% were Ab positive. Among those positive for antibodies, 41.7% had active hepatitis C infections, and among these, 90% were linked to care, and 14 new positive individuals were identified. Following the success of LHEs, these were adapted and implemented in 10 other communities in this region, resulting in 17 additional LHEs. This intervention is reaching the undiagnosed and linking clients to care through a low-barrier and de-stigmatizing approach. It has facilitated collaboration, knowledge exchange and mentorship between Indigenous communities, significantly impacting health outcomes of Indigenous people in this region., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Internationally, increasing numbers of children and adolescents with gender dysphoria are presenting for care. In response, gender-affirming therapeutic interventions that seek to align bodily characteristics with an individual's gender identity are more commonly being used. Depending on a young person's circumstances and goals, hormonal interventions may aim to achieve full pubertal suppression, modulation of endogenous pubertal sex hormone effects, and/or development of secondary sex characteristics congruent with their affirmed gender. This is a relatively novel therapeutic area and, although short-term outcomes are encouraging, longer term data from prospective longitudinal adolescent cohorts are still lacking, which may create clinical and ethical decision-making challenges. Here, we review current treatment options, reported outcomes, and clinical challenges in the pharmacological management of trans and gender-diverse adolescents., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Alveolar echinococcosis (AE) is a life-threatening parasitic disease caused by the zoonotic cestode Echinococcus multilocularis. Our goals were to confirm infection, identify species, and analyze biogeographical origin of metacestode tissues from a suspected human AE case in Saskatchewan, Canada. We conducted polymerase chain reaction (PCR) targeting the nad1 mitochondrial gene for E. multilocularis and the rrnS ribosomal RNA gene for E. granulosus and conducted haplotype analysis at the nad2 locus. Our analysis confirmed AE and indicated that sequences matched infected Saskatchewan coyotes and European E3/E4 haplotypes. The patient had no travel history outside North America. This suggests autochthonous transmission of a European-type strain., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: Enzyme replacement therapies (ERTs) are expensive drugs that can be used to treat certain inherited diseases. ERTs are not universally covered across provinces and costs are beyond the means of most patients. Media reports are commonly used to lobby for provincial ERT funding for specific patients. As physicians may be confronted with these media reports by patients, this study explored medical reporting regarding ERTs in print media., Methods: Canadian Newsstream database was searched for articles about three ERTs-Elaprase™, Naglazyme™ and Vimizim™. Articles meeting inclusion criteria were reviewed for data regarding efficacy and adverse events, mention of role of health care professionals and medical information sources. Thematic analysis explored how efficacy was described within the articles. Data from product monographs and recent meta-analyses served as a basis for comparison., Results: Of 57 articles retained for the study, 9% mentioned clinical trial data regarding drug efficacy; 7% mentioned adverse events. Only 23% of opinions about medical necessity or efficacy of the drug were from a physician. The majority were those of politicians. Information describing the condition was accurate in 90% of cases, although usually incompletely., Discussion: Incomplete or inaccurate reporting about efficacy and safety may influence families that appear to be candidates for ERT. Poor reporting of medical information may also influence the social pressures placed on the government and affect funding approval for these drugs. Physicians should be aware that their patients may be exposed to misleading information.

Introduction: A quadrivalent human papillomavirus vaccination program targeting females aged 12-13 years commenced in Australia in 2007, with catch-up vaccination of 14-26 year olds through 2009. We evaluated the program's impact on HPV prevalence among women aged 18-35 in 2015., Methods: HPV prevalence among women aged 18-24 and 25-35 was compared with prevalence in these age groups in 2005-2007. For women aged 18-24, we also compared prevalence with that in a postvaccine study conducted in 2010-2012., Results: For the 2015 sample, Vaccination Register-confirmed 3-dose coverage was 53.3% (65.0% and 40.3% aged 18-24 and 25-35, respectively). Prevalence of vaccine HPV types decreased from 22.7% (2005-2007) and 7.3% (2010-2012), to 1.5% (2015) (P trend < .001) among women aged 18-24, and from 11.8% (2005-2007) to 1.1% (2015) (P = .001) among those aged 25-35., Conclusions: This study, reporting the longest surveillance follow-up to date, shows prevalence of vaccine-targeted HPV types has continued to decline among young women. A substantial fall also occurred in women aged 25-35, despite lower coverage. Strong herd protection and effectiveness of less than 3 vaccine doses likely contributed to these reductions.

Understanding the processes and the factors influencing intersectoral collaboration is vital for the ongoing success of programmes that rely on effective partnerships between sectors, such as the school-based immunization programme, the school dental health programme and health promotion interventions delivered in school settings. We studied school-based health programmes delivered by partnerships between health, education and the local government sectors. We used purposive sampling to identify 19 people working in school-based health programmes and interviewed them about the barriers and enablers of successful collaboration. Data were analysed thematically. We found that collaboration between complex systems was a skilled endeavour which relied on a strong foundation of communication and interpersonal professional relationships. Understanding the core business, operational context and intersectoral point-of-view of collaborative partners was important both for establishing good intersectoral programmes and sustaining them as contexts and personnel changed. Aligning divergent sectoral agendas early in the collaborative process was essential for ensuring that all partners could meet their core business needs while also delivering the programme outcomes., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Current HPV vaccines do not protect against all oncogenic HPV types. Following vaccination, type replacement may occur, especially if different HPV types competitively interact during natural infection. Because of their common route of transmission, it is difficult to assess type interactions in observational studies. Our aim was to evaluate type replacement in the setting of HPV vaccine randomized controlled trials (RCTs)., Methods: Data were pooled from the Costa Rica Vaccine Trial (CVT; NCT00128661) and PATRICIA trial (NCT001226810)-two large-scale, double-blind RCTs of the HPV-16/18 AS04-adjuvanted vaccine-to compare cumulative incidence of nonprotected HPV infections across trial arms after four years. Negative rate difference estimates (rate in control minus vaccine arm) were interpreted as evidence of replacement if the associated 95% confidence interval excluded zero. All statistical tests were two-sided., Results: After applying relevant exclusion criteria, 21 596 women were included in our analysis (HPV arm = 10 750; control arm = 10 846). Incidence rates (per 1000 infection-years) were lower in the HPV arm than in the control arm for grouped nonprotected oncogenic types (rate difference = 1.6, 95% confidence interval [CI] = 0.9 to 2.3) and oncogenic/nononcogenic types (rate difference = 0.2, 95% CI = -0.3 to 0.7). Focusing on individual HPV types separately, no deleterious effect was observed. In contrast, a statistically significant protective effect (positive rate difference and 95% CI excluded zero) was observed against oncogenic HPV types 35, 52, 58, and 68/73, as well as nononcogenic types 6 and 70., Conclusion: HPV type replacement does not occur among vaccinated individuals within four years and is unlikely to occur in vaccinated populations., (Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.)

Background: Liver diseases progress faster in human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected persons than HIV-monoinfected persons. The aim of this study was to compare rates of liver fibrosis progression (measured by the aspartate-to-platelet ratio index [APRI]) among HIV-HCV-coinfected users of modern protease inhibitor (PI)- and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens with a backbone of tenofovir/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC)., Methods: Data from a Canadian multicenter cohort study were analyzed, including 315 HCV polymerase chain reaction-positive persons who initiated antiretroviral therapy with a PI or NNRTI and a backbone containing either TDF/FTC or ABC/3TC. Multivariate linear regression analyses with generalized estimating equations were performed after propensity score matching to balance covariates across classes of anchor agent., Results: A backbone of TDF/FTC was received by 67% of PI users and 69% of NNRTI users. Both PI and NNRTI use was associated with increases in APRI over time when paired with a backbone of ABC/3TC: 16% per 5 years (95% confidence interval [CI], 4%, 29%) and 11% per 5 years (95% CI, 2%, 20%), respectively. With TDF/FTC use, no clear association was found among PI users (8% per 5 years, 95% CI, -3%, 19%) or NNRTI users (3% per 5 years, 95% CI, -7%, 12%)., Conclusions: Liver fibrosis progression was more influenced by the backbone than by the class of anchor agent in HIV-HCV-coinfected persons. Only ABC/3TC-containing regimens were associated with an increase of APRI score over time, regardless of the class of anchor agent used., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: We examined risk of newly detected human papillomavirus (HPV) infection and cervical abnormalities in relation to HPV type 16/18 antibody levels at enrollment in PATRICIA (Papilloma Trial Against Cancer in Young Adults; NCT00122681)., Methods: Using Poisson regression, we compared risk of newly detected infection and cervical abnormalities associated with HPV-16/18 between seronegative vs seropositive women (15-25 years) in the control arm (DNA negative at baseline for the corresponding HPV type [HPV-16: n = 8193; HPV-18: n = 8463])., Results: High titers of naturally acquired HPV-16 antibodies and/or linear trend for increasing antibody levels were significantly associated with lower risk of incident and persistent infection, atypical squamous cells of undetermined significance or greater (ASCUS+), and cervical intraepithelial neoplasia grades 1/2 or greater (CIN1+, CIN2+). For HPV-18, although seropositivity was associated with lower risk of ASCUS+ and CIN1+, no association between naturally acquired antibodies and infection was demonstrated. Naturally acquired HPV-16 antibody levels of 371 (95% confidence interval [CI], 242-794), 204 (95% CI, 129-480), and 480 (95% CI, 250-5756) EU/mL were associated with 90% reduction of incident infection, 6-month persistent infection, and ASCUS+, respectively., Conclusions: Naturally acquired antibodies to HPV-16, and to a lesser extent HPV-18, are associated with some reduced risk of subsequent infection and cervical abnormalities associated with the same HPV type., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Epithelioid hemangioendotheliomas are rare vascular tumors, often arising from medium to large veins in the extremities. Symptoms of these tumors vary depending upon location. Rarely, tumors may arise in chest and involve large vessels in the mediastinum. We present a case of a 17-year-old male presenting with compressive symptoms of the left upper extremity who was found to have a large epithelioid hemangioendothelioma encasing the left brachiocephalic vein., (Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author 2014.)

Background: Public Health England has reported a decrease of up to 20.8% in new diagnoses of external genital warts (GWs) among women aged <19 years since the national vaccination program with the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine began in 2008. A post hoc analysis of the phase III PATRICIA (PApilloma TRIal against Cancer In young Adults) trial (NCT00122681) was performed to ascertain whether protection against low-risk HPV types was apparent., Methods: Vaccine efficacy (VE) at 48 months was assessed against 6-month persistent infection (6MPI) with low-risk HPV types in the total vaccinated cohort (TVC) and in the TVC naive (for 25 HPV types tested) populations., Results: In the TVC naive cohort, VE against 6MPI (95% confidence interval) was 34.5% (11.3 to 51.8) for HPV-6/11, 34.9% (9.1 to 53.7) for HPV-6, 30.3% (-45.0 to 67.5) for HPV-11, and 49.5% (21.0 to 68.3) for HPV-74., Conclusions: The HPV-16/18 AS04-adjuvanted vaccine appears to have moderate efficacy against persistent infections with a number of low-risk HPV types (HPV-6/11/74), which are responsible for the majority of external GWs, and recently, antibody and cell-mediated immune response to HPV-6/11 have been observed. These findings may help to explain the decrease in external GW diagnoses seen in England.

Background: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection., Methods: In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort., Results: A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9 × 10(-4)). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05-2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16-1.96), diabetes (OR = 1.66; 95% CI, 1.10-2.49), ≥ 1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06-1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD., Conclusions: In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.

Background: In April 2007, Australia became the first country to introduce a national government-funded human papillomavirus (HPV) vaccination program. We evaluated the program's impact on genotype-specific HPV infection prevalence through a repeat survey of women attending clinical services., Methods: HPV genoprevalence in women aged 18-24 years attending family planning clinics in the prevaccine period (2005-2007) was compared with prevalence among women of the same age group in the postvaccine period (2010-2011). The same recruitment and testing strategies were utilized for both sets of samples, and comparisons were adjusted for potentially confounding variables., Results: The prevalence of vaccine HPV genotypes (6, 11, 16, and 18) was significantly lower in the postvaccine sample than in the prevaccine sample (6.7% vs 28.7%; P < .001), with lower prevalence observed in both vaccinated and unvaccinated women compared with the prevaccine population (5.0% [adjusted odds ratio, 0.11; 95% confidence interval, 0.06-0.21] and 15.8% [adjusted odds ratio, 0.42; 95% confidence interval, 0.19-0.93], respectively). A slightly lower prevalence of nonvaccine oncogenic HPV genotypes was also found in vaccinated women (30.8% vs 37.6%; adjusted odds ratio, 0.68; 95% confidence interval, 0.46-0.99)., Conclusions: Four years after the commencement of the Australian HPV vaccination program, a substantial decrease in vaccine-targeted genotypes is evident and should, in time, translate into reductions in HPV-related lesions.

Blastomyces dermatitidis, a thermally dimorphic fungus endemic to areas of North America, causes a granulomatous infection which may affect any organ system. Since limited clinical data exist about pediatric blastomycosis, we conducted a retrospective review of medical records of pediatric patients with a laboratory-confirmed diagnosis of blastomycosis treated during a 30-year period at a tertiary care center. Thirty-four pediatric patients with blastomycosis were identified (20 [59%] male), with a mean age at diagnosis of 10 ± 5 years. Two patients were immunocompromised. Pulmonary disease was noted in 27 (79%) patients, and extrapulmonary disease was found in 13 (38%) patients (concurrent pulmonary and extrapulmonary disease, six patients), including five cases of central nervous system (CNS) disease. Delay in diagnosis was greater with extrapulmonary or central nervous system infections as compared with pulmonary blastomycosis. All patients received antifungal chemotherapy, with 19 (56%) patients receiving amphotericin B as initial therapy for 27.5 ± 17 days. Five patients required treatment in the intensive care unit. One patient died of non-Hodgkins lymphoma. Blastomycosis may occur in healthy children, including very young infants. Due to the frequency of extra-pulmonary disease, diagnosis may be difficult and frequently delayed, especially in cases of CNS infection., (© 2011 ISHAM)

Background: To understand the concurrent effects of human immunodeficiency virus (HIV) infection, the immune system, and antiretroviral therapy on body composition alterations, we examined annualized composition changes in HIV-infected adults who were receiving stable antiretroviral therapy., Methods: With use of data from the Nutrition For Healthy Living Study, we performed multivariate analyses using longitudinal models to evaluate the relationship of CD4+ cell count, viral load, and highly active antiretroviral therapy (HAART) or antiretroviral therapy (ART) with changes in trunk and extremity composition for 110 men and 42 women who provided data relating to 194 study intervals (i.e., intervals of time between 2 assessment visits). Of these intervals, 165 involved HAART use (89.7% involved protease inhibitor-based regimens), and 29 did not involve HAART use. Patients receiving HAART or ART (who had continuous use during the interval) were compared with HAART- or ART-naive subjects., Results: The median length of intervals between visits was 12.9 months (interquartile range, 12.1-17.6 months). In models adjusted for HAART or ART use, baseline CD4+ cell count was positively associated with increased trunk fat (mean increase per year, 2.3% per 100 cells/mm3; 95% confidence interval [CI], 0.7%-3.9%]) and, in men, with increased extremity fat (mean increase per year, 1.8% per 100 cells/mm3; 95% CI, 0.6%-3.0%). Increase in CD4+ cell count predicted increased extremity lean mass (mean increase per year, 0.6% per 100 cells/mm3; 95% CI, 0.05%-1.1%). Higher baseline viral load predicted fat loss (trunk fat loss per year, -5.0% per log10 copies/mL; 95% CI, -9.4% to -0.7%; extremity fat loss per year, -3.4% per log10 copies/mL; 95% CI, -6.1% to -0.6%), as did zidovudine use (trunk fat loss per year, -10.8%; 95% CI, -20.4% to -1.4%; extremity fat loss per year, -4.9%; 95% CI, -9.8% to -0.01%). HAART use independently predicted decreased bone mineral content (extremity bone mineral content loss per year, -1.6%; 95% CI, -3.1% to -0.08%) but did not predict changes in fat or lean mass. Receipt of protease inhibitor-based HAART predicted a -1.9% decrease in extremity bone mineral content per year (95% CI, -3.6% to -0.2%), and zidovudine use predicted a -2.6% decrease in trunk bone mineral content per year (95% CI, -4.4% to -0.8%)., Conclusions: Baseline viral load, CD4+ cell count, and change in CD4+ cell count predicted alterations in trunk fat, extremity fat, and lean mass. HAART use and zidovudine use were associated with bone loss, and zidovudine use was associated with fat loss, but HAART use was not associated with fat mass changes.

Background: At present, no uniform definition of human immunodeficiency virus (HIV)-associated lipoatrophy exists. The risk factors for fat atrophy (FA) and central fat deposition (FD) are multifactorial. We assessed the evolution and predictors of FA and FD in HIV-infected men and women., Methods: Participants (n = 452) were evaluated at baseline (starting in November 1998) and 1 year later. FA was defined as triceps skin-fold measurement less than the 10th percentile on the National Health and Nutrition Examination Survey for sex and age. FD was defined as a waist-to-hip ratio of > 0.95 for men and of > 0.85 for women. Predictors of the baseline prevalence of FA and FD and new cases of each syndrome after 1 year were determined., Results: The baseline prevalences of FA, FD, and combined FA and FD were 35%, 44%, and 14%, respectively. Twenty-two percent of subjects had newly developed FA at 1 year, and 16% of subjects with FA at baseline did not have it at 1 year. Also, 23% of subjects had newly developed FD at 1 year, and 15% of those with FD at baseline did not have it at 1 year. The risk of developing new FA was increased among participants with low triceps skin-fold values (P < .001), smaller hips (P < .001), higher nadir HIV load (P = .006), abacavir use (P < .001), stavudine use (P < .001), and use of highly active antiretroviral therapy (P = .002). The risk of developing new FD was higher among women (P < .001) and among participants with greater body fat levels (P = .005) and higher triglyceride levels (P < .001), and it was lower among those with a high school education (P = .003) and higher triceps skin-fold values (P = .026)., Conclusions: FA and FD are common in HIV-infected patients, but may change over time in the individual. FA and FD appear to be different syndromes, because risk factors for the development differ, and the prevalence of the combined syndrome differs from the prevalences of the 2 independent syndromes.

A lactosaminoglycan-associated antigen is associated with a carbohydrate moiety of all three zona pellucida (ZP) glycoproteins of pig and rabbit but is absent in the mouse and rat. A monoclonal antibody (PS1) recognizing this determinant was obtained by immunizing mice with a porcine ZP glycoprotein isoform purified by two-dimensional polyacrylamide gel electrophoresis. Conditions known to remove O-linked or sialic acid carbohydrate moieties (alkaline reduction; O-glycanase or neuraminidase enzymatic cleavage) did not remove the carbohydrate epitope. However, treatment with endo-beta-glycosidase, endoglycosidase F, or combinations of neuraminidase plus beta-galactosidase, totally removed the determinant, indicating that it is associated with a poly-N-acetyllactosaminoglycan structure present on an N-linked oligosaccharide. Molecular morphology studies using immunofluorescence and confocal microscopy techniques demonstrate that the PS1 antigen is localized at the surface of the ZP. Confirmation of this localization was obtained through studies that show that this antibody will inhibit homologous sperm binding to the pig ZP. Additional analyses using modular contrast microscopy and immunocytochemistry demonstrate that this carbohydrate-associated antigen is localized in discrete layers throughout the ZP matrix. These studies are the first to demonstrate the presence of a lactosaminoglycan type carbohydrate moiety in all three ZP proteins using a monoclonal antibody that appears to be involved in sperm recognition and structural organization.

Background: We have previously reported that severe glomerulosclerosis progressively develops in the streptozotocin (STZ) diabetic transgenic (mRen-2)27 rat. In this diabetic model, monotherapy with either angiotensin converting enzyme inhibition (ACEI) or angiotensin type 1 (AT(1)) receptor blockade is largely renoprotective. The objective of the present study was to determine if a combination therapy at lower doses than monotherapy would confer greater renoprotection., Methods: At 6 weeks of age, non-diabetic control and STZ diabetic female heterozygous Ren-2 rats were randomized to receive vehicle, the AT(1) receptor blocker valsartan (V, 20 mg/kg/day), the ACEI perindopril (P, 6 mg/kg/day), or a combination of low-dose V+P (V, 3 mg/kg/day plus P, 0.5 mg/kg/day) for 12 weeks., Results: Systolic blood pressure was lowered with all treatments, but the greatest reductions were observed with V monotherapy and combination V+P therapy. All treatments reduced albuminuria, the decline in glomerular filtration rate, and cortical collagen staining, to the same extent. The glomerulosclerotic index was increased with diabetes and reduced with V and P monotherapy. However, the low-dose combination therapy was more effective than single therapy and reduced severe glomerulosclerosis to levels observed in non-diabetic controls., Conclusions: Monotherapy with either V or P reduced blood pressure and retarded the decline in renal function and glomerulosclerosis in the diabetic Ren-2 rat. Combination therapy has the additional benefit of requiring only low doses of AT(1) receptor blockade and ACEI to achieve superior renoprotective effects in this diabetic nephropathy model.

Background: The optimal haemoglobin concentration ([Hb]) for patients with end-stage renal failure is uncertain. In particular, it is unclear whether Hb normalization may be an advantage to such patients who are otherwise well., Methods: A prospective, randomized, double-blind cross-over study was completed in 14 haemodialysis patients (12 male) aged between 23 and 65 years over a period of 18 months, using a variety of measures to examine the effect of epoetin at target [Hb] of 10 g/dl ([Hb](10)) and 14 g/dl ([Hb](14)). Patients were randomized to maintain one or other of the target levels for 6 weeks before being crossed over to the alternative [Hb]. Baseline data (mean [Hb]: 8.5+/-0.2 g/dl) were also included selectively. Six patients were known to be hypertensive. Comparisons were made between 24-h ambulatory blood pressure levels (ABP), echocardiographic findings and estimates of blood volume (BV), plasma volume (PV) and Hb mass. Quality of life estimates were obtained using the Sickness Impact Profile (SIP), and epoetin dosage requirements at target [Hb] were assessed., Results: Daytime and nocturnal ABP (systolic and diastolic) were not different at the respective target [Hb], although nocturnal diastolic levels were higher compared with baseline (73+/-4 mmHg) at both [Hb](10) (83+/-3, P:<0.01) and [Hb](14) (81+/-6, P:<0.05). Significant reductions in cardiac output (5.2+/-0.3 vs 6.6+/-0.5 l/min, P:<0.01) and left ventricular end-diastolic diameter (4.8+/-0.2 vs 5.2+/-0.2 cm, P:<0. 001) were found at [Hb](14) compared with [Hb](10). Left ventricular mass index was correlated with both PV (P:<0.001) and BV (P:<0.01), but not with Hb mass. The PV decreased as the [Hb] rose (P:<0.001) but BV remained unchanged. Quality of life was significantly improved at [Hb](14) compared with [Hb](10) for both total score (6. 5+/-1.7 vs 13.4+/-3.0, P:=0.01) and psychosocial dimension score (5. 4+/-1.9 vs 15.4+/-4.0, P:<0.01). The maintenance weekly dose of epoetin required was 80% higher at [Hb](14) compared with [Hb](10) (P:<0.001)., Conclusion: These data suggest there may be a significant haemodynamic and symptomatic advantage in maintaining a physiological [Hb] in haemodialysis patients. Although untoward effects were not identified in this study at [Hb](14), a substantially higher dose of epoetin is required to maintain this level.

Zona pellucida (ZP) glycoproteins contain numerous antigenic determinants including carbohydrate, protein, and conformational epitopes; and the immunogenicity of these complex glycoproteins varies in different mammalian hosts. Studies have now shown that antibodies from primates immunized with a cDNA-expressed recombinant rabbit ZP protein (the homologue of the human ZP1 [hZP1]) inhibit sperm binding to the ZP without altering ovarian function, unlike immunization with ZP3 and ZP2 protein families. The ZP1 protein or peptides derived from it (recombinant or synthetic) are therefore primary candidates for use in designing safe and reversible human and animal contraceptive vaccines. In order to define peptide epitope(s) that may be critical for eliciting an immune response sufficient to effect immunological contraception without causing any adverse effects on ovarian physiology, studies have been carried out to identify immunodominant B-cell epitopes of the ZP1 protein. The amino acid sequence of the hZP1 was used to design a set of 94 (15-mer) biotinylated peptides having an overlap of 9 amino acids. Using these peptides in a modified enzyme-linked immunoassay, antibodies in sera from rabbits or baboons immunized with native porcine ZP protein were screened for ZP1 peptide recognition. These studies demonstrate that there are a limited number of peptides recognized by primate antibodies but that the overlapping peptides sharing the sequence GPLTLELQI are recognized by both rabbit and baboon antibodies regardless of the adjuvant system used to induce the immune response. This peptide is 100% conserved in amino acid sequence between the human and pig, although the rabbit protein has two conserved amino acid substitutions (100% similar, 77% identical). Because this peptide is immunogenic as well as antigenic in primates, it could play a major role in the development of human contraceptive vaccines.

Background: To determine the effects of different haemoglobin (Hb) levels on exercise performance and associated electrolyte changes, a prospective, randomized, double-blinded crossover study was completed in 14 haemodialysis patients., Methods: Performance and changes in arterial [K+] and lactate were compared at rest and during a maximal incremental cycling exercise at a Hb concentration ([Hb]) of 10 g/dl ([Hb]10) and 14 g/dl ([Hb]14) following an initial baseline test (Hb: 8.3 +/- 0.2 g/dl, mean +/- SEM). Ages ranged from 23 to 65 years and patients were divided into younger (age 23-45 years, n = 9) and older (aged 55-65 years, n = 5) groups., Results: Peak work rate and VO2 peak were higher at [Hb]14 than at [Hb]10. 145 +/- 9 vs 134 +/- 9 W, mu +/- SEM, P < 0.01, and 1.90 +/- 0.11 vs 1.61 +/- 0.11 l/min, P < 0.01, respectively. Improvements were demonstrated in both younger and older groups at the higher target [Hb], with an improved aerobic performance evident particularly in younger patients. However, performance remained below that predicted for comparable sedentary controls. Resting plasma [K+] was raised at both [Hb]10 and [Hb]14 compared with baseline (P < 0.01) although the change in [K+] from rest to peak exercise (delta[K+]) was similar at each level. The delta[K+] per unit work performed (used as a marker of K+ regulation) was, however, inversely related to the [Hb] (baseline: 80 +/- 12 micromol/l/kJ vs [Hb]10, 61 +/- 8, P < 0.01, vs [Hb]14. 49 +/- 7, P < 0.05). Exercise induced a significant but similar rise in lactate concentration at both target [Hb] (P < 0.001), which remained markedly elevated for at least 10 min after exercise in both younger and older groups., Conclusions: These data demonstrate that a physiological [Hb] improves, but does not normalize, exercise performance in end-stage renal failure. Both younger and older patients appear to benefit similarly from the enhanced oxygen transport. Impaired K+ regulation is apparently related to [Hb] and could well contribute to the observed limitations in performance.

Background and Purpose: This study compared the effects of dynamic ankle-foot orthoses (DAFOs) with a plantar-flexion stop, polypropylene solid ankle-foot orthoses (AFOs), and no AFOs on the gait of children with cerebral palsy (CP). These orthoses were used to reduce the excessive ankle plantar flexion during the stance phase of gait., Subjects and Methods: Ten children with spastic CP (6 with diplegia and 4 with hemiplegia) were tested after wearing no AFOs for an initial 2-week period, solid AFOs for 1 month, no AFOs for an additional 2 weeks, and DAFOs for 1 month. The effects of the two orthoses and no AFOs on lower-extremity muscle timing, joint motions, and temporal-distance characteristics were compared., Results: Both orthoses increased stride length, decreased cadence, and reduced excessive ankle plantar flexion when compared with no orthoses. No differences were found for the gait variables when comparing the two orthoses., Conclusion and Discussion: Based on the data, the authors believe that although both orthoses would be recommended for children with spastic CP and excessive ankle plantar flexion during stance, additional individual factors should be considered when selecting either orthosis.

Insulin-like growth factor (IGF)-1, IGF binding protein (IGFBP)-2, and IGFBP-3 are expressed in the rat brain in regions of neuronal loss by 3 days after hypoxic- ischemic (HI) brain injury and IGF-2 somewhat later. Central administration of rh-IGF-1 after HI injury reduces neuronal loss in vivo. To clarify the mode of action of IGF-1 and the potential role of IGFBPs, the effects of IGF-1, IGF-2, des(1-3)-N-IGF-1 (des-IGF-1), an analogue of IGF-1 with low affinity for IGFBPs, and IGF-1 combined with IGF-2 were compared 2 h after administration into the lateral cerebral ventricle after an HI injury. Unilateral HI was induced in adult rats by right carotid artery ligation followed by 10- min exposure to 6%O2. The extent of neuronal loss was determined in the cortex, striatum, hippocampus, dentate gyrus, and thalamus 5 days later. Central administration of 20 micrograms IGF-1 (n = 17) reduced neuronal loss in all regions (P < 0.01). Neither 20 micrograms IGF-2 (n = 17), 2 micrograms des-IGF-1 (n = 10), nor 20 micrograms des-IGF-1 (n = 17) reduced neuronal loss. There was a trend towards a reduction in neuronal loss after 150 micrograms des-IGF-1 (n = 20). IGF-2 alone increased neuronal loss in the hippocampus and dentate gyrus compared with the same regions in vehicle-treated animals (P < 0.05). Coadministration of 30 micrograms IGF-2 blocked the neuroprotective effects of 20 micrograms IGF-1 (n = 18, P < 0.05) and reduced the accumulation of [3H]IGF-1 in the injured hemisphere (n = 4) (P < 0.05). These observations suggest a role for IGFBPs in targeting the neuroprotective actions of IGF-1. IGF-2 may antagonize the protective effect of IGF-1 by displacing it from IGFBPs.

Total renin protein concentration (TRC) was measured in stored follicular fluid (FF) samples from 42 women. Samples were selected according to their origin from follicles either without recovered ova ('empty', n = 38) or fertilized but with failed implantation ('failed', n = 36) or successful deliveries ('deliveries', n = 71). Ratios of number of embryos transferred to number of infants delivered were 2:1, 3:1 or 4:2 but 1:1 was not available. Non-parametric testing was applied to FF-TRC, volume and outcome. TRC was significantly higher in the delivery than the failed (P = 0.001) or empty (P = 0.002) categories. Assuming that the range of renin in failed follicles can identify the sub-population of unsuccessful follicles in the delivery category, then elevated FF-TRC was clearly associated with successful outcome. For individual women, the odds of infant delivery increased 17-fold as a function of average FF-TRC between 10,000 and 25,000 microIU/ml. For failed and delivery but not empty follicles, higher renin levels occurred in the smaller follicles, consistent with a burst of renin synthesis associated with the presence of an oocyte. The results suggest that FF-TRC relates to ovum viability with ovarian hyperstimulation and may have predictive use in IVF programmes.

A number of cytokines have been found to be potent regulators of bone resorption and to share the properties originally attributed to osteoclast-activating factor. One such activity, differentiation-inducing factor (DIF, D-factor) from mouse spleen cells, shares a number of biological and biochemical properties with the recently characterized and cloned leukemia inhibitory factor (LIF). We have assessed the effects of recombinant LIF on bone resorption and other parameters in neonatal mouse calvaria. Both recombinant murine and human (h) LIFs stimulated 45Ca release from prelabeled calvaria in a dose-dependent manner. The increase in bone resorption was associated with an increase in the number of osteoclasts per mm2 bone. The osteolytic effect of hLIF were blocked by 10(-7) M indomethacin. hLIF also stimulated incorporation of [3H] thymidine into calvaria, but the dose-response relationship was distinct from that for bone resorption, and this effect was not blocked by indomethacin. Similarly, hLIF increased [3H]phenylalanine incorporation into calvaria, and this was also not inhibited by indomethacin. It is concluded that LIF stimulates bone resorption by a mechanism involving prostaglandin production, but that a distinct mechanism is responsible for its stimulation of DNA and protein synthesis. The primary structure of LIF differs from that of other fully characterized, bone-active cytokines, and it, thus, represents a novel factor which may be involved in the normal regulation of bone cell function.

Biochemical and immunological characteristics of renin secreted by two malignant renin-secreting tumors [pulmonary (PT) and paraovarian (POT)] were studied. They both contain inactive renin (IR), as renin activity of tumoral extracts was able to be increased after acid activation or trypsin treatment (10.1 to 20.8 Goldblatt units/g tissue for PT and 1.4 to 3.71 for POT). Renin activity after activation reached the value obtained by direct RIA of human renin (23 and 3.4, respectively), as both forms are recognized by renin antiserum. Both enzymatic activities could be completely inhibited by renin antiserum. Displacement curves for the two tumoral renins paralleled the MRC renin in the direct RIA. After chromatography on affigel blue, active renin was not bound to the gel, and inactive renin eluted only with 1 M NaCl. On pepstatin A Sepharose and CBL-pepstatin Sepharose (an N-modified-pepstatin), a separation of the two forms of pulmonary renin was obtained; inactive renin eluted with breakthrough proteins, whereas active renin was strongly bound to the gel. After this affinity chromatography, the molecular weights of inactive and active renin, determined on Ultrogel, were very close (46,000 and 42,500). We conclude that 1) ectopic renin in these cases in similar to the renal enzyme; 2) renin can be secreted in an inactive form, supporting the hypothesis of an inactive initial state of renin; and 3) molecular weight differences between the two forms are very slight.

Changes in rabbit ovarian hormonal responses and cellular differentiation of ovarian follicles after immunization with porcine zona pellucida (ZP) have been examined. Steroid and peptide hormone levels were monitored after immunization to evaluate ovulation and pseudopregnancy cycles in immunized and control animals. All immunized rabbits developed serum antibodies to specific ZP antigens and failed to form functional corpora lutea in response to hCG administration, as evidenced by the absence of elevated serum progesterone concentrations. This is in contrast to control rabbits, which had elevated progesterone levels 8-9 days after hCG administration. Furthermore, all immunized animals showed greatly increased serum levels of FSH and LH compared to those of control animals. These effects on ovarian function were apparent within 20 weeks of the primary immunization. Follicular development was analyzed by light and electron microscopies. The numbers of primary, secondary, and tertiary follicles in ovaries of immunized animals were markedly reduced within 7 weeks compared with control values. By 23 weeks, few if any growing follicles were present. Although numerous distinct clusters of cells with ultrastructural properties that resemble those of normal follicular cells were present in immunized animals, they contained no oocytes. These studies suggest that antibodies to ZP glycoprotein alter ovarian function by interfering with cells during the stage of follicle differentiation at which the ZP proteins are being synthesized and secreted. This system should provide an excellent model with which to study the early events associated with ovarian follicular cell differentiation and subsequent hormonal responsiveness.

A 23-yr-old male student presented with clinical and biochemical evidence of Cushing's syndrome. One month later, his elevated plasma and urinary adrenal steroids had returned to normal. At surgery, an adrenal adenoma was removed from his right side. We postulate that he either underwent a temporary spontaneous remission of his disease without treatment, prior to surgery, or that his adenoma secreted glucocorticoids in a cyclical fashion.

An extrachromosomal factor, termed son-killer (sk), affects the sex ratio in a parasitoid wasp, Nasonia (=Mormoniella) vitripennis. The factor is maternally transmitted and alters the secondary sex ratio of an infected female through mortality of approximately 80% of the male embryos. No effect on the primary (zygotic) sex ratio is observed. Ninety-five percent of the daughters of an infected female inherit son-killer. The factor can also be transmitted contagiously when the progeny of infected and uninfected females develop simultaneously on a single host. In newly infected strains, the sex ratio effects are equivalent to those in the original.