Anne Thomas

PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans

Ichthyoses comprise a heterogeneous group of genodermatoses characterized by abnormal desquamation over the whole body, for which the genetic causes of several human forms remain unknown. We used a spontaneous dog model in the golden retriever breed, which is affected by a lamellar ichthyosis resembling human autosomal recessive congenital ichthyoses (ARCI), to carry out a genome-wide association study. We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs. We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families. Further experiments highlighted the importance of PNPLA1 in the formation of the epidermal lipid barrier. This study identifies a new gene involved in human ichthyoses and provides insights into the localization and function of this yet uncharacterized member of the PNPLA protein family.

Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate in the First Protease Inhibitor-Based Single-Tablet Regimen for Initial HIV-1 Therapy: A Randomized Phase 2 Study.

Objectives:To evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of the first protease inhibitor–based single-tablet regimen (STR) for initial treatment of HIV-1 infection. Methods:Antiretroviral therapy (ART)-naive adults with estimated glomerular filtration rate ≥70 mL/min were randomized 2:1 to receive the darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) STR (TAF: N = 103) or darunavir + cobicistat + emtricitabine/tenofovir disoproxil fumarate (TDF: N = 50) once daily with matched placebos for 48 weeks. Results:At week 24, viral suppression (HIV-1 RNA <50 copies/mL) rates were similar (TAF 74.8% vs. TDF 74.0%). At week 48, rates were TAF 76.7% vs. TDF 84.0%; the difference was driven by higher rate of discontinuations in TAF (6.8%) vs. TDF (2%). Among those with virologic failure, none developed resistance. Most adverse events were of mild/moderate severity. The mean change in serum creatinine from baseline at week 48 was 0.06 mg/dL (95% confidence interval: 0.04 to 0.08) for TAF vs. 0.09 mg/dL (95% confidence interval: 0.05 to 0.14) for TDF (P = 0.053). The % change in retinol binding protein/Cr ratio was +9 (TAF) vs. +54 (TDF), P = 0.003; the % change in urine &bgr;-2 microglobulin/Cr ratio was −42.0 (TAF) vs. +2.3 (TDF), P = 0.002. The % change in hip bone mineral density (BMD) was −0.84 (TAF) vs. −3.82 (TDF), P < 0.001 and in spine BMD was −1.57 (TAF) vs. −3.62 (TDF), P = 0.003. There were no fractures in either group. Conclusions:The TAF arm had significantly improved renal and bone safety parameters: less proteinuria and less change in hip and spine BMD, consistent with results from a similarly designed study of the elvitegravir/C/F/TAF STR. This D/C/F/TAF STR offers a promising option for initial HIV treatment, with the high barrier to resistance of darunavir, and the potential for improved long-term renal and bone safety with TAF.

Voluntary medical male circumcision: an HIV prevention priority for PEPFAR.

Abstract: As the science demonstrating strong evidence for voluntary medical male circumcision (VMMC) for HIV prevention has evolved, the Presidents Emergency Plan for AIDS Relief (PEPFAR) has collaborated with international agencies, donors, and partner country governments supporting VMMC programming. Mathematical models forecast that quickly reaching a large number of uncircumcised men with VMMC in strategically chosen populations may dramatically reduce community-level HIV incidence and save billions of dollars in HIV care and treatment costs. Because VMMC is a 1-time procedure that confers life-long partial protection against HIV, programs for adult men are vital short-term investments with long-term benefits. VMMC also provides a unique opportunity to reach boys and men with HIV testing and counseling services and referrals for other HIV services, including treatment. After formal recommendations by WHO in 2007, priority countries have pursued expansion of VMMC. More than 1 million males have received VMMC thus far, with the most notable successes coming from Kenyas Nyanza Province. However, a myriad of necessary cultural, political, and ethical considerations have moderated the pace of overall success. Because many millions more uncircumcised men would benefit from VMMC services now, US President Barack Obama committed PEPFAR to provide 4.7 million males with VMMC by 2014. Innovative circumcision methods—such as medical devices that remove the foreskin without injected anesthesia and/or sutures—are being rigorously evaluated. Incorporation of safe innovations into surgical VMMC programs may provide the opportunity to reach more men more quickly with services and dramatically reduce HIV incidence for all.

Voluntary Medical Male Circumcision: A Cross-Sectional Study Comparing Circumcision Self-Report and Physical Examination Findings in Lesotho

Background Overwhelming evidence, including three clinical trials, shows that male circumcision (MC) reduces the risk of HIV infection among men. However, data from recent Lesotho Demographic and Health Surveys do not demonstrate MC to be protective against HIV. These contradictory findings could partially be due to inaccurate self-reported MC status used to estimate MC prevalence. This study describes MC characteristics among men applying for Lesotho Defence Force recruitment and seeks to assess MC self-reported accuracy through comparison with physical-examination-based data. Methods and Findings During Lesotho Defence Force applicant screening in 2009, 241 (77%) of 312 men, aged 18–25 y, consented to a self-administered demographic and MC characteristic survey and physician-performed genital examination. The extent of foreskin removal was graded on a scale of 1 (no evidence of MC) to 4 (complete MC). MC was self-reported by 27% (n = 64/239) of participants. Of the 64 men self-reporting being circumcised, physical exam showed that 23% had no evidence of circumcision, 27% had partial circumcision, and 50% had complete circumcision. Of the MCs reportedly performed by a medical provider, 3% were Grade 1 and 73% were Grade 4. Of the MCs reportedly performed by traditional circumcisers, 41% were Grade 1, while 28% were Grade 4. Among participants self-reporting being circumcised, the odds of MC status misclassification were seven times higher among those reportedly circumcised by initiation school personnel (odds ratio = 7.22; 95% CI = 2.29–22.75). Conclusions Approximately 27% of participants self-reported being circumcised. However, only 50% of these men had complete MC as determined by a physical exam. Given this low MC self-report accuracy, countries scaling up voluntary medical MC (VMMC) should obtain physical-exam-based MC data to guide service delivery and cost estimates. HIV prevention messages promoting VMMC should provide comprehensive education regarding the definition of VMMC.

Environmental Effects on Compulsive Tail Chasing in Dogs

Obsessive Compulsive Disorder (OCD) is a neuropsychiatric disorder observed both in humans and animals. Examples of Canine Compulsive Disorder (CD) include excessive tail chasing (TC), light/shadow chasing and flank sucking. We performed a questionnaire survey to investigate the characteristics of compulsive (TC) and its possible associations with environmental correlates and personality in a pet population of 368 dogs from four dog breeds. We observed an early onset of TC at 3–6 months of age and a large variation in TC frequency in all breeds, with an overrepresentation of milder cases. Almost half of the TC dogs showed lowered responsiveness during bouts and displayed also other types of compulsions more often than the controls. Interestingly, dogs that received dietary supplements, especially vitamins and minerals, expressed less TC compared to dogs that did not receive any supplements. Neutered females had less TC, suggesting an influence of ovarian hormones on TC. Tail chasers were shyer and had separated earlier from their mothers than the controls. Finally, our genetic study did not find an association between TC and CDH2, a locus previously associated with the canine flank sucking compulsion. In conclusion, the early-onset and the variable nature of the repetitive behaviour, which is affected by environmental factors such as micronutrients, neutering and maternal care, share several similar components between canine and human compulsions and supports canine TC as a model for human OCD.

ADAMTS17 mutation associated with primary lens luxation is widespread among breeds

Primary lens luxation (PLL) is a well-recognized, painful and potentially blinding inherited ocular condition in dogs. We screened PLL-affected dogs of 30 different breeds, to identify those which carried a previously described c.1473+1 G>A mutation in ADAMTS17 that is associated with PLL in Miniature Bull terriers, Lancashire Heelers, and Jack Russell terriers. This ADAMTS17 mutation was identified in PLL-affected dogs from 14 additional breeds. PLL-affected dogs from some breeds (most notably the Shar pei and the Brittany spaniel) did not carry the G1473+1A ADAMTS17 mutation, indicating they must suffer from a genetically distinct form of the condition. We also estimated the frequency of this ADAMTS17 mutation in some of the breeds. Our findings indicate the mutation segregates in a large number of different breeds of dog, many of which are terriers or breeds with terrier co-ancestry, but some of which have more diverse origins. Our results also indicate that the mutation is present at high frequency within most of the breeds in which it segregates. In the miniature bull terrier breed estimates of mutation frequency ranged from 0.27 to 0.39, corresponding to 7.3-15.2% PLL-affected dogs in this breed. We also identified an increased risk of PLL associated with heterozygosity at ADAMTS17, suggesting that carriers carry a low risk of developing PLL.

Voluntary Medical Male Circumcision: Logistics, Commodities, and Waste Management Requirements for Scale-Up of Services

Dianna Edgil and colleagues evaluate the supply chain and waste management costs needed to deliver mobile medical male circumcision services to 152,000 men in Swaziland, finding that per-procedure costs almost double when these factors are taken into account.

Chlamydial Infection and Unplanned Pregnancy in Women With Ready Access to Health Care

OBJECTIVE To apply urine‐based ligase chain reaction for Chlamydia trachomatis (C. trachomatis) and Neisseria gonorrhoeae (N. gonorrhoeae) detection and standard urine‐based pregnancy testing for Navy‐enlisted women, and to compare the prevalence and epidemiologic correlates of these adverse reproductive outcomes. METHODS Participants were surveyed and urine was collected for pregnancy testing using standard laboratory methods and detection of C. trachomatis and N. gonorrhoeae infection by ligase chain reaction. Self‐administered surveys facilitated collection of demographics, sexual behavior, including contraceptive use, sexual partners, sexually transmitted disease, and pregnancy history. RESULTS Among 299 of 314 participants, the prevalence of chlamydial infection was 4.7% and of pregnancy was 9.7%, with 48.3% of the pregnancies unplanned. Chlamydia trachomatis infection was univariately associated with having a new sex partner within the last 6 months, more sexual partners, single marital status, condom use, drinking until passing out or vomiting in the past 30 days (alcohol misuse), and current pregnancy. Unplanned pregnancy was univariately associated with young age, single marital status, inconsistent condom use, having a new sex partner within the last 6 months, and more recent sexual partners. Among the pregnant women, four (13.8%) were infected with C. trachomatis. CONCLUSION The high rates of chlamydial infection and unplanned pregnancy found in this population of employed young women with ready access to health care and health education underscore the challenge of enhancing reproductive health via compliance with effective contraceptive and sexually transmitted disease prevention methods. This is a challenge that remains unmet.

A Mutation in the FAM83G Gene in Dogs with Hereditary Footpad Hyperkeratosis (HFH)

Hereditary footpad hyperkeratosis (HFH) represents a palmoplantar hyperkeratosis, which is inherited as a monogenic autosomal recessive trait in several dog breeds, such as e.g. Kromfohrländer and Irish Terriers. We performed genome-wide association studies (GWAS) in both breeds. In Kromfohrländer we obtained a single strong association signal on chromosome 5 (praw = 1.0×10−13) using 13 HFH cases and 29 controls. The association signal replicated in an independent cohort of Irish Terriers with 10 cases and 21 controls (praw = 6.9×10−10). The analysis of shared haplotypes among the combined Kromfohrländer and Irish Terrier cases defined a critical interval of 611 kb with 13 predicted genes. We re-sequenced the genome of one affected Kromfohrländer at 23.5× coverage. The comparison of the sequence data with 46 genomes of non-affected dogs from other breeds revealed a single private non-synonymous variant in the critical interval with respect to the reference genome assembly. The variant is a missense variant (c.155G>C) in the FAM83G gene encoding a protein with largely unknown function. It is predicted to change an evolutionary conserved arginine into a proline residue (p.R52P). We genotyped this variant in a larger cohort of dogs and found perfect association with the HFH phenotype. We further studied the clinical and histopathological alterations in the epidermis in vivo. Affected dogs show a moderate to severe orthokeratotic hyperplasia of the palmoplantar epidermis. Thus, our data provide the first evidence that FAM83G has an essential role for maintaining the integrity of the palmoplantar epidermis.

Multiple Loci Are Associated with Dilated Cardiomyopathy in Irish Wolfhounds

Dilated cardiomyopathy (DCM) is a highly prevalent and often lethal disease in Irish wolfhounds. Complex segregation analysis indicated different loci involved in pathogenesis. Linear fixed and mixed models were used for the genome-wide association study. Using 106 DCM cases and 84 controls we identified one SNP significantly associated with DCM on CFA37 and five SNPs suggestively associated with DCM on CFA1, 10, 15, 21 and 17. On CFA37 MOGAT1 and ACSL3 two enzymes of the lipid metabolism were located near the identified SNP.