Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

Next‐generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co‐immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin‐488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway.     

Fumes from meat cooking and lung cancer risk in Chinese women.

Chinese women are recognized to have a high incidence of lung cancer despite a low smoking prevalence. Several studies have implicated domestic exposure to cooking fumes as a possible risk factor, although the exact carcinogens have yet to be identified. Heterocyclic amines are known carcinogens, which have been identified in cooked meat, and also in fumes generated during frying or grilling of meats. We conducted a case-control study of 303 Chinese women with pathologically confirmed, primary carcinomas of the lung and 765 controls to examine the association between exposure to meat cooking and lung cancer risk. Data on demographic background, smoking status, and domestic cooking exposure, including stir-frying of meat, were obtained by in-person interview while in hospital. The response rates among eligible cases and controls were 95.0 and 96.9%, respectively. The proportion of smokers (current or ex-smokers) among cases and controls was 41.7 and 13.1%, respectively. Adenocarcinomas comprised 31.5% of cancers among smokers and 71.6% among nonsmokers. When cases were compared with controls, the odds ratio (OR) for lung cancer (all subtypes) among ex-smokers was 4.3 [95% confidence interval (CI) 2.7-6.8] and that among current smokers was 5.0 (95% CI, 3.4-7.3). Among smokers, women who reported that they stir-fried daily in the past had a significantly increased risk of lung cancer (adjusted OR, 2.0; 95% CI, 1.0-3.8) and among these women, risk was enhanced for those who stir-fried meat daily (OR, 2.7; 95% CI, 1.3-5.5). Women who stir-fried daily but cooked meat less often than daily did not show an elevated risk (OR, 1.0. 95% CI, 0.5-2.4). Risk was further increased among women stir-frying meat daily who reported that their kitchen was filled with oily fumes during cooking (OR, 3.7; 95% CI, 1.8-7.5). These cooking practices on their own did not increase risk among nonsmokers in our study population. Our results suggest that inhalation of carcinogens, such as heterocyclic amines generated during frying of meat, may increase the risk of lung cancer among smokers. Further studies in different settings are warranted to examine this possibility, which may also help to explain the higher risk observed among women smokers compared with men.     

Women living with HIV: Disclosure, violence, and social support

This paper describes the frequency of women's disclosure of their HIV status, examines the extent to which they experience adverse social and physical consequences when others learn they are infected, and analyzes correlates of these negative outcomes. There were 257 HIV-positive women between the ages of 18 and 44, recruited from HIV/AIDS primary care clinics and from community sites, who completed a face-to-face interview. Women in the sample were 33 years old on average; 92% were African-American; 54% had less than 12 years of education; 56% had used intravenous drugs; and 30% knew they were HIV positive for 5 or more years. There were 97% who disclosed their HIV status; 64% told more than 5 people. Negative consequences associated with others knowing they were HIV-positive were reported by 44%, most commonly the loss of friends (24%), being insulted or sworn at (23%), and being rejected by family (21%). There were 10 women (4%) who reported being physically or sexually assaulted as a result of their being HIV positive, and 16% reported having no one they could count on for money or a place to stay. Violence was widespread in this sample, with 62% having experienced physical or sexual violence, including sexual abuse or rape (27%), being beaten up (34%), and weapon-related violence (26%). Logistic regression analysis indicated that women with a history of physical and sexual violence were significantly more likely to experience negative social and physical consequences when their infection became known to others, adjusting for age and the number of people women had disclosed to, both of which were only marginally significant. Partner notification policies and support programs must be responsive to the potential negative consequences associated with others learning that a woman is HIV positive. The high rates of historical violence in the lives of women living with HIV underscore the need for routine screening and intervention for domestic violence in all settings that provide health care to HIV-positive women.     

Anti‐DFS70 antibodies in 597 healthy hospital workers

Objective

Autoantibodies against DFS70 (dense fine speckles 70) antigen (also known as lens epithelium–derived growth factor) have been recently identified among the antinuclear antibodies (ANAs) in patients with atopic disorders. We undertook this study to examine the frequency of anti‐DFS70 antibodies in a large number of healthy people.

Methods

Sera of 597 healthy individuals working in a hospital (142 men, 455 women) were analyzed for ANAs and for anti‐DFS70 antibodies by indirect immunofluorescence (IIF) with HEp‐2 cells as a substrate and by immunoblotting using DFS70 recombinant protein and whole HeLa cell extract.

Results

ANAs were present in 20% of all individuals by IIF. Nine percent of subjects were ANA positive at a serum dilution of 1:40, 4.0% at 1:80, 5.5% at 1:160, 1.0% at 1:320, and 0.3% at 1:640. There were 64 anti‐DFS70 antibody–positive individuals. Surprisingly, this was 11% of the whole population and 54% of the ANA‐positive population. The percentage of female anti‐DFS70 antibody–positive subjects (86%; 55 of 64 subjects) was higher than the percentage of female anti‐DFS70 antibody–negative subjects (75%; 398 of 533 subjects) (P < 0.05). The prevalence of anti‐DFS70 antibody–positive sera decreased with increasing age (P = 0.0017).

Conclusion

Considering that anti‐DFS70 antibody positivity is rare in patients with systemic autoimmune diseases, introducing the anti‐DFS70 antibody examination as a screening test for ANA‐positive persons could be used to rule out systemic autoimmune diseases, resulting in considerable cost‐saving potential. In addition, this test defines a subpopulation of healthy people in whom long‐term followup might reveal health‐related implications of this finding, since anti‐DFS70 antibodies have been shown to be associated with some illnesses.

     

Minimum 10-year results of a tapered cementless hip replacement.

Seventy-one total hip arthroplasties with a cementless, wedge fit, cobalt chrome femoral component were reviewed in 60 patients at a minimum 10-year followup (mean, 11.5 years). For the femoral component, the mechanical failure rate was 5% and the revision rate for aseptic loosening was 0%. The mean Charnley scores for pain, function, and motion changed from preoperative mean values of 3.0, 2.7, and 3.2 to followup mean values of 5.7, 5.5, and 5.2, respectively. The followup mean Harris hip Score was 91. The incidence of thigh pain was 1.4% at 10-year followup. Ninety-five percent of femoral components showed radiologic evidence of stable, bone ingrowth fixation, whereas loosening was seen in 5% of stems. Despite the high incidence of acetabular osteolysis, no osteolysis was seen on the femoral side distal to the lesser trochanter. Nonmodularity of the femoral component led to unavoidable revision of stably fixed femoral components in seven (9.8%) hips during the revision of a loose socket. Design features (collarless, tapered, wedge fit, and circumferentially porous coated) were thought to be crucial to the superlative results with the cobalt chrome femoral component.     

CSF lipocalin-2 increases early in subarachnoid hemorrhage are associated with neuroinflammation and unfavorable outcome

Lipocalin-2 mediates neuro-inflammation and iron homeostasis in vascular injuries of the central nervous system (CNS) and is upregulated in extra-CNS systemic inflammation. We postulate that cerebrospinal fluid (CSF) and blood lipocalin-2 levels are associated with markers of inflammation and functional outcome in subarachnoid hemorrhage (SAH). We prospectively enrolled 67 SAH subjects, serially measured CSF and plasma lipocalin-2, matrix metallopeptidase 9 (MMP-9), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) on post-SAH days 1-5 and assessed outcome by modified Rankin Scale (mRS) every 3 months. Unfavorable outcome is defined as mRS > 2. Twenty non-SAH patients undergoing lumbar drain trial were enrolled as controls. Lipocalin-2 was detectable in the CSF and significantly higher in SAH compared to controls (p < 0.0001). Higher CSF LCN2 throughout post-SAH days 1-5 was associated with unfavorable outcome at 3 (p = 0.0031) and 6 months (p = 0.014). Specifically, higher CSF lipocalin-2 on post-SAH days 3 (p = 0.036) and 5 (p = 0.016) were associated with unfavorable 3-month outcome. CSF lipocalin-2 levels positively correlated with CSF IL-6, TNF-α and MMP-9 levels. Higher plasma lipocalin-2 levels over time were associated with worse 6-month outcome. Additional studies are required to understand the role of lipocalin-2 in SAH and to validate CSF lipocalin-2 as a potential biomarker for SAH outcome.