A genome wide association study identifies new genes potentially associated with eyelid sagging

Sagging eyelid is considered as an outward of skin ageing and may cause medical issues. However, little is known about the factors involved in sagging eyelid. The study, which aims at determining genetic risk factors for eyelid sagging, was conducted in a cohort of 502 unrelated Caucasian women living in the Paris region. All included participants were aged between 44 and 70 years old (mean age, 57.6 years old). The severity of sagging eyelid was graded in 6 categories by a dermatologist using standardized photographs of the face. A genome wide association study adjusted on potential risk factors (including age and smoking habits) was conducted to identify genetic associations. Two single nucleotide polymorphisms in total linkage disequilibrium on chromosome 10, rs16927253 (P = 7.07 × 10^‐10) and rs4746957 (P = 1.06 × 10^‐8), were significantly associated with eyelid sagging severity. The rs16927253‐T and rs4746957‐A alleles showed a dominant protective effect towards eyelid sagging. These polymorphisms are located in intronic parts of the H2AFY2 gene which encodes a member of the H2A histone family and very close to the AIFM2 gene that induces apoptosis. Additionally, single nucleotide polymorphisms with a false discovery rate below 0.25 were located nearby the type XIII collagen COL13A1 gene on chromosome 10 and in the ADAMTS18 gene on chromosome 16. Several relevant genes were identified by the genome wide association study for their potential role in the sagging eyelid severity.     

From the Cover: PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain

Defense of the central nervous system (CNS) against infection must be accomplished without generation of potentially injurious immune cell-mediated or off-target inflammation which could impair key functions. As the CNS is an immune-privileged compartment, inducible innate defense mechanisms endogenous to the CNS likely play an essential role in this regard. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide known to regulate neurodevelopment, emotion, and certain stress responses. While PACAP is known to interact with the immune system, its significance in direct defense of brain or other tissues is not established. Here, we show that our machine-learning classifier can screen for immune activity in neuropeptides, and correctly identified PACAP as an antimicrobial neuropeptide in agreement with previous experimental work. Furthermore, synchrotron X-ray scattering, antimicrobial assays, and mechanistic fingerprinting provided precise insights into how PACAP exerts antimicrobial activities vs. pathogens via multiple and synergistic mechanisms, including dysregulation of membrane integrity and energetics and activation of cell death pathways. Importantly, resident PACAP is selectively induced up to 50-fold in the brain in mouse models of Staphylococcus aureus or Candida albicans infection in vivo, without inducing immune cell infiltration. We show differential PACAP induction even in various tissues outside the CNS, and how these observed patterns of induction are consistent with the antimicrobial efficacy of PACAP measured in conditions simulating specific physiologic contexts of those tissues. Phylogenetic analysis of PACAP revealed close conservation of predicted antimicrobial properties spanning primitive invertebrates to modern mammals. Together, these findings substantiate our hypothesis that PACAP is an ancient neuro-endocrine-immune effector that defends the CNS against infection while minimizing potentially injurious neuroinflammation.

Neuropeptides enable interneuronal communication and signaling (1), mediating diverse functions ranging from endocrine stimulation and homeostatic regulation to immune signaling, pain modulation, and circadian rhythm maintenance. At present, over 100 neuropeptides are known in mammals (2). These peptides originate from neurons in the central, enteric, or peripheral nervous systems and within immune organs (3). Canonically, neuropeptides exert their biological function by binding to a cognate receptor (usually a G-coupled protein receptor [GPCR]), triggering a signal transduction pathway that leads to a functional change in the target cell (1). Neuropeptides are typically considered neurotransmitters or neurohormones, but recent work has illuminated their potential roles in modulating immune responses and neuroinflammation (4–8).Human innate and adaptive immunity have evolved via two parallel and complementary paradigms in host defense against microbial invasion: molecular and cellular. Molecular defense mediators are secreted or activated rapidly and locally to directly inhibit pathogens. Prototypic examples include host-defense peptides (HDPs), the acute-phase reactants, and the complement cascade. Cellular defense involves infiltration of professional immune phagocytes (neutrophils and macrophages) and lymphocytes into infected tissues. Cellular infiltration into the central nervous system (CNS) is a double-edged sword, given its anatomically confined space and physiologically delicate context. On one hand cellular defense may be necessary to control or clear certain pathogens. On the other hand, neutrophils and other phagocytes can cause counterproductive damage to tissue parenchyma due to production and release of reactive oxygen species and other cytotoxic constituents from phagolysosomes. Thus, molecular defenses that are rapidly deployable in immediate settings of infection to obviate the need for infiltration of potentially harmful immune cells would be of special relevance in context of the CNS.To explore putative molecular host-defense mediators within the CNS that may have both neuro- and immunomodulatory properties, we used a support vector machine (SVM) trained on HDPs (9, 10) to identify neuropeptides with potential host defense capabilities. Among the human neuropeptides identified as potential HDPs for molecular host defense of the CNS is pituitary adenylate cyclase-activating polypeptide (PACAP). PACAP is a member of the vasoactive intestinal peptide (VIP)/PACAP/secretin family (11) that regulates neurodevelopment (12), metabolism, emotion, mood, and stress responses via GPCRs (13). PACAP is known to interact with the immune system (14, 15) and modulate T helper type 1 (TH1)/TH2 cytokine production (3). Important previous work on structure activity relationships (SAR) of PACAP have also shown that it possess antimicrobial activity in vitro against a range of organisms (16–18), as well as anti-cancer activity against tumor cell lines. (Interestingly, our use of an SVM classifier that can scan different fragments of the same peptide allows us to identify antimicrobial activity in previously identified metabolites of PACAP as well^* (19)). However, host defense functions, contextual bioactivity, or pathogen-specific inducibility of PACAP or other neuropeptides regarding antimicrobial activity in vivo are not known. More specifically, the role of PACAP in the larger context of innate immunity and its in vivo relevance to antimicrobial defense of the CNS and in other tissues remains unclear, given that antimicrobial activity is strongly dependent on biochemical and physiological context (20, 21, 22). Here, we examine PACAP inducibility in response to infection in the CNS and other tissues, and whether PACAP exerts antimicrobial activity against relevant organisms in the specific biochemical context relevant to those tissues. Bioinformatic and structural analyses showed PACAP to possess almost identical structural similarity to human cathelicidin LL-37, despite having overall low sequence similarity to other known HDPs. Synchrotron X-ray scattering revealed that PACAP can induce negative Gaussian curvature (NGC) in microbial membranes, a general requirement for membrane-permeating antimicrobial processes such as pore formation, blebbing, and other membrane-perturbing events (23–25). Moreover, extending from prior work (18), antimicrobial assays and mechanistic fingerprinting analyses showed that PACAP exerts potent antimicrobial mechanisms against drug-resistant bacteria and fungi via multiple synergistic pathways, including permeabilization, disruption of cellular energetics, and activation of regulated cell death pathways. In mouse models of bacterial or fungal infection, we demonstrated that PACAP is strongly induced up to 50-fold in brain, spleen, or kidney. Further, in media simulating these tissue contexts, PACAP exerted robust microbiostatic and microbicidal efficacy. Taken together, these findings imply that PACAP is an infection-inducible, tissue-specific host-defense effector that affords rapid and contextual antimicrobial host defense in the CNS and periphery. Beyond immediate contributions to better understanding of antimicrobial defense, the present discoveries reveal specific intersections of neurological and immunological systems and establish insights into antiinfective strategies that preserve critical functions of the CNS.     

Prolonged grief following the recent death of a daughter among mothers who experienced distal losses during the Khmer Rouge era: Validity of the prolonged grief construct in Cambodia

This study addressed the validity of the prolonged grief (PG) construct in a Cambodian context. Eighty mothers who lost a young adult daughter stemming from a crowd stampede incident during the annual water festival were interviewed at the six-month post-loss point along with a control group of similarly aged women who were not recently bereaved. Both groups were assessed for PG, PTSD, anxiety, and depression symptoms and well as for the number of distal losses experienced during the Khmer Rouge (KR) regime – knowing that all the women were old enough to have lived through the KR regime. Support for the discriminant validity of PG was shown in a factor analysis in which its core symptoms were distinguished from anxiety, depression, and PTSD symptoms. Also, support was found for its incremental validity as shown in the unique sensitivity of PG in distinguishing the two groups when controlling for the other symptoms. Lastly, a positive relationship was found between the number of distal deaths experienced during the KR regime and PG symptom severity among the group of recently bereaved mothers, providing support for the predictive validity of PG. Implications as well as study limitations are discussed.     

Rural health care in Malaysia

ABSTRACT:   Malaysia has a population of 21.2 million of which 44% resides in rural areas. A major priority of healthcare providers has been the enhancement of health of 'disadvantaged' rural communities particularly the rural poor, women, infants, children and the disabled. The Ministry of Health is the main healthcare provider for rural communities with general practitioners playing a complimentary role. With an extensive network of rural health clinics, rural residents today have access to modern healthcare with adequate referral facilities. Mobile teams, the flying doctor service and village health promoters provide healthcare to remote areas. The improvement in health status of the rural population using universal health status indicators has been remarkable. However, differentials in health status continue to exist between urban and rural populations. Malaysia's telemedicine project is seen as a means of achieving health for all rural people.     

Quantitative assessment of fatty degeneration in rotator cuff muscles determined with computed tomography

OBJECTIVES: Reliable assessment of fatty degeneration of rotator cuff muscles is desirable to predict the outcome of shoulder surgery. Currently used qualitative assessments are limited by relatively high inter- and intraobserver variability. It was hypothesized that a quantitative measurement of muscle density using computed tomography (CT) was more reliable and reproducible. MATERIALS AND METHODS: Thirty shoulders from patients with rheumatoid arthritis were analyzed using parasagittal multiplanar reconstructions acquired from a 16-slice CT scanner. Three observers visually rated the severity of fatty degeneration and independently outlined the rotator cuff muscles, after which the mean density was calculated. Inter- and intraobserver agreement on both measurements was expressed by the interclass correlation coefficient (ICC) and the standard deviation of the differences (SDD) between the measurements. RESULTS: A strong correlation was found between the quantitative measure and the visual rating (R2 = 0.94; P < 0.0001). The SDD in muscle density did not exceed 2.3 Hounsfield units, and the mean rotator cuff ICC (0.98) was substantially greater than that of the visual rating (0.63). CONCLUSIONS: This study describes a reproducible method to quantify fatty degeneration of the rotator cuff muscles in CT images, with a higher interobserver agreement than the visual score, and may prove a reliable tool to evaluate the quality of the rotator cuff muscles.     

Uterine rupture after laparoscopic myomectomy

Myomectomy is performed frequently to preserve or increase fertility, although the risk of future uterine rupture is a major concern of any surgery of the uterus. A 36-year-old woman underwent laparoscopic removal of a pendunculated myoma, and 6 weeks later she conceived after IVF. At 35.5 weeks' gestation she was admitted to the hospital because of abdominal pain. Cesarean section revealed rupture of the uterine wall at the site of the myoma. This and similar case reports indicate that inadequate laparoscopic suturing is not the only factor involved in rupture of the uterine wall during pregnancy after laparoscopic myomectomy.     

针灸治疗前列腺增生症的研究近况

目的：总结近年来国内有关针灸治疗前列腺增生症的临床、实验研究近况，以期为临床治疗提供毒考资料，并探讨进一步发展针灸治疗的策略。资料来源：检索中国期刊全文数据库1998—01／2005—10针灸治疗前列腺增生症的相关文章，检索词“针灸，针刺，前列腺增生症”。资料选择：对资料进行初筛，选取近年发表的针对性强的文献，同一领域的文献则选择近期发表或权威杂志的文章，排除综述类文章及重复研究的文章，对所选文献开始查找全文。资料提炼：收集到57篇相关文章，其中37篇属于重复性研究和综述文献，对其余20篇进行分类整理用于综述。资料综合：15篇临床报道和5篇实验研究中包括约1301例患者和230只动物，通过临床观察（国际前列腺症状评分标准、生活质量评定指数、前列腺体积变化等）及实验观察均证实针灸疗法是治疗此病的有效方法。同时针灸治疗方法多样，如体针、耳针、电针、芒针、针灸并用、综合治疗等。结论：针灸疗法是治疗前列腺增生症的一种有效的方法，具有操作简便、费用低廉等优点，对于针灸治疗前列腺增生症的临床、实验研究有待进一步深入。     

Diagnostic value of mitral annular velocity for constrictive pericarditis in the absence of respiratory variation in mitral inflow velocity

Respiratory variation of 25% or more in transmitral early diastolic filling (E) velocity is a well-recognized diagnostic feature of constrictive pericarditis (CP) that is useful for distinguishing it from restrictive cardiomyopathy. However, a subset of patients with CP do not exhibit the typical respiratory change. Recent data showed that mitral annular (E') velocity measured by Doppler tissue echocardiography (DTE) is markedly reduced in patients with restrictive cardiomyopathy whereas E' velocity is well-preserved in CP. This study evaluated the role of DTE for the diagnosis of CP when there is no characteristic respiratory variation of E velocity. From September 1999 to March 2001, 19 patients (17 men, 2 women; mean age, 57 +/- 13 years) with surgically confirmed CP underwent comprehensive echocardiography preoperatively, including pulsed wave and DTE examination with simultaneous recording of respiration. Nine (47%) of the 19 patients had less than 25% respiratory variation in E velocity. There was no significant difference in mitral inflow peak velocity, deceleration time, early-to-late ventricular filling ratio, and E' velocity between patients with and patients without respiratory variation of E velocity of 25% or more. Regardless of the presence or absence of a significant respiratory variation of E velocity, E' velocity was relatively normal (mean, 12 +/- 4 cm/s) in all patients with CP. In conclusion, E' velocity is well preserved in patients with isolated CP even when there is no characteristic respiratory variation of E velocity. Thus, when the respiratory variation in Doppler E velocity is blunted or absent during the evaluation of suspected CP in patients with restrictive mitral inflow velocity, preserved E' velocity shown by DTE should support the diagnosis of CP over a primary myocardial disease.