This Viewpoint discusses the importance of protecting health care workers caring for patients with coronavirus disease 2019 (COVID-19) and measures that can be taken in and out of the hospital to ...prevent their and their families' exposure to SARS-CoV-2.
Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously ...undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions.
We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants.
Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.Arg26Glnx1, p.Gly36Valx1, p.Arg38Trpx2, p.Arg38Glnx1, p.Gly51Argx2, p.Ser54Argx2, p.Asn124Lysx5) and one the homeodomain (p.Asn260Tyrx1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease.
Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The September 11, 2001 (9/11), terrorist attacks were unprecedented in their magnitude and aftermath. In the wake of the attacks, researchers reported a wide range of mental and physical health ...outcomes, with posttraumatic stress disorder (PTSD) the one most commonly studied. In this review, we aim to assess the evidence about PTSD among highly exposed populations in the first 10 years after the 9/11 attacks. We performed a systematic review. Eligible studies included original reports based on the full Diagnostic and Statistical Manual of Mental Disorders (4th ed., rev.; American Psychiatric Association, 2000) criteria of PTSD among highly exposed populations such as those living or working within close proximity to the World Trade Center (WTC) and the Pentagon in New York City and Washington, DC, respectively, and first responders, including rescue, cleaning, and recovery workers. The large body of research conducted after the 9/11 attacks in the past decade suggests that the burden of PTSD among persons with high exposure to 9/11 was substantial. PTSD that was 9/11-related was associated with a wide range of correlates, including sociodemographic and background factors, event exposure characteristics, loss of life of significant others, and social support factors. Few studies used longitudinal study design or clinical assessments, and no studies reported findings beyond six years post-9/11, thus hindering documentation of the long-term course of confirmed PTSD. Future directions for research are discussed.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
Major depressive disorder (MDD) is a common and debilitating psychiatric disorder. Traditional antidepressants are of limited efficacy and take weeks to months to yield full therapeutic effects. ...Thus, there is a clear need for effective rapid‐acting antidepressant medications. The N‐methyl‐d‐aspartate receptor (NMDA‐R) antagonist, ketamine, has received a great deal of attention over the last 20 years due to the discovery that a single subanesthetic dose leads to a rapid antidepressant effect in individuals with treatment‐resistant depression. Animal and human research suggest that ketamine's antidepressant effects are mediated by a glutamate surge that leads to a cascade of events that result in synaptogenesis and reversal of the negative effects of chronic stress and depression, particularly within the prefrontal cortex (PFC). Preclinical and clinical data have provided compelling insights into the mechanisms underlying the rapid‐acting antidepressant effects of ketamine. This review discusses stress‐related neurobiology of depression and the safety, tolerability, and efficacy of ketamine for MDD, along with a review of ketamine's mechanism of action and prospective predictors of treatment response. Research limitations and future clinical prospects are also discussed.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The Gram-negative opportunistic bacterium
is a significant cause of hospital-borne infections worldwide. Alarmingly, the rapid development of antimicrobial resistance coupled with the remarkable ...ability of isolates to persist on surfaces for extended periods of time has led to infiltration of
into our healthcare environments. A major virulence determinant of
is the presence of a capsule that surrounds the bacterial surface. This capsule is comprised of tightly packed repeating polysaccharide units which forms a barrier around the bacterial cell wall, providing protection from environmental pressures including desiccation and disinfection regimes as well as host immune responses such as serum complement. Additionally, capsule has been shown to confer resistance to a range of clinically relevant antimicrobial compounds. Distressingly, treatment options for
infections are becoming increasingly limited, and the urgency to develop effective infection control strategies and therapies to combat infections is apparent. An increased understanding of the contribution of capsule to the pathobiology of
is required to determine its feasibility as a target for new strategies to combat drug resistant infections. Significant variation in capsular polysaccharide structures between
isolates has been identified, with over 100 distinct capsule types, incorporating a vast variety of sugars. This review examines the studies undertaken to elucidate capsule diversity and advance our understanding of the role of capsule in
pathogenesis.
Abstract Background Despite several studies suggesting higher depression severity and dysfunction occurring in individuals with major depressive disorder (MDD) comorbid with social anxiety disorder ...(SAD), a clear understanding of the specific risks associated with this comorbidity is lacking. In this study we compared the disease characteristics and level of disability of individuals with MDD-SAD with other comorbidities between depression and anxiety. Methods Data from the Collaborative Psychiatric Epidemiology Surveys (CPES) (N= 20,013) were used. Individuals were divided in four groups comparing MDD-SAD with MDD alone, as well as other comorbidities between MDD and one anxiety (MDD-1ANX) or more than two anxiety disorders (MDD≥2ANX), with respect to several clinical, demographic, and functional characteristics. Results MDD-SAD comorbidity in the general population occurred in younger people, particularly men, and seemed to have an earlier onset of MDD. Occupational and social dysfunction was similar between individuals with MDD-SAD and those with MDD-1ANX. However, individuals with MDD≥2ANX had significantly higher severity as measured by suicidality as well as substance abuse and social and occupational dysfunction. SAD was the most prevalent comorbid anxiety in this group. Limitations The findings of this study were derived from the cross-sectional data. Conclusion Our results suggest that the particular risks associated with MDD-SAD are the early onset and likelihood of additional anxiety, leading to higher severity and disability levels. Clinicians should increase the screening and treatment of SAD and other anxiety disorders in individuals with MDD given the higher associated health risk and functional impairment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
A coastwide bloom of the toxigenic diatom Pseudo‐nitzschia in spring 2015 resulted in the largest recorded outbreak of the neurotoxin, domoic acid, along the North American west coast. Elevated ...toxins were measured in numerous stranded marine mammals and resulted in geographically extensive and prolonged closures of razor clam, rock crab, and Dungeness crab fisheries. We demonstrate that this outbreak was initiated by anomalously warm ocean conditions. Pseudo‐nitzschia australis thrived north of its typical range in the warm, nutrient‐poor water that spanned the northeast Pacific in early 2015. The seasonal transition to upwelling provided the nutrients necessary for a large‐scale bloom; a series of spring storms delivered the bloom to the coast. Laboratory and field experiments confirming maximum growth rates with elevated temperatures and enhanced toxin production with nutrient enrichment, together with a retrospective analysis of toxic events, demonstrate the potential for similarly devastating ecological and economic disruptions in the future.
Key Points
The 2015 U.S. West Coast wide toxic Pseudo‐nitzschia australis bloom was facilitated by anomalous ocean conditions
The seasonal transition to upwelling provided nutrients for the bloom, and spring storms delivered toxic cells to the nearshore environment
West Coast toxic Pseudo‐nitzschia events are triggered by warm anomalies associated with El Niño and the Pacific Decadal Oscillation
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
IL-6-induced skeletal muscle atrophy Haddad, F; Zaldivar, F; Cooper, D. M ...
Journal of applied physiology,
03/2005, Volume:
98, Issue:
3
Journal Article
Peer reviewed
Open access
Departments of 1 Physiology and Biophysics and 2 Pediatrics, University of California, Irvine, California
Submitted 16 September 2004
; accepted in final form 4 November 2004
Chronic, low-level ...elevation of circulating interleukin (IL)-6 is observed in disease states as well as in many outwardly healthy elderly individuals. Increased plasma IL-6 is also observed after intense, prolonged exercise. In the context of skeletal muscle, IL-6 has variously been reported to regulate carbohydrate and lipid metabolism, increase satellite cell proliferation, or cause muscle wasting. In the present study, we used a rodent local infusion model to deliver modest levels of IL-6, comparable to that present after exercise or with chronic low-level inflammation in the elderly, directly into a single target muscle in vivo. The aim of this study was to examine the direct effects of IL-6 on skeletal muscle in the absence of systemic changes in this cytokine. Data included cellular and molecular markers of cytokine and growth factor signaling (phosphorylation and mRNA content) as well as measurements to detect muscle atrophy. IL-6 infusion resulted in muscle atrophy characterized by a preferential loss of myofibrillar protein (17%). IL-6 induced a decrease in the phosphorylation of ribosomal S6 kinase (60%) and STAT5 (33%), whereas that of STAT3 was increased approximately twofold. The changes seen in the IL-6-infused muscles suggest alterations in the balance of growth factor-related signaling in favor of a more catabolic profile. This suggests that downregulation of growth factor-mediated intracellular signaling may be a mechanism contributing to the development of muscle atrophy induced by elevated IL-6.
suppressor of cytokine signaling; signal transducer activator of transcription; insulin-like growth factor I; 70-kDa ribosomal S6 kinase
Address for reprint requests and other correspondence: G. R. Adams, Associate Researcher, Dept. of Physiology & Biophysics, Univ. of California, Irvine, Medical Sciences 1, Rm. D335, Irvine, CA 92697-4560 (E-mail: GRAdams{at}uci.edu )
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