Mutation L437P in the 2B domain of keratin 1 causes diffuse palmoplantar keratoderma in a Chinese pedigree

Diffuse palmoplantar keratoderma (DPPK) is an autosomal dominant genodermatosis characterized by uniform hyperkeratosis of the palm and sole epidermis. This disorder can be caused by mutations in the genes keratin 1 , keratin 9 , keratin 16 , desmoglein 1 and plakoglobin . Here we present a DPPK Chinese pedigree and identify the aetiology as a novel missense mutation, L437P, located in a highly conserved helix motif in domain 2B of KRT1. Functional analysis shows that overexpression of the L437P mutant in cultured cells leads to abnormal intermediate filament networks and filament aggregation. This gain-of-function mutation highlights the role of domain 2B in mediating filament assembly.

Conflicts of interest

The authors declare that they have no actual or potential conflicts of interest to disclose. Appropriate approval and procedures were used concerning human subjects.     

FK506 (Tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation

FK506 (Tacrolimus) is an immunosuppressive drug that blocks the activation of antigen-specific T lymphocytes, a major component in the pathogenesis of graft-versus-host disease (GVHD). This study was designed to obtain first estimates of the safety and efficacy of FK506 monotherapy in the prevention of GVHD following HLA-identical sibling marrow transplantation. Additionally, a subset of patients was studied to define the pharmacokinetic profile of FK506. Twenty-seven adult patients with leukemia or myelodysplasia received FK506 starting the day before transplant at a dose of 0.04 mg/kg/d by continuous intravenous infusion. When clinically possible, FK506 was given orally in two divided doses starting at five times the daily intravenous dose. FK506 doses were adjusted to target a steady state or trough blood level between 10 to 30 ng/mL. These patients were followed for 6 months posttransplant. All patients had sustained marrow engraftment. Frequently noted adverse events included reversible renal dysfunction, diarrhea, fever, nausea, vomiting, and headache. Most patients required FK506 dose reductions associated with elevated serum creatinine. Two (7%) patients relapsed, one of whom died of the disease within the 6- month study period. A second patient died due to pulmonary mucor. Whole blood pharmacokinetic parameters indicated a half-life of 18.2 +/- 12.1 hours; volume of distribution of 1.67 +/- 1.02 L/kg; clearance of 71 +/- 34 mL/h/kg; and bioavailability of 32 +/- 24%. Eleven of 27 (41%) patients developed grade II to IV acute GVHD, including 10 grade II and one grade III. Six of 24 (25%) evaluable patients developed chronic GVHD. These data indicate that FK506 monotherapy has activity in preventing GVHD. Further studies of FK506 with lower doses to improve tolerability and in combination with other immunosuppressants to augment efficacy are warranted.     

Characteristics of national registries for occupational diseases: international development and validation of an audit tool (ODIT)

Background-  

The aim of the study was to develop quality indicators that can be used for quality assessment of registries of occupational diseases in relation to preventive policy on a national level. The research questions were: 1. Which indicators determine the quality of national registries of occupational diseases with respect to their ability to provide appropriate information for preventive policy? 2. What are the criteria that can distinguish low quality from high quality?     

Challenges at work and financial rewards to stimulate longer workforce participation

Background  

Because of the demographic changes, appropriate measures are needed to prevent early exit from work and to encourage workers to prolong their working life. To date, few studies have been performed on the factors motivating continuing to work after the official age of retirement. In addition, most of those studies were based on quantitative data. The aims of this study were to examine, using both quantitative and qualitative data: (1) the reasons for voluntary early retirement; (2) the reasons for continuing working life after the official retirement age; and (3) the predictive value of the reasons mentioned.     

Patterns of adolescent physical activity and dietary behaviours

Background  

The potential synergistic effects of multiple dietary and physical activity behaviours on the risk of chronic conditions and health outcomes is a key issue for public health. This study examined the prevalence and clustering patterns of multiple health behaviours among a sample of adolescents in the UK.     

Aestivation in the South American lungfish, Lepidosiren paradoxa: effects on cardiovascular function, blood gases, osmolality and leptin levels

The African (Protopterus sp.) and South American lungfish (Lepidosiren paradoxa) inhabit shallow waters, that seasonally dry out, which induces aestivation and cocoon formation in Protopterus. Differently, L. paradoxa has no cocoon, and it aestivates in a simple burrow. In water PaCO(2) is 21.8+/-0.4mmHg (mean values+/-S.E.M.; n=5), whereas aestivation for 20 days increased PaCO(2) to as much as 37.6+/-2.1mmHg, which remained the same after 40 days (35.8+/-3.3mmHg). Concomitantly, the plasma [HCO(3)(-)]-values for animals in water were 22.5+/-0.5mM, which after 20 days increased to 40.2+/-2.3mM and after 40 days to 35.8+/-3.3mM. Initially in water, PaO(2) was 87.7+/-2.0mmHg, but 20 days in aestivation reduced the value to 80.5+/-2.2 and later (40 days) to 77.1+/-3.0mmHg. Meanwhile, aestivation had no effect on pHa and hematocrit. The blood pressures were equal for animals in the water or in the burrow (P(mean) approximately 30mmHg), and cardiac frequency (f(H)) fell from 31beats min(-1) to 22beats min(-1) during 40 days of aestivation. The osmolality (mOsmkgH(2)O(-1)) was elevated after 20 and 40 days of aestivation but declined upon return to water. The transition from activity to aestivation involves new set-points for the variables that determine the acid-base status and PaO(2) of the animals, along with a reduction of cardiac frequency.     

Gamma-glutamyltransferase activity in human atherosclerotic plaques--biochemical similarities with the circulating enzyme

Background and purposeSerum γ-glutamyltransferase (GGT) activity has been identified as a predictor of complications of atherosclerosis, with a prognostic value for cardiovascular diseases and stroke. Human atherosclerotic lesions contain active GGT, which can give rise to pro-oxidant molecular species; thus a direct contribution of GGT to atherosclerosis progression is conceivable. The relationship between plaque and serum GGT is however unclear.Methods and resultsHuman carotid plaques obtained from 18 consecutive patients undergoing carotid endoarteriectomy were analyzed, of which 6 were used for anion exchange and gel filtration chromatography/western blot studies, 7 for β-lipoprotein precipitation, and 5 for RNA extraction and determination of low molecular weight thiols. Mean GGT activity in crude plaque homogenates was 60.9 ± 21.5 (S.D.) mU/g tissue. The characteristics of GGT activity were compared in plaque homogenates and in serum obtained from controls (healthy blood donors). The methods employed (anion exchange and gel chromatography, western blot) showed the presence in plaque homogenates of two distinct complexes containing GGT activity, one of which comparable with plasma LDL/GGT complexes. Accordingly, precipitation of β-lipoproteins from plaque homogenates resulted in removal of GGT activity. RT-PCR indicated in plaques the presence of GGT mRNA transcribed from GGT-I gene. Analysis of plaque extracts also revealed the presence of enzyme product cysteinyl-glycine both as free and protein-bound form, confirming that GGT-dependent pro-oxidant reactions may occur within the plaque environment.ConclusionsThe results obtained suggest the presence in plaques of a serum-like GGT protein, indicating that a direct contribution of serum GGT to enzyme activity found within atherosclerotic lesions is possible. Data also indicate the occurrence of GGT-mediated redox reactions within plaque environment, which might influence plaque progression.     

Influence of fluid resuscitation on renal microvascular PO2 in a normotensive rat model of endotoxemia

Introduction  

Septic renal failure is often seen in the intensive care unit but its pathogenesis is only partly understood. This study, performed in a normotensive rat model of endotoxemia, tests the hypotheses that endotoxemia impairs renal microvascular PO₂ (μPO₂) and oxygen consumption (VO_2,ren), that endotoxemia is associated with a diminished kidney function, that fluid resuscitation can restore μPO₂, VO_2,ren and kidney function, and that colloids are more effective than crystalloids.     

An online network tool for quality information to answer questions about occupational safety and health: usability and applicability

Background  

Common information facilities do not always provide the quality information needed to answer questions on health or health-related issues, such as Occupational Safety and Health (OSH) matters. Barriers may be the accessibility, quantity and readability of information. Online Question & Answer (Q&A) network tools, which link questioners directly to experts can overcome some of these barriers. When designing and testing online tools, assessing the usability and applicability is essential. Therefore, the purpose of this study is to assess the usability and applicability of a new online Q&A network tool for answers on OSH questions.     

光度法测定咖啡因、烟酰胺、水杨酸等配体与萘普生在水溶液中的形成常数

本文通过萘普生和咖啡因、烟酰胺、水杨酸等配体紫外光谱的测定,Job连续递变法实验,确定了它们之间的相互作用。其形成物的比值均为1:1。并用紫外分光光度法测定了形成常数,进而推算了热力学函数,推测了其可能的形成机理。