Sputum proteomic signature of gastro-oesophageal reflux in patients with severe asthma.

Gastro-oesophageal reflux disease (GORD) has long been associated with poor asthma control without an established cause-effect relationship. 610 asthmatics (421 severe/88 mild-moderate) and 101 healthy controls were assessed clinically and a subset of 154 severe asthmatics underwent proteomic analysis of induced sputum using untargeted mass spectrometry, LC-IMS-MSE. Univariate and multiple logistic regression analyses (MLR) were conducted to identify proteins associated with GORD in this cohort. When compared to mild/moderate asthmatics and healthy individuals, respectively, GORD was three- and ten-fold more prevalent in severe asthmatics and was associated with increased asthma symptoms and oral corticosteroid use, poorer quality of life, depression/anxiety, obesity and symptoms of sino-nasal disease. Comparison of sputum proteomes in severe asthmatics with and without active GORD showed five differentially abundant proteins with described roles in anti-microbial defences, systemic inflammation and epithelial integrity. Three of these were associated with active GORD by multiple linear regression analysis: Ig lambda variable 1-47 (p = 0·017) and plasma protease C1 inhibitor (p = 0·043), both in lower concentrations, and lipocalin-1 (p = 0·034) in higher concentrations in active GORD. This study provides evidence which suggests that reflux can cause subtle perturbation of proteins detectable in the airways lining fluid and that severe asthmatics with GORD may represent a distinct phenotype of asthma.

An interaction network of mental disorder proteins in neural stem cells.

Mental disorders (MDs) such as intellectual disability (ID), autism spectrum disorders (ASD) and schizophrenia have a strong genetic component. Recently, many gene mutations associated with ID, ASD or schizophrenia have been identified by high-throughput sequencing. A substantial fraction of these mutations are in genes encoding transcriptional regulators. Transcriptional regulators associated with different MDs but acting in the same gene regulatory network provide information on the molecular relation between MDs. Physical interaction between transcriptional regulators is a strong predictor for their cooperation in gene regulation. Here, we biochemically purified transcriptional regulators from neural stem cells, identified their interaction partners by mass spectrometry and assembled a protein interaction network containing 206 proteins, including 68 proteins mutated in MD patients and 52 proteins significantly lacking coding variation in humans. Our network shows molecular connections between established MD proteins and provides a discovery tool for novel MD genes. Network proteins preferentially co-localize on the genome and cooperate in disease-relevant gene regulation. Our results suggest that the observed transcriptional regulators associated with ID, ASD or schizophrenia are part of a transcriptional network in neural stem cells. We find that more severe mutations in network proteins are associated with MDs that include lower intelligence quotient (IQ), suggesting that the level of disruption of a shared transcriptional network correlates with cognitive dysfunction.

Rehabilitation of leprosy-affected people: An overview.

Leprosy is mainly a disease of the skin and nerves. The involvement of nerves may lead to impairments that have, contributed to the fact that leprosy is often still seen as a disease to be feared. In non-leprosy-endemic Western countries, beliefs continue to prevail about the inevitability of deformities and the lack of a cure. I review the pathogenesis of deformity and to present a discourse on how deformities can, to a very large extent, be prevented and corrected.

Human Q fever incidence is associated to spatiotemporal environmental conditions.

Airborne pathogenic transmission from sources to humans is characterised by atmospheric dispersion and influence of environmental conditions on deposition and reaerosolisation. We applied a One Health approach using human, veterinary and environmental data regarding the 2009 epidemic in The Netherlands, and investigated whether observed human Q fever incidence rates were correlated to environmental risk factors. We identified 158 putative sources (dairy goat and sheep farms) and included 2339 human cases. We performed a high-resolution (1 × 1 km) zero-inflated regression analysis to predict incidence rates by Coxiella burnetii concentration (using an atmospheric dispersion model and meteorological data), and environmental factors - including vegetation density, soil moisture, soil erosion sensitivity, and land use data - at a yearly and monthly time-resolution. With respect to the annual data, airborne concentration was the most important predictor variable (positively correlated to incidence rate), followed by vegetation density (negatively). The other variables were also important, but to a less extent. High erosion sensitive soils and the land-use fractions "city" and "forest" were positively correlated. Soil moisture and land-use "open nature" were negatively associated. The geographical prediction map identified the largest Q fever outbreak areas. The hazard map identified highest hazards in a livestock dense area. We conclude that environmental conditions are correlated to human Q fever incidence rate. Similar research with data from other outbreaks would be needed to more firmly establish our findings. This could lead to better estimations of the public health risk of a C. burnetii outbreak, and to more detailed and accurate hazard maps that could be used for spatial planning of livestock operations.

Rehabilitation of leprosy-affected people: an overview

Leprosy is mainly a disease of the skin and nerves. The involvement of nerves may lead to impairments that have, contributed to the fact that leprosy is often still seen as a disease to be feared. In non­leprosy-endemic Western countries, beliefs continue to prevail about the inevitability of deformities and the lack of a cure. I review the pathogenesis of deformity and to present a discourse on how deformities can, to a very large extent, be prevented and corrected.

Reliability of clinical nerve function assessment in peripheral neuropathies.

INTRODUCTION: Sensory and/or motor nerve function impairment as a consequence of neuropathy is often assessed using electroneurophysiological tests. However, in low-resource countries where the required equipment is rarely available, manual muscle strength testing (MMST) and monofilament testing (MFT) offer very reliable alternatives. In six leprosy programmes in four Asian countries, a multi-centre randomised clinical trial (RCT) was carried out to assess the effect of corticosteroids on neuropathy in leprosy-affected people. The sensory and motor nerve function was tested using MMST and MFT, including new test sites for the sural and radial cutaneous nerves (MFT) and the posterior tibial and common peroneal nerves (MMST). The reliability studies of the MMST and MFT tests of the TENLEP (Treatment of Early Neuropathy in LEProsy) trials are presented here. METHODS: Two assessors in each centre independently used the MFT and MMST in 30 leprosy-affected people. RESULTS: Reliability is good to very good for MFT in nearly all nerves. MMST also shows good to very good agreement, with a few exceptions. CONCLUSION: Our study confirms that MMST and MFT can be performed reliably, and that the new tests also have acceptable reliability.

The concurrent validity of the Amharic version of Screening of Activity Limitation and Safety Awareness (SALSA) in persons affected by leprosy.

OBJECTIVES: Leprosy is endemic in many countries and results in activity limitations. There is a need for assessment tools to guide professionals in their evaluation and choice of intervention in order to improve conditions for leprosy-affected people. The purpose of our study was to evaluate the concurrent validity of the Amharic version of Screening of Activity Limitation and Safety Awareness (SALSA-am) scale with Amharic version of Disability of the Arm, Shoulder and Hand (DASH-am) questionnaire. DESIGN: Thirty-eight individuals with nerve damage due to leprosy completed the SALSA-am and DASH-am questionnaires. Spearman's rank correlation was used to determine relationships between SALSA and DASH scores. Specificity, sensitivity and accuracy were calculated. RESULTS: There was a good correlation 0.87 (P < 0.001) between SALSA-am and DASH-am scores. Sensitivity, specificity and accuracy were calculated with acceptable results. CONCLUSIONS: SALSA-am is considered a useful questionnaire for determining activity limitations in persons affected by leprosy, and showed good correlation with DASH-am. The concurrent validity was considered good.

Arginine metabolism in sugar deprived Lactococcus lactis enhances survival and cellular activity, while supporting flavour production.

Flavour development in cheese is affected by the integrity of Lactococcus lactis cells. Disintegrated cells enhance for instance the enzymatic degradation of casein to free amino acids, while integer cells are needed to produce specific flavour compounds from amino acids. The impact of the cellular activity of these integer cells on flavour production remains to be elucidated. In this study we investigated whether lactose-deprived L. lactis cells that use arginine as an alternative energy source can extend cellular activity and produce more specific flavours. In cheese experiments we demonstrated that arginine metabolising cells survived about 3 times longer than non-arginine metabolising cells, which suggests prolonged cellular activity. Cellular activity and flavour production of L. lactis was further studied in vitro to enable controlled arginine supplementation. Comparable with the results found in cheese, the survival rates of in vitro incubated cells improved when arginine was metabolised. Furthermore, elongated cellular activity was reflected in 3-4-fold increased activity of flavour generating enzymes. The observed prolonged cellular activity resulted in about 2-fold higher concentrations of typical Gouda cheese flavours. These findings provide new leads for composing starter cultures that will produce specific flavour compounds.

Prevention of disability in leprosy: the different levels.

Prevention of disability in people affected by leprosy is primarily seen as prevention and management of impairments secondary to nerve function impairment. This article describes four different levels at which appropriate interventions may lead to the overall prevention of disability. These are--prevention of disease, timely diagnosis and adequate treatment of the disease, early recognition and adequate treatment of nerve function impairment and finally, prevention and treatment of secondary impairments due to nerve function loss.

Enhanced human papillomavirus type 8 oncogene expression levels are crucial for skin tumorigenesis in transgenic mice.

Human papillomavirus 8 (HPV8) is involved in skin cancer development in epidermodysplasia verruciformis patients. Transgenic mice expressing HPV8 early genes (HPV8-CER) developed papillomas, dysplasias and squamous cell carcinomas. UVA/B-irradiation and mechanical wounding of HPV8-CER mouse skin led to prompt papilloma induction in about 3 weeks. The aim of this study was to analyze the kinetics and level of transgene expression in response to skin irritations. Transgene expression was already enhanced 1 to 2 days after UVA/B-irradiation or tape-stripping and maintained during papilloma development. The enhanced transgene expression could be assigned to UVB and not to UVA. Papilloma development was thus always paralleled by an increased transgene expression irrespective of the type of skin irritation. A knock-down of E6 mRNA by tattooing HPV8-E6-specific siRNA led to a delay and a lower incidence of papilloma development. This indicates that the early increase of viral oncogene expression is crucial for induction of papillomatosis.

A review of the biomechanics of intrinsic replacement in ulnar palsy.

The actions of the interossei and lumbricals are many and their loss causes significant impairment of hand function. Many procedures have been described to restore intrinsic function following ulnar nerve palsy. There are many biomechanical issues involved in tendon transfers, including choice of muscle-tendon unit, route, insertion site, tension and drag. The surgeon, therefore, should have a good understanding of biomechanical principles to ensure optimal results. In this article the principles of biomechanics are reviewed with specific reference to tendon transfers for intrinsic reconstruction in ulnar palsy, along with their practical implications.

Erythema nodosum leprosum in Nepal: a retrospective study of clinical features and response to treatment with prednisolone or thalidomide.

INTRODUCTION: Erythema nodosum leprosum (ENL) is an inflammatory reaction, which may occur in the course of leprosy and may result in nerve function impairment and subsequent disability. METHODS: This retrospective study explores demographic and disease specific parameters. Severity of ENL was assessed using the Reaction Severity Scale (RSS). Records of 94 patients were reviewed. The study reports also on the treatment of 76 of these patients who were treated with prednisolone alone or thalidomide in addition to prednisolone. RESULTS Thirty percent of patients presented with ENL at time of diagnosis; 41% developed ENL-reaction in the first year of MDT. Forty-eight percent of patients were treated for ENL-reaction for less than 12 months; 13% for more than 5 years. High RSS-scores correlated with a longer duration of treatment. In group A (prednisolone) 51.7% and in group B (prednisolone and thalidomide) 76.6% of patients were male. Age, leprosy classification, delay of multidrug treatment (MDT) and interval between MDT and first ENL-symptoms did not differ significantly in both groups. Median duration of ENL-treatment was 15 months in group A versus 38 months in group B (P < 0.001). At the start of treatment, ENL-reaction was less severe in group A (RSS = 12) than in group B (RSS = 18; P = 0.003). DISCUSSION: ENL-symptoms may be of help in the early diagnosis and adequate treatment of ENL. Characterisation of (sub) groups of patients with ENL based on presence and severity of symptoms is important for future prospective studies to better evaluate the efficacy of interventions.

Partnership for rehabilitation: looking beyond impairments.

Rehabilitation of leprosy-affected persons extends beyond the physical domain of prevention and treatment of impairments. A holistic rehabilitative approach should include addressing those problems that people may have in activities and difficulties that may prevent people from fully participating in social functions, i.e. being fully accepted as integrated members of the societies and communities to which they belong. This article highlights the activities of the Partnership for the Rehabilitation Program (PFR) of the International Nepal Fellowship (INF), Pokhara, Nepal. These activities aim to prevent, reduce or alleviate problems and difficulties that leprosy-affected persons may face in being respected and being contributing members of the communities of which they are a part.

Particle-mediated gene delivery and human skin: ultrastructural observations on stratum corneum barrier structures.

The particle-mediated delivery systems are becoming a clinically relevant tool in dermatology and immunology. We investigated the qualitative ultrastructural morphology of skin following pressure-driven delivery of gold particles to ex vivo human breast skin, at different pressures ranging from 350 to 1,000 psi. Pressures of 800 and 1,000 psi appear to be more effective, as indicated by distribution of particles in the viable epidermis and dermis. Particle bombardment of the skin with gold beads caused microwounds that spanned the stratum corneum (SC). The SC lipids did not reseal these wounds in the SC after 24 h in organ culture. The implications of particle-mediated delivery to permeability barrier functions of the SC are discussed.

Re-enablement of the neurologically impaired hand--2: surgical correction. report of a surgical workshop held at Green Pastures Hospital and Rehabilitation Centre, November 2004, Pokhara, Nepal.

The last half-century has seen tremendous advances in the surgical treatment of neuropathic conditions of the hand. Many of these procedures give clear benefit to patients and have been established by clinical practice and well-formulated assessment. However, much remains to be discovered, especially with respect to which procedures should be used on which hands, and the impact of various procedures on the ability to carry out activities of daily living. Increased communication between the 'West', where funding is available for well designed trials and where reference textbooks are usually published, and the 'East', where the surgery is most commonly performed, will undoubtedly lead to an even better understanding of the treatment of the neuropathic hand.

Leprosy acquired by inoculation from a knee injury.

This case study reports on the development of clinical leprosy in a young Caucasian female from a non-endemic country who contracted the disease while living in a leprosy endemic country. In the presentation and discussion, some relevant factors will be reviewed and discussed that may play a role in the transmission, susceptibility and clinical development of the disease.