Lack of evidence for the presence of leprosy bacilli in red squirrels from North-West Europe.

Leprosy is a human infectious disease caused by Mycobacterium leprae or Mycobacterium lepromatosis that can also occur in animals and even manifest as zoonosis. Recently, both mycobacteria were detected in red squirrels (Sciurus vulgaris) from the British Isles. To further explore the presence of leprosy bacilli in North-West Europe, we screened Belgian and Dutch squirrels. Tissue samples from 115 animals tested by qPCR were negative for both pathogens. No molecular or pathological evidence was found of the presence of these zoonotic pathogens in North-West Europe.

Whole blood RNA signatures in leprosy patients identify reversal reactions before clinical onset: a prospective, multicenter study.

Early diagnosis of leprosy is challenging, particularly its inflammatory reactions, the major cause of irreversible neuropathy in leprosy. Current diagnostics cannot identify which patients are at risk of developing reactions. This study assessed blood RNA expression levels as potential biomarkers for leprosy. Prospective cohorts of newly diagnosed leprosy patients, including reactions, and healthy controls were recruited in Bangladesh, Brazil, Ethiopia and Nepal. RNA expression in 1,090 whole blood samples was determined for 103 target genes for innate and adaptive immune profiling by dual color Reverse-Transcription Multiplex Ligation-dependent Probe Amplification (dcRT-MLPA) followed by cluster analysis. We identified transcriptomic biomarkers associated with leprosy disease, different leprosy phenotypes as well as high exposure to Mycobacterium leprae which respectively allow improved diagnosis and classification of leprosy patients and detection of infection. Importantly, a transcriptomic signature of risk for reversal reactions consisting of five genes (CCL2, CD8A, IL2, IL15 and MARCO) was identified based on cross-sectional comparison of RNA expression. In addition, intra-individual longitudinal analyses of leprosy patients before, during and after treatment of reversal reactions, indicated that several IFN-induced genes increased significantly at onset of reaction whereas IL15 decreased. This multi-site study, situated in four leprosy endemic areas, demonstrates the potential of host transcriptomic biomarkers as correlates of risk for leprosy. Importantly, a prospective five-gene signature for reversal reactions could predict reversal reactions at least 2 weeks before onset. Thus, transcriptomic biomarkers provide promise for early detection of these acute inflammatory episodes and thereby help prevent permanent neuropathy and disability in leprosy patients.

An enhanced regimen as post-exposure chemoprophylaxis for leprosy: PEP+.

The ongoing transmission of Mycobacterium (M.) leprae reflected in a very slow decline in leprosy incidence, forces us to be innovative and conduct cutting-edge research. Single dose rifampicin (SDR) as post-exposure prophylaxis (PEP) for contacts of leprosy patients, reduces their risk to develop leprosy by 60%. This is a promising new preventive measure that can be integrated into routine leprosy control programmes, as is being demonstrated in the Leprosy Post-Exposure Programme that is currently ongoing in eight countries.The limited (60%) effectiveness of SDR is likely due to the fact that some contacts have a preclinical infection beyond the early stages for which SDR is not sufficient to prevent the development of clinical signs and symptoms of leprosy. An enhanced regimen, more potent against a higher load of leprosy bacteria, would increase the effectiveness of this preventive measure significantly.The Netherlands Leprosy Relief (NLR) is developing a multi-country study aiming to show that breaking the chain of transmission of M. leprae is possible, evidenced by a dramatic reduction in incidence. In this study the assessment of the effectiveness of an enhanced prophylactic regimen for leprosy is an important component. To define the so called PEP++ regimen for this intervention study, NLR convened an Expert Meeting that was attended by clinical leprologists, public health experts, pharmacologists, dermatologists and microbiologists.The Expert Meeting advised on combinations of available drugs, with known efficacy against leprosy, as well as on the duration of the intake, aiming at a risk reduction of 80-90%. To come to a conclusion the Expert Meeting considered the bactericidal, sterilising and bacteriostatic activity of the potential drugs. The criteria used to determine an optimal enhanced regimen were: effectiveness, safety, acceptability, availability, affordability, feasibility and not inducing drug resistance.The Expert Meeting concluded that the enhanced regimen for the PEP++ study should comprise three standard doses of rifampicin 600 mg (weight adjusted when given to children) plus moxifloxacin 400 mg given at four-weekly intervals. For children and for adults with contraindications for moxifloxacin, moxifloxacin should be replaced by clarithromycin 300 mg (weight adjusted).

Factors Associated With Wound- and Implant-Related Complications After Surgical Treatment of Ankle Fractures.

We have described the epidemiology of complications after surgical treatment of ankle fractures and assessed which factors are associated with the most frequent complications. We conducted a retrospective cohort study at 2 level 2 and 1 level 1 trauma center in a single trauma region in the Netherlands. The study variables were collected from the electronic medical patient records; all ankle fractures were classified using the Lauge-Hansen classification, and the complications were recorded. A total of 989 patients were included from 3 hospitals, with 173 complications in 156 patients (15.8%). The most frequent complication was wound related, occurring in 101 patients (10.2%). Implant-related complications occurred in 44 patients (4.4%). Other complications, such as cast pressure spots, posttraumatic dystrophy, nonunion, impingement, and pneumonia occurred in 28 patients (2.8%). The 2 most important complications were further analyzed for risk factors. Multivariate analysis showed the risk factors for wound-related complications were advanced age, increased American Society of Anesthesiologists classification, smoking, right side symptomatic, open fracture, and initial external fixation. Most implant-related complications were caused by malreduction (n = 22) or untreated syndesmotic injury (n = 19). Malreduction was associated with supination eversion fractures (p = .059), and untreated syndesmotic injury occurred more often with pronation external rotation fractures (p < .001). The most frequent complications after ankle fracture surgery were wound- and implant-related complications. Postoperative wound-related complications were multifactorial and dependent on a combination of trauma-, patient-, and treatment-related factors. In contrast, implant-related complications resulted from the interaction between the fracture type and subsequent surgical treatment.

Extensive sonographic ulnar nerve enlargement above the medial epicondyle is a characteristic sign in Hansen's neuropathy.

OBJECTIVE: Earlier studies have shown sonographic enlargement of the ulnar nerve in patients with Hansen's neuropathy. The present study was performed to determine whether sonography or electrophysiological studies can detect the specific site of ulnar nerve pathology in leprosy. METHODS: Eighteen patients (thirty arms) with Hansen's disease and an ulnar neuropathy of whom 66% had borderline tuberculoid (BT), 27% lepromatous leprosy (LL) and 7% mid-borderline (BB) leprosy were included in the study. Cross-sectional area (CSA) of ulnar nerve was measured every two centimeters from wrist to medial epicondyle and from there to axilla. All patients underwent standard motor and sensory nerve conduction studies of the ulnar nerve. Thirty age and sex matched controls underwent similar ulnar nerve CSA measurements and conduction studies. RESULTS: Ulnar nerve was clinically palpable in 19 of the 30 arms of patients. Motor and sensory nerve conduction studies of the ulnar nerve showed a reduced compound motor action potential and sensory nerve action potential amplitude in all patients. Motor Conduction Velocity (MCV) in patients were slower in comparison to controls, especially at the elbow and upper arm, but unable to exactly locate the site of the lesion. In comparison to controls the ulnar nerveCSA was larger in the whole arm in patients and quite specific the maximum enlargement was seen between nulnar sulcus and axilla, peaking at four centimeters above the sulcus. CONCLUSIONS: A unique sonographic pattern of nerve enlargement is noted in patients with ulnar neuropathy due to Hansen's disease, while this was not the case for the technique used until now, the electrodiagnostic testing. The enlargement starts at ulnar sulcus and is maximum four centimeters above the medial epicondyle and starts reducing further along the tract. This characteristic finding can help especially in diagnosing pure neuritic type of Hansen's disease, in which skin lesions are absent, and alsoto differentiate leprosy from other neuropathies in which nerve enlargement can occur.

Weight bearing or non-weight bearing after surgically fixed ankle fractures, the WOW! Study: study protocol for a randomized controlled trial.

BACKGROUND: The optimal post-operative care regimen after surgically fixed Lauge Hansen supination exorotation injuries remains to be established. This study compares whether unprotected weight bearing as tolerated is superior to protected weight bearing and unprotected non-weight bearing in terms of functional outcome and safety. METHODS/DESIGN: The WOW! Study is a prospective multicenter clinical trial. Patients between 18 and 65 years of age with a Lauge Hansen supination exorotation type 2, 3 or 4 ankle fractures requiring surgical treatment are eligible for inclusion. An expert panel validates the classification and inclusion eligibility. After surgery, patients are randomized to either the 1) unprotected non-weight-bearing, 2) protected weight-bearing, or 3) unprotected weight-bearing group. The primary outcome measure is ankle-specific disability measured by the Olerud-Molander ankle score. Secondary outcomes are 1) quality of life (e.g., return to work and resumption of sport), 2) complications, 3) range of motion, 4) calf wasting, and 5) maximum pressure load after 3 months and 1 year. DISCUSSION: This trial is designed to compare the effectiveness and safety of unprotected weight bearing with two commonly used post-operative treatment regimens after internal fixation of specified, intrinsically stable but displaced ankle fractures. An expert panel has been established to evaluate every potential subject, which ensures that every patient is strictly screened according to the inclusion and exclusion criteria and that there is a clear indication for surgical fixation. TRIAL REGISTRATION: The WOW! Study is registered in the Dutch Trial Register ( NTR3727 ). Date of registration: 28-11-2012.

The combined effect of chemoprophylaxis with single dose rifampicin and immunoprophylaxis with BCG to prevent leprosy in contacts of newly diagnosed leprosy cases: a cluster randomized controlled trial (MALTALEP study).

BACKGROUND: Despite almost 30 years of effective chemotherapy with MDT, the global new case detection rate of leprosy has remained quite constant over the past years. New tools and methodologies are necessary to interrupt the transmission of M. leprae. Single-dose rifampicin (SDR) has been shown to prevent 57% of incident cases of leprosy in the first two years, when given to contacts of newly diagnosed cases. Immunization of contacts with BCG has been less well documented, but appears to have a preventive effect lasting up to 9 years. However, one major disadvantage is the occurrence of excess cases within the first year after immunization. The objective of this study is to examine the effect of chemoprophylaxis with SDR and immunoprophylaxis with BCG on the clinical outcome as well as on host immune responses and gene expression profiles in contacts of newly diagnosed leprosy patients. We hypothesize that the effects of both interventions may be complementary, causing the combined preventive outcome to be significant and long-lasting. METHODS/DESIGN: Through a cluster randomized controlled trial we compare immunization with BCG alone with BCG plus SDR in contacts of new leprosy cases. Contact groups of around 15 persons will be established for each of the 1300 leprosy patients included in the trial, resulting in approximately 20,000 contacts in total. BCG will be administered to the intervention group followed by SDR, 2 months later. The control group will receive BCG only. In total 10,000 contacts will be included in both intervention arms over a 2-year period. Follow-up will take place one year as well as two years after intake. The primary outcome is the occurrence of clinical leprosy within two years. Simultaneously with vaccination and SDR, blood samples for in vitro analyses will be obtained from 300 contacts participating in the trial to determine the effect of these chemo- and immunoprophylactic interventions on immune and genetic host parameters. DISCUSSION: Combined chemoprophylaxis and immunoprophylaxis is potentially a very powerful and innovative tool aimed at contacts of leprosy patients that could reduce the transmission of M. leprae markedly. The trial intends to substantiate this potential preventive effect. Evaluation of immune and genetic biomarker profiles will allow identification of pathogenic versus (BCG-induced) protective host biomarkers and could lead to effective prophylactic interventions for leprosy using optimized tools for identification of individuals who are most at risk of developing disease. TRIAL REGISTRATION: Netherlands Trial Register: NTR3087.

An international multicenter study on quality of life and family quality of life in children with atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) has severe impact on the quality of life (QoL) of children suffering from the disease and their families. The infant's dermatitis quality of life index (IDQoL) and the dermatitis family impact questionnaire (DFI) were designed to study this impact. AIMS: To compare the impact of AD on children and their families in different countries. METHODS: 419 children with AD from six countries representing three continents under the age of 4 years were included into the study. English, Ukrainian, Czech, Portuguese, and Korean versions of the IDQoL and the DFI and Dutch version of the IDQoL questionnaires were used. RESULTS: The highest scored items for the IDQoL and the DFI were rather similar. The IDQoL and the DFI results were well correlated with parental assessment of disease severity and between each other in all countries. Some differences mostly in the IDQoL assessment were found. CONCLUSION: Despite some reported peculiarities, parents in different counties assessed QoL and family QoL of their AD children in a similar way. The IDQoL and the DFI may be reliable initial measures for international studies. International study on the influence of the same treatment methods on the IDQoL and the DFI assessments is important.

[A man with a white macula]. / Een man met witte vlekken.

A man from the Dominican Republic presented with a white macula on the arm with sensibility loss. Skin biopsy showed a dermatitis with infiltration of dermal nerves. The diagnosis was indeterminate leprosy.

Social implications of leprosy in the Netherlands--stigma among ex-leprosy patients in a non-endemic setting.

BACKGROUND: In the Netherlands, leprosy is a rare and non-endemic disease, still occurring as an 'import disease'. Moreover a considerable group of people affected by leprosy, originating mainly from the former Dutch colonies, suffer from neuropathic complications. This study investigates the social implications of leprosy for those affected in the Netherlands. METHODS: Thirty-one people affected were interviewed as well as six medical leprosy experts. The social implications were measured by means of semi-structured interviews and the Participation Scale. RESULTS: Self-stigma, shame and secrecy were often reported. Discrimination and stigmatisation of ex-leprosy patients by people around them seems a less frequent problem. Yet, people affected by leprosy seem to be a forgotten group with a high social burden due to low self-esteem and reduced social participation. Medical experts do not seem to be aware of the severity of leprosy-related forms of stigma in their patients. Ex-leprosy patients lack sound disease-related information and support groups. Due to the low incidence and as a consequence, the lack of awareness among doctors, leprosy patients in the Netherlands are faced with substantial diagnostic delay (mean delay 1-8 years). CONCLUSIONS: Leprosy and its stigma affect the social lives of patients, even in a non-endemic area such as the Netherlands. Almost all respondents were affected by self-stigma. There is a need for 1) more information and support groups for patients, and 2) increased awareness among professionals.

Report of the Stigma Research Workshop for the development of scientific consensus papers and field guidelines on health-related stigma, held in Amsterdam, the Netherlands from 11-14 october 2010.

Summary In concurrence with the broad body of literature published on health-related stigma, there is a need for practical field guidance to contribute to the fight against leprosy-related stigma and discrimination. To this end, much can be gained by considering the accumulated knowledge and learned from experience with different stigmatising conditions; primarily HIV/AIDS, disability, tuberculosis, and mental health. Therefore a Stigma Research Workshop was organised from 11-14 October in Amsterdam, The Netherlands. The primary aim of the workshop was to produce scientific papers and field guidelines that could be used to target actions against health-related stigma and discrimination. Keynote presentations were offered by scientists and professionals from different health domains who shared their knowledge, experiences and research findings regarding health-related stigma. Group work was subsequently conducted to work towards agreed outputs on four different themes: i.e. research priorities, measurement, interventions, and counselling. The spectrum of expertise present enabled an interdisciplinary and inter-profession sharing of knowledge and practices. This resulted in the commencement of consensus papers and field guidelines related to the four themes. An evaluation by participants concluded that the workshop had been an informative and worthwhile activity that will strengthen the fight against stigma.

Effects of impairments on activities and participation in people affected by leprosy in The Netherlands.

OBJECTIVE: To assess the prevalence of impairments and evaluate the relationships between impairments, activity limitations and participation restrictions in people affected by leprosy living in The Netherlands. DESIGN: A cross-sectional study. SUBJECTS: Eighty-two people affected by leprosy living in The Netherlands. METHODS: A postal questionnaire was performed. Impairments were inventoried with the Total Impairment Score. Activity limitations were assessed with the World Health Organization Disability Schedule II (WHODAS-II) and participation restrictions with the Impact on Participation and Autonomy (IPA) questionnaire. RESULTS: A high prevalence of impairments was found (83%), mostly in hands and feet. Activity limitations were substantial, and highest for the WHODAS-II domains "household/work" and "getting around". The severity of impairments correlated significantly with activity limitations. Eye and foot impairments independently contributed to the domains "household/work" and "getting around", explaining 34% and 40% of variance. Poor or very poor participation (IPA) was reported by 13-32% of persons, mostly in the "autonomy outdoors" and "family role" domains. These domains were associated with activity limitations and hand impairments CONCLUSIONS: People affected by leprosy in The Netherlands encounter limitations in activities and participation restrictions, which are related to the severity of impairments. The high prevalence of disability suggests rehabilitation care should be considered for a substantial proportion of people affected by leprosy.

['Rheumatoid arthritis' in a Surinamese man: leprosy]. / 'Reumatoïde artritis' bij een Surinaamse man: lepra.

Rheumatoid arthritis was diagnosed in a 65-year-old man from Suriname, on the basis of clinical and radiological findings. However, he was eventually diagnosed with leprosy. This emerged when the patient developed skin lesions and complained of increasing sensibility disorders during treatment for the alleged rheumatoid arthritis. He was treated with a combination therapy consisting of rifampicin, clofazimine, dapsone, and prednisone. The skin lesions and joint symptoms were resolved as a result of this, but the sensibility disorders persisted. As physicians are not sufficiently familiar with leprosy and the condition has many manifestations that can mimic more frequently occurring diseases, leprosy is often diagnosed at a later stage. This may result in irreversible damage, especially to the peripheral nerves, which may lead to disability. Therefore, for patients who originate from areas where leprosy is endemic and who suffer from joint complaints in combination with skin or sensibility disorders, the diagnosis of leprosy should be considered.

Rational combination of peptides derived from different Mycobacterium leprae proteins improves sensitivity for immunodiagnosis of M. leprae infection.

The stable incidence of new leprosy cases suggests that transmission of infection is continuing despite the worldwide implementation of multidrug therapy programs. Highly specific tools are required to accurately diagnose asymptomatic and early stage Mycobacterium leprae infections which are the likely sources of transmission and cannot be identified by using the detection of antibodies against phenolic glycolipid I. One of the hurdles hampering T-cell-based diagnostic tests is that M. leprae antigens cross-react at the T-cell level with antigens present in other mycobacteria, like M. tuberculosis or M. bovis bacillus Calmette-Guerin (BCG). Using comparative genomics, we previously identified five candidate proteins highly restricted to M. leprae which showed promising features with respect to application in leprosy diagnostics. However, despite the lack of overall sequence homology, the use of recombinant proteins includes the risk of detecting T-cell responses that are cross-reactive with other antigens. To improve the diagnostic potential of these M. leprae sequences, we used 50 synthetic peptides spanning the sequences of all five proteins for the induction of T-cell responses (gamma interferon) in leprosy patients, healthy household contacts (HHC) of leprosy patients, and healthy controls in Brazil, as well as in tuberculosis patients, BCG vaccinees, and healthy subjects from an area of nonendemicity. Using the combined T-cell responses toward four of these peptides, all paucibacillary patients and 13 out of 14 HHC were detected without compromising specificity. The peptides contain HLA binding motifs for various HLA class I and II alleles, thereby meeting an important requirement for the applicability of diagnostic tools in genetically diverse populations. Thus, this study provides the first evidence for the possibility of immunodiagnostics for leprosy based on mixtures of peptides recognized in the context of different HLA alleles.

[Contributions of the Netherlands and its colonies to the knowledge of the cause of leprosy in the 19th century]. / Bijdragen van Nederland en zijn koloniën aan de kennis over de oorzaak van lepra in de 19e eeuw.

OBJECTIVE: To determine the Dutch contributions to the formulation of the concept that leprosy is an infectious disease. DESIGN: Literature study. METHOD: A search for relevant publications was made in the Nederlands Tijdschrift voor Geneeskunde (Dutch journal of Medicine; NTvG) and the Geneeskundig Tijdschrift voor Nederlandsch-Indië (Medical Journal of the Dutch Indies; GTNI) with the aid of the search terms 'lepra [leprosy]', 'lepra Arabum [Arab leprosy]', 'melaatsheid [leprosy]' and 'elephantiasis Graecorum [Greek elephantiasis]'. In addition, on the basis of references in the publications in the NTvG and the GTNI, as well as via searches in the catalogues of the Royal Library in The Hague and the libraries of Dutch universities, an inventory was made of the Dutch medical dissertations and other monographs on leprosy, as well as the medical historical review articles, from the 19th century. RESULTS: For a long time, physicians described the aetiology of leprosy in terms of 'a substrate' to which all sorts of mixtures of infection, heredity and hygiene contributed. From the middle of the 19th century onwards, this explanatory model with multiple possible solutions gave way to a controversy between two explanatory models: heredity as an 'anti-contagious' principle versus contagiosity. These two explanatory models were mutually exclusive in their universal aspirations. The debate in the Netherlands took place in the field of tension between European concepts on the one hand and on the other hand ideas and practices resulting from the interaction between the Netherlands and its colonies. Inspired in part by the writings of the Dutch physician C L Drognat Landré, who based his contagion theory on observations in Surinam, the Norwegian G. H. A. Hansen discovered the leprosy bacillus in 1873. It was not until 1897, at the international leprosy conference in Berlin, however, that consensus was to be reached on leprosy being an infectious disease. CONCLUSION: An essential contribution to the development of the contemporary ideas as to the cause of leprosy was made from the Netherlands.

[Thalidomide: new uses for an old drug]. / Thalidomide: nieuwe toepassingen voor een oud geneesmiddel.

Thalidomide was withdrawn from the market in the early sixties because of its teratogenic effects. Despite forty years of research, the mechanism of thalidomide embryopathy has remained unsolved. Thalidomide has various immunomodulatory effects. Thalidomide inhibits TNF alpha production, has T-cell costimulatory properties and modulates the expression of cell surface molecules on leukocytes in vivo. Thalidomide also has anti-angiogenic activity in vivo. Angiogenesis plays an important role in the pathogenesis of both solid tumours and hematologic malignancies such as multiple myeloma and lymphoma. In clinical studies, thalidomide has been used as an inhibitor of angiogenesis. Erythema nodosum leprosum is the only registered indication for the use of thalidomide in the United States of America. Thalidomide is also effective in the treatment of chronic graft-versus-host disease, mucocutaneous lesions in Behçet's syndrome and HIV infections, and multiple myeloma.