The Mortality Associated with Erythema Nodosum Leprosum in Ethiopia: A Retrospective Hospital-Based Study

Background

Erythema nodosum leprosum (ENL) is a debilitating multisystem disorder which complicates leprosy. It is characterised by fever, malaise and painful erythematous cutaneous nodules. ENL is often recurrent or chronic in nature and frequently severe. Patients often require prolonged treatment with high doses of oral corticosteroids. There are no data on the mortality associated with treated ENL.

Methodology

The notes of patients who were admitted, discharged, transferred to another facility or died with a diagnosis of leprosy or a leprosy-related complication for a five year period were reviewed.

Result/Discussion

414 individuals were identified from the ward database. 312 (75.4%) patient records were located and reviewed. Ninety-nine individuals had ENL and 145 had a Type 1 reaction. The median age of individuals with ENLwas 25 years. Eight patients with erythema nodosum leprosum died compared with two diagnosed with Type 1 reaction. This difference is statistically significant (p = 0.0168, Fisher''s Exact Test). There is a significant mortality and morbidity associated with ENL in this Ethiopian cohort. The adverse outcomes seen are largely attributable to the chronic administration of oral corticosteroids used to control the inflammatory and debilitating symptoms of the condition.     

Expression of CD64 on Circulating Neutrophils Favoring Systemic Inflammatory Status in Erythema Nodosum Leprosum

Erythema Nodosum Leprosum (ENL) is an immune reaction in leprosy that aggravates the patient´s clinical condition. ENL presents systemic symptoms of an acute infectious syndrome with high leukocytosis and intense malaise clinically similar to sepsis. The treatment of ENL patients requires immunosuppression and thus needs to be early and efficient to prevent both disabilities and permanent nerve damage. Some patients experience multiple episodes of ENL and prolonged use of immunosuppressive drugs may lead to serious adverse effects. Thalidomide treatment is extremely effective at ameliorating ENL symptoms. Several mechanisms have been proposed to explain the efficacy of thalidomide in ENL, including the inhibition of TNF production. Given its teratogenicity, thalidomide is prohibitive for women of childbearing age. A rational search for molecular targets during ENL episodes is essential to better understand the disease mechanisms involved, which may also lead to the discovery of new drugs and diagnostic tests. Previous studies have demonstrated that IFN-γ and GM-CSF, involved in the induction of CD64 expression, increase during ENL. The aim of the present study was to investigate CD64 expression during ENL and whether thalidomide treatment modulated its expression. Leprosy patients were allocated to one of five groups: (1) Lepromatous leprosy, (2) Borderline leprosy, (3) Reversal reaction, (4) ENL, and (5) ENL 7 days after thalidomide treatment. The present study demonstrated that CD64 mRNA and protein were expressed in ENL lesions and that thalidomide treatment reduced CD64 expression and neutrophil infiltrates—a hallmark of ENL. We also showed that ENL blood neutrophils exclusively expressed CD64 on the cell surface and that thalidomide diminished overall expression. Patient classification based on clinical symptoms found that severe ENL presented high levels of neutrophil CD64. Collectively, these data revealed that ENL neutrophils express CD64, presumably contributing to the immunopathogenesis of the disease.     

A Systematic Review on the Epidemiological Data of Erythema Nodosum Leprosum,a Type 2 Leprosy Reaction

Background

Erythema Nodosum Leprosum (ENL) is a humoral immunological response in leprosy that leads to inflammatory skin nodules which may result in nerve and organ damage, and may occur years after antibiotic treatment. Multiple episodes are frequent and suppression requires high doses of immunosuppressive drugs. Global occurrence is unknown.

Methodology/Principal Findings

Systematic review of evidence on ENL incidence resulted in 65 papers, predominantly from India (24) and Brazil (9), and inclusive of four reviews. Average incidences are based on cumulative incidence and size of study populations (n>100). In field-based studies 653/54,737 (1.2%) of all leprosy cases, 194/4,279 (4.5%) of MB cases, and 86/560 (15.4%) of LL cases develop ENL. Some studies found a range of 1–8 per 100 person-years-at-risk (PYAR) amongst MB cases. Hospital samples indicate that 2,393/17,513 (13.7%) of MB cases develop ENL. Regional differences could not be confirmed. Multiple ENL episodes occurred in 39 to 77% of ENL patients, with an average of 2.6. Some studies find a peak in ENL incidence in the first year of treatment, others during the second and third year after starting MDT. The main risk factor for ENL is a high bacteriological index.

Conclusions/Significance

Few studies reported on ENL as a primary outcome, and definitions of ENL differed between studies. Although, in this review averages are presented, accurate data on global and regional ENL incidence is lacking. Large prospective studies or accurate surveillance data would be required to clarify this. Health staff needs to be aware of late reactions, as new ENL may develop as late as five years after MDT completion, and reoccurrences up to 8 years afterwards.     

Comparison of Efficacy and Safety of Ciclosporin to Prednisolone in the Treatment of Erythema Nodosum Leprosum: Two Randomised,Double Blind,Controlled Pilot Studies in Ethiopia

Background

Erythema Nodosum Leprosum (ENL) is a serious complication of leprosy. It is normally treated with high dose steroids, but its recurrent nature leads to prolonged steroid usage and associated side effects. There is little evidence on the efficacy of alternative treatments for ENL, especially for patients who have become steroid resistant or have steroid side effects. These two pilot studies compare the efficacy and side effect profile of ciclosporin plus prednisolone against prednisolone alone in the treatment of patients with either new ENL or chronic and recurrent ENL.

Methods and Results

Thirteen patients with new ENL and twenty patients with chronic ENL were recruited into two double-blinded randomised controlled trials. Patients were randomised to receive ciclosporin and prednisolone or prednisolone treatment only. Patients with acute ENL had a delay of 16 weeks in the occurrence of ENL flare-up episode, with less severe flare-ups and decreased requirements for additional prednisolone. Patients with chronic ENL on ciclosporin had the first episode of ENL flare-up 4 weeks earlier than those on prednisolone, as well as more severe ENL flare-ups requiring 2.5 times more additional prednisolone. Adverse events attributable to prednisolone were more common that those attributable to ciclosporin.

Conclusions

This is the first clinical trial on ENL management set in the African context, and also the first trial in leprosy to use patients’ assessment of outcomes. Patients on ciclosporin showed promising results in the management of acute ENL in this small pilot study. But ciclosporin, did not appear to have a significant steroid–sparing effects in patients with chronic ENL, which may have been due to the prolonged use of steroids in these patients in combination with a too rapid decrease of steroids in patients given ciclosporin. Further research is needed to determine whether the promising results of ciclosporin in acute ENL can be reproduced on a larger scale.     

Development and Dematerialization: An International Study

Economic development and growth depend on growing levels of resource use, and result in environmental impacts from large scale resource extraction and emissions of waste. In this study, we examine the resource dependency of economic activities over the past several decades for a set of countries comprising developing, emerging and mature industrialized economies. Rather than a single universal industrial development pathway, we find a diversity of economic dependencies on material use, made evident through cluster analysis. We conduct tests for relative and absolute decoupling of the economy from material use, and compare these with similar tests for decoupling from carbon emissions, both for single countries and country groupings using panel analysis. We show that, over the longer term, emerging and developing countries tend to have significantly larger material-economic coupling than mature industrialized economies (although this effect may be enhanced by trade patterns), but that the contrary is true for short-term coupling. Moreover, we demonstrate that absolute dematerialization limits economic growth rates, while the successful industrialization of developing countries inevitably requires a strong material component. Alternative development priorities are thus urgently needed both for mature and emerging economies: reducing absolute consumption levels for the former, and avoiding the trap of resource-intensive economic and human development for the latter.     

Optimizing Viable Leukocyte Sampling from the Female Genital Tract for Clinical Trials: An International Multi-Site Study

Background

Functional analysis of mononuclear leukocytes in the female genital mucosa is essential for understanding the immunologic effects of HIV vaccines and microbicides at the site of HIV exposure. However, the best female genital tract sampling technique is unclear.

Methods and Findings

We enrolled women from four sites in Africa and the US to compare three genital leukocyte sampling methods: cervicovaginal lavages (CVL), endocervical cytobrushes, and ectocervical biopsies. Absolute yields of mononuclear leukocyte subpopulations were determined by flow cytometric bead-based cell counting. Of the non-invasive sampling types, two combined sequential cytobrushes yielded significantly more viable mononuclear leukocytes than a CVL (p<0.0001). In a subsequent comparison, two cytobrushes yielded as many leukocytes (∼10,000) as one biopsy, with macrophages/monocytes being more prominent in cytobrushes and T lymphocytes in biopsies. Sample yields were consistent between sites. In a subgroup analysis, we observed significant reproducibility between replicate same-day biopsies (r = 0.89, p = 0.0123). Visible red blood cells in cytobrushes increased leukocyte yields more than three-fold (p = 0.0078), but did not change their subpopulation profile, indicating that these leukocytes were still largely derived from the mucosa and not peripheral blood. We also confirmed that many CD4⁺ T cells in the female genital tract express the α4β7 integrin, an HIV envelope-binding mucosal homing receptor.

Conclusions

CVL sampling recovered the lowest number of viable mononuclear leukocytes. Two cervical cytobrushes yielded comparable total numbers of viable leukocytes to one biopsy, but cytobrushes and biopsies were biased toward macrophages and T lymphocytes, respectively. Our study also established the feasibility of obtaining consistent flow cytometric analyses of isolated genital cells from four study sites in the US and Africa. These data represent an important step towards implementing mucosal cell sampling in international clinical trials of HIV prevention.     

Hepatitis A Immunoglobulin: An International Collaborative Study to Establish the Second International Standard

A collaborative study was carried out to assess the suitability of a candidate replacement material for the International Standard for hepatitis A immunoglobulin, which was found to be reactive for HCV RNA, and to calibrate it in International Units. The candidate standard, coded 97/646, was derived from a bulk of 16% immunoglobulin supplied by the Central Laboratory of the Netherlands Red Cross, Amsterdam, and diluted 1 in 2 in H2O resulting in a final immunoglobulin concentration of 8%. Sixteen laboratories from 11 countries participated in the study and contributed data from 64 assays performed using six commercial assay kits and four in-house methods. All assays were analysed as parallel line bioassays comparing assay response with log concentration. The overall mean potency of the candidate replacement immunoglobulin standard, 97/646, relative to the International Standard for hepatitis A immunoglobulin, was 98.6 IU/ml. A freeze-dried serum preparation, 97/648, was also calibrated in this study and had a potency of 22.64 IU/ml. The Second International Standard for hepatitis A immunoglobulin, human, was established by the World Health Organisation Expert Committee on Biological Standardisation in 1998 with a potency of 49 IU per ampoule when reconstituted in 0.5 ml.     

Visualizing Typical Features of Breast Fibroadenomas Using Phase-Contrast CT: An Ex-Vivo Study

Background

Fibroadenoma is the most common benign solid breast lesion type and a very common cause for histologic assessment. To justify a conservative therapy, a highly specific discrimination between fibroadenomas and other breast lesions is crucial. Phase-contrast imaging offers improved soft-tissue contrast and differentiability of fine structures combined with the potential of 3-dimensional imaging. In this study we assessed the potential of grating-based phase-contrast CT imaging for visualizing diagnostically relevant features of fibroadenomas.

Materials and Methods

Grating-based phase-contrast CT was performed on six ex-vivo formalin-fixed breast specimens containing a fibroadenoma and three samples containing benign changes that resemble fibroadenomas using Talbot Lau interferometry and a polychromatic X-ray source. Phase-contrast and simultaneously acquired absorption-based 3D-datasets were manually matched with corresponding histological slices. The visibility of diagnostically valuable features was assessed in comparison with histology as the gold-standard.

Results

In all cases, matching of grating-based phase-contrast CT images and histology was successfully completed. Grating-based phase-contrast CT showed greatly improved differentiation of fine structures and provided accurate depiction of strands of fibrous tissue within the fibroadenomas as well as of the diagnostically valuable dilated, branched ductuli of the fibroadenomas. A clear demarcation of tumor boundaries in all cases was provided by phase- but not absorption-contrast CT.

Conclusions

Pending successful translation of the technology to a clinical setting and considerable reduction of the required dose, the data presented here suggest that grating-based phase-contrast CT may be used as a supplementary non-invasive diagnostic tool in breast diagnostics. Phase-contrast CT may thus contribute to the reduction of false positive findings and reduce the recall and core biopsy rate in population-based screening. Phase-contrast CT may further be used to assist during histopathological workup, offering a 3D view of the tumor and helping to identify diagnostically valuable tissue sections within large tumors.     

Improving the Manchester Triage System for Pediatric Emergency Care: An International Multicenter Study

Objectives

This multicenter study examines the performance of the Manchester Triage System (MTS) after changing discriminators, and with the addition use of abnormal vital sign in patients presenting to pediatric emergency departments (EDs).

Design

International multicenter study

Settings

EDs of two hospitals in The Netherlands (2006–2009), one in Portugal (November–December 2010), and one in UK (June–November 2010).

Patients

Children (<16years) triaged with the MTS who presented at the ED.

Methods

Changes to discriminators (MTS 1) and the value of including abnormal vital signs (MTS 2) were studied to test if this would decrease the number of incorrect assignment. Admission to hospital using the new MTS was compared with those in the original MTS. Likelihood ratios, diagnostic odds ratios (DORs), and c-statistics were calculated as measures for performance and compared with the original MTS. To calculate likelihood ratios and DORs, the MTS had to be dichotomized in low urgent and high urgent.

Results

60,375 patients were included, of whom 13% were admitted. When MTS 1 was used, admission to hospital increased from 25% to 29% for MTS ‘very urgent’ patients and remained similar in lower MTS urgency levels. The diagnostic odds ratio improved from 4.8 (95%CI 4.5–5.1) to 6.2 (95%CI 5.9–6.6) and the c-statistic remained 0.74. MTS 2 did not improve the performance of the MTS.

Conclusions

MTS 1 performed slightly better than the original MTS. The use of vital signs (MTS 2) did not improve the MTS performance.     

Complexity in Non-Pharmacological Caregiving Activities at the End of Life: An International Qualitative Study

Background

In late-stage palliative cancer care, relief of distress and optimized well-being become primary treatment goals. Great strides have been made in improving and researching pharmacological treatments for symptom relief; however, little systematic knowledge exists about the range of non-pharmacological caregiving activities (NPCAs) staff use in the last days of a patient''s life.

Methods and Findings

Within a European Commission Seventh Framework Programme project to optimize research and clinical care in the last days of life for patients with cancer, OPCARE9, we used a free-listing technique to identify the variety of NPCAs performed in the last days of life. Palliative care staff at 16 units in nine countries listed in detail NPCAs they performed over several weeks. In total, 914 statements were analyzed in relation to (a) the character of the statement and (b) the recipient of the NPCA. A substantial portion of NPCAs addressed bodily care and contact with patients and family members, with refraining from bodily care also described as a purposeful caregiving activity. Several forms for communication were described; information and advice was at one end of a continuum, and communicating through nonverbal presence and bodily contact at the other. Rituals surrounding death and dying included not only spiritual/religious issues, but also more subtle existential, legal, and professional rituals. An unexpected and hitherto under-researched area of focus was on creating an aesthetic, safe, and pleasing environment, both at home and in institutional care settings.

Conclusions

Based on these data, we argue that palliative care in the last days of life is multifaceted, with physical, psychological, social, spiritual, and existential care interwoven in caregiving activities. Providing for fundamental human needs close to death appears complex and sophisticated; it is necessary to better distinguish nuances in such caregiving to acknowledge, respect, and further develop end-of-life care. Please see later in the article for the Editors'' Summary     

Association Between Serum Magnesium and the Prevalence of Kidney Stones: a Cross-sectional Study

Biological Trace Element Research - Kidney stones, a painful and costly disease, have become a public health problem worldwide. The aim of this study was to evaluate the association between serum...     

肠系膜上动脉栓塞临床表现及影像特征研究

目的:探讨肠系膜上动脉栓塞(superior mesenteric artery embolism,SMA embolism)临床及影像特征,以及时准确诊断从而改善病人预后。方法:搜集我院2011年7月至2014年8月临床诊断为SMA栓塞的患者24例,回顾性分析其临床及影像资料。结果:24例SMA栓塞发病年龄51~84岁,平均71.9±8.1岁;临床均表现为突发腹痛(24/24,100%),腹痛多持续不缓解(18/24,75%),少有放射痛(1/24,4.17%),多伴有恶心呕吐(16/24,66.67%)、腹泻便血(15/24,62.5%),体格检查多有肠鸣音亢进(19/24,79.17%),少有腹膜刺激征(2/24,8.33%)。多合并高血压(18/24,75%)、房颤(16/24,66.67%)、冠心病(14/24,58.33%)、心脏瓣膜病变(6/24,25%)及其他周围动脉栓塞(9/24,37.5%)。临床上符合SMA栓塞三联征中至少两项特征20例(83.33%),具备典型三联征13例(54.17%)。MSCTA或DSA均表现为SMA主干截断或充盈缺损(24/24,100%),栓塞位置多位于第1空肠动脉起始至回结肠动脉起始水平段(18/24,75%),栓塞远端分支血管多显影不良(23/24,95.83%),少有侧枝循环形成(3/24,12.5%)。MSCTA显示栓塞段血管密度多有增高(12/17,70.59%),少有管径增粗(3/17,17.65%)及脂肪间隙模糊(2/17,11.76%)。肠管多有缺血改变(15/17,88.24%),肠系膜多增粗模糊(15/17,88.24%),腹水少见(1/17,5.82%)。结论:SMA栓塞临床和影像具有一定的特征性,临床怀疑SMA栓塞应及早行MSCTA或DSA明确诊断。     

Thrombocytopenia Is Associated with Acute Respiratory Distress Syndrome Mortality: An International Study

Background

Early detection of the Acute Respiratory Distress Syndrome (ARDS) has the potential to improvethe prognosis of critically ill patients admitted to the intensive care unit (ICU). However, no reliable biomarkers are currently available for accurate early detection of ARDS in patients with predisposing conditions.

Objectives

This study examined risk factors and biomarkers for ARDS development and mortality in two prospective cohort studies.

Methods

We examined clinical risk factors for ARDS in a cohort of 178 patients in Beijing, China who were admitted to the ICU and were at high risk for ARDS. Identified biomarkers were then replicated in a second cohort of1,878 patients in Boston, USA.

Results

Of 178 patients recruited from participating hospitals in Beijing, 75 developed ARDS. After multivariate adjustment, sepsis (odds ratio [OR]:5.58, 95% CI: 1.70–18.3), pulmonary injury (OR: 3.22; 95% CI: 1.60–6.47), and thrombocytopenia, defined as platelet count <80×10³/µL, (OR: 2.67; 95% CI: 1.27–5.62)were significantly associated with increased risk of developing ARDS. Thrombocytopenia was also associated with increased mortality in patients who developed ARDS (adjusted hazard ratio [AHR]: 1.38, 95% CI: 1.07–1.57) but not in those who did not develop ARDS(AHR: 1.25, 95% CI: 0.96–1.62). The presence of both thrombocytopenia and ARDS substantially increased 60-daymortality. Sensitivity analyses showed that a platelet count of <100×10³/µLin combination with ARDS provide the highest prognostic value for mortality. These associations were replicated in the cohort of US patients.

Conclusions

This study of ICU patients in both China and US showed that thrombocytopenia is associated with an increased risk of ARDS and platelet count in combination with ARDS had a high predictive value for patient mortality.     

Dementia of the Alzheimer Type: An Oral and Biochemical Study1

Alzheimer's disease, or pre-senile dementia, may occur as early as 40 years. Pathologically, there is, besides a loss of brain weight, a conical atrophy with ventricular dilatation and typical microscopic lesions in the cortex and the hippocampus. Previously, the authors [Sanchez & Gonzalez, 1986] have studied the modifications of the amino acids (AA) composition in the cerebrospinal fluid (CSF), Even if some were increased without specificity, three of them were decreased significantly in this type of dementia (Serine, Glutamate and Aspartate). Twenty subjects were studied (15 with Alzheimer's disease and 5 non-patients) having a mean age of 72 years. For each subject, two samples were tested (one blood and one saliva sample). In this study we tried to determine if our results would be similar to those previously obtained in the CSF, but in a different biological fluid, the saliva. Of the 13 AA of the saliva, tested by gas-liquid chromatology (Spectra Physics 7100), 3 were increased significantly, and curiously, these were similar to those found to be decreased in CSF. We attempted to find the possible biological and oral repercussions of this dementia, which is the most frequent type in elderly patients.