Cesar Ugarte-Gil

MMP-1 drives immunopathology in human tuberculosis and transgenic mice

Mycobacterium tuberculosis can cause lung tissue damage to spread, but the mechanisms driving this immunopathology are poorly understood. The breakdown of lung matrix involves MMPs, which have a unique ability to degrade fibrillar collagens at neutral pH. To determine whether MMPs play a role in the immunopathology of tuberculosis (TB), we profiled MMPs and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs), in sputum and bronchoalveolar lavage fluid from patients with TB and symptomatic controls. MMP-1 concentrations were significantly increased in both HIV-negative and HIV-positive patients with TB, while TIMP concentrations were lower in HIV-negative TB patients. In primary human monocytes, M. tuberculosis infection selectively upregulated MMP1 gene expression and secretion, and Ro32-3555, a specific MMP inhibitor, suppressed M. tuberculosis-driven MMP-1 activity. Since the mouse MMP-1 ortholog is not expressed in the lung and mice infected with M. tuberculosis do not develop tissue destruction equivalent to humans, we infected transgenic mice expressing human MMP-1 with M. tuberculosis to investigate whether MMP-1 caused lung immunopathology. In the MMP-1 transgenic mice, M. tuberculosis infection increased MMP-1 expression, resulting in alveolar destruction in lung granulomas and significantly greater collagen breakdown. In summary, MMP-1 may drive tissue destruction in TB and represents a therapeutic target to limit immunopathology.

Bartonella bacilliformis: a systematic review of the literature to guide the research agenda for elimination.

Background Carrions disease affects small Andean communities in Peru, Colombia and Ecuador and is characterized by two distinct disease manifestations: an abrupt acute bacteraemic illness (Oroya fever) and an indolent cutaneous eruptive condition (verruga Peruana). Case fatality rates of untreated acute disease can exceed 80% during outbreaks. Despite being an ancient disease that has affected populations since pre-Inca times, research in this area has been limited and diagnostic and treatment guidelines are based on very low evidence reports. The apparently limited geographical distribution and ecology of Bartonella bacilliformis may present an opportunity for disease elimination if a clear understanding of the epidemiology and optimal case and outbreak management can be gained. Methods All available databases were searched for English and Spanish language articles on Carrions disease. In addition, experts in the field were consulted for recent un-published work and conference papers. The highest level evidence studies in the fields of diagnostics, treatment, vector control and epidemiology were critically reviewed and allocated a level of evidence, using the Oxford Centre for Evidence-Based Medicine (CEBM) guidelines. Results A total of 44 studies were considered to be of sufficient quality to be included in the analysis. The majority of these were level 4 or 5 (low quality) evidence and based on small sample sizes. Few studies had been carried out in endemic areas. Conclusions Current approaches to the diagnosis and management of Carrions disease are based on small retrospective or observational studies and expert opinion. Few studies take a public health perspective or examine vector control and prevention. High quality studies performed in endemic areas are required to define optimal diagnostic and treatment strategies.

Induced Sputum MMP-1, -3 & -8 concentrations during treatment of tuberculosis

Introduction Tuberculosis (TB) destroys lung tissues and this immunopathology is mediated in part by Matrix Metalloproteinases (MMPs). There are no data on the relationship between local tissue MMPs concentrations, anti-tuberculosis therapy and sputum conversion. Materials and Methods Induced sputum was collected from 68 TB patients and 69 controls in a cross-sectional study. MMPs concentrations were measured by Luminex array, TIMP concentrations by ELISA and were correlated with a disease severity score (TBscore). 46 TB patients were then studied longitudinally at the 2nd, 8th week and end of treatment. Results Sputum MMP-1,-2,-3,-8,-9 and TIMP-1 and -2 concentrations are increased in TB. Elevated MMP-1 and -3 concentrations are independently associated with higher TB severity scores (p<0.05). MMP-1, -3 and -8 concentrations decreased rapidly during treatment (p<0.05) whilst there was a transient increase in TIMP-1/2 concentrations at week 2. MMP-2, -8 and -9 and TIMP-2 concentrations were higher at TB diagnosis in patients who remain sputum culture positive at 2 weeks and MMP-3, -8 and TIMP-1 concentrations were higher in these patients at 2nd week of TB treatment. Conclusions MMPs are elevated in TB patients and associate with disease severity. This matrix-degrading phenotype resolves rapidly with treatment. The MMP profile at presentation correlates with a delayed treatment response.

Private sector contributions and their effect on physician emigration in the developing world.

The contribution made by the private sector to health care in a low- or middle-income country may affect levels of physician emigration from that country. The increasing importance of the private sector in health care in the developing world has resulted in newfound academic interest in that sectors influences on many aspects of national health systems. The growth in physician emigration from the developing world has led to several attempts to identify both the factors that cause physicians to emigrate and the effects of physician emigration on primary care and population health in the countries that the physicians leave. When the relevant data on the emerging economies of Ghana, India and Peru were investigated, it appeared that the proportion of physicians participating in private health-care delivery, the percentage of health-care costs financed publicly and the amount of private health-care financing per capita were each inversely related to the level of physician expatriation. It therefore appears that private health-care delivery and financing may decrease physician emigration. There is clearly a need for similar research in other low- and middle-income countries, and for studies to see if, at the country level, temporal trends in the contribution made to health care by the private sector can be related to the corresponding trends in physician emigration. The ways in which private health care may be associated with access problems for the poor and therefore reduced equity also merit further investigation. The results should be of interest to policy-makers who aim to improve health systems worldwide.

Diagnostic accuracy of nucleic acid amplification tests (NAATs) in urine for genitourinary tuberculosis: a systematic review and meta-analysis

BackgroundGenitourinary tuberculosis is the third most common form of extrapulmonary tuberculosis. Diagnosis is difficult because of unspecific clinical manifestations and low accuracy of conventional tests. Unfortunately, the delayed diagnosis impacts the urinary tract severely. Nucleic acid amplification tests yield fast results, and among these, new technologies can also detect drug resistance. There is lack of consensus regarding the use of these tests in genitourinary tuberculosis; we therefore aimed to assess the accuracy of nucleic acid amplification tests in the diagnosis of genitourinary tuberculosis and to evaluate the heterogeneity between studies.MethodsWe did a systematic review and meta-analysis of research articles comparing the accuracy of a reference standard and a nucleic acid amplification test for diagnosis of urinary tract tuberculosis. We searched Medline, EMBASE, Web of Science, LILACS, Cochrane Library, and Scopus for articles published between Jan 1, 1990, and Apr 14, 2016. Two investigators identified eligible articles and extracted data for individual study sites. We analyzed data in groups with the same index test. Then, we generated pooled summary estimates (95% CIs) for sensitivity and specificity by use of random-effects meta-analysis when studies were not heterogeneous.ResultsWe identified eleven relevant studies from ten articles, giving information on PCR, LCR and Xpert MTB/RIF tests. All PCR studies were “in-house” tests, with different gene targets and had several quality concerns therefore we did not proceed with a pooled analysis. Only one study used LCR. Xpert studies were of good quality and not heterogeneous, pooled sensitivity was 0·87 (0·66–0·96) and specificity was 0·91 (0·84–0·95).ConclusionPCR studies were highly heterogeneous. Among Xpert MTB/RIF studies, specificity was favorable with an acceptable confidence interval, however new studies can update meta-analysis and get more precise estimates. Further high-quality studies are urgently needed to improve diagnosis of genitourinary tuberculosis.Protocol registrationPROSPERO CRD42016039020.

Conocimientos, actitudes y prácticas sobre la enfermedad de Carrión en población rural de Ancash, Perú

OBJETIVO: Evaluar el conocimiento, las practicas y las actitudes sobre la enfermedad de Carrion (bartonelosis) en poblaciones rurales con antecedentes de brotes epidemicos. METODOS: Estudio transversal realizado en las poblaciones de Huaripampa, Orcosh y Opayaco (Ancash, Peru) durante el mes de julio del 2010, utilizando una encuesta para evaluar el conocimiento, las practicas y las actitudes sobre la enfermedad de Carrion. Se entrevisto solo a mayores de 18 anos que tuviesen una antiguedad minima de un ano residiendo en esos poblados. RESULTADOS: Se realizaron encuestas a un total de 276 pobladores, de los cuales 36,6% fueron hombres y 72,5% no habia oido hablar de la enfermedad de Carrion. Entre los que la conocian, la mayoria (38,7%) indico que se contagia mediante picaduras, mientras que 26% manifesto no conocer la forma de contagio. Con respecto a las acciones que deberian tomarse en caso de presentar la enfermedad de Carrion, 69,3% de los encuestados refirieron que acudirian a un centro de salud y mas de la mitad informo haber recomendado practicas preventivas a familiares o conocidos en el pasado. CONCLUSIONES: A pesar de tratarse de comunidades historicamente afectadas por la enfermedad de Carrion, los pobladores de estas tres comunidades no mostraron un nivel adecuado de conocimientos, actitudes o practicas para su prevencion. En vista de ello, y teniendo en cuenta que este padecimiento ha presentado brotes ciclicos, se hace perentorio disenar e implementar un programa que eduque a los habitantes de estos poblados -poniendo el foco en el papel de los usos y costumbres- sobre como prevenir la enfermedad de Carrion, asi como el resto de las principales enfermedades endemicas de la region.

Association between the use of protease inhibitors in highly active antiretroviral therapy and incidence of diabetes mellitus and/or metabolic syndrome in HIV-infected patients: A systematic review and meta-analysis.

This systematic review and meta-analysis tries to determine whether there is an association between the use of protease inhibitors (PIs) and the incidence of diabetes mellitus (DM) and/or metabolic syndrome (MS) in HIV-infected patients. A systematic literature search was performed using MEDLINE/PubMed, CENTRAL, LILACS, and EMBASE. Included articles were observational studies published on or prior to November 2015 that met specific inclusion criteria. Pooled relative risks (RRs) and hazard ratios (HRs) were calculated. Nine articles met the inclusion criteria, describing 13,742 HIV patients. Use of PIs was associated with the development of MS (RR: 2.11; 95% CI 1.28–3.48; p-value 0.003). No association between the use of PIs and development of DM was found: the HR for the incidence of DM among patients using PIs was 1.23 (95% CI 0.66–2.30; p-value: 0.51) and the RR was 1.25 (95% CI 0.99–1.58; p-value 0.06). Use of PIs in HIV-infected patients is associated with an increased risk of MS. No evidence of an increased risk of DM was found. However, because MS is a precursor to DM, it is possible that studies with a longer follow-up duration are needed in order to detect an association between PI use and onset of DM.

Induced sputum is safe and well-tolerated for TB diagnosis in a resource-poor primary healthcare setting

Improved tuberculosis (TB) diagnostics are required. Induced sputum sampling is superior to spontaneous sputum analysis for diagnosis of pulmonary TB. Therefore, we examined the applicability of induced sputum in primary health centers of the Peruvian TB program and studied the safety and tolerability of this procedure. We show that induced sputum is safe, inexpensive, and well-tolerated in a resource-limited environment. Widespread use of induced sputum at primary health centers can be implemented and may improve TB diagnosis.

Disease characteristics and treatment of patients with diabetes mellitus attending government health services in Indonesia, Peru, Romania and South Africa

To describe the characteristics and management of Diabetes mellitus (DM) patients from low‐ and middle‐income countries (LMIC).

Histological Examination in Obtaining a Diagnosis in Patients with Lymphadenopathy in Lima, Peru.

Abstract. The differential diagnosis for lymphadenopathy is wide and clinical presentations overlap, making obtaining an accurate diagnosis challenging. We sought to characterize the clinical and radiological characteristics, histological findings, and diagnoses for a cohort of patients with lymphadenopathy of unknown etiology. 121 Peruvian adults with lymphadenopathy underwent lymph node biopsy for microbiological and histopathological evaluation. Mean patient age was 41 years (Interquartile Range 26–52), 56% were males, and 39% were HIV positive. Patients reported fever (31%), weight loss (23%), and headache (22%); HIV infection was associated with fever (P < 0.05) and gastrointestinal symptoms (P < 0.05). Abnormalities were reported in 40% of chest X-rays (N = 101). Physicians suspected TB in 92 patients (76%), lymphoma in 19 patients (16%), and other malignancy in seven patients (5.8%). Histological diagnoses (N = 117) included tuberculosis (34%), hyperplasia (27%), lymphoma (13%), and nonlymphoma malignancy (14%). Hyperplasia was more common (P < 0.001) and lymphoma less common (P = 0.005) among HIV-positive than HIV-negative patients. There was a trend toward reduced frequency of caseous necrosis in samples from HIV-positive than HIV-negative TB patients (67 versus 93%, P = 0.055). The spectrum of diagnoses was broad, and clinical and radiological features correlated poorly with diagnosis. On the basis of clinical features, physicians over-diagnosed TB, and under-diagnosed malignancy. Although this may not be inappropriate in resource-limited settings where TB is the most frequent easily treatable cause of lymphadenopathy, diagnostic delays can be detrimental to patients with malignancy. It is important that patients with lymphadenopathy undergo a full diagnostic work-up including sampling for histological evaluation to obtain an accurate diagnosis.