Phenotypes of lung mononuclear phagocytes in HIV seronegative tuberculosis patients: evidence for new recruitment and cell activation

Mycobacterium tuberculosis preferentially resides in mononuclear phagocytes. The mechanisms by which mononuclear phagocytes keep M. tuberculosis in check or by which the microbe evades control to cause disease remain poorly understood. As an initial effort to delineate these mechanisms, we examined by immunostaining the phenotype of mononuclear phagocytes obtained from lungs of patients with active tuberculosis. From August 1994 to March 1995, consecutive patients who had an abnormal chest X-ray, no demostrable acid-fast bacilli in sputum specimens and required a diagnostic bronchoalveolar lavage (BAL) were enrolled. Of the 39 patients enrolled, 21 had microbiologically diagnosed tuberculosis. Thirteen of the 21 tuberculosis patients were either HIV seronegative (n = 12) or had no risk factor for HIV and constituted the tuberculosis group. For comparison, M. tuberculosis negative patients who had BAL samples taken during this time (n = 9) or normal healthy volunteers (n = 3) served as control group. Compared to the control group, the tuberculosis group had significantly higher proportion of cells expressing markers of young monocytes (UCHM1) and RFD7, a marker for phagocytic cells, and increased expression of HLA-DR, a marker of cell activation. In addition, tuberculosis group had significantly higher proportion of cells expressing dendritic cell marker (RFD1) and epithelioid cell marker (RFD9). These data suggest that despite recruitment of monocytes probably from the peripheral blood and local cell activation, host defense of the resident lung cells is insufficient to control M. tuberculosis.

Tuberculosis in HIV-negative and HIV-infected patients in a low-incidence country: clinical characteristics and treatment outcomes.

BACKGROUND: In Switzerland and other developed countries, the number of tuberculosis (TB) cases has been decreasing for decades, but HIV-infected patients and migrants remain risk groups. The aim of this study was to compare characteristics of TB in HIV-negative and HIV-infected patients diagnosed in Switzerland, and between coinfected patients enrolled and not enrolled in the national Swiss HIV Cohort Study (SHCS). METHODS AND FINDINGS: All patients diagnosed with culture-confirmed TB in the SHCS and a random sample of culture-confirmed cases reported to the national TB registry 2000-2008 were included. Outcomes were assessed in HIV-infected patients and considered successful in case of cure or treatment completion. Ninety-three SHCS patients and 288 patients selected randomly from 4221 registered patients were analyzed. The registry sample included 10 (3.5%) coinfected patients not enrolled in the SHCS: the estimated number of HIV-infected patients not enrolled in the SHCS but reported to the registry 2000-2008 was 146 (95% CI 122-173). Coinfected patients were more likely to be from sub-Saharan Africa (51.5% versus 15.8%, P<0.0001) and to present disseminated disease (23.9% vs. 3.4%, P<0.0001) than HIV-negative patients. Coinfected patients not enrolled in the SHCS were asylum seekers or migrant workers, with lower CD4 cell counts at TB diagnosis (median CD4 count 79 cells/µL compared to 149 cells/µL among SHCS patients, P = 0.07). There were 6 patients (60.0%) with successful outcomes compared to 82 (88.2%) patients in the SHCS (P = 0.023). CONCLUSIONS: The clinical presentation of coinfected patients differed from HIV-negative TB patients. The number of HIV-infected patients diagnosed with TB outside the SHCS is similar to the number diagnosed within the cohort but outcomes are poorer in patients not followed up in the national cohort. Special efforts are required to address the needs of this vulnerable population.

Interim analysis of the Reitan Catheter Pump (RCP) heart failure efficacy study: RCP improves cardiovascular and renal function in acute decompensated heart failure (ADHF)

Background: The RCP is a 14 French collapsable percutaneous cardiovascular support device positioned in the descending part of the thoracic aorta via the femoral artery. A 10 patient first in man study demonstrated device safety and significant improvement in renal function among high risk PCI patients. We now report haemodynamic and renal efficacy in patients with ADHF.Methods: Prospective non randomised study seeking to recruit 20 patients with ADHF with a need for inotropic or mechanical circulatory support with: i) EF < 30% ii)Cardiac index(CI) < 2.2 L / min / m2 Outcome measures included: 1) Cardiac index (CI) 2) Pulmonary Capillary Wedge Pressure (PCWP) 3) Urine output / serum creatinine 4) Vascular / device complications 5) 30 day mortalityResults: INTERIM ANALYSIS (n=12) The mean age of the study group was 64 years, with a mean baseline creatinine of 193 umol/L, eGFR 38 ml/min. The intended RCP treatment period was 24 hours. During RCP treatment there was a significant mean reduction of PCWP at 4 hours of 17% (25 to 21 mmHg p=0.04). Mean CI increased at 12 hours by 11%, though not reaching significance (1.78 to 1.96 L/min/m2 p=0.08). RCP insertion prompted substantial diuresis. Urine output tripled over the first 12 hours compared to baseline (55 ml/hr vs 213 ml/hr p=0.03). This was associated with significantly improved renal function, a 28% reduction in serum creatinine at 12 hours (193 to 151 umol/L p=0.003), and a increase in eGFR from 38 ml/min to 50 ml/min (p=0.0007). 2 patients previously refused cardiac transplantation were reassessed and successfully transplanted within 9 months of RCP treatment on the basis of demonstrable renal reversibility. There were no vascular or device complications. There were 2 deaths at 30 days, one from multi-organ failure and sepsis, and one from intractable heart failure - neither were device related.Conclusion: RCP support in ADHF patients was associated with improved haemodynamics, and an improvement in renal function. The Reitan Catheter Pump may have a role in providing percutaneous cardiovascular and renal support in the acutely decompensated cardiac patient, and may have a role in suggesting renal reversibility in potential cardiac transplant patients. Further data will be reported at recruitment completion.

The Changing Face of the Epidemiology of Tuberculosis due to Molecular Strain Typing: A Review

About one third of the world population is infected with tubercle bacilli, causing eight million new cases of tuberculosis (TB) and three million deaths each year. After years of lack of interest in the disease, World Health Organization recently declared TB a global emergency and it is clear that there is need for more efficient national TB programs and newly defined research priorities. A more complete epidemiology of tuberculosis will lead to a better identification of index cases and to a more efficient treatment of the disease. Recently, new molecular tools became available for the identification of strains of Mycobacterium tuberculosis (M. tuberculosis), allowing a better recognition of transmission routes of defined strains. Both a standardized restriction-fragment-length-polymorphism-based methodology for epidemiological studies on a large scale and deoxyribonucleic acids (DNA) amplification-based methods that allow rapid detection of outbreaks with multidrug-resistant (MDR) strains, often characterized by high mortality rates, have been developed. This review comments on the existing methods of DNA-based recognition of M. tuberculosis strains and their peculiarities. It also summarizes literature data on the application of molecular fingerprinting for detection of outbreaks of M. tuberculosis, for identification of index cases, for study of interaction between TB and infection with the human immunodeficiency virus, for analysis of the behavior of MDR strains, for a better understanding of risk factors for transmission of TB within communities and for population-based studies of TB transmission within and between countries

Use of a renal-specific oral supplement by haemodialysis patients with low protein intake does not increase the need for phosphate binders and may prevent a decline in nutritional status and quality of life.

BACKGROUND: Protein-energy wasting is a frequent and debilitating condition in maintenance dialysis. We randomly tested if an energy-dense, phosphate-restricted, renal-specific oral supplement could maintain adequate nutritional intake and prevent malnutrition in maintenance haemodialysis patients with insufficient intake. METHODS: Eighty-six patients were assigned to a standard care (CTRL) group or were prescribed two 125-ml packs of Renilon 7.5(R) daily for 3 months (SUPP). Dietary intake, serum (S) albumin, prealbumin, protein nitrogen appearance (nPNA), C-reactive protein, subjective global assessment (SGA) and quality of life (QOL) were recorded at baseline and after 3 months. RESULTS: While intention to treat analysis (ITT) did not reveal strong statistically significant changes in dietary intake between groups, per protocol (PP) analysis showed that the SUPP group increased protein (P < 0.01) and energy (P < 0.01) intakes. In contrast, protein and energy intakes further deteriorated in the CTRL group (PP). Although there was no difference in serum albumin and prealbumin changes between groups, in the total population serum albumin and prealbumin changes were positively associated with the increment in protein intake (r = 0.29, P = 0.01 and r = 0.27, P = 0.02, respectively). The SUPP group did not increase phosphate intake, phosphataemia remained unaffected, and the use of phosphate binders remained stable or decreased. The SUPP group exhibited improved SGA and QOL (P < 0.05). CONCLUSION: This study shows that providing maintenance haemodialysis patients with insufficient intake with a renal-specific oral supplement may prevent deterioration in nutritional indices and QOL without increasing the need for phosphate binders.

Molecular Genetic Analysis of Multi-drug Resistance in Indian Isolates of Mycobacterium tuberculosis

A total of 116 isolates from patients attending the out-patient department at the All India Institute of Medical Sciences, New Delhi and the New Delhi Tuberculosis Centre, New Delhi, India were collected. They were analyzed for resistance to drugs prescribed in the treatment for tuberculosis. The drug resistance was initially determined by microbiological techniques. The Bactec 460TB system was employed to determine the type and level of resistance in each isolate. The isolates were further characterized at molecular level. The multi-drug loci corresponding to rpo b, gyr A, kat G were studied for mutation(s) by the polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) technique. The SSCP positive samples were sequenced to characterize the mutations in rpo b, and gyr A loci. While previously reported mutations in the gyr A and rpo b loci were found to be present, several novel mutations were also scored in the rpo b locus. Interestingly, analysis of the gyr A locus showed the presence of point mutation(s) that could not be detected by PCR-SSCP. Furthermore, rifampicin resistance was found to be an important marker for checking multi-drug resistance (MDR) in clinical isolates of Mycobacterium tuberculosis. This is the first report on molecular genetic analysis of MDR tuberculosis one from India, highlights the increasing incidence of MDR in the Indian isolates of M. tuberculosis.

Pioglitazone improves fat distribution, the adipokine profile and hepatic insulin sensitivity in non-diabetic end-stage renal disease subjects on maintenance dialysis: a randomized cross-over pilot study.

BACKGROUND: Fat redistribution, increased inflammation and insulin resistance are prevalent in non-diabetic subjects treated with maintenance dialysis. The aim of this study was to test whether pioglitazone, a powerful insulin sensitizer, alters body fat distribution and adipokine secretion in these subjects and whether it is associated with improved insulin sensitivity. TRIAL DESIGN: This was a double blind cross-over study with 16 weeks of pioglitazone 45 mg vs placebo involving 12 subjects. METHODS: At the end of each phase, body composition (anthropometric measurements, dual energy X-ray absorptometry (DEXA), abdominal CT), hepatic and muscle insulin sensitivity (2-step hyperinsulinemic euglycemic clamp with 2H2-glucose) were measured and fasting blood adipokines and cardiometabolic risk markers were monitored. RESULTS: Four months treatment with pioglitazone had no effect on total body weight or total fat but decreased the visceral/sub-cutaneous adipose tissue ratio by 16% and decreased the leptin/adiponectin (L/A) ratio from 3.63×10-3 to 0.76×10-3. This was associated with a 20% increase in hepatic insulin sensitivity without changes in muscle insulin sensitivity, a 12% increase in HDL cholesterol and a 50% decrease in CRP. CONCLUSIONS/LIMITATIONS: Pioglitazone significantly changes the visceral-subcutaneous fat distribution and plasma L/A ratio in non diabetic subjects on maintenance dialysis. This was associated with improved hepatic insulin sensitivity and a reduction of cardio-metabolic risk markers. Whether these effects may improve the outcome of non diabetic end-stage renal disease subjects on maintenance dialysis still needs further evaluation. TRIAL REGISTRATION: ClinicalTrial.gov NCT01253928.

Active screening for pulmonary tuberculosis by chest x-ray among immigrants at the Swiss border

Summary : Aim: To assess the number of immigrants with pulmonary tuberculosis detected by chest x-ray screening at the Swiss border. Method: All adult immigrants entering Switzerland in 2004 were screened by chest x-ray (CXR). The number of radiological abnormalities suggestive of pulmonary tuberculosis, and the proportion requiring treatment for tuberculosis, were assessed retrospectively. The frequency of symptoms among immigrants with documented TB was compared with a sample of immigrants with a normal CXR. Results: Among 8995 immigrants, 8240 had a normal CXR, 630 had some abnormality not suggestive of active TB and 125 (1.4%) had a CXR suggestive of pulmonary TB. A final diagnosis of tuberculosis requiring treatment was made in SO (1 l with positive smear and culture, 16 with positive culture and 23 with negative culture), 57 had fibrotic lesions and 18 had another disease or a normal x-ray on control. The prevalence of symptoms did not differ between 27 immigrants with documented TB (smear+/culture+: 82%, smear-/ culture+: 75%), and 23 with smear-/culturetuberculosis (91%), but lower in 57 immigrants with fibrotic lesions (60%). Cough was more frequent among the 27 immigrants with documented TB (70%) than among 198 smokers without TB (37%) and among 229 non-smokers without TB (15%) Conclusions: Only 22% (27/125) of immigrants with CXR abnormalities suggestive of pulrnonary tuberculosis were documented by smear and/or culture and 40% (50/125) needed antituberculous treatment. 2/11 smear-positive immigrants would not have been detected by a questionnaire on symptoms. Rapport de synthèse : Le but de l'étude est d'évaluer le rendement du dépistage radiologique de la tuberculose pulmonaire chez les immigrés à l'entrée en Suisse. Méthode: parmi les immigrés adultes entrés en Suisse en 2004, qui ont tous passé un contrôle radiologique, le nombre de porteurs de clichés thoraciques suspects de tuberculose et la proportion de cas chez lesquels un traitement antituberculeux a été prescrit ont été évalués rétrospectivement. La fréquence des symptômes chez les immigrés atteints de tuberculose a été comparée à celle d'un groupe contrôle sans tuberculose. Résultats: parmi 8995 immigrés, 8240 avaient un cliché thoracique normal, 630 étaient porteurs d'une anomalie non suspecte de tuberculose active et 125 (1.4%) montraient des signes radiologiques suspects de tuberculose. Un diagnostic final de tuberculose nécessitant un traitement a été posé dans 50 cas (11 cas à frottis et culture positifs, 16 cas à culture positive, 23 cas à culture négative), 57 présentaient des lésions cicatricielles compatibles avec une ancienne tuberculose et 18 avaient une autre affection pulmonaire ou un cliché normal au contrôle. La prévalence des plaintes n'était pas différente entre les 27 immigrés porteurs d'une tuberculose documentée (frottis+ /culture+: 82%, frottis-/culture+ : 75%) et les 23 immigrés atteints d'une tuberculose non documentée (frottis-/culture-: 91%), mais elle était plus élevée que chez les 57 immigrés porteurs de lésions cicatricielles (59%). La toux était plus fréquente chez les 27 tuberculeux documentés (70%) que chez 198 fumeurs sans tuberculose (37%) et chez 229 non fumeurs sans tuberculose (15%). Conclusions: seuls 22% (27/125) des immigrés dont le cliché thoracique est suspect de tuberculose sont porteurs d'une tuberculose documentée par examen direct ou culture et 40% (50/125) nécessitent un traitement antituberculeux. Deux immigrants sur les 11 cas frottis positifs n'auraient pas été dépistés par un questionnaire.

Hyperresponders vs. nonresponder patients after renal denervation: do they differ?

BACKGROUND: Blood pressure (BP) response after renal denervation (RDN) is highly variable. Besides baseline BP, no reliable predictors of response have been consistently identified. The differences between patients showing a major BP decrease after RDN vs. nonresponders have not been studied so far. AIM AND METHODS: We identified extreme BP responders (first quintile) and nonresponders (fifth quintile) to RDN defined according to office or 24-h ambulatory BP in the European Network COordinating research on Renal Denervation database (n = 109) and compared the baseline characteristics and BP changes 6 months after RDN in both subsets. RESULTS: In extreme responders defined according to ambulatory BP, baseline BP and BP changes 6 months after RDN were similar for office and out-of-the office BP. In contrast, extreme responders defined according to office BP were characterized by a huge white-coat effect at baseline, with dramatic shrinkage at 6 months. Compared with nonresponders, extreme responders defined according to office BP were more frequently women, had higher baseline office--but not ambulatory--BP, and higher estimated glomerular filtration rate (eGFR). In contrast, when considering ambulatory BP decrease to define extreme responders and nonresponders, the single relevant difference between both subsets was baseline ambulatory BP. CONCLUSION: This study suggests a major overestimation of BP response after RDN in extreme responders defined according to office, but not ambulatory BP. The association of lower eGFR with poor response to RDN is consistent with our previous analysis. The increased proportion of women in extreme responders may reflect sex differences in drug adherence.

Nimesulide, a cyclooxygenase-2 preferential inhibitor, impairs renal function in the newborn rabbit.

Tocolysis with nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely accepted for several years. Recently, the use of the cyclooxygenase-2 (COX2) preferential NSAID nimesulide has been proposed. However, data reporting neonatal acute renal failure or irreversible end-stage renal failure after maternal ingestion of nimesulide question the safety of this drug for the fetus and the neonate. Therefore, this study was designed to define the renal effects of nimesulide in newborn rabbits. Experiments were performed in 28 newborn rabbits. Renal function and hemodynamic parameters were measured using inulin and para-aminohippuric acid clearances as markers of GFR and renal blood flow, respectively. After a control period, nimesulide 2, 20, or 200 microg/kg was given as an i.v. bolus, followed by a 0.05, 0.5, or 5 microg.kg(-1).min(-1) infusion. Nimesulide administration induced a significant dose-dependent increase in renal vascular resistance (29, 37, and 92%, respectively), with a concomitant decrease in diuresis (-5, -23, and -44%), GFR (-12, -23, and -47%), and renal blood flow (-23, -23, and -48%). These results are in contrast with recent reports claiming that selective COX2 inhibition could be safer for the kidney than nonselective NSAIDs. These experiments confirm that prostaglandins, by maintaining renal vasodilation, play a key role in the delicate balance regulating neonatal GFR. We conclude that COX2-selective/preferential inhibitors thus should be prescribed with the same caution as nonselective NSAIDs during pregnancy and in the neonatal period.

Renal protection with calcium antagonists: the role of lercanidipine.

Abstract Background: Clinical research in the field of hypertension is now increasingly focusing on the potential effects of antihypertensive treatments that may go beyond the reduction of blood pressure (BP). In particular, renal protection appears as a desirable goal, especially considering that hypertension is associated with an increased risk of developing kidney damage, which may eventually lead to end-stage renal disease and a higher mortality. Dihydropyridine calcium channel blockers (CCBs) are widely used in the field of hypertension therapy but the different renal effects of the various CCBs have been poorly explored to date. Scope: This review will discuss available evidence on the renal effects of two calcium channel blockers: amlodipine and lercanidipine, on the basis of clinical data. Methods: MEDLINE and EMBASE were searched for inclusion of relevant studies. No limitations in time were considered. Results: Results from preclinical and clinical studies suggest that amlodipine is overall less effective in terms of renal protection when compared with other antihypertensive tested agents. Its beneficial effect in retarding the progression of renal disease is achievable only when combined with a blocker of the renin-angiotensin system. Conversely lercanidipine seems to provide renal protection in a similar way to ACE inhibitors, probably thanks to its mechanism of action which acts directly on the afferent and efferent renal arterioles. Conclusions: Treatment of hypertension with CCBs should take into consideration the special effects of each single agent at different levels; lercanidipine for example may play a useful role in the management not only of hypertension but also in renal protection of hypertensive patients.