Tuberculosis Bacilli Research Articles

Targeting dormant tuberculosis bacilli: results for molecules with a novel pyrimidone scaffold.

Our inability to completely control TB has been due in part to the presence of dormant mycobacteria. This also renders drug regimens ineffective and is the prime cause of the appearance of drug-resistant strains. In continuation of our efforts to develop novel antitubercular agents that especially target dormant mycobacteria, a set of 55 new compounds belonging to the pyrimidone class were designed on the basis of CoMFA and CoMSIA studies, and these were synthesized and subsequently tested against both the dormant and virulent BCG strain of M. tuberculosis. Some novel compounds have been identified which selectively inhibit the dormant tuberculosis bacilli with significantly low IC50 values. This study reports the second molecule after TMC-207, having the ability to inhibit tuberculosis bacilli exclusively in its dormant phase. The synthesis was accomplished by a modified multicomponent Biginelli reaction. A classification model was generated using the binary QSAR approach--recursive partitioning (RP) to identify structural characteristics related to the activity. Physicochemical, structural, topological, connectivity indices, and E-state key descriptors were used for generation of the decision tree. The decision tree could provide insights into structure-activity relationships that will guide the design of more potent inhibitors.

English

The tuberculosis (TB) Bacillus Calmette-Guerin (BCG) vaccine, which is based on Mycobacterium bovis, has variable protective efficacy in humans; therefore, safe and effective vaccines are urgently required to prevent this disease. The antigen 85A from Mycobacterium tuberculosis (M. tuberculosis) is a prime target for immunity in the early phase of tuberculosis in various animal models. The purpose of this study was to confirm whether Ag85A could elicit protective immune responses in mice. Dimethyldioctadecylammonium (DDA), an adjuvant with Th1-promoting activities and monophosphoryl lipid A (MPL), an immunostimulatory component that has strong adjuvant activity for both cellular and humoral immune responses, has been used as the adjuvant to study the biological and immunological characteristics of tuberculosis proteins in the researches previously. The gene coding Ag85A (fbpA), was cloned into a pET-30a(+) prokaryotic expression vector, and the induced amino acid sequence corresponds to a 33 kDa protein, which was confirmed by mass spectrometry and western blots. Mice were subcutaneously immunized with Ag85A protein emulsified with DDA and MPL and the results showed that the 85A antigen, when combined with these adjuvants, elicited strong Ag85A-specific T-cell responses and humoral responses as compared with vaccination with BCG. Based on the fact that this vaccine combination induced strong antigen-specific immune responses, it is a prime candidate as a component of a future TB vaccine. Key words: Tuberculosis, Ag85A, prokaryotic expression, cellular immune response, humoral response.

PWE-011 Diagnosing Abdominal Tuberculosis In The Acute Abdomen

IntroductionDespite recent improvements in medical treatments, the incidence of abdominal tuberculosis (ATB) in the United Kingdom has increased over the past two decades. This case series examined the difficulties encountered...

Rapid diagnosis of childhood pulmonary TB using bronchoalveolar lavage fluid by Xpert MTB/RIF assay

Background: In Zambia, tuberculosis (TB) remains amajor issue despite the availability of free anti-TB drugs and sensitization programs. Based on analysis of TB perceptions and health care seeking behaviour of TB patients, this case study demonstrates how cultural, socio-economic, and structural factors influencing patient adherence and compliance impair successful implementation of the TB control program. Methods & Materials: TB patient recruitment took place at the Kanyama clinic in Lusaka, Zambia. A combination of quantitative and qualitativemethodswere used, including 300 structured interviews at the clinic, various in-depth interviews with 30 patients at home, 6 focus group discussions, and participant observation. Additionally, 10 biomedical health care providers and 20 traditional/spiritual healers were interviewed. Results: Many TB patients (some repeatedly) relapsed (around 40%) and HIV co-infection rate was around 50%. Almost all patients did a VCT and about three quarters of TB-HIV patients were on ARV’s. Etiological principles were promiscuity (due to association with HIV), sleepingwithwomenwho aborted (the spirit of Kapopo) or on their menses, eating food with salt added by a woman on her menses, witchcraft, drinking beer, smoking, and inheritance (family TB).Meanwhile, the biomedical explanation about TB bacilli and its airborne nature was recognised by most patients. Poverty was problematic causing around three quarters of patients struggling with foodprovision.Aminorityofpatients combineddifferenthealing methods, mostly pharmacy or spiritual healing, some opted for traditional healing. Abandoning treatment or poor compliancewas rare but frequently related to alcohol consumption. Patient delay remained a challenge partly caused by stigma, long queues at the clinic, and preference for private clinics. Conclusion: There is a need to enhance cooperation between hospitals, patients, traditional/spiritual healers and communities to stimulate patient adherence. Employment of volunteers at the clinic could enhance already existing programs like patient follow up, (family) sensitization, and counselling. Discussion programs should be organised aiming at both educating and changing attitudes considering stigma and alcohol-consumption. It is necessary to eliminate structural obstacles like long queues at the clinic and to organise a food aid program for most needed patients in order to cope with TB medication.

Assessing key influence factors on patient adherence and compliance for the implementation of a tuberculosis control program in Lusaka, Zambia

Background: In Zambia, tuberculosis (TB) remains amajor issue despite the availability of free anti-TB drugs and sensitization programs. Based on analysis of TB perceptions and health care seeking behaviour of TB patients, this case study demonstrates how cultural, socio-economic, and structural factors influencing patient adherence and compliance impair successful implementation of the TB control program. Methods & Materials: TB patient recruitment took place at the Kanyama clinic in Lusaka, Zambia. A combination of quantitative and qualitativemethodswere used, including 300 structured interviews at the clinic, various in-depth interviews with 30 patients at home, 6 focus group discussions, and participant observation. Additionally, 10 biomedical health care providers and 20 traditional/spiritual healers were interviewed. Results: Many TB patients (some repeatedly) relapsed (around 40%) and HIV co-infection rate was around 50%. Almost all patients did a VCT and about three quarters of TB-HIV patients were on ARV’s. Etiological principles were promiscuity (due to association with HIV), sleepingwithwomenwho aborted (the spirit of Kapopo) or on their menses, eating food with salt added by a woman on her menses, witchcraft, drinking beer, smoking, and inheritance (family TB).Meanwhile, the biomedical explanation about TB bacilli and its airborne nature was recognised by most patients. Poverty was problematic causing around three quarters of patients struggling with foodprovision.Aminorityofpatients combineddifferenthealing methods, mostly pharmacy or spiritual healing, some opted for traditional healing. Abandoning treatment or poor compliancewas rare but frequently related to alcohol consumption. Patient delay remained a challenge partly caused by stigma, long queues at the clinic, and preference for private clinics. Conclusion: There is a need to enhance cooperation between hospitals, patients, traditional/spiritual healers and communities to stimulate patient adherence. Employment of volunteers at the clinic could enhance already existing programs like patient follow up, (family) sensitization, and counselling. Discussion programs should be organised aiming at both educating and changing attitudes considering stigma and alcohol-consumption. It is necessary to eliminate structural obstacles like long queues at the clinic and to organise a food aid program for most needed patients in order to cope with TB medication.

Crystal structure of the Mycobacterium tuberculosis phosphate binding protein PstS3

Mycobacterium tuberculosis evades host immune responses by colonizing macrophages. Intraphagosomal M. tuberculosis is exposed to environmental stresses such as reactive oxygen and nitrogen intermediates as well as acid shock and inorganic phosphate (Pi) depletion. Experimental evidence suggests that expression levels of mycobacterial protein PstS3 (Rv0928) are significantly increased when M. tuberculosis bacilli are exposed to Pi starvation. Hence, PstS3 may be important for survival of Mtb in conditions where there is limited supply of Pi. We report here the structure of PstS3 from M. tuberculosis at 2.3-Å resolution. The protein presents a structure typical for ABC phosphate transfer receptors. Comparison with its cognate receptor PstS1 showed a different pattern distribution of surface charges in proximity to the Pi recognition site, suggesting complementary roles of the two proteins in Pi uptake.

Diagnosing abdominal tuberculosis in the acute abdomen

BackgroundDespite recent improvements in medical treatments, the incidence of abdominal tuberculosis (ATB) in the United Kingdom has increased over the past two decades. This case series examined the difficulties encountered in correctly diagnosing this infection. Patients and methodsA retrospective study was undertaken, reviewing the records of 36 patients diagnosed with ATB from 2000 to 2012 at a district general hospital in outer East London. ResultsThe commonest presenting feature was abdominal pain in 67% of patients, and the most common sites of infection were the iliocaecal junction and peritoneum, seen in 36.1% and 33.3% respectively. Six patients were initially investigated for Crohn's disease and one for ileitis. The highest disease prevalence was seen in patients born in India and Pakistan, which was 27.8% and 19.4% of patients respectively.Colonoscopy was performed in nine patients, and three of these reported normal findings. The other six reported visible non-specific inflammatory changes. Three patients had abdominal X-rays reported and one patient had an abdominal ultrasound, all of which were normal. An abdominal computerised topography (CT) scan was performed in 26 patients and a chest CT was undertaken in 19 patients. Varying degrees of inflammatory changes were seen in all of the patients who had CT scans. Microbiological culture was positive for Mycobacterium tuberculosis or acid-fast bacilli in 71% of patients. ConclusionsAbdominal tuberculosis can be very difficult to diagnose as symptoms are non-specific and can mimic other types of granulomatous inflammatory bowel diseases. Radiology appears largely unhelpful due to the non-specificity of any positive imaging findings, and there is a lack of diagnostic procedural and microbiological tests with high specificity and sensitivity. In view of the increasing incidence of tuberculosis in London, there should be a high index of suspicion for ATB in individuals from high-incidence countries who present with non-specific abdominal symptoms.

Comparative study between using Lowenstein Jensen, Bio-FM media and mycobacteria growth indicator tube (MGIT) system in identification of Mycobacterium tuberculosis

Background/aimTuberculosis (TB) continues to be one of the most important infectious diseases threatening the human health. Culture systems are used for isolation of tuberculous bacilli as they are more sensitive than smear microscopy. The aim of the work was to evaluate the detection rate and time of Mycobacterium tuberculosis by using the Bio FM system and mycobacteria growth indicator tube (MGIT) system in comparison with the Lowenstein–Jensen medium. MethodsThis study was carried out on a total 60 smear acid fast bacilli positive sputum samples obtained from patients attending the Chest Department and Outpatient Clinic of Benha University Hospital, Benha Chest Hospital, from June 2012 to September of the same year. Patients were classified into three groups: Group I: included 40 patients with fresh sputum smear +ve (new cases), Group II: included 13 relapsed cases and Group III: included 7 treatment failure cases. All sputum samples were cultured in parallel on Bio-FM, MGIT and LJ media. The mycobacterial detection rate and time were compared. ResultsThe mycobacteria recovery rate on MGIT, Bio-FM and LJ was not significantly different (respectively 98.3%, 95% and 93%, P>0.05). The growth of M. tuberculosis bacilli was faster on MGIT than on Bio-FM (mean 10.7±2.9days, 11.1±4.3days, respectively vs. 23.6±8.1days for LJ), there was statistically significant difference between LJ and Bio-FM and LJ and MGIT. However there was no statistical significance when comparing MGIT and Bio-FM. ConclusionMGIT and Bio-FM are good culture systems for accurate and rapid detection of M. tuberculosis.

Cervical tuberculosis masquerading as cancer

Tuberculosis (TB) is prevalent in developing countries and extrapulmonary involvement is now a frequent manifestation. However, cervical tuberculosis is a rare form of genital tuberculosis and is a cause of diagnostic confusion due to the non-specific nature of presenting symptoms which may simulate malignant disease processes. A high index of suspicion is required for making prompt diagnosis. The definitive diagnosis is based on the demonstration of the characteristic lesion on histopathology and Ziehl-Neelsen stain to identify the acid fast bacilli of mycobacterium tuberculosis. We present a case of a 35-year-old woman who presented with dyspareunia, post coital bleeding and vaginal discharge. Clinically, cervical carcinoma was suspected, but pathologic diagnosis eventually revealed tuberculosis of the cervix. Despite the rare incidence, tuberculosis of the cervix should be considered in the differential diagnosis when cervical carcinoma is initially suspected in TB endemic areas.

Clinical features of endobronchial tuberculosis

Endobronchial tuberculosis (EBTB) is a specific type of pulmonary tuberculosis which often affect the tracheobronchial tree, and can be microbiologically and/or pathohistologically confirmed. The aim of the study was to determine the clinical features and diagnostic aspects of EBTB. This retrospective study was conducted at the Clinic for Lung Diseases, Clinical Center of Serbia, Belgrade, from January 1997 to December 2007. All patients with EBTB confirmed by bronchoscopy with biopsy during a study period were analysed. Data included the patient's medical history, a physical exam, chest X-ray, mycobacterial analysis of sputum samples, endoscopic types and patohistological confirmation. In the study, 57.6% of the patients were males. The most frequent symptoms were cough (71.2%), malaise (54.20%), fever (49.2%), weight loss (40.7%), and hemoptysis (13.60%). Most of the patients were diagnosed within 30 days of symptoms onset. Sputum examination showed acid-fast bacilli in 31.4% of the patients, while sputum culture for tuberculosis bacilli were positive in 55.9% of the patients. The most common radiographic localization was in the upper lung lobes (63.5%). Cavities were present in 60.4% of the patients. The most common endoscopic subtype determined by bronchoscopy were nonspecific bronchitis (39.9%) and edematous-hyperemic subtype (36.4%). EBTB was more frequent among men, and among people in their fifties in our country. Detailed bronchoscopic examination, correlated with clinical and laboratory findings, will improve diagnostic rate and provide timely therapy.

Trehalose 6,6′-dimycolate – A coat to regulate tuberculosis immunopathogenesis

Tuberculosis (TB) remains a significant public health burden worldwide. Treatment of this disease requires a minimum of six months and there is no vaccine available for the most common form of the disease. Increasing evidence suggests that the mycobacterial glycolipid trehalose 6,6′ dimycolate (TDM; cord factor) plays a key role in the pathogenesis of TB disease. TDM protects the TB bacilli from macrophage-mediated killing, inhibits effective antigen presentation, and reduces the formation of protective T-cell responses. TDM promotes initiation of granuloma formation and likely plays a role in caseation. Furthermore, TDM may contribute to the development of post primary disease. Receptors for TDM were recently described and are expected to contribute to our knowledge of the molecular pathogenesis of TB disease. In this manner, understanding TDM may prove promising towards development of targeted TB therapeutics to limit clinical pathologies.

New Approaches to Target the Mycolic Acid Biosynthesis Pathway for the Development of Tuberculosis Therapeutics

Mycolic acids are the major lipid components of the unique mycobacterial cell wall responsible for the protection of the tuberculosis bacilli from many outside threats. Mycolic acids are synthesized in the cytoplasm and transported to the outer membrane as trehalose- containing glycolipids before being esterified to the arabinogalactan portion of the cell wall and outer membrane glycolipids. The large size of these unique fatty acids is a result of a huge metabolic investment that has been evolutionarily conserved, indicating the importance of these lipids to the mycobacterial cellular survival. There are many key enzymes involved in the mycolic acid biosynthetic pathway, including fatty acid synthesis (KasA, KasB, MabA, InhA, HadABC), mycolic acid modifying enzymes (SAM-dependent methyltransferases, aNAT), fatty acid activating and condensing enzymes (FadD32, Acc, Pks13), transporters (MmpL3) and tranferases (Antigen 85A-C) all of which are excellent potential drug targets. Not surprisingly, in recent years many new compounds have been reported to inhibit specific portions of this pathway, discovered through both phenotypic screening and target enzyme screening. In this review, we analyze the new and emerging inhibitors of this pathway discovered in the post-genomic era of tuberculosis drug discovery, several of which show great promise as selective tuberculosis therapeutics.

The Scavenger Protein Apoptosis Inhibitor of Macrophages (AIM) Potentiates the Antimicrobial Response against Mycobacterium tuberculosis by Enhancing Autophagy

Apoptosis inhibitor of macrophages (AIM), a scavenger protein secreted by tissue macrophages, is transcriptionally regulated by the nuclear receptor Liver X Receptor (LXR) and Retinoid X Receptor (RXR) heterodimer. Given that LXR exerts a protective immune response against M. tuberculosis, here we analyzed whether AIM is involved in this response. In an experimental murine model of tuberculosis, AIM serum levels peaked dramatically early after infection with M. tuberculosis, providing an in vivo biological link to the disease. We therefore studied the participation of AIM in macrophage response to M. tuberculosis in vitro. For this purpose, we used the H37Rv strain to infect THP-1 macrophages transfected to stably express AIM, thereby increasing infected macrophage survival. Furthermore, the expression of this protein enlarged foam cell formation by enhancing intracellular lipid content. Phagocytosis assays with FITC-labeled M. tuberculosis bacilli indicated that this protein was not involved in bacterial uptake; however, AIM expression decreased the number of intracellular cfus by up to 70% in bacterial killing assays, suggesting that AIM enhances macrophage mycobactericidal activity. Accordingly, M. tuberculosis-infected AIM-expressing cells upregulated the production of reactive oxygen species. Moreover, real-time PCR analysis showed increased mRNA levels of the antimicrobial peptides cathelicidin and defensin 4B. These increases were concomitant with greater cellular concentrations of the autophagy-related molecules Beclin 1 and LC3II, as well as enhanced acidification of mycobacterial phagosomes and LC3 co-localization. In summary, our data support the notion that AIM contributes to key macrophage responses to M. tuberculosis.

NF-κB Repressing Factor Inhibits Chemokine Synthesis by Peripheral Blood Mononuclear Cells and Alveolar Macrophages in Active Pulmonary Tuberculosis

NF-κB repressing factor (NRF) is a transcriptional silencer implicated in the basal silencing of specific NF-κB targeting genes, including iNOS, IFN-β and IL-8/CXCL8. IP-10/CXCL10 and IL-8/CXCL8 are involved in neutrophil and lymphocyte recruitment against M. tuberculosis (MTb) and disease progression of pulmonary tuberculosis (TB). Alveolar macrophages (AM) and peripheral blood mononuclear cells (PBMC) were used to study the regulatory role of NRF in pulmonary TB. AM and PBMC were purified from 19 TB patients and 15 normal subjects. To study the underlying mechanism, PBMC were exposed to heated TB bacilli. The regulation role of NRF in IP-10/CXCL10 and IL-8/CXCL8 was determined by NRF knock-down or over-expression. NRF binding capabilities in promoter sites were measured by chromatin immunoprecipitation (ChIP) assay. The levels of IP-10/CXCL10, IL-8/CXCL8 and NRF were significantly higher in AM and PBMC in patients with active TB. NRF played an inhibitory role in IP-10/CXCL10 and IL-8/CXCL8 inductions. We delineate the role of NRF in pulmonary TB, which inhibits the expressions of IP-10/CXCL10 and IL-8/CXCL8 in AM and PBMC of patients with high bacterial load. NRF may serve as an endogenous repressor to prevent robust increase in IP-10/CXCL10 and IL-8/CXCL8 when TB bacterial load is high.

Mathematical model on pulmonary and multidrug-resistant tuberculosis patients with vaccination

Abstract Tuberculosis is a global epidemic disease and almost two billion people across the globe are infected with the tuberculosis bacilli. Many countries like China, Europe and United States has achieved dramatic decrease in TB mortality rate but country like India is still struggling hard to control this epidemic. Jharkhand one of the states of India is highly epidemic toward this disease. We propose a mathematical model to understand the spread of tuberculosis disease in human population for both pulmonary and drug-resistant subjects. A number of new vaccines are currently in development. Keeping in mind, vaccination as one of the treatment for TB patients may be infant or adult in future; an assumption for the transfer of proportion of susceptible population to the vaccination class is considered. Quarantine class is also considered in our epidemic model for multidrug-resistant patients, and it is observed that it may play a vital role for controlling the disease. Threshold and equilibria are obtained and the condition for epidemic under different conditions of threshold is established. Real parametric values of the Jharkhand state are taken into account to simulate the system developed, and the results so obtained validate our analytical results.

Antimycobacterial activity of Citrullus colocynthis (L.) Schrad. against drug sensitive and drug resistant Mycobacterium tuberculosis and MOTT clinical isolates

Ethnopharmacological relevanceCitrullus colocynthis (Cucurbitaceae), a folk herbal medicine and traditionally used natural remedy for tuberculosis in India has been studied to validate its antitubercular activity against drug sensitive and drug resistant (including multidrug resistant) Mycobacterium tuberculosis and Mycobacterium other than tuberculosis (MOTT) bacilli. Materials and methodsInhibitory and bactericidal activities of crude extracts, fractions and compounds of Citrullus colocynthis plant, consisting of aerial parts and ripe deseeded fruits were performed against the drug sensitive standard strain of Mycobacterium tuberculosis H37Rv (ATCC 27294), 16 drug resistant strains of Mycobacterium tuberculosis and two MOTT strains, using radiometric BACTEC 460TB system. ResultsMethanolic extract of ripe deseeded fruit of Citrullus colocynthis has shown good activity (MIC≤62.5µg/ml), whereas among the bioactive fractions, FC IX demonstrated the best activity (MIC 31.2µg/ml) against Mycobacterium tuberculosis H37Rv. Bioactive FC III, IX and X also inhibited 16 clinical isolates of Mycobacterium tuberculosis consisting of seven non-multidrug resistants, eight multidrug resistants, one extensively drug resistant and two of MOTTs with MICs in the range of 50–125, 31.2–125 and 62.5–125µg/ml, respectively. Ursolic acid and cucurbitacin E 2-0-β-d-glucopyranoside were identified as the main biomarkers active against Mycobacterium tuberculosis H37Rv (MICs 50 and 25µg/ml respectively), as well as against the 18 clinical isolates. FC III and FC IX showed better inhibition of drug resistant and MOTT clinical isolates. Minimal bactericidal concentrations of extracts, fractions and compound C-2 were ≥two-fold MIC values. ConclusionsThe study provides a scientific rationale for the traditional use of Citrullus colocynthis fruit in the treatment of tuberculosis. In addition, the study elucidates a broad spectrum antimycobacterial action of Citrullus colocynthis fruit, which can contribute to the development of improved preparation of an antitubercular natural drug for the treatment of drug resistant tuberculosis and MOTT infection as well.

The liver Metastatic Adenocarcinoma of Colorectal Cancer With Synchronous Isolated Hepatic Tuberculosis

Dear Editor, Tuberculosis is a global problem. According to the World Health Organization, more than 2 billion people are currently infected with tuberculosis bacilli and 1.7 million deaths attributed to TB in 2006 (1). TB usually occurs in lung and other form of it like primary abdominal TB is not uncommon and 6-38% of patients with active pulmonary TB have abdominal TB (2). Hepatic tuberculosis is usually associated with military tuberculosis or active pulmonary and isolated liver tuberculosis (ILT) is a rare type of TB (3, 4). Hereby we report a case of isolated hepatic tuberculosis. A 54 year old Iranian man has suffered from gastrointestinal symptoms, changes in bowel habits and rectal bleeding and abdominal pain for 3 month. Laboratory data revealed hematocrit 33%; hemoglobin 10.2 g/dL; white blood cells 9400/mm³ (71% neutrophils). Liver enzymes showed: total bilirubin of 9 mg/L with a direct bilirubin of 4.3 mg/L; SGOT and SGPT were 138 U/L and 192 U/L respectively (normal range for SGOT is 17-59 U/L and for SGPT is 21-72 U/L). Abdominal examination was unremarkable except for mild tenderness in RUQ. Patients had not history of colon cancer or TB in familial history. The patient was undergoing colonoscopy, a lesion measuring 3.0 × 4.1 × 1.5 cm in the sigmoid colon was found. The biopsy of the lesion was referred to the lab. Colon adenocarcinoma diagnosed before surgery. For metastatic work up, the patient undergoing CT and a lesion in the right lobe of the liver was observed which a biopsy was taken from. Our initial diagnosis according to the patient with adenocarcinoma and colonoscopy results, before operation, and the finding of patients CT were metastatic lesion. For the final diagnosis of the lesion we used biopsy and pathologic findings which were positive for tuberculosis and metastatic adenocarcinoma in liver. Lung was cleared for tuberculosis in studies and isolated hepatic tuberculosis diagnosed. However TB can diffuse in other organ like mesenteric lymph nodes, gastrointestinal tract and Urinary tract but isolated hepatic tuberculosis is rare condition. Overall we know 3 forms of hepatic tuberculosis. Diffuse hepatic with pulmonary or miliary tuberculosis, which is the most common form. Diffuse hepatic infiltration without recognizable pulmonary involvement and third form usually presents as a focal – local or abscess. This form is very rare (5, 6). In Kok KY study, Incidence of isolated hepatic tuberculosis estimated as0.3% (7). Many studies confirm that Clinical presentation of isolated hepatic tuberculosis is so atypical and we can`t only use imaging for diagnosing the ILT, because many other of focal lesions in liver, such as metastases, hepatocellular carcinoma are similar to that, so pathology examination is necessary for distinguishing tuberculosis from lymphoproliferative disorder and other granulomatous diseases (7-9). Usually Pathologic finding in tuberculosis liver is a necrotizing and granolomatus. likely gaint cells are found in the granuloma which are surrounded by lymphohistiocytic cells, plasma cells and eosinophils (10). Unfortunately, in most of cases the diagnosis of liver TB is made only after exploratory laboratory or biopsy, as the present case. Therefore the diagnosis of liver TB should be considered in the context of a mass in the right lobe of the liver in patients from endemic TB zone or in the immunocompromised patients. Figure 1. Images of a Necrosis Granulomatous in Biopsy of Liver and Pleomorphic Tumor Cells are Hyperchromatic With Irregular Nuclear Borders (× 400 H&E stain)

Pulmonary aspergillosis in an immunocompetent patient

A 59-year-old man with no medical history presented withproductive cough and hemoptysis for two months. Low-grade fever, fatigue and body weight loss were noted.Physical examination disclosed crackles in both lungs andcachectic appearance. Blood examination revealed hypoal-buminemia and generalized inflammation with a highC-reactive protein level. Chest radiography and computedtomography showed multiple cavities of various sizes andsegmental consolidations in both lungs with upper lobespredominance (Fig. 1A and B). He was admitted underthe impression of pulmonary tuberculosis initially. Sputumacid-fast stain and tuberculosis culture did not yield tuber-culosis bacilli. Sputum culture yielded

Factors Associated With Health System Delay in Accessing Pulmonary Tuberculosis Care in Gezira State, Sudan

Background: Tuberculosis (TB) is still a major cause of morbidity and mortality in both developed and developing countries. Delay in accessing tuberculosis care is associated with the highest densities of Mycobacterium tuberculosis (M. tuberculosis) bacilli on sputum smears. Objectives: The current study aimed to determine the extent of delay, and the major health system contributing factors to delays in the diagnosis and treatment of TB patients in Gezira state, Sudan. Patients and Methods: This study had a case-control design to explore the delay in the diagnosis and treatment of TB in Gezira state, Sudan. A cross-sectional phase was conducted to determine the extent of delay, and afterwards, a nested case-control phase was applied. Patients reporting a total delay which was longer than the median were considered as “cases”, whereas those with the total delay inferior to the median were considered as “controls”. The study population included the newly diagnosed (within 2 weeks) smear-positive pulmonary TB cases aged 15 years old and above, who attended the selected TB management units (TBMUs) during the study period. The sample size included 292 cases. Data were collected by a questionnaire and analyzed with statistical software. Results: The mean duration of total delay in accessing TB care was 65.6 days. Total delay was more prevalent in the general and private hospitals (73.8% and 64.7%, respectively), followed by the health centers (45.7%). Tuberculosis basic management units and chest hospitals showed the least delay in accessing TB care, ranging around 34% and 14.3%, respectively. Total delay in accessing TB care was more prevalent when the time and distance to reach the service was short. Conclusions: Total delay in TB care is too long (65.6 days) in average and occurs more frequently in the general and private hospitals. Total delay in TB care is more prevalent when the time to reach health facilities that provide TB services is short and the location in close proximity.

Thioridazine lacks bactericidal activity in an animal model of extracellular tuberculosis

The antipsychotic drug thioridazine is active in the murine model of tuberculosis infection, which is predominantly intracellular in nature. Recent clinical reports suggest that thioridazine may play a role in the treatment of drug-resistant tuberculosis. We studied the tuberculocidal activity of thioridazine in guinea pigs, which develop necrotic lung granulomas histologically resembling their human counterparts. Pharmacokinetic studies were performed in guinea pigs to establish human-equivalent doses of thioridazine. Guinea pigs were aerosol-infected with ∼100 bacilli of Mycobacterium tuberculosis and single-drug treatment was started 4 weeks later with a range of thioridazine doses daily (5 days/week) for up to 4 weeks. Control animals received no treatment or 60 mg/kg isoniazid. The human-equivalent dose of thioridazine was determined to be 5 mg/kg with saturable absorption noted above 50 mg/kg. At the start of treatment, the lung bacterial burden was ∼6.2 log10 cfu. Although isoniazid reduced bacillary counts more than 10-fold, thioridazine monotherapy showed limited killing over the range of doses tested, reducing lung bacillary counts by 0.3-0.5 log10 following 1 month of treatment. Thioridazine was tolerated up to 40 mg/kg. Thioridazine has limited bactericidal activity against extracellular bacilli within necrotic granulomas. Its contribution to the sterilizing activity of combination regimens against drug-susceptible and drug-resistant tuberculosis remains to be determined.