Is 6 months of bedaquiline enough? Results from the compassionate use of bedaquiline in Armenia and Georgia.

BACKGROUND AND SETTING: Bedaquiline (BDQ) was initially only available through compassionate use programmes. OBJECTIVE: To assess the effectiveness and safety of multidrug-resistant tuberculosis (MDR-TB) treatment containing BDQ. METHOD: Retrospective analysis of data from patients receiving BDQ through compassionate use in Armenia and Georgia from April 2013 to April 2015. Logistic regression was used to assess the risk factors associated with unsuccessful treatment outcomes. RESULTS: Of 82 patients included, 84.2% (69/82) had fluoroquinolone-resistant MDR-TB and 43.4% (23/53) were seropositive for the hepatitis C virus (HCV). The culture conversion rate was 84.4% (54/64), and 18.5% (10/54) reverted back to positive. In total, 79.3% (65/82) of the patients reported at least one adverse event. Serious adverse events were reported in 14 patients, with 10/14 patients experiencing fatal outcomes-6/10 related to advanced TB and 2/10 assessed as possibly related to BDQ. Treatment outcomes were as follows: 58.5% treatment success, 12.2% deaths, 7.3% failures and 21.9% lost to follow-up. HCV coinfection was associated with unsuccessful outcomes (adjusted OR 4.45, 95%CI 1.23-16.13). CONCLUSION: BDQ through compassionate use showed relatively good success rates and safety profiles in a cohort with difficult-to-treat MDR-TB. High rates of reversion may indicate that >24 weeks of BDQ is necessary in some cases. HCV coinfection should be diagnosed and treatment considered in MDR-TB patients.

Pattern of first- and second-line drug resistance among pulmonary tuberculosis retreatment cases in Pakistan.

BACKGROUND: Drug resistance in general, and multidrug-resistant tuberculosis (MDR-TB) in particular, threatens global tuberculosis (TB) control efforts. Population-based estimates of drug resistance are needed to develop strategies for controlling drug-resistant TB in Pakistan. OBJECTIVE: To obtain population-based data on Mycobacterium tuberculosis drug resistance in Pakistan. METHODS: To obtain drug resistance data, we conducted a population-based study of TB cases in all provinces of Pakistan. We performed culture and drug susceptibility testing on M. tuberculosis isolates from patients with a prior history of anti-tuberculosis treatment (retreatment cases) from all over the country. RESULTS: Of 544 isolates from previously treated cases, 289 (53.1%) were susceptible to all first-line drugs, 255 (46.9%) were resistant to at least one anti-tuberculosis drug and 132 (24.3%) were MDR-TB. Among MDR-TB isolates, 47.0% were ofloxacin (OFX) resistant. Extensively drug-resistant TB was found in two (0.4%) isolates. CONCLUSION: Prevalence of drug resistance in retreatment isolates was high. The alarmingly high prevalence of OFX resistance among MDR-TB isolates may threaten the success of efforts to control and treat MDR-TB.

Reasons for defaulting from drug-resistant tuberculosis treatment in Armenia: a quantitative and qualitative study.

SETTING: Armenia, a country with a high prevalence of drug-resistant tuberculosis (DR-TB). OBJECTIVE: To identify factors related to default from DR-TB treatment in Yerevan. DESIGN: Using a retrospective cohort design, we compared defaulters with patients who were cured, completed or failed treatment. Patients who initiated DR-TB treatment from 2005 to 2011 were included in the study. A qualitative survey was conducted including semi-structured interviews with defaulters and focus group discussions with care providers. RESULTS: Of 381 patients, 193 had achieved treatment success, 24 had died, 51 had failed treatment and 97 had defaulted. The number of drugs to which the patient was resistant at admission (aRR 1.16, 95%CI 1.05-1.27), the rate of treatment interruption based on patient's decision (aRR 1.03, 95%CI 1.02-1.05), the rate of side effects (aRR 1.18, 95%CI 1.09-1.27), and absence of culture conversion during the intensive phase (aRR 0.47, 95%CI 0.31-0.71) were independently associated with default from treatment. In the qualitative study, poor treatment tolerance, a perception that treatment was inefficient, lack of information, incorrect perception of being cured, working factors and behavioural problems were factors related to treatment default. CONCLUSION: In addition to economic reasons, poor tolerance of and poor response to treatment were the main factors associated with treatment default.

Active contact investigation and treatment support: an integrated approach in rural and urban Sindh, Pakistan.

BACKGROUND: Although household contacts of persons with tuberculosis (TB) have high rates of active TB, contact investigations are often not conducted. We present the results from a large-scale active contact investigation combined with treatment support in Sindh, Pakistan. METHODS: Trained lay workers visited consenting smear-positive index patient homes in seven urban and 15 rural facilities. People with suspected TB were provided free transport to diagnostic centres, and sputum samples were collected for microscopy. Those diagnosed with smear-positive TB were given food baskets and sent text reminders to promote adherence. RESULTS: From 3037 index cases, 19,191 household contacts were screened for TB symptoms and 3478 (18.1%) symptomatic persons were identified. Of these, 2160 (62.1%) produced sputum samples on the spot for testing and 490 (22.7%) had smear-positive results. TB prevalence in urban households was 1504 per 100,000 population compared to 4044/100,000 in rural households (P < 0.001) and 2553/100,000 overall. Treatment success was high, with 80.4% cured and 17.6% completing treatment. DISCUSSION: Lay workers given basic training can conduct active contact investigations and provide treatment support to improve case detection and treatment outcomes in urban and rural areas of Pakistan. In areas with high levels of undiagnosed TB, particularly in rural areas, contact investigation should be prioritised as a means of improving case detection and early diagnosis.

Transformation of membranous into anti-GBM nephritis.

Membranous nephropathy is a common glomerular disease. We report a 50-year-old man with a history of membranous nephropathy in remission, who presented with acute kidney injury, proteinuria, hematuria, and hypertension. He also had a high anti-glomerular basement membrane (anti-GBM) antibody titer and crescent transformation of primary pathology. The kidney functions deteriorated rapidly despite aggressive therapy with cyclophosphamide, methylprednisolone, and plasmapheresis.

Lead-induced oxidative stress adversely affects health of the occupational workers.

Lead is a persistent toxic metal and associated with impairment of various body functions in occupational workers. The main objective was to determine the lead-induced oxidative stress and adverse health effects by biochemical markers in industrial workers. One hundred and forty-eight males consisting of 87 lead-exposed industrial workers and 61 controls were included. Blood lead level (BLL) was determined on a 3010B ESA lead analyzer. Blood complete counts were done on a hematology analyzer. Biochemical markers including serum uric acid, urea, creatinine, phosphate, alanine aminotransferase (ALT), and gamma glutamyltransferase (GGT) were measured on a Selectra E auto analyzer. Serum malondialdehyde (MDA) was measured spectrophotometrically and C-reactive protein (CRP) on Immulite-1000. Results revealed that lead-exposed workers had significantly high BLLs, median (range), 29.1 (9.0-61.1) microg/dL compared with controls, 8.3 (1.0-21.7) microg/dL. Oxidative stress (MDA, GGT) and inflammatory markers (high-sensitivity CRP) were significantly increased (P < or = 0.05). Blood pressure was raised, whereas hemoglobin was decreased in exposed group (P < or = 0.002). Serum urea, uric acid, phosphate, and ALT were significantly raised in lead-exposed workers (P < or = 0.001). Serum albumin, total proteins, and glomerular filtration rate (GFR) were decreased. Blood lead showed a significant positive correlation with serum GGT (r = 0.63), MDA (r = 0.71), CRP (r = 0.75), urea (r = 0.34), creatinine (r = 0.51), and uric acid (r = 0.29) (P < or = 0.01). It is concluded that lead exposure increases oxidative stress that correlates with adverse changes in hematological, renal, and hepatic function in the occupational workers. Elevated blood lead has positive correlation with oxidative stress, inflammatory and biochemical markers that might be used to detect impairment in the body function in lead exposed workers.

Evaluation of femur length during the second and third trimesters in fetuses with myelomeningocele.

OBJECTIVES: To determine if the femur length of fetuses with myelomeningocele is shorter in the second and third trimesters compared with that of normal fetuses. METHODS: We retrospectively collected measurements of femur length, head circumference, biparietal diameter and abdominal circumference from detailed obstetric ultrasound studies performed during the second and third trimesters in 31 fetuses with myelomeningocele and 43 fetuses with no detectable anomaly. The gestational age predicted by each parameter (based on Hadlock's tables) was compared with the true gestational age (based on last menstrual period), using the ANCOVA test to determine if there was a statistically significant difference between the two groups of fetuses. RESULTS: There was no significant difference in femur length (P = 0.60) or in abdominal circumference (P = 0.85) between fetuses with myelomeningocele and normal fetuses. Fetuses with myelomeningocele did have a significantly lower biparietal diameter and head circumference (P < or = 0.001). CONCLUSIONS: Myelomeningocele is not associated with reduced femur length in the second and third trimesters, suggesting that the known postnatal lower extremity foreshortening in patients with myelomeningocele develops late in gestation or after birth.

Septation and valvar formation in the outflow tract of the embryonic chick heart.

There is no agreement, in the chick, about the number of the endocardial cushions within the outflow tract or their pattern of fusion. Also, little is known of their relative contributions to the formation of the arterial valves, the subpulmonary infundibulum, and the arterial valvar sinuses. As the chick heart is an important model for studying septation of the outflow tract, our objective was to clarify these issues. Normal septation of the outflow tract was studied in a series of 60 staged chick hearts, by using stained whole-mount preparations, serial sections, and scanning electron microscopy. A further six hearts were examined subsequent to hatching. At stage 21, two pairs of endocardial cushions were seen within the developing outflow tract. One pair was positioned proximally, with the other pair located distally. By stage 25, a third distal cushion had developed. This finding was before the appearance of two further, intercalated, endocardial cushions, also distally positioned, which were first seen at stage 29. In the arterial segment, the aortic and pulmonary channels were separated by the structure known as the aortopulmonary septum. The dorsal limb of this septum penetrated the distal dorsal cushion, whereas the ventral limb grew between the remaining two distal cushions, both of which were positioned ventrally. The three distal endocardial cushions, and the two intercalated endocardial cushions, contributed to the formation of the leaflets and sinuses of the arterial roots. The two proximal cushions gave rise to a transient septum, which later became transformed into the muscular component of the subpulmonary infundibulum. Concomitant with these changes, an extracardiac tissue plane was formed which separated this newly formed structure from the sinuses of the aortic root. Our study confirms that three endocardial cushions are positioned distally, and two proximally, within the developing outflow tract of the chick. The pattern of the distal cushions, and the position of the ventral limb of the aortopulmonary septum, differs significantly from that seen in mammals.

Misexpression of noggin leads to septal defects in the outflow tract of the chick heart.

BMP-2 and BMP-4 are known to be involved in the early events which specify the cardiac lineage. Their later patterns of expression in the developing mouse and chick heart, in the myocardium overlying the atrioventricular canal (AV) and outflow tract (OFT) cushions, also suggest that they may play a role in valvoseptal development. In this study, we have used a recombinant retrovirus expressing noggin to inhibit the function of BMP-2/4 in the developing chick heart. This procedure resulted in abnormal development of the OFT and the ventricular septum. A spectrum of abnormalities was seen ranging from common arterial trunk to double outlet right ventricle. In hearts infected with noggin virus, where the neural crest cells have been labelled, the results show that BMP-2/4 function is required for the migration of neural crest cells into the developing OFT to form the aortopulmonary septum. Prior to septation, misexpression of noggin also leads to a decrease in the number of proliferating mesenchymal cells within the proximal cushions of the outflow tract. These results suggest that BMP-2/4 function may mediate several key events during cardiac development.

Localization of a locus for Charcot-Marie-Tooth neuropathy type Ia (CMT1A) to chromosome 17.

Phenotypic data for 71 genetic markers for members of five Caucasian kindreds were tested for linkage with the autosomal dominant mutations causing Charcot-Marie-Tooth (hereditary motor sensory) neuropathy type I, characterized by markedly reduced nerve conduction velocities. Lod score analysis gave no evidence of linkage to the closely linked chromosome 1 loci SPTA1-FY-F5-AT3 and APOA2. In contrast, these mutations were found to map closely (zeta = 10.828, theta = 0.0) to D17S58, an anonymous segment of DNA from 17p11.2-p11.1, and thus define the CMT1A locus. Segregation information data for an inferred recombinant offspring indicated that the CMT1A locus is probably proximal to MYH2, the locus encoding adult skeletal muscle myosin heavy polypeptide 2, which maps to 17p13. Analysis of the lod scores on a per kindred basis gave no evidence of genetic heterogeneity.