Controversies in tuberculosis

Tuberculous infection among children continues to be a significant cause of morbidity. The symptom complex are so variable among children that the final diagnosis often rests on the laboratory tests. Proper interpretation of the tests, specially tuberculin test and radiographic studies, are necessary for establishing correct diagnosis. The usefulness of tuberculin test in both unimmunized and BCG vaccinated children is highlighted. BCG accelerated response as a test should be reserved for identifying serious form of pulmonary disease or CNS tuberculosis when the tuberculin test is negative. Radiographic assessment may be sensitive in some instances but not always specific and hence needs cautious interpretation. Tuberculosis among BCG vaccinated children though not uncommon, needs proper documentation. Current trends in the management of tuberculosis including CNS forms are briefly outlined.     

Mechanisms of cell signaling by nitric oxide and peroxynitrite: from mitochondria to MAP kinases

Many of the biological and pathological effects of nitric oxide (NO) are mediated through cell signaling pathways that are initiated by NO reacting with metalloproteins. More recently, it has been recognized that the reaction of NO with free radicals such as superoxide and the lipid peroxyl radical also has the potential to modulate redox signaling. Although it is clear that NO can exert both cytotoxic and cytoprotective actions, the focus of this overview are those reactions that could lead to protection of the cell against oxidative stress in the vasculature. This will include the induction of antioxidant defenses such as glutathione, activation of mitogen-activated protein kinases in response to blood flow, and modulation of mitochondrial function and its impact on apoptosis. Models are presented that show the increased synthesis of glutathione in response to shear stress and inhibition of cytochrome c release from mitochondria. It appears that in the vasculature NO-dependent signaling pathways are of three types: (i) those involving NO itself, leading to modulation of mitochondrial respiration and soluble guanylate cyclase; (ii) those that involve S-nitrosation, including inhibition of caspases; and (iii) autocrine signaling that involves the intracellular formation of peroxynitrite and the activation of the mitogen-activated protein kinases. Taken together, NO plays a major role in the modulation of redox cell signaling through a number of distinct pathways in a cellular setting.     

Comparison of nasal pressure transducer and thermistor for detection of respiratory events during polysomnography in children

STUDY OBJECTIVES: The results of small studies have suggested that a nasal-cannula pressure transducer has a higher sensitivity than a thermistor in detecting hypopneas and diagnosing sleep-disordered breathing in both adults and children. We compared a thermistor alone, and in conjunction with a pressure transducer, for detection of sleep-disordered breathing in children during in-home polysomnography. DESIGN: Retrospective analysis of a subsample of a prospective cohort study. SETTING: Students attending elementary school in the Tucson Unified School District. PARTICIPANTS: A subsample of the Tucson Children's Assessment of Sleep Apnea study population. MEASUREMENTS AND RESULTS: Polysomnographic recordings of 40 children (24 girls and 16 boys, mean age 9.2 +/- 1.7 years; range 6-11 years) were analyzed to compare the detection of sleep-disordered breathing events by 2 different methods of measuring airflow: thermistor alone and thermistor with nasal-cannula pressure transducer (transducer) used simultaneously. The transducer detected all the respiratory events detected by the thermistor, but the thermistor detected only 84% of the transducer-defined events. Consequently, the transducer-derived mean respiratory disturbance index was higher than that detected by the thermistor (7.0 +/- 3.8 vs 5.9 +/- 3.4, P < .001). The bias error between transducer respiratory disturbance index and thermistor respiratory disturbance index on a Bland-Altman plot was 1.08 (95% confidence interval, 0.8 - 1.4). There was good agreement between the thermistor and the transducer for making the diagnosis of sleep apnea using a cutoff of a respiratory disturbance index greater than 5 (kappa = 0.69). The quality of the tracings with the transducer was comparable to that of the thermistor, but the transducer dislodged more frequently. CONCLUSION: The use of a nasal transducer in conjunction with a thermistor was more sensitive than the thermistor alone in detecting sleep-disordered breathing in children during unattended polysomnography.     

Conformation of O6-alkylguanosines: molecular mechanism of mutagenesis

The O⁶-alkylation of guanine residues in DNA treated with alkylatingagents induce mutations due to mis-pairing resulting from thedeprotonation of N1. In addition to the deprotonation of N1,the conformation of the O⁶-alkyl group with respect to N7 ofguanine is very important. Here, we present X-ray crystallographicevidence that shows that the methyl group in O⁶-methylguanosinehas a preference for the distal conformation, blocking the Watson-Cricksites. This distal conformation persists in the solid statefor several analogs of O⁶-alkylguanosine also. This preferredconformation agrees with the result that poly(O⁶-methyl GMP)does not form any stable complex with poly(U). However, themispairing of O⁶-methylguanine with thymine and the resultantGA transition is known from in vitro studies. The above twoopposite results strongly indicate that the conformation ofthe O⁶-alkyl group and the base pairing properties of O⁶-alkylguanineat the monomer and polymer levels must be different from thesituation when the modified base is embedded with a small frequencyin a duplex. It is interesting to note that the sterical blockingof the Watson-Crick site at the monomer level and the alteredbase pairing properties when present as occasional bases ina duplex emerge as a common property for several mutagenic baseslike O⁶-alkylguanmes, O⁴ -methyluracil and N⁴-hydroxycytosine.     

Altered metabolism of all-trans-retinoic acid in liposome-encapsulated form

Treatment with all-trans-retinoic acid (ATRA) induces complete remission in many acute promyelocytic leukemia patients. However, plasma drug levels progressively decrease following prolonged treatment with oral ATRA. This decrease is due, at least in part, to the induced cytochrome P-450-dependent metabolism of ATRA. To investigate if incorporation of ATRA in liposomes could alter its metabolism, we compared the cellular metabolism of liposomal-ATRA (L-ATRA) with free drug. Microsomes isolated from the rat liver metabolized L-ATRA to a significantly lower extent than they did free-ATRA. Similarly, in F9 cells, L-ATRA was metabolized at a slower rate than the free drug. These results suggest that L-ATRA may have important clinical implications in terms of slowing down the rate of ATRA metabolism and producing long-term remission in APL patients.     

Charge-based interactions of mammalian sperm with oocytes: inhibition of fertilization of mouse oocytes by ligands of macrophage scavenger receptor(s)

Objective: To determine whether anionic ligands for the macrophage scavenger receptor inhibit the fertilization of mouse oocytes by mouse spermatozoa.

Design: In vitro study of sperm binding and two-cell embryo formation in the presence of scavenger receptor ligands. Sperm-oocyte interaction may be mediated by sulfated sugars. In this study, we tested other nonsulfated anionic ligands for the scavenger receptor for their ability to affect fertilization. The only common feature of these ligands is their anionic nature.

Setting: Oocytes and sperm from mice were used.

Main Outcome Measure(s): Binding of sperm to oocytes and subsequent formation of two cell embryos were determined.

Result(s): Fucoidin, polyinosinic acid, oxidized low-density lipoprotein, acetyl low-density lipoprotein, and malondialdehyde-modified LDL inhibited the binding and fertilization of mouse sperm to mouse oocytes. Addition of fresh sperm to oocytes previously treated with sperm in the presence of these agents restored the binding and fertilization.

Conclusion(s): These results show that charge-based interactions analogous to the interactions of the scavenger receptor with its ligands may play an important role in mammalian fertilization.     

Potential applications of lactic acid bacteria and bacteriocins in antimycobacterial therapy

Tuberculosis(TB) is a communicable disease caused by Mycobacterium tuberculosis(M. tuberculosis). WHO estimated that 10.4 million new(incident) TB cases worldwide in year 2016. The increased prevalence of drug resistant strains and side effects associated with the current anti-tubercular drugs make the treatment options more complicated. Hence, there are necessities to identify new drug candidates to fight against various sub-populations of M. tuberculosis with less or no toxicity/side effects and shorter treatment duration. Bacteriocins produced by lactic acid bacteria(LAB) attract attention of researchers because of its "Generally recognized as safe" status. LAB and its bacteriocins possess an effective antimicrobial activity against various bacteria and fungi. Interestingly bacteriocins such as nisin and lacticin 3147 have shown antimycobacterial activity in vitro. As probiotics, LAB plays a vital role in promoting various health benefits including ability to modulate immune response against various infectious diseases. LAB and its metabolic products activate immune system and thereby limiting the M. tuberculosis pathogenesis. The protein and peptide engineering techniques paved the ways to obtain hybrid bacteriocin derivatives from the known peptide sequence of existing bacteriocin. In this review, we focus on the antimycobacterial property and immunomodulatory role of LAB and its metabolic products. Techniques for large scale synthesis of potential bacteriocin with multifunctional activity and enhanced stability are also discussed.