Natural resistance-associated macrophage protein 1 polymorphisms are associated with microscopy-positive tuberculosis

The natural resistance-associated macrophage protein 1 (NRAMP1) is implicated in the pathophysiology of mycobacterial infections. We investigated by polymerase chain reaction previously published Nramp1 genotypes at 4 loci-INT4, N543D, 3'UTR, and 5'(CA)(n) microsatellite markers-in 104 human immunodeficiency virus-negative patients with tuberculosis and 176 healthy control subjects living in Denmark. No significant difference in genotype frequency was found between white patients with tuberculosis and control subjects (P>.16), but carriage of Nramp1 variant alleles at loci INT4 and 5'(CA)(n) conferred a significantly increased risk of having microscopy-positive compared with microscopy-negative tuberculosis (65% vs. 35% [P=.0004] and 63% vs. 38% [P=.047], respectively). The Nramp1 alleles were not associated with increased risk for the development of cavities seen on chest radiographs, or with extrapulmonary tuberculosis. These results indicate that variant alleles in the Nramp1 gene are associated with increased mycobacterial replication rather than susceptibility for tuberculosis and may thus confer increased risk of severe disease.     

A study of the biological characteristics of a hybrid line between male Schistosoma haematobium (Dar es Salaam, Tanzania) and female S. intercalatum (Edea, Cameroun)

The viability of a hybrid between male Schistosoma haematobium (Dar es Salaam, Tanzania) and female S. intercalatum (Edea, Cameroun) was studied for up to the F7 hybrid generation and the biological characteristics of the hybrid were compared with those of each of the parental species. Using the total cercarial production/100 exposed snails/5 weeks value (TCP) as an index the hybrid miracidial infectivity to Bulinus forskalii (Kinshasa, Zaire), the host snail for S. intercalatum, remained comparable to that of S. intercalatum for up to at least the F5 generation and the TCP values for the hybrid/B. wrighti combination remained for up to the F7 generation intermediate between those of the parental species in B. wrighti. The hybrid also retained the infectivity for up to at least the F5 generation to B. globosus (Mazeras, Kenya), the host snail for S. haematobium, but the TCP values for the hybrid/B. globosus combination remained consistently lower than that of the S. haematobium/B. globosus combination. The hybrid cercarial infectivity to hamsters was for up to the F7 generation comparable to that of both parental species and the egg production capacity/worm pair/day of production of the F1 hybrid generation exceeded in both hamsters and mice that of both parental species. However, the egg production capacity subsequently decreased with that of the F3 to F6 generations in hamsters and with that of the F2 and F5 generations in mice being comparable to that of S. intercalatum. The pattern of distribution of eggs in tissue of hamsters of the F1 and F2 generations resembled that of S. haematobium and S. intercalatum, respectively, but the distributional pattern of the F3 to F6 generations deviated markedly from that of both the parental species and the preceding hybrid generations. The hybrid cercarial infectivity to mice and the pattern of egg distribution corresponded to that of S. intercalatum. The egg morphology of the P1 generation corresponded to that of S. intercalatum while that of the F1, F2 and F3 hybrid generations exhibited great polymorphism with a range of shapes through those of the parental species but with most eggs being intermediate in shape. However, the eggs of the F4 to F7 hybrid generations exhibited less polymorphism and resembled those of S. bovis in both size and shape.     

Nutritional Supplementation Increases Rifampin Exposure among Tuberculosis Patients Coinfected with HIV

Nutritional supplementation to tuberculosis (TB) patients has been associated with increased weight and reduced mortality, but its effect on the pharmacokinetics of first-line anti-TB drugs is unknown. A cohort of 100 TB patients (58 men; median age, 35 [interquartile range {IQR}, 29 to 40] years, and median body mass index [BMI], 18.8 [17.3 to 19.9] kg/m²) were randomized to receive nutritional supplementation during the intensive phase of TB treatment. Rifampin plasma concentrations were determined after 1 week and 2 months of treatment. The effects of nutritional supplementation, HIV, time on treatment, body weight, and SLCO1B1 rs4149032 genotype were examined using a population pharmacokinetic model. The model adjusted for body size via allometric scaling, accounted for clearance autoinduction, and detected an increase in bioavailability (+14%) for the patients in the continuation phase. HIV coinfection in patients not receiving the supplementation was found to decrease bioavailability by 21.8%, with a median maximum concentration of drug in serum (C_max) and area under the concentration-time curve from 0 to 24 h (AUC_0–24) of 5.6 μg/ml and 28.6 μg · h/ml, respectively. HIV-coinfected patients on nutritional supplementation achieved higher C_max and AUC_0–24 values of 6.4 μg/ml and 31.6 μg · h/ml, respectively, and only 13.3% bioavailability reduction. No effect of the SLCO1B1 rs4149032 genotype was observed. In conclusion, nutritional supplementation during the first 2 months of TB treatment reduces the decrease in rifampin exposure observed in HIV-coinfected patients but does not affect exposure in HIV-uninfected patients. If confirmed in other studies, the use of defined nutritional supplementation in HIV-coinfected TB patients should be considered in TB control programs. (This study has the controlled trial registration number ISRCTN 16552219.)     

Knee arthroscopy and arthrotomy under local anesthesia

We report our experience with knee arthroscopy in local anesthesia in 64 patients with subsequent arthrotomy in 14 of these. The effectiveness of the anesthetic method was evaluated by both the patient and the anesthetic personnel. There was no difference in pain assessment between arthroscopy alone and arthroscopy followed by arthrotomy. Half of the patients had no pain and only one regarded the procedure as very painful. Supplementary analgesia with 0.05 mg fentanyl was given to half of the patients not undergoing arthrotomy and to two thirds of those who had arthrotomy. It was not necessary to abandon any arthroscopic or surgical procedure because of pain. We conclude that local anesthesia is a safe and practical method for diagnostic arthroscopy, arthroscopic surgery, and minor arthrotomy.     

Parallel expression of synaptophysin and evoked neurotransmitter release during development of cultured neurons.

Primary cultures of GABAergic cerebral cortex neurons and glutamatergic cerebellar granule cells were used to study the expression of synaptophysin, a synaptic vesicle marker protein, along with the ability of each cell type to release neurotransmitter upon stimulation. The synaptophysin expression and neurotransmitter release were measured in each of the culture types as a function of development for up to 8 days in vitro, using the same batch of cells for both sets of measurements to obtain optimal comparisons. The content and the distribution of synaptophysin in the developing cells were assessed by quantitative immunoblotting and light microscope immunocytochemistry, respectively. In both cell types, a close parallelism was found between the temporal pattern of development in synaptophysin expression and neurotransmitter release. This temporal pattern differed between the two types of neurons. The cerebral cortex neurons showed a biphasic time course of increase in synaptophysin content, paralleled by a biphasic pattern of development in their ability to release [3H]GABA in response to depolarization by glutamate or elevated K+ concentrations. In contrast, a monophasic, approximately linear increase in the synaptophysin content and stimulated [3H]D-aspartate release was found in the cerebellar granule cells. These results, particularly regarding the GABAergic neurons, offer correlative evidence in support of the notion that a vesicular pool of these amino acid neurotransmitters may be intimately involved in their release, subsequent to depolarization stimuli.     

Proximal gastric vagotomy in dyspeptic patients without an ulcer

Proximal gastric vagotomy (PGV) was performed in 40 patients who had suffered from dyspepsia for several years, but who did not have any demonstrable ulcer. Great care was taken to obtain a thorough history of the disease. Patients with symptoms not likely to be caused by gastric hypersecretion were not treated surgically. There was a distinctive reduction of both basal and pentagastrin-stimulated acid secretion after the operation. The decrease in acid output was accompanied by a marked relief of symptoms. Most patients noted the improvement within 3 months after surgery. Thirty patients were interviewed after 5 years. Of these, 23 were either completely cured of dyspepsia or were at least much better than before the operation. Only 1 person reported no relief 5 years after PGV. It is concluded that surgical treatment may be of value in patients with chronic dyspepsia even in the absence of a peptic ulcer.

---

Resumen La vagotomía gástrica proximal fué realizada en 40 pacientes que sufrían de dispepsia por varios años, pero quienes no poseían úlcera gástrica demostrable. Se prestó especial cuidado a la obtención de una meticulosa historia de la enfermedad. Aquellos pacientes con síntomas que posiblemente no eran causados por hipersecreción gástrica no fueron sometidos a tratamiento quirúrgico. La operación produjo una clara reductión tanto de la secreción ácida basai como de la secreción en respuesta a la estimulación con pentagastrina, y la disminución de la secreción ácida se acompa¯nó de marcada mejoría de los síntomas. La mayoría de los pacientes notó mejoría dentro de los primeros tres meses después de la cirugía. Treinta pacientes fueron entrevistados después de cinco años de la operación, y de éstos, 23 se hallaron completamente curados de la dispepsia, o por lo menos mucho mejor que antes de la cirugía; sólo una persona informó que no había mejoría 5 años después de la vagotomía gástrica proximal. Se concluye que el tratamiento quirúrgico puede tener valor en pacientes con dispepsia crónica aún en ausencia de úlcera péptica.

---

Résumé Une vagotomie hypersélective a été practiquée chez 40 malades qui présentaient un état dyspeptique depuis plusieurs années mais qui n'étaient pas atteints d'ulcère duodénal. Leur histoire pathologique fut étudiée avec grand soin et les sujets qui n'accusaient pas de troubles identiques à ceux provoqués par l'hypersécrétion gastrique ne furent pas traités chirurgicalement.Apres l'intervention il fut possible de constater une réduction de la secrétion basale et de la secrétion stimulée par la Pentagastrine. La diminution de la secrétion acide s'accompagna d'une amélioration marquée des symptômes accusés antérieurement par les patients, 3 mois après l'intervention.Trente malades ont été revus 5 ans après avoir été opérés. Parmi eux 23 se considéraient comme guéris ou très améliorés. Un seul accusait le même état dyspeptique qu'avant l'opération.On peut conclure de ces faits que la vagotomie hypersélective est susceptible de contrôler les troubles dyspeptiques qui existent en l'absence d'ulcère.

     

Vasoactive intestinal polypeptide promotes cyclic adenosine 3'',5''-monophosphate accumulation in guinea-pig trachea.

Cyclic adenosine 3',5'-monophosphage (cyclic AMP) levels in guinea-pig tracheal rings increased on incubation with the vasoactive intestinal peptide (VIP). The effect was potentiated by the addition of theophylline. The results suggest that the tracheo-bronchial relaxant action of VIP may be mediated by stimulation of tracheal adenylyl cyclase.     

Cytotoxic actions and effects on intracellular Ca2+ and cGMP concentrations of sulphur-containing excitatory amino acids in cultured cerebral cortical neurons

Effects of the sulphur-containing acidic amino acids (SAAs) cysteic acid (CA), homocysteic acid (HCA), cysteine sulphinic acid (CSA), homocysteine sulphinic acid (HCSA), and S-sulphocysteine (SC) on intracellular concentrations of Ca²⁺ ([Ca²⁺]_i) and cGMP ([cGMP]_i) as well as their cytotoxic actions were investigated in cultured cerebral cortical neurons. The glutamate receptor subtype selective antagonists APV (D-(?)-2-amino-5-phosphonopentanoate) acting on N-methyl-D-aspartate (NMDA) receptors and DNQX (6,7-dinitroquinoxaline-2,3-dione) acting on non-NMDA receptors were employed to obtain information about the involvement of glutamate receptor subtypes in these actions of the SAAs. It was found that all SAAs exerted a cytotoxic action on the neurons. The ED₅₀ values for CSA, CA, HCSA, and HCA were around 30 to 50 μM and that for SC was about 150 μM. The glutamate transport blocker L-aspartate-β-hydroxamate increased the efficacy of CSA and CA but had no effect on the cytotoxic actions of the remaining SAAs. In case of CA, HCA, and SC the cytotoxicity could be prevented by APV alone and for HCSA, DNQX could block the toxic action. DNQX reduced the toxicity of HCA somewhat but the presence of APV was required for complete protection. CSA toxicity could only be blocked by the combination of APV and DNQX. All SAAs induced an increase in [cGMP]_i and [Ca²⁺]_i and with regard to [Ca²⁺]_i SC was the most potent and CA the least potent SAA. The effect of all SAAs on [cGMP]_i could be blocked by APV alone whereas DNQX had no effect except in the case of HCSA where the response was blocked completely and HCA where the response was inhibited by 75%. The SAA-induced increase in [Ca²⁺]_i could in all cases be significantly reduced by 0.6 mM Mg²⁺ and in the presence of Mg²⁺, APV dose dependently blocked the remaining SAA induced increase in [Ca²⁺]_i completely. Under these conditions DNQX was also found to block the SAA-induced increase in [Ca²⁺]_i dose dependently. In the absence of Mg²⁺, DNQX (25 μM) inhibited the response of the SAAs only by 65–75%. Under these conditions all SAA responses except that to SC could be fully antagonized by 300 μM APV. The SC-induced increase in [Ca²⁺]_i was inhibited by 60% by APV. The results show that no simple correlation exists between SAA-induced cytotoxicity and their ability to increase intracellular levels of Ca²⁺ and cGMP. However, when both NMDA and non-NMDA receptors were antagonized no toxicity or changes in calcium or cGMP were observed. © 1993 Wiley-Liss, Inc.