Characteristics of TPT initiation and completion among people living with HIV.

BACKGROUND: TB preventive treatment (TPT) reduces morbidity and mortality among people living with HIV (PLHIV). Despite the successful scale-up of TPT in Malawi, monitoring and evaluation have been suboptimal. We utilized the Malawi Population-Based HIV Impact Assessment (MPHIA) 2020-2021 survey data to estimate TPT uptake and completion among self-reported HIV-positive persons. METHODS: We estimated the proportion of HIV-positive respondents who had ever undergone TPT, and determined the percentage of those currently on TPT who had completed more than 6 months of treatment. Bivariate and multivariable logistic regression were performed to calculate the odds ratios for factors associated with ever-taking TPT. All variables were self-reported, and the analysis was weighted and accounted for in the survey design. RESULTS: Of the HIV+ respondents, 38.8% (95% CI 36.4-41.3) had ever taken TPT. The adjusted odds of ever taking TPT were 8.0 and 5.2 times as high in the Central and Southern regions, respectively, compared to the Northern region; 1.9 times higher among those in the highest wealth quintile, and 2.1 times higher for those on antiretroviral therapy >10 years. Of those currently taking TPT, 56.2% completed >6 months of TPT. CONCLUSION: These results suggest low TPT uptake and >6 months' completion rates among self-reported HIV+ persons. Initiatives to create demand and strengthen adherence would improve TPT uptake.

CONTEXTE: Le traitement préventif de la TB (TPT) réduit la morbidité et la mortalité chez les personnes vivant avec le VIH (PVVIH). Malgré l'extension réussie du TPT au Malawi, le suivi et l'évaluation n'ont pas été optimaux. Nous avons utilisé les données de l'enquête MPHIA (Malawi Population-Based HIV Impact Assessment) 2020­2021 pour estimer l'adoption et l'achèvement du TPT parmi les personnes se déclarant séropositives. MÉTHODES: Nous avons estimé la proportion de répondants séropositifs qui avaient déjà subi un TPT et déterminé le pourcentage de ceux qui sont actuellement sous TPT et qui ont terminé plus de 6 mois de traitement. Une régression logistique bivariée et multivariable a été effectuée pour calculer les rapports de cotes des facteurs associés au fait d'avoir déjà pris un TPT. Toutes les variables étaient autodéclarées et l'analyse a été pondérée et prise en compte dans la conception de l'enquête. RÉSULTATS: Parmi les répondants séropositifs, 38,8% (IC 95% 36,4­41,3) avaient déjà pris du TPT. Les probabilités ajustées de prise de TPT étaient 8,0 et 5,2 fois plus élevées dans les régions du centre et du sud, respectivement, que dans la région du nord ; 1,9 fois plus élevées chez les personnes appartenant au quintile de richesse le plus élevé, et 2,1 fois plus élevées chez les personnes suivant une thérapie antirétrovirale depuis plus de 10 ans. Parmi ceux qui prennent actuellement un TPT, 56,2% ont terminé >6 mois de TPT. CONCLUSION: Ces résultats suggèrent un faible taux d'utilisation du TPT et des taux d'achèvement de >6 mois parmi les personnes déclarées séropositives. Des initiatives visant à créer une demande et à renforcer l'adhésion permettraient d'améliorer l'utilisation du TPT.

Identification and characterization of alternative splice variants of the mouse Trek2/Kcnk10 gene.

Two-pore domain K(+) (K(2P)) channels underlie leak or background potassium conductances in many cells. The Trek subfamily of K(2P) channels, which includes Trek1/Kcnk2 and Trek2/Kcnk10 and has been implicated in depression, nociception, and cognition, exhibits complex regulation and can modulate cell excitability in response to a wide array of stimuli. While alternative translation initiation and alternative splicing contribute to the structural and functional diversity of Trek1, the impact of post-transcriptional modifications on the expression and function of Trek2 is unclear. Here, we characterized two novel splice isoforms of the mouse Trek2 gene. One variant is a truncated form of Trek2 that possesses two transmembrane segments and one pore domain (Trek2-1p), while the other (Trek2b) differs from two known mouse Trek2 isoforms (Trek2a and Trek2c) at the extreme amino terminus. Both Trek2-1p and Trek2b, and Trek2a and Trek2c, showed prominent expression in the mouse CNS. Expression patterns of the Trek2 variants within the CNS were largely overlapping, though some isoform-specific differences were noted. Heterologous expression of Trek2-1p yielded no novel whole-cell currents in transfected human embryonic kidney (HEK) 293 cells. In contrast, expression of Trek2b correlated with robust K(+) currents that were ~fivefold larger than currents measured in cells expressing Trek2a or Trek2c, a difference mirrored by significantly higher levels of Trek2b found at the plasma membrane. This study provides new insights into the molecular diversity of Trek channels and suggests a potential role for the Trek2 amino terminus in channel trafficking and/or stability.

[3H]Flunitrazepam binding to recombinant alpha1beta2gamma2S GABAA receptors stably expressed in HEK 293 cells.

The interaction of selected compounds with the binding of the benzodiazepine [3H]flunitrazepam to membranes isolated from human embryonic kidney (HEK) 293 cells, stably transfected with the aI( 2 2S subtype of GABAA receptors, was studied. This subtype of GABAA receptors is the most common type of GABAA receptor found in the brain, and benzodiazepines are drugs known to enhance the effects of the inhibitory neurotransmitter gamma-amino butyric acid (GABA) by binding to the benzodiazepine binding sites which are part of the GABAA receptor complex. Scatchard analysis of binding data revealed the existence of a single type of binding site for [3H]flunitrazepam. GABA and thiopental enhanced, while the antagonist of central benzodiazepine binding sites--flumazenil, benzodiazepines such as clonazepam, flunitrazepam and diazepam, and the triazolopyridazine CI 218,872--displaced with nanomolar potency the binding of [3H]flunitrazepam. A partial displacement was obtained with the antagonist of the peripheral benzodiazepine binding sites--PK 11195--and with the neurosteroid dehydroepiandrosterone sulfate. The potency of drugs to enhance or inhibit [3H]flunitrazepam binding mainly corresponded to that observed for the modulation of the binding of [3H]flunitrazepam to the native type 1 benzodiazepine binding sites. This, as well as a high density of expressed binding sites, makes the cell line under study a very reliable and economical model for the testing of effects of different compounds at the GABAA receptor.

Swim stress alters the behavioural response of mice to GABA-related and some GABA-unrelated convulsants.

To elucidate the relationship between stress and seizures, the effect of a single swim stress on the convulsive signs and death produced by several GABA-related and GABA-unrelated convulsants, and the effect of repeated swim stress on picrotoxin-induced convulsions was studied. Mice were subjected to swim stress (10 min swimming at 18-19 degrees C), and the i.v. infusion of convulsants started 15 min thereafter. The latency to the onset of several convulsant signs and death was measured, and the doses of convulsants producing convulsions and death were calculated. Additional experiments included mice swimming at room temperature, and those which were stressed repeatedly (twice a day for four consecutive days, plus one stressful procedure on the fifth day). Swim stress increased the dose needed to produce convulsant signs and death after bicuculline, picrotoxin, pentylenetetrazole, strychnine and 4-aminopyridine, while kainic acid-induced convulsions were not affected. Using picrotoxin infusion, the effect of swimming in room temperature water was less than the effect of swimming in 18-19 degrees C water. In addition, the effect of repeated stress was less than the effect of acute stress on picrotoxin-induced convulsions. The results demonstrate that acute swim stress lowers the convulsive potency of GABA-related and some GABA-unrelated convulsants. Repeatedly stressed animals develop tolerance to anticonvulsive effect of swim stress.

Anticonvulsive effect of swim stress in mice.

To explore the possible involvement of glucocorticoids in the previously observed anticonvulsive effect of swim stress, mice were, prior to administration of convulsants, subjected to treatments that diminish or enhance plasma corticosterone levels. Aminoglutethimide, the inhibitor of steroid synthesis, failed to modify convulsant doses of picrotoxin, but enhanced threshold doses of pentylenetetrazole producing myoclonus and death, both in unstressed and stressed animals. The same drug prevented the effect of stress on pentylenetetrazole-induced running bouncing clonus (RB clonus) and abolished the appearance of tonic hindlimb extension (THE). Doses of kainic acid producing convulsions and death were not affected by stress, but they were enhanced by aminoglutethimide. Corticosterone administration could not imitate the effect of swim stress. Finasteride, a 5 alpha-reductase inhibitor, did not interfere with the effect of stress on picrotoxin-induced convulsions. Swim stress failed to modify the binding of the convulsant t[3H]-butylbicycloorthobenzoate [3H]TBOB, to washed mouse forebrain membranes. The results confirmed an anticonvulsant effect of swim stress against convulsions produced by GABA-related convulsants, but they do not support the hypothesis suggesting the involvement of glucocorticoids or neurosteroids in this effect.

Beta-1 adrenoceptor antagonists potentiate the anticonvulsive effect of swim stress in mice.

To explore the possible involvement of beta adrenoceptor antagonists in the previously observed anticonvulsive effect of swim stress, the mice were, prior to administration of convulsants, pre-treated with propranolol (a non-selective beta adrenoceptor antagonist), betaxolol (a selective beta-1 adrenoreceptor antagonist), or ICI 118,551 (a selective beta-2 adrenoreceptor antagonist). In control unstressed animals, only propranolol [10 mg/kg, intraperitoneally (ip)] produced a significant change. It enhanced the threshold dose of picrotoxin producing tonic hindlimb extension. However, in swim-stressed animals, propranolol enhanced doses of picrotoxin producing tonic hindlimb extension and death, while betaxolol (20 mg/kg, i.p.) enhanced doses of picrotoxin producing running/bouncing clonus, tonic hindlimb extension and death. Pre-treatment with ICI 118,551 (4 mg/kg, i.p.) failed to affect doses of picrotoxin producing convulsions and death. The results demonstrate that blockade of beta-1 adrenoceptors potentiates the anticonvulsant effect of swim stress against convulsions produced by picrotoxin, a noncompetitive GABA(A) receptor antagonist.

Effects of adrenalectomy and gonadectomy on sex and stress-induced differences in bicuculline-induced convulsions.

The effects of adrenalectomy, gonadectomy and combined adrenalectomy plus gonadectomy on the previously described sex-dependent anticonvulsive effect of swim stress were studied in rats. The convulsive signs (myoclonic twitch, generalized convulsions, tonic hindlimb extension) were produced by constant i.v. infusion of gamma-aminobutyric acid(A) (GABA(A)) antagonist bicuculline, which started 15 min after termination of swim stress (10-min swim at 18-19 degrees C). Adrenalectomy decreased the threshold doses of bicuculline producing the first myoclonic twitch and the onset of generalized convulsions only in females. In adrenalectomized females, but not in males, swim stress enhanced the threshold dose of bicuculline producing generalized convulsions, but, unlike in adrenal-intact animals, it failed to enhance the dose of bicuculline producing tonic hindlimb extension. In gonadectomized stressed and unstressed animals all sex differences disappeared, and swim stress enhanced in both sexes only the threshold doses of bicuculline producing tonic hindlimb extension. Adrenalectomized plus gonadectomized animals displayed clear sex differences in doses of bicuculline necessary to produce all the convulsive signs. In the same animals swim stress postponed, especially in females, the onset of the first myoclonic twitch and generalized convulsions, but not the onset of tonic hindlimb extension. In summary, our results suggest that hormones of the adrenal and gonadal glands are only partly responsible for decreased susceptibility, especially of female rats, to the GABA(A) antagonist bicuculline. Moreover, they have demonstrated that stress produces a gender-specific anticonvulsive effect even in the animals completely deprived of steroid hormones of peripheral origin.

[3H]t-butylbicycloorthobenzoate binding to recombinant alpha1beta2gamma2s GABA(A) receptor.

The interaction of several selected compounds with the binding of the cage convulsant t-[3H]butylbicycloorthobenzoate ([3H]TBOB) to membranes isolated from human embryonic kidney (HEK) 293 cells stably transfected with alpha1beta2gamma2s subtype of GABA(A) receptors was studied. Scatchard analysis of binding data revealed the existence of a single type of binding site for [3H]TBOB with a Kd of 47.06+/-4.06 nM and a Bmax value of 6.72+/-0.52 pmol/mg protein. GABA, thiopental, TBOB, picrotoxin and the neurosteroid dehydroepiandrosterone sulfate displaced concentration-dependently the binding of [3H]TBOB to this recombinant receptor. Dehydroepiandrosterone sulfate reversed the 5 microM GABA-induced inhibition of specific [3H]TBOB binding. It is concluded that membranes isolated from HEK 293 cells stably transfected with alpha1beta2gamma2s subunits exhibit specific high-affinity [3H]TBOB binding. The potency of drugs to inhibit [3H]TBOB binding mainly corresponded to that observed for the inhibition of the binding of cage convulsants to the native receptors or to transiently transfected HEK 293 cells.