Pharmacological interventions for preventing acute mountain sickness: a network meta-analysis and trial sequential analysis of randomized clinical trials

Background: Individuals ascending to high altitude are at a risk of getting acute mountain sickness (AMS). The present study is a network meta-analysis comparing all the interventions available to prevent AMS.

Methods: Electronic databases were searched for randomized clinical trials evaluating the use of drugs to prevent AMS. Incidence of AMS was the primary outcome and incidence of severe AMS, paraesthesia (as side effect of acetazolamide use), headache and severe headache, and oxygen saturation were the secondary outcomes. Odds ratio [95% confidence interval] was the effect estimate for categorical outcomes and weighted mean difference for oxygen saturation. Random effects model was used to derive the direct and mixed treatment comparison pooled estimates. Trial sequential analysis and grading of the evidence for key comparisons were carried out.

Results: A total of 24 studies were included. Acetazolamide at 125, 250 and 375?mg twice daily, dexamethasone and ibuprofen had statistically significant lower incidence of AMS compared to placebo. All the above agents except ibuprofen were also observed to significantly reduce the incidence of severe AMS. Acetazolamide alone or in combination with Ginkgo biloba were associated with lower incidence of headache, but higher risk of paraesthesia. Acetazolamide at 125?mg and 375?mg twice daily significantly reduce the incidence of severe headache as like ibuprofen. Trial sequential analysis indicates that the current evidence is adequate for the incidence of AMS only for acetazolamide 125 and 250?mg twice daily. Similarly, the strength of evidence for acetazolamide 125 and 250?mg twice daily was moderate while it was either low or very low for all other comparisons.

Conclusions: Acetazolamide at 125, 250 and 375?mg twice daily, ibuprofen and dexamethasone significantly reduce the incidence of AMS of which adequate evidence exists only for acetazolamide 125 and 250?mg twice daily therapy. Acetazolamide 125?mg twice daily could be the best in the pool considering the presence of enough evidence for preventing AMS and associated with lower incidence of paraesthesia.

• Key messages

• Acetazolamide 125, 250 and 375?mg twice daily, dexamethasone and ibuprofen reduce the incidence of AMS in high altitudes.

• Adequate evidence exists supporting the use of acetazolamide 125?mg and 250?mg twice daily for preventing AMS of which acetazolamide 125?mg twice daily could be the best.

     

Haploidentical Hematopoietic Stem Cell Transplantation in Leukemia’s: Experience from a Cancer Center in India

There has been a surge in haploidentical hematopoietic stem cell transplantation (HSCT) in India recently. However, there is a paucity of data on haploidentical HSCT from India. The report is an analysis of data of haploidentical HSCT performed at our center. Analysis of patients with acute leukemia or chronic myeloid leukemia who underwent haploidentical HSCT during 2014–2019 was performed. The graft versus host disease (GVHD) prophylaxis was post-transplant Cyclophosphamide with Mycophenolate-mofetil and Cyclosporine. All patients were transfused peripheral blood stem cells from donors. Overall survival (OS) was calculated using the Kaplan–Meier method. Twenty-one patients underwent haploidentical HSCT. Fourteen-patients were males. The median age of patients was 15 years. Fludarabine with total body irradiation was the most common conditioning regimen (n = 15, 71.4%). The median duration for neutrophil and platelet engraftment was 14 days. Cumulative incidence of acute and chronic GVHD was 19%, and 38% respectively. The median follow-up was 26 months and the two-year OS was 38%. Twelve (57%) patients died during the study period, 8 patients (38%) died from transplant-related mortality (TRM), and 4 from disease relapse. Sepsis was the cause of death in six of the eight TRM. Nine out of 21 patients (42.8%) are leukemia-free on follow-up. Haploidentical HSCT is a promising modality of treatment in patients who have no suitable matched donors. Though the TRM remains high, good disease control was achieved in 42.8% of patients. Multi-drug resistant bacterial infection remains a challenge in performing haploidentical HSCT in developing countries.     

Intronic sequence elements impede exon ligation and trigger a discard pathway that yields functional telomerase RNA in fission yeast

The fission yeast telomerase RNA (TER1) precursor harbors an intron immediately downstream from its mature 3′ end. Unlike most introns, which are removed from precursor RNAs by the spliceosome in two sequential but tightly coupled transesterification reactions, TER1 only undergoes the first cleavage reaction during telomerase RNA maturation. The mechanism underlying spliceosome-mediated 3′ end processing has remained unclear. We now demonstrate that a strong branch site (BS), a long distance to the 3′ splice site (3′ SS), and a weak polypyrimidine (Py) tract act synergistically to attenuate the transition from the first to the second step of splicing. The observation that a strong BS antagonizes the second step of splicing in the context of TER1 suggests that the BS–U2 snRNA interaction is disrupted after the first step and thus much earlier than previously thought. The slow transition from first to second step triggers the Prp22 DExD/H-box helicase-dependent rejection of the cleaved products and Prp43-dependent “discard” of the splicing intermediates. Our findings explain how the spliceosome can function in 3′ end processing and provide new insights into the mechanism of splicing.     

Mild Renal Artery Stenosis Can Induce Renovascular Hypertension and is Associated with Elevated Renal Vein Renin Secretion

Renovascular hypertension is a syndrome which encompasses the physiological response of the kidney to changes in renal blood flow and renal perfusion pressure. Such physiological changes can occur with renal artery occlusion irrespective of the severity of the lesion. We have analyzed hypertensive patients with mild renal artery stenosis and compared them to patients with no stenosis. Renal vein renin sampling from catheterization of the renal vein was performed in all these patients. Patients with mild stenosis had higher renal vein renin ratio (3.01 ± 1.5) than the patients with no stenosis (1.10 ± 0.29; p = 0.002). Patients with mild stenosis were also found to have higher diastolic blood pressure and renal artery resistive indices when compared to patients with no stenosis. We therefore conclude that mild stenosis can precipitate renin‐mediated hypertension in renovascular stenosis and also emphasis that parameters pertinent to renal physiology need to be evaluated before considering treatment options in patients with renal artery stenosis and medical management with RAAS blockade is the preferred modality of therapy for patients with renin‐mediated hypertension.     

Demonstration of a ubiquitin binding site on murine haemopoietic progenitor cells: implication of ubiquitin in homing and adhesion

Summary. Investigations into the nature of the molecular interactions mediating the recognition of the haemopoietic progenitor cells by the haemopoietic stroma, indicate that ubiquitin mediates the binding between murine haemopoietic progenitors and the haemopoietic stroma. The adhesion of haemopoietic progenitors to anti-ubiquitin antibody treated bone marrow stromal cultures, shows inhibition of binding by approximately 78%. Affinity purification of the 1% Triton X-100 soluble stromal membrane fraction, on anti-ubiquitin-sepharose revealed a ubiquitinated 55 kD subunit. Progenitor cells treated with ubiquitin show approximately 58% inhibition in their ability to home into spleen, indicating the direct involvement of ubiquitin in homing. Histochemical staining of bone marrow cells using ubiquitin as a probe further delineates a population of cells possessing specific binding sites for ubiquitin. We demonstrate here the presence of a ubiquitin binding site on the haemopoietic progenitor cells, which may play a major role in the targeting of such progenitors to their 'niche' within the haemopoietic tissue. Such ubiquitin-mediated recognition may thus constitute a common molecular mechanism for homing and adhesion to both bone marrow and spleen, and may be implicated in the homing of more primitive, less differentiated haemopoietic progenitors. The results also indicate that the homing of haemopoietic progenitors within the haemopoietic micro-environment may be mediated by both a ubiquitin dependent and another ubiquitin independent mechanism.     

Pharmacokinetics of First-Line Antituberculosis Drugs in HIV-Infected Children with Tuberculosis Treated with Intermittent Regimens in India

The objective of this report was to study the pharmacokinetics of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) in HIV-infected children with tuberculosis (TB) treated with a thrice-weekly anti-TB regimen in the government program in India. Seventy-seven HIV-infected children with TB aged 1 to 15 years from six hospitals in India were recruited. During the intensive phase of TB treatment with directly observed administration of the drugs, a complete pharmacokinetic study was performed. Drug concentrations were measured by high-performance liquid chromatography. A multivariable regression analysis was done to explore the factors impacting drug levels and treatment outcomes. The proportions of children with subnormal peak concentrations (C_max) of RMP, INH, and PZA were 97%, 28%, and 33%, respectively. Children less than 5 years old had a lower median C_max and lower exposure (area under the time-concentration curve from 0 to 8 h [AUC_0–8]) of INH (C_max, 2.5 versus 5.1 μg/ml, respectively [P = 0.016]; AUC_0–8, 11.1 versus 22.0 μg/ml · h, respectively [P = 0.047[) and PZA (C_max, 34.1 versus 42.3 μg/ml, respectively [P = 0.055]; AUC_0–8, 177.9 versus 221.7 μg/ml · h, respectively [P = 0.05]) than those more than 5 years old. In children with unfavorable versus favorable outcomes, the median C_max of RMP (1.0 versus 2.8 μg/ml, respectively; P = 0.002) and PZA (31.9 versus 44.4 μg/ml, respectively; P = 0.045) were significantly lower. Among all factors studied, the PZA C_max influenced TB treatment outcome (P = 0.011; adjusted odds ratio, 1.094; 95% confidence interval, 1.021 to 1.173). A high proportion of children with HIV and TB had a subnormal RMP C_max. The PZA C_max significantly influenced treatment outcome. These findings have important clinical implications and emphasize that drug doses in HIV-infected children with TB have to be optimized.     

Reentrant para‐Hisian ventricular tachycardia eliminated from the noncoronary cusp: Importance of regional anatomy for vantage‐point ablation

We present a rare case of reentrant ventricular tachycardia proven by entrainment maneuvers that was successfully ablated from the noncoronary cusp. The case highlights regional anatomy, pacing maneuvers with multi‐modality images from fluoroscopy, intracardiac echo, and electroanatomical mapping.