Fixed-dose combination therapy-based protocol compared with free pill combination protocol: Results of a cluster randomized trial

Fixed-dose combination (FDC) therapy is recommended for hypertension management in Nigeria based on randomized trials at the individual level. This cluster-randomized trial evaluates effectiveness and safety of a treatment protocol that used two-drug FDC therapy as the second and third steps for hypertension control compared with a protocol that used free pill combinations. From January 2021 to June 2021, 60 primary healthcare centers in the Federal Capital Territory of Nigeria were randomized to a protocol using FDC therapy as second and third steps compared with a protocol that used the same medications in free pill combination therapy for these steps. Eligible patients were adults (≥18 years) with hypertension. The primary outcome was the odds of a patient being controlled at their last visit between baseline to 6-month follow-up in the FDC group compared to the free pill group. 4427 patients (mean [SD] age: 49.0 [12.4] years, 70.5% female) were registered with mean (SD) baseline systolic/diastolic blood pressure 155 (20.6)/96 (13.1) mm Hg. Baseline characteristics of groups were similar. After 6-months, hypertension control rate improved in the two treatment protocols, but there were no differences between the groups after adjustment (FDC = 53.9% versus free pill combination = 47.9%, cluster-adjusted p = .29). Adverse events were similarly low (<1%) in both groups. Both protocols improved hypertension control rates at 6-months in comparison to baseline, though no differences were observed between groups. Further work is needed to determine if upfront FDC therapy is more effective and efficient to improve hypertension control rates.     

PGJ2 inhibition of LPS-induced inflammatory mediator expression from rat alveolar macrophages

Studies suggested that 15-deoxy-delta-(12,14)-prostaglandin J2 (PGJ2) may exert anti-inflammatory effects, including in the lung. Thus, in vitro studies were conducted to (1) investigate whether PGJ2 inhibited the production of inflammatory mediators from lipopolysaccharide (LPS)-exposed primary rat alveolar macrophages (AM), and (2) investigate possible mechanisms underlying PGJ2-mediated inhibition of inflammatory mediator production. These studies determined that PGJ2 inhibited LPS-induced nitric oxide (NO) production in a concentration- and time-dependent manner. PGJ2-mediated inhibition of NO, as well as of tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 (MIP-2), was also determined to be dependent on the time of addition of PGJ2 relative to LPS, and suggested the PGJ2 inhibitory mechanism is an early event. PGJ2 was shown not to interfere with binding or internalization of LPS by AM, indicating this was not responsible for PGJ2 inhibitory effects. Another possible mechanism underlying PGJ2-mediated inhibition was via peroxisome proliferator-activated receptor-gamma (PPAR-gamma). However, biochemical studies suggested that PGJ2-mediated inhibition was not occurring through PPAR-gamma dependent mechanism, and molecular studies further established that both LPS and PGJ2 decrease PPAR-gamma mRNA expression. A third possible mechanism underlying PGJ2-mediated inhibition was by alteration of nuclear factor (NF)-kappaB. Molecular studies confirmed that LPS stimulated NF-kappaB mRNA expression, and PGJ2 reduced this stimulation, which is consistent with PGJ2 effect on LPS-induced production of NO, TNF-alpha and MIP-2. Thus, data in this study established that PGJ2 inhibited LPS-induced inflammatory mediator production in rat AM, and this inhibition is mediated, at least in part, by reducing the expression of NF-kappaB mRNA.     

The systemic inflammatory response syndrome as a predictor of bacteraemia and outcome from sepsis

Criteria defining the <it>systemic inflammatory response syndrome</it> (SIRS) were used to assess prospectively 270 clinical episodes in which blood cultures were taken from patients in general medicine. SIRS, severe sepsis and septic shock occurred in 149 (55%), 13 (5%) and 9 (3%) episodes, respectively. However, evidence of organ hypoperfusion indicating severe sepsis was recorded as sought in only 26% of episodes of SIRS. Crude mortality at 28 days increased sequentially as more SIRS criteria were met, rising from 12% in non-SIRS blood culture episodes, to 36% when all four criteria were met. Mortality from severe sepsis and septic shock was 38% and 56%, respectively. In 61/64 (95%) episodes of clinically important bacteraemia, patients fulfilled SIRS criteria when the blood culture was taken. However, the positive predictive value of SIRS for predicting bacteraemia was only 7%. Patients who did not fulfill SIRS criteria when blood cultures were taken were at low risk of bacteraemia and comprised 45% (121/270) of the study population. Three patients in this low-risk group had bacteraemia. Mortality in bacteraemic patients with severe sepsis or septic shock who were initially treated with ineffective antibiotics for up to 48 h was 80%, compared to 42% in those always treated appropriately.      

Recent Southeast Asian domestication and Lapita dispersal of sacred male pseudohermaphroditic "tuskers" and hairless pigs of Vanuatu

Recent analyses of global pig populations revealed strict correlations between mtDNA phylogenies and geographic locations. An exception was the monophyletic "Pacific clade" (PC) of pigs not previously linked to any specific location. We examined mtDNA sequences of two varieties of Vanuatu sacred pigs, the male pseudohermaphroditic Narave from the island of Malo (n = 9) and the hairless Kapia from the island of Tanna (n = 9), as well as control pigs (n = 21) from the islands of Malo, Tanna, and Epi and compared them with GenBank sequences to determine (i) the distribution of PC and introduced domestic lineages within Vanuatu, (ii) relationship between the Narave and Kapia, and (iii) origin of the PC. All of the Narave share two PC mtDNA sequences, one of which matches the sequence of a Narave collected in 1927, consistent with an unbroken maternal descent of these intersex pigs from the original pigs brought to Vanuatu 3,200 years ago. One-third of the Kapia share a single PC lineage also found in the Narave. The remaining Kapia lineages are associated with recently introduced, globally distributed domestic breeds. The predominant Narave lineage is also shared with two wild boars from Vietnam. These data suggest that PC pigs were recently domesticated within Southeast Asia and dispersed during the human colonization of Remote Oceania associated with the Lapita cultural complex. More extensive sampling of Southeast Asian wild boar diversity may refine the location of Pacific pig domestication and potentially the proximate homeland of the Lapita cultural complex.     

Daunorubicin Metabolism in Acute Myelocytic Leukemia

Daunorubicin reductase is a cytoplasmic enzyme that converts daunorubicin to a principal metabolite, daunorubicinol, in the presence of NADPH.This enzyme, found in mammalian tissues and studied in rat tissue preparations and normal human blood components, is also present in humanleukemic myeloblasts. The enzymesfrom both normal and leukemic leukocytes require NADPH for activity, havesimilar kinetics and substrate saturation characteristics, and have a K_m, of1.7 x 10^-4 M. When daunorubicin reductase levels in leukemic myeloblastsare related to the clinical response todaunorubicin therapy, we find that patients with a high enzyme level respond favorably to daunorubicin therapy with either a complete or partialremission, whereas those patients witha lower enzyme level experience eitherno response or die during therapy.These observations suggest that thelevel of daunorubicin reductase in theleukemic myeloblast may be importantin determining the susceptibility ofthat cell to daunorubicin. Moreover,the measurement of daunorubicin reductase level may have prognosticvalue regarding the clinical responseto daunorubicin therapy.

Submitted on August 19, 1971 Revised on October 7, 1971 Accepted on November 8, 1971