Using models to shape measles control and elimination strategies in low- and middle-income countries: A review of recent applications.

After many decades of vaccination, measles epidemiology varies greatly between and within countries. National immunization programs are therefore encouraged to conduct regular situation analyses and to leverage models to adapt interventions to local needs. Here, we review applications of models to develop locally tailored interventions to support control and elimination efforts. In general, statistical and semi-mechanistic transmission models can be used to synthesize information from vaccination coverage, measles incidence, demographic, and/or serological data, offering a means to estimate the spatial and age-specific distribution of measles susceptibility. These estimates complete the picture provided by vaccination coverage alone, by accounting for natural immunity. Dynamic transmission models can then be used to evaluate the relative impact of candidate interventions for measles control and elimination and the expected future epidemiology. In most countries, models predict substantial numbers of susceptible individuals outside the age range of routine vaccination, which affects outbreak risk and necessitates additional intervention to achieve elimination. More effective use of models to inform both vaccination program planning and evaluation requires the development of training to enhance broader understanding of models and where feasible, building capacity for modelling in-country, pipelines for rapid evaluation of model predictions using surveillance data, and clear protocols for incorporating model results into decision-making.

An opportunistic study evaluating pharmacokinetics of sildenafil for the treatment of pulmonary hypertension in infants.

OBJECTIVE: The objective of this study is to assess sildenafil and N-desmethyl sildenafil (DMS) exposure in infants receiving sildenafil for the treatment of pulmonary hypertension (PH). STUDY DESIGN: Data were collected from six infants receiving sildenafil for the treatment of PH and plasma samples were collected at the time of routine laboratory blood draws. The echocardiography results were assessed for improvement in right ventricular (RV) hypertension following sildenafil treatment. RESULT: The median (range) sildenafil and DMS concentrations were 27.4 ng ml(-1) (2.6 to 434.0) and 105.5 ng ml(-1) (3.6 to 314.0), respectively. The median metabolite-to-parent ratio was higher in infants receiving co-medications that can induce cytochrome P450 (CYP) enzymes (5.2 vs 0.7). The echocardiography results showed improvement in RV hypertension for the majority of infants (5/6). CONCLUSION: The concentrations of sildenafil and DMS were within the previously observed ranges. Our results suggest that caution may be warranted when CYP-related co-medications are administered during sildenafil treatment for PH.

Development and characterization of solid lipid nanoparticles for enhancement of oral bioavailability of Raloxifene.

The objective of this study was to increase the oral bioavailability of Raloxifene having an absolute bioavailability only 2% due to extensive first pass hepatic metabolism by incorporating it in Solid Lipid Nanoparticles (SLNs). The optimized RSLNs prepared by Ultrasonic Emulsification and Low Temperature Solidification method showed the mean particle size, zeta potential and percentage drug entrapment of 101.4±3.5 nm, 19.4±0.279 mv, 97.67±1.02% respectively. The in-vitro intestinal permeability study indicated significantly higher permeation of the RSLNs than the marketed preparation. The in-vivo studies showed that pharmacokinetic parameters for the RSLNs were 3.5 times higher than the marketed preparation indicating significant increase in the oral bioavailability of the Raloxifene.

Midregional pro-atrial natriuretic peptide and procalcitonin improve survival prediction in VAP.

Ventilator-associated pneumonia (VAP) affects mortality, morbidity and cost of critical care. Reliable risk estimation might improve end-of-life decisions, resource allocation and outcome. Several scoring systems for survival prediction have been established and optimised over the last decades. Recently, new biomarkers have gained interest in the prognostic field. We assessed whether midregional pro-atrial natriuretic peptide (MR-proANP) and procalcitonin (PCT) improve the predictive value of the Simplified Acute Physiologic Score (SAPS) II and Sequential Related Organ Failure Assessment (SOFA) in VAP. Specified end-points of a prospective multinational trial including 101 patients with VAP were analysed. Death <28 days after VAP onset was the primary end-point. MR-proANP and PCT were elevated at the onset of VAP in nonsurvivors compared with survivors (p = 0.003 and p = 0.017, respectively) and their slope of decline differed significantly (p = 0.018 and p = 0.039, respectively). Patients with the highest MR-proANP quartile at VAP onset were at increased risk for death (log rank p = 0.013). In a logistic regression model, MR-proANP was identified as the best predictor of survival. Adding MR-proANP and PCT to SAPS II and SOFA improved their predictive properties (area under the curve 0.895 and 0.880). We conclude that the combination of two biomarkers, MR-proANP and PCT, improve survival prediction of clinical severity scores in VAP.

Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study.

In patients with ventilator-associated pneumonia (VAP), guidelines recommend antibiotic therapy adjustment according to microbiology results after 72 h. Circulating procalcitonin levels may provide evidence that facilitates the reduction of antibiotic therapy. In a multicentre, randomised, controlled trial, 101 patients with VAP were assigned to an antibiotic discontinuation strategy according to guidelines (control group) or to serum procalcitonin concentrations (procalcitonin group) with an antibiotic regimen selected by the treating physician. The primary end-point was antibiotic-free days alive assessed 28 days after VAP onset and analysed on an intent-to-treat basis. Procalcitonin determination significantly increased the number of antibiotic free-days alive 28 days after VAP onset (13 (2-21) days versus 9.5 (1.5-17) days). This translated into a reduction in the overall duration of antibiotic therapy of 27% in the procalcitonin group (p = 0.038). After adjustment for age, microbiology and centre effect, the rate of antibiotic discontinuation on day 28 remained higher in the procalcitonin group compared with patients treated according to guidelines (hazard rate 1.6, 95% CI 1.02-2.71). The number of mechanical ventilation-free days alive, intensive care unit-free days alive, length of hospital stay and mortality rate on day 28 for the two groups were similar. Serum procalcitonin reduces antibiotic therapy exposure in patients with ventilator associated pneumonia.

Synthesis and antimicrobial activity of bis[6-phenyl-4-methyl-3-substituted-pyrazo[4,5-d] pyrazol-1-yl]thioketones.

New bis[6-phenyl-4-methyl-3-substituted-pyrazo[4,5-d] pyrazol-1-yl]thioketones have been obtained in good yield by the reaction of thiocarbohydrazine with 1-phenyl-3-methyl-4-acetyl/benzoyl-pyrazol-5-one, followed by cyclization of the intermediate. The new compounds exhibit excellent antimicrobial activity.

Oral manifestations of infantile systemic hyalinosis.

Oral manifestations of infantile systemic hyalinosis in a child of Asian origin are presented. Infantile systemic hyalinosis is a rare fatal condition with probably an autosomal recessive mode of inheritance. The symptoms become apparent soon after birth and death usually occurs before the age of two years. The systemic features are essentially due to widespread deposition of hyaline material in tissues. These include thickening and nodularity of skin, growth failure, joint contractures, osteoporosis, diarrhoea and recurrent infections. The oral changes in the case reported here included thickening of the oral mucosa, extensive overgrowth of gingival tissue, osteoporosis, marked curvature of the dental roots, and replacement of periodontal ligament by hyaline fibrous material. Immunohistochemistry revealed widespread presence of Type VI collagen in the connective tissue with particularly intense staining in the hyaline material.

Inhibition of doxorubicin-induced apoptosis in vivo by 2-deoxy-D-glucose.

Previous studies have shown that DNA cleavage by mammalian topoisomerase II is ATP dependent and can be inhibited by metabolic inhibitors. Furthermore, it has been shown that metabolic inhibitors also have a cytoprotective effect in vitro against topoisomerase II-targeting antitumor drugs. However, the nature of the ATP-dependent process is not known. We have previously shown that doxorubicin induces apoptosis (programmed cell death) in the murine small intestine which can be inhibited by the protein synthesis inhibitor cycloheximide. In the present study, we have demonstrated that 2-deoxy-D-glucose reduces the incidence of doxorubicin-induced apoptosis in vivo if administered within 45 min of the doxorubicin. Maximum reduction was observed at 2 h after treatment (approximately 66%); however, significant reduction was still observable at 9 h after treatment (approximately 33%). Significant positive correlation was observed between protein synthesis inhibition and apoptosis inhibition. Other possible mechanisms of action of the inhibitor do not appear to be important in cytoprotection. The inhibitor did not reduce the uptake of doxorubicin into the intestinal epithelium; however, it caused a significant increase in retention of the drug. The kinetics of inhibition suggest that alteration of cell cycle kinetics, inhibition of formation of doxorubicin-topoisomerase II complex or induction of glucose-regulated proteins are not significant factors in cytoprotection. These studies indicate that at least in the mouse small intestinal epithelium, the ATP-dependent process in cell killing by doxorubicin may involve protein synthesis.

Familial occurrence of periapical cemental dysplasia.

A family with periapical cemental dysplasia is reported. The affected individuals displayed classical features of periapical cemental dysplasia on radiographic examination. The lesions consisted chiefly of radiolucent areas; however, some had central areas of radiodensity. Histopathological examination of one of the lesions revealed fibrous elements containing fused dense sclerotic cemental masses. Familial incidence of florid cemento-osseous dysplasia with an autosomal mode of inheritance has been reported previously. The condition described in this report appears to be different. However, the two conditions may be part of a spectrum occurring in a single genetic entity with the diversity possibly resulting from variable expressivity of a single gene.

Abrogation of adriamycin toxicity in vivo by cycloheximide.

The processes involved in cell killing by Adriamycin (ADR) and other agents that interact with topoisomerase II are unclear. To investigate the mode of ADR cytotoxicity in vivo, we have investigated the effects of the protein synthesis inhibitor, cycloheximide (CH), on cell killing by ADR in the murine intestinal tract. We have used morphological criteria to assay the cell death. ADR rapidly induces cell death in this tissue that has the morphology of apoptosis or programmed cell death. CH, when administered immediately after ADR, reduced the incidence of cell death by approximately 81% at 3 hr and approximately 51% at 6 hr after treatment. The inhibitor was only effective when administered within 0.5 hr of ADR suggesting that critical events leading to cell death may occur during this period. The inhibitor did not interfere with the ADR uptake or retention. Significant positive correlation was observed between protein and DNA synthesis inhibition (as measured by precursor uptake) and apoptosis inhibition. CH delayed progression of cells through all phases of the cell cycle except mitosis. However, ADR also had a similar effect, suggesting that progression through the cell cycle is not necessary for the expression of apoptosis. The effectiveness of CH in apoptosis inhibition, even when administered 0.5 hr after the ADR, coupled with the rapid uptake of ADR by the intestinal epithelium suggests that the mode of inhibition is unlikely to be modulation of cellular targets of ADR such as topoisomerase II or inhibition of formation of ADR-topoisomerase II complex. These data indicate that topoisomerase II-interacting agents such as ADR may induce apoptosis; the processes leading to cell death in this situation are thought to be gene dependent and require protein synthesis for their expression. Thus, the cytoprotective effect of CH may be due directly to the inhibition of protein synthesis.

Determination of selenium(IV) and tellurium(IV) by differential pulse polarography.

Differential pulse polarographic methods for the determination of selenium(IV) and tellurium(IV) in nitric acid medium are described. The peak current is maximal when 0.25M nitric acid medium is used, the DPP peaks for Se(IV) and Te(IV) being at -0.54 and -0.8 V vs. Ag/AgCl respectively. The peak current is a linear function of selenium concentration over three ranges, 5.1 x 10(-6)-1.3 x 10(-5), 1.27 x 10(-5)-1.27 x 10(-4) and 1.27 x 10(-4)-7.60 x 10(-4)M Se(IV), with different slopes. The plot for Te(IV) is linear over the range 0.78 x 10(-6)-9.40 x 10(-5)M.

Möbius syndrome due to brain stem tegmental necrosis.

Möbius syndrome undoubtedly results from a variety of disorders affecting central or peripheral portions of appropriate cranial nerves or their target muscles. Pathological alterations observed in cranial nuclei are most often viewed as aplastic or dysplastic lesions. Two patients with Möbius syndrome with associated facial and skeletal malformations showed mineralized necrotic foci in multiple brain stem nuclei. Prenatal encephalomalacic lesions represent the pathological basis for some cases of congenital static Möbius syndrome.