Routine delivery of artemisinin-based combination treatment at fixed health facilities reduces malaria prevalence in Tanzania: an observational study.

BACKGROUND: Artemisinin-based combination therapy (ACT) has been promoted as a means to reduce malaria transmission due to their ability to kill both asexual blood stages of malaria parasites, which sustain infections over long periods and the immature derived sexual stages responsible for infecting mosquitoes and onward transmission. Early studies reported a temporal association between ACT introduction and reduced malaria transmission in a number of ecological settings. However, these reports have come from areas with low to moderate malaria transmission, been confounded by the presence of other interventions or environmental changes that may have reduced malaria transmission, and have not included a comparison group without ACT. This report presents results from the first large-scale observational study to assess the impact of case management with ACT on population-level measures of malaria endemicity in an area with intense transmission where the benefits of effective infection clearance might be compromised by frequent and repeated re-infection. METHODS: A pre-post observational study with a non-randomized comparison group was conducted at two sites in Tanzania. Both sites used sulphadoxine-pyrimethamine (SP) monotherapy as a first-line anti-malarial from mid-2001 through 2002. In 2003, the ACT, artesunate (AS) co-administered with SP (AS + SP), was introduced in all fixed health facilities in the intervention site, including both public and registered non-governmental facilities. Population-level prevalence of Plasmodium falciparum asexual parasitaemia and gametocytaemia were assessed using light microscopy from samples collected during representative household surveys in 2001, 2002, 2004, 2005 and 2006. FINDINGS: Among 37,309 observations included in the analysis, annual asexual parasitaemia prevalence in persons of all ages ranged from 11% to 28% and gametocytaemia prevalence ranged from <1% to 2% between the two sites and across the five survey years. A multivariable logistic regression model was fitted to adjust for age, socioeconomic status, bed net use and rainfall. In the presence of consistently high coverage and efficacy of SP monotherapy and AS + SP in the comparison and intervention areas, the introduction of ACT in the intervention site was associated with a modest reduction in the adjusted asexual parasitaemia prevalence of 5 percentage-points or 23% (p < 0.0001) relative to the comparison site. Gametocytaemia prevalence did not differ significantly (p = 0.30). INTERPRETATION: The introduction of ACT at fixed health facilities only modestly reduced asexual parasitaemia prevalence. ACT is effective for treatment of uncomplicated malaria and should have substantial public health impact on morbidity and mortality, but is unlikely to reduce malaria transmission substantially in much of sub-Saharan Africa where individuals are rapidly re-infected.

Intrathecal drug delivery systems for cancer pain

Introduction: A substantial number of patients with cancer suffer considerable pain at some point during their disease, and approximately 25% of cancer patients die in pain. In cases of uncontrolled pain or intolerable side effects, intrathecal drug delivery system (IDDS) is a recognised management option. Indeed, IDDS offer rapid and effective pain relief with less drug side effects compared to oral or parenteral administration. The aim of this study is to retrospectively review our series of cancer patients treated with IDDS. Method: Data was extracted from the institutional neuromodulation registry. Patients with cancer pain treated with IDDS from 01.01.1997 to 30.12.2009 were analysed for subjective improvement, changes in pain intensity (VAS) and survival time after implantation. Measurements were available for a decreasing number of patients as time since baseline increased. Results: During the studied period, 78 patients were implanted with IDDS for cancer pain. The mean survival time was 11.1 months (median: 3.8 months) and 14 patients (18%) were still alive at the end of the studied period. Subjective improvement was graded between 55 and 83% during the first year. Mean VAS during the first year remained lower than VAS at baseline. Discussion: IDDS has been shown to be cost-effective in several studies. Although initial costs of implantation are high, the cost benefits favour analgesia with implanted intrathecal pumps over epidural external systems after 3 to 6 months in cancer patients. Improved survival has been associated with IDDS and in this series both the mean and median survival times were above the cut-off value of three months. The mean subjective improvement was above 50% during the whole first year, suggesting a good efficacy of the treatment, a finding that is consistent with the results from other groups. Changes in pain intensity are difficult to interpret in the context of rapidly progressive disease such as in terminal cancer. However, mean VAS from 1 thru12 months were lower than baseline, suggesting improved pain control with IDDS, or at least a stabilisation of the pain symptoms. Conclusion: Our retrospective series suggests IDDS is effective in intractable cancer pain and we believe it should be considered even in terminally ill patients with limited life expectancies.

Effect of selective phosphodiesterase inhibitors on response of ovine pulmonary arteries to prostaglandin E2.

Several adenosine 3',5'-cyclic monophosphate (cAMP)-hydrolyzing phosphodiesterase isozymes are present in the pulmonary vasculature. The present study was designed to determine the effect of selective inhibitors of phosphodiesterase subtypes on prostaglandin E2 (PGE2)-induced relaxation of isolated fourth-generation pulmonary arteries of newborn lambs. PGE2 and forskolin caused pulmonary arteries to relax and induced an increase in the intracellular cAMP content in the vessels. The relaxation and change in cAMP content were augmented by milrinone and rolipram, inhibitors of phosphodiesterase type 3 (PDE3) and type 4 (PDE4), respectively. The augmentation in relaxation and the increase in cAMP content caused by milrinone plus rolipram was greater than the sum of the responses caused by either of the inhibitors alone. 8-Methoxymethyl-1-methyl-3-(2-methylpropyl)xanthine, an inhibitor of phosphodiesterase type 1, had no effect on relaxation and change in cAMP induced by PGE2 and forskolin. Acetylcholine alone had no effect on cAMP content in the vessels but augmented the relaxation and the increase in cAMP induced by PGE2 and forskolin in arteries with endothelium. This effect was not observed in arteries without endothelium or in arteries with endothelium treated with NG-nitro-L-arginine. These results suggest that PDE3 and PDE4 are the primary enzymes hydrolyzing cAMP of pulmonary arteries of newborn lambs and that an inhibition of both PDE3 and PDE4 would result in a greater effect than that caused by inhibition of either one of the subtype isozymes alone. Furthermore, endothelium-derived nitric oxide may enhance cAMP-mediated relaxation by inhibition of PDE3.

Vascular postpneumonectomy syndrome: inferior vena cava and pulmonary vein compression as unusual cause for platypnea-orthodeoxia following pneumonectomy

Background: Excessive mediastinal shift into the vacated thoracic cavity after pneumonectomy can result in dyspnea without hypoxemia by compression of the tracheobronchial tree, a phenomenon called postpneumonectomy syndrome. More rarely hypoxemia in upright position (platypnea-orthodeoxia syndrome, POS) after pneumonectomy can result from re-opening of an atrial right-to-left shunt through a patent foramen ovale (PFO) due to mediastinal distorsion. Review of literature also shows a unique report of pulmonary veins stenosis resulting in POS without intracardiac shunt after pneumonectomy. Methods: We report the case of a 32-year-old woman who presented POS 6 months after right pneumonectomy for destroyed lung post tuberculosis. Results: The patient described severe dyspnea disappearing when lying. SpO2 decreased from 94% when lying to 60% sitting. Transthoracic echocardiography (TTE) suspected a possible PFO. We first tried to highlight clinical repercussions of PFO by noninvasive exams. Hyperoxia shunt quantification was not tolerated because of increased dyspnea in sitting position. Contrast bubbles TTE was difficult because of the important mediastinal shift but identified only rare left heart bubbles with/without Valsalva both in lying and sitting position, excluding a significant right-to-left shunt. A lung perfusion scintigraphy (injection while sitting) confirmed the absence of systemic isotope uptake. Computed tomographic pulmonary angiography (angio-CT) revealed a stretched but not stenosed left main bronchus, while the shift of the heart into the right cavity was major. Pulmonary angiography did not show embolism but revealed compression of the inferior vena cava (IVC) with impaired venous return to the right heart, as well as compression of the left pulmonary veins. There was no arteriovenous shunt. Cardiac MRI showed torsion of IVC at the level of the diaphragm, and strong atrial contraction contributing to a passive filling of the RV, while the right ventricle was normal. Right catheterism showed major hemodynamic disturbances with negative diastolic pressure in right heart cavities (atrium -12 mm Hg ventricle pressure -7 mm Hg). SaO2 measured in the pulmonary artery decreased from 58% when lying to 45% sitting. Conclusion: We described here an exceedingly rare and complex mechanism explaining POS after right pneumonectomy. Mediastinal repositioning with a silicone breast implant of appropriate size has been scheduled.

Reduced choroidal neovascularization by AAV-anti-VEGF shRNA delivery

VEGF plays an essential role in ocular angiogenic diseases including the late-stage form of AMD, the primary cause of vision loss in the western world. Over-expression of VEGF leads to development of vasculature emanating from the choroid, invading the subretinal space through breaks in Bruch's membrane. Strategies leading to long-term suppression of inappropriate ocular angiogenesis are required. A panel of 10 shRNAs targeting the coding region of human VEGF165 was tested in HEK293 cells and in the human retinal pigment epithelial cell line, ARPE-19. VEGF knock-down up to 92% was achieved by co-transfecting shRNAexpressing constructs with plasmid encoding the Renilla luciferase gene fused to the VEGF165 sequence. For in vivo delivery of the most potent shRNA cassette, both single-stranded and self-complementary rAAV vectors were packaged in serotype 8 capsids. Intramuscular administration in mice led to localized expression and 96% knock-down of endogenous VEGF. Using eGFP as a marker, efficient gene transfer of retinal pigment epithelial cells, the cells thought to be responsible for the abnormal VEGF production, was obtained by subretinal delivery of rAAV2.8 vectors. The capacity of rAAV-encoded shRNAs to silence endogenous VEGF gene expression was evaluated in the laser-induced murine model of choroidal neovascularization (CNV). In this mouse model of AMD, sizes of the CNV were found to be significantly reduced following rAAV-shRNA subretinal delivery. Thus, our results indicate that gene transfer combining AAV-mediated delivery with triggering of the endogenous RNAi pathway can be used for anti-VEGF therapy and holds great promise for the treatment of AMD.

Evaluating in vivo delivery of riboflavin with coulomb-controlled iontophoresis for corneal collagen cross-linking: a pilot study.

PURPOSE: To evaluate the efficacy of coulomb-controlled iontophoresis (CCI) for delivery of riboflavin prior to corneal collagen cross-linking (CXL). METHODS: The eyes of 20 8-week-old Lewis rats, subject to epithelium-ON (epi-ON, n = 20 eyes) or epithelium-OFF (epi-OFF, n = 20 eyes) conditions, were used to evaluate the in vivo delivery of two riboflavin solutions: 0.1% riboflavin-20% dextran T500 solution (riboflavin-dextran) and 0.1% riboflavin 5'-phosphate (riboflavin-phosphate). After systemic intramuscular anesthesia, 0.25 mL of the photosensitizing agent was delivered by either instillation or CCI (2.11 mA/cm(2) for 4 or 10 minutes) into either epithelial condition. The CCI probe on the eye without current served as control. Confocal microscopy of flat-mounted corneas was used to analyze intracorneal penetration and fluorometry was used to quantify riboflavin in the aqueous within 30 minutes of treatment. RESULTS: Instillation and CCI allowed for uniform delivery of riboflavin-dextran throughout the stroma after epithelial debridement. Transepithelial delivery of riboflavin-dextran was not efficacious. Riboflavin-phosphate was successfully delivered in both epithelium conditions. Complete saturation of the cornea was achieved using CCI after removing the epithelium, the epi-ON case allowed for limited diffusion. Increasing the time from 4 to 10 minutes greatly increased the amount of riboflavin detected in the cornea and aqueous humor. CONCLUSIONS: Coulomb-controlled iontophoresis is an effective technique for transepithelial delivery of riboflavin-phosphate into the cornea. This drug delivery method would allow clinicians to significantly shorten the time required for the CXL procedure, with or without epithelial debridement. Whether efficient crosslinking can be achieved through an intact epithelium remains to be demonstrated.

Iowa Prisoner Re-Entry Initiative (PRI) Rural Service Delivery Model Iowa Department of Correctional Services, November 2009

The Iowa Department of Corrections (DOC) and the Department of Human Rights, Division of Criminal and Juvenile Justice Planning (CJJP) entered into a contract for services from September 12, 2007 to June 30, 2009 for the purposes of assisting in the evaluation component for the two-year Iowa Prisoner Re-Entry Initiative (PRI) Rural Service Delivery Model. This contract was extended to November 2009. The Rural PRI grant period ran from July 1, 2007 to June 30, 2009 and was extended to November 30, 2009. The purpose of the program was to improve community safety by providing pre-release services and successful transition planning and aftercare services to offenders released from state institutions to the Second Judicial District Department of Correctional Services. Participants included all offenders released to the Second Judicial District during the grant period.

Trace element supplementation modulates pulmonary infection rates after major burns: a double-blind, placebo-controlled trial.

Infections remain the leading cause of death after major burns. Trace elements are involved in immunity and burn patients suffer acute trace element depletion after injury. In a previous nonrandomized study, trace element supplementation was associated with increased leukocyte counts and shortened hospital stays. This randomized, placebo-controlled trial studied clinical and immune effects of trace element supplements. Twenty patients, aged 40 +/- 16 y (mean +/- SD), burned on 48 +/- 17% of their body surfaces, were studied for 30 d after injury. They consumed either standard trace element intakes plus supplements (40.4 micromol Cu, 2.9 micromol Se, and 406 micromol Zn; group TE) or standard trace element intakes plus placebo (20 micromol Cu, 0.4 micromol Se, and 100 micromol Zn; group C) for 8 d. Demographic data were similar for both groups. Mean plasma copper and zinc concentrations were below normal until days 20 and 15, respectively (NS). Plasma selenium remained normal for group TE but decreased for group C (P < 0.05 on days 1 and 5). Total leukocyte counts tended to be higher in group TE because of higher neutrophil counts. Proliferation to mitogens was depressed compared with healthy control subjects (NS). The number of infections per patient was significantly (P < 0.05) lower in group TE (1.9 +/- 0.9) than in group C (3.1 +/- 1.1) because of fewer pulmonary infections. Early trace element supplementation appears beneficial after major burns; it was associated with a significant decrease in the number of bronchopneumonia infections and with a shorter hospital stay when data were normalized for burn size.

La programmmation foetale de la dysfonction vasculaire pulmonaire chez la souris : rôle des mécanismes épigénétiques = Fetal programming of pulmonary vascular dysfunction in mice : role of epigenetic mechanisms

Rapport de synthèseDes événements pathologiques survenant pendant la période foetale prédisposent la descendance aux maladies cardiovasculaires systémiques. Il existe peu de connaissances au sujet de la circulation pulmonaire et encore moins quant aux mécanismes sous-jacents. La sous-alimentation maternelle pendant la grossesse peut représenter un modèle d'investigation de ces mécanismes, parce que chez l'animal et l'homme elle est associée à une dysfonction vasculaire systémique chez la progéniture. Chez le rat, la diète restrictive pendant la grossesse induit une augmentation du stress oxydatif dans le placenta. Les dérivés de l'oxygène sont connus pour induire des altérations épigénétiques et peuvent traverser la barrière placentaire. Nous avons dès lors spéculé que chez la souris la diète restrictive pendant la grossesse induit une dysfonction vasculaire pulmonaire chez sa progéniture qui serait liée à un mécanisme épigénétique.Pour tester cette hypothèse, nous avons examiné la fonction vasculaire pulmonaire et la méthylation de l'ADN pulmonaire à la fin de 2 semaines d'exposition à l'hypoxie chez la progéniture de souris soumises à une diète restrictive pendant la grossesse et des souris contrôles. Nous avons trouvé que la vasodilatation endothélium-dépendante de l'artère pulmonaire in vitro était défectueuse, et que l'hypertension pulmonaire et l'hypertrophie ventriculaire droite induites par l'hypoxie in vivo étaient exagérées chez la progéniture de souris soumises à une diète restrictive pendant la grossesse. Cette dysfonction vasculaire pulmonaire était associée avec une altération de la méthylation de l'ADN pulmonaire. L'administration d'inhibiteurs de la déacétylase des histones, le Butyrate et la Trichostatine-A à la progéniture de souris soumises à une diète restrictive pendant la grossesse a normalisé la méthylation de l'ADN et la fonction vasculaire pulmonaire. Finalement, l'administration du nitroxyde Tempol aux mères durant la diète restrictive pendant la grossesse a prévenu la dysfonction vasculaire et la dysméthylation chez la progéniture.Ces découvertes démontrent que chez la souris la sous-alimentation pendant la gestation induit une dysfonction vasculaire chez la progéniture qui est causée par un mécanisme épigénétique. Il est possible qu'un mécanisme similaire soit impliqué dans la programmation foetale de la dysfonction vasculaire chez les humains.

Diagnosis of pulmonary embolism by multidetector CT alone or combined with venous ultrasonography of the leg: a randomised non-inferiority trial.

BACKGROUND: Multislice CT (MSCT) combined with D-dimer measurement can safely exclude pulmonary embolism in patients with a low or intermediate clinical probability of this disease. We compared this combination with a strategy in which both a negative venous ultrasonography of the leg and MSCT were needed to exclude pulmonary embolism. METHODS: We included 1819 consecutive outpatients with clinically suspected pulmonary embolism in a multicentre non-inferiority randomised controlled trial comparing two strategies: clinical probability assessment and either D-dimer measurement and MSCT (DD-CT strategy [n=903]) or D-dimer measurement, venous compression ultrasonography of the leg, and MSCT (DD-US-CT strategy [n=916]). Randomisation was by computer-generated blocks with stratification according to centre. Patients with a high clinical probability according to the revised Geneva score and a negative work-up for pulmonary embolism were further investigated in both groups. The primary outcome was the 3-month thromboembolic risk in patients who were left untreated on the basis of the exclusion of pulmonary embolism by diagnostic strategy. Clinicians assessing outcome were blinded to group assignment. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00117169. FINDINGS: The prevalence of pulmonary embolism was 20.6% in both groups (189 cases in DD-US-CT group and 186 in DD-CT group). We analysed 855 patients in the DD-US-CT group and 838 in the DD-CT group per protocol. The 3-month thromboembolic risk was 0.3% (95% CI 0.1-1.1) in the DD-US-CT group and 0.3% (0.1-1.2) in the DD-CT group (difference 0.0% [-0.9 to 0.8]). In the DD-US-CT group, ultrasonography showed a deep-venous thrombosis in 53 (9% [7-12]) of 574 patients, and thus MSCT was not undertaken. INTERPRETATION: The strategy combining D-dimer and MSCT is as safe as the strategy using D-dimer followed by venous compression ultrasonography of the leg and MSCT for exclusion of pulmonary embolism. An ultrasound could be of use in patients with a contraindication to CT.

The pulmonary embolism rule-out criteria (PERC) rule does not safely exclude pulmonary embolism.

Background: The Pulmonary Embolism Rule-out Criteria (PERC) rule is a clinical diagnostic rule designed to exclude pulmonary embolism (PE) without further testing. We sought to externally validate the diagnostic performance of the PERC rule alone and combined with clinical probability assessment based on the revised Geneva score. Methods: The PERC rule was applied retrospectively to consecutive patients who presented with a clinical suspicion of PE to six emergency departments, and who were enrolled in a randomized trial of PE diagnosis. Patients who met all eight PERC criteria [PERC(-)] were considered to be at a very low risk for PE. We calculated the prevalence of PE among PERC(-) patients according to their clinical pretest probability of PE. We estimated the negative likelihood ratio of the PERC rule to predict PE. Results: Among 1675 patients, the prevalence of PE was 21.3%. Overall, 13.2% of patients were PERC(-). The prevalence of PE was 5.4% [95% confidence interval (CI): 3.1-9.3%] among PERC(-) patients overall and 6.4% (95% CI: 3.7-10.8%) among those PERC(-) patients with a low clinical pretest probability of PE. The PERC rule had a negative likelihood ratio of 0.70 (95% CI: 0.67-0.73) for predicting PE overall, and 0.63 (95% CI: 0.38-1.06) in low-risk patients. Conclusions: Our results suggest that the PERC rule alone or even when combined with the revised Geneva score cannot safely identify very low risk patients in whom PE can be ruled out without additional testing, at least in populations with a relatively high prevalence of PE.

Hyponatremia and short-term outcomes in patients with acute pulmonary embolism

BACKGROUND: Hyponatremia, a marker of neurohormonal activation, is associated with poor outcomes in acute cardiorespiratory diseases such as myocardial infarction, right and left ventricular heart failure, and pneumonia. The prognostic value of hyponatremia in patients with acute pulmonary embolism (PE) is unknown. We sought to assess whether hyponatremia at presentation was associated with mortality and hospital readmission in patients hospitalized with PE. METHODS: We studied patient discharges with a primary diagnosis of PE from 185 acute care hospitals in Pennsylvania (1/2000-11/2002). We defined hyponatremia as a serum sodium level ≤135 mmol/l, measured at the time of patient presentation. The study outcomes were 30-day all-cause mortality and hospital readmission. We used random-intercept logistic regression to examine the association between hyponatremia and mortality. We adjusted for baseline patient (race, insurance, severity of illness using the Pulmonary Embolism Severity Index) and hospital characteristics (region, hospital size and teaching status). We used the same approach to examine the association between hyponatremia and readmission among patients who were discharged alive. RESULTS: Among 13,728 patient discharges with PE, 2907 (21.1%) had hyponatremia at the time of presentation. Patients with hyponatremia were older (P<0.001) and more likely to have a history of cancer (P<0.001), heart failure (P<0.001), or chronic lung disease (P=0.002) than patients without hyponatremia. Patients with hyponatremia had a higher unadjusted cumulative 30-day mortality (15.2% vs 8.0%;P<0.001) and readmission rate (15.9% vs 11.8%; P< 0.001) than patients without hyponatremia (Figure). After adjustment for race, insurance, severity of illness, and hospital factors, hyponatremia was associated with a significantly greater odds of death (OR 1.71, 95% CI: 1.50-1.95) and hospital readmission (OR 1.29, 95% CI: 1.14-1.46). CONCLUSIONS: In this large, statewide sample of unselected patients with acute PE, hyponatremia was relatively common and was an independent predictor of short-term mortality and hospital readmission. Given that sodium is a low-cost, easily available laboratory parameter, it may be potentially useful in risk-stratifying patients with PE.

Neurodevelopmental outcome of neonates treated with nitric oxide for persistent pulmonary hypertension

Persistent pulmonary hypertension of the newborn (PPHN) is a life threatening condition associated with an increased risk of neurodevelopmental impairment. The recommended treatment for this condition is inhaled nitric oxide (iNO) and has been used in our Neonatal Intensive Care Unit since 1998. We prospectively offered neurodevelopmental follow-up to children treated with iNO for PPHN, including extensive neurological evaluation, developmental/cognitive evaluation at 18 months and 3.5-5 years old, and evaluated the rate of severe and moderate handicap and normal neurodevelopmental outcome, compared to a control group and the literature. Population consisted of 29 patients treated only with iNO, born between 01.01.1999 and 31.12.2005 (study group), and 32 healthy term infants born in 1998 in our maternity (control group). During those seven years, 65 infants were admitted in our Unit with PPHN, of whom 40 were treated with iNO alone. 34 children survived (85%) and were offered neurodevelopmental follow-up, 7 children were lost to follow-up due to various reasons. 22 children were examined at the age of 18 months (76%) with a rate of moderate handicap of 22% (2 with expressive language delay, 2 with difficult behavior, and 1 child with moderate hearing loss), and a rate of major handicap of 4.5% (1 child with cerebral palsy due to perinatal stroke, and moderate hearing loss). At preschool age, 17 (50%) were examined, the rate of moderate handicap was 22% (4 borderline intelligence, 1 hearing loss), and the rate of major handicap was 4.5% (one child with cerebral palsy and hearing loss), compared to 26.9% and 0% in the control group. Mean developmental quotient at 18 months was 100.3 ± 8.7 (control group 118.3), and at preschool age mean cognitive indices were within normal limits for the 2 tests performed at 3.5 or 5 years (108 ± 21, 94.4 ± 17). Most of the children with a less favorable neurodevelopmental outcome suffered from birth asphyxia (ruptured uterus, placental abruption, maternal hypotension, diabetic cardiomyopathy), and notably, the 2 children with sensorineural hearing loss both suffered from severe hypoxic-ischemic enkelopathy. Treatment with iNO was not the direct cause of the neurodevelopmental impairments observed in children treated for PPHN.