The Effects of ACT Treatment and TS Prophylaxis on Plasmodium falciparum Gametocytemia in a Cohort of Young Ugandan Children

Artemisinin-based combination therapies (ACTs) and trimethoprim-sulfamethoxazole (TS) prophylaxis are important tools for malaria control, but there are concerns about their effect on gametocytes, the stage of the parasite responsible for transmission. We conducted a longitudinal clinical trial in a cohort of HIV-infected and uninfected children living in an area of high malaria transmission intensity in Uganda. Study participants were randomized to artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) for all treatments of uncomplicated malaria (N = 4,380) as well as TS prophylaxis for different durations. The risks of gametocytemia detected by microscopy in the 28 days after antimalarial therapy were compared using multivariate analyses. The risk of gametocyte detection was significantly higher in patients treated with DP compared with AL (adjusted relative risk = 1.85, P < 0.001) and among children prescribed TS prophylaxis (adjusted relative risk = 1.76, P < 0.001). The risk of gametocytemia and its potential for increasing transmission should be considered when evaluating different ACTs and TS prophylaxis for malaria control.     

Clinical Pharmacokinetics of Buffered Propranolol Sublingual Tablet (Promptol™)—Application of a New “Physiologically Based” Model to Assess Absorption and Disposition

Sublingual administration of certain buffered propranolol may improve the rate and extent of absorption compared to oral administration. The main objectives of this study were to (1) compare the plasma propranolol concentrations (Cp-prop) following sublingual administration of a specially buffered formulation (Promptol™) to that following oral administration of Inderal^® and (2) evaluate the utility of a special pharmacokinetic model in describing the Cp-prop following sublingual administration. Eighteen healthy volunteers received 10 mg sublingual Promptol™ or oral Inderal^®. Multiple Cp-prop were determined and their pharmacokinetics compared. Additional data following sublingual 40 mg Promptol™ or Inderal^® were utilized for evaluation of a special advanced compartmental absorption and transit (ACAT) model. For model simulation, the physicochemical parameters were imported from AMET predictor, whereas the pharmacokinetic parameters were calculated and optimized by Gastroplus^®. Based on this model, the quantity of drug absorbed via buccal/sublingual mucosa was estimated. Cp-prop was higher at earlier times with 3-fold greater relative bioavailability following sublingual Promptol™ compared to that from oral Inderal^®. The special ACAT model provided excellent goodness of fit of Cp-prop-time curve and estimated a 56.6% increase in absorption rate from Promptol™ and higher initial Cp-prop compared to the regular formulation. The modified ACAT model provided a useful approach to describe sublingual absorption of propranolol and clearly demonstrated an improvement of absorption of Promptol™. The sublingual 10 mg Promptol™ achieved not only a similar systemic exposure as 30 mg oral Inderal^® but an earlier effective Cp-prop which may be advantageous for certain clinical conditions.Key words: ACAT, buffered, pharmacokinetics, propranolol, sublingual     

Reference values for pulse oximetry in healthy children in coastal Papua New Guinea

We expected oxygen saturation (SpO2) in children in coastal Papua New Guinea (PNG) to be higher than in PNG highlands children. Therefore, SpO2 was documented to determine the reference values of SpO2 in neonates and young children; 149 healthy neonates and 100 healthy infants and children < 5 years old were studied in Port Moresby. SpO2 ranged from 93% to 100% in both groups. The median SpO2 in neonates was 97% (CI 96.9-97.4) and in young children 98% (CI 97.5-98.0). We recommend 93% as the cutoff for administering oxygen to children under 5 years old in coastal PNG.     

Prevalent herpes simplex virus type 2 infection is associated with altered vaginal flora and an increased susceptibility to multiple sexually transmitted infections

BACKGROUND: Prevalent herpes simplex virus type 2 (HSV-2) infection increases human immunodeficiency virus acquisition. We hypothesized that HSV-2 infection might also predispose individuals to acquire other common sexually transmitted infections (STIs). Methods: We studied the association between prevalent HSV-2 infection and STI incidence in a prospective, randomized trial of periodic STI therapy among Kenyan female sex workers. Participants were screened monthly for infection with Neisseria gonorrhoeae and Chlamydia trachomatis, and at least every 6 months for bacterial vaginosis (BV) and infection with Treponema pallidum, Trichomonas vaginalis, and/or HSV-2. RESULTS: Increased prevalence of HSV-2 infection and increased prevalence of BV were each associated with the other; the direction of causality could not be determined. After stratifying for sexual risk-taking, BV status, and antibiotic use, prevalent HSV-2 infection remained associated with an increased incidence of infection with N. gonorrhoeae (incidence rate ratio [IRR], 4.3 [95% confidence interval {CI}, 1.5-12.2]), T. vaginalis (IRR, 2.3 [95% CI, 1.3-4.2]), and syphilis (IRR, 4.7 [95% CI, 1.1-19.9]). BV was associated with increased rates of infection with C. trachomatis (IRR, 2.1 [95% CI, 1.1-3.8]) and T. vaginalis (IRR, 8.0 [95% CI, 3.2-19.8]). CONCLUSION; Increased prevalences of HSV-2 infection and BV were associated with each other and also associated with enhanced susceptibility to an overlapping spectrum of other STIs. Demonstration of causality will require clinical trials that suppress HSV-2 infection, BV, or both.     

The opiorphin gene (ProL1) and its homologues function in erectile physiology

OBJECTIVE

To determine if ProL1, a member of the opiorphin family of genes, can modulate erectile physiology, as it encodes a peptide which acts as a neutral endopeptidase inhibitor, other examples of which (Vcsa1, hSMR3A) modulate erectile physiology.

MATERIALS AND METHODS

We cloned members of the opiorphin family of genes into the same mammalian expression backbone (pVAX); 100 µg of these plasmids (pVAX‐Vcsa1, ‐hSMR3A, ‐hSMR3B and ‐ProL1) were injected intracorporally into retired breeder rats and the affect on erectile physiology assessed visually, by histology and by measuring the intracavernous pressure (ICP) and blood pressure (BP). As a positive control, rats were treated with pVAX‐hSlo (expressing the MaxiK potassium channel) and as a negative control the empty backbone plasmid was injected (pVAX). We also compared the level of expression of ProL1 in corporal tissue of patients not reporting erectile dysfunction (ED), ED associated with diabetes and ED not caused by diabetes.

RESULTS

Gene transfer of plasmids expressing all members of the opiorphin family had a similar and significant effect on erectile physiology. At the concentration used in these experiments (100 µg) they resulted in higher resting ICP, and histological and visual analysis showed evidence of a priapic‐like condition. After electrostimulation of the cavernous nerve, rats had significantly better ICP/BP than the negative control (pVAX). Gene transfer of pVAX‐hSlo increased the ICP/BP ratio to a similar extent to the opiorphin homologues, but with no evidence for a priapic‐like condition. Corpora cavernosa tissue samples obtained from men with ED, regardless of underlying causes, had significant down‐regulation of both hSMR3A and ProL1.

CONCLUSION

All members of the human opiorphin family of genes can potentially modulate erectile physiology. Both hSMR3 and ProL1 are down‐regulated in the corpora of men with ED, and therefore both genes can potentially act as markers of ED.     

Structural and functional investigations of the murine cavernosal nerve: a model system for serial spatio-temporal study of autonomic neuropathy

OBJECTIVE: To illustrate the ultrastructural fibre composition of the rat cavernosal nerve at serial levels, from its origin in the main pelvic ganglion to its termination in the corpus cavernosum of the distal penile shaft, and to develop a technique that permits repeated electrophysiological recording from the fibres that form the cavernosal nerve distinct from the axons of the dorsal nerve of the penis (DNP). MATERIALS AND METHODS: For the light microscope and ultrastructural studies, Sprague-Dawley rats were anaesthetized and the pelvic organs and lower limbs were perfused with glutaraldehyde through the distal aorta. Tissue samples were embedded in epoxy resin and prepared for light and electron microscopy. Frozen tissue was used for the immunohistochemical studies and sections were stained with rabbit anti-nitric oxide synthetase 1 (NOS1). For the electrophysiology, anaesthetized rats were used in sterile conditions. Nerve conduction velocity for the cavernosal nerve was assessed from a point 2 mm below the main (major) pelvic ganglion after stimulating the nerve at the crus penis; multi-unit averaging techniques were used to enhance the recording of slow-conduction activity. Recordings from the DNP were obtained over the proximal shaft after stimulation at the base of the penis. RESULTS: Step-serial sections of the cavernosal nerve revealed numerous ganglion cells in the initial segments and gradually fewer myelinated fibres at distal levels. At the point of crural entry, the nerve contained almost exclusively unmyelinated axons. As it descended the penile shaft, the nerve separated into small fascicles containing only one to four axons at the level of the distal shaft. In the corpus cavernosum, vesicle-filled presynaptic axon preterminals were close to smooth muscle fibres, but did not seem to be in direct contact. Immunohistochemical evaluation of NOS1 activity showed intense staining of the fibres of the DNP and most of the neurones in the main pelvic ganglion. There was also scattered NOS1 activity in the nerve bundles of the corpus cavernosum. Electrophysiology identified activity in C fibres on the cavernosal nerve and in Aalpha-Adelta fibres in the DNP. CONCLUSION: These results show that it is possible to perform integrated cavernosal pressure monitoring and ultrastructural and electrophysiological studies in this model. These yielded accurate data about the erectile status of the penis, and the state of unmyelinated and myelinated fibres in the DNP and cavernosal nerves of the same animal. This study provides a useful template for future studies of experimental diabetic autonomic neuropathy.     

Health-related quality of life after stroke: what are we measuring?

As there is no single, accepted definition of health-related quality of life (HRQOL), it is assumed to be a broad, multidimensional construct referring to those aspects of people's lives that reasonably relate to their health. Although many scales are used to assess HRQOL, the operationalization of this construct within each tool is unclear. To clarify what each tool is measuring, this study reviewed eight scales commonly used to evaluate HRQOL after stroke. Two reviewers classified scale items from five generic and three stroke-specific scales within an established framework with nine dimensions; physical functioning, symptoms, global judgments of health, psychological well-being, social well-being, cognitive functioning, role activities, personal constructs, and satisfaction with care. All scales reviewed provide multidimensional assessment, but vary in number and combination of dimensions. All include assessment of physical functioning and most incorporate concepts, such as psychological well-being, social well-being, and role activities. One generic (Sickness Impact Profile) and two stroke-specific scales (Stroke Impact Scale and Stroke-Specific Quality of Life Scale) seemed most comprehensive. Evaluated against a common framework of dimensions, scales commonly used in the assessment of HRQOL after stroke provide varying multidimensional assessments of aspects of life function related to health. Whether any of these assessments are sufficient to describe HRQOL in its entirety is unclear.     

Discovery of a novel class of AKT pleckstrin homology domain inhibitors

AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non-lipid-based compounds that bind selectively to the PH domain of AKT, with "in silico" calculated K(D) values ranging from 0.8 to 3.0 mumol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide-dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro K(D)s for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 mumol/L. Some of the compounds exhibited PH domain-binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide-dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT. [Mol Cancer Ther 2008;7(9):2621-32].