18F‐fluoride PET as a noninvasive imaging biomarker for determining treatment efficacy of bone active agents at the hip: A prospective,randomized, controlled clinical study

The functional imaging technique of ¹⁸F‐fluoride positron emission tomography (¹⁸F‐PET) allows the noninvasive quantitative assessment of regional bone formation at any skeletal site, including the spine and hip. The aim of this study was to determine if ¹⁸F‐PET can be used as an early biomarker of treatment efficacy at the hip. Twenty‐seven treatment‐naive postmenopausal women with osteopenia were randomized to receive teriparatide and calcium and vitamin D (TPT group, n = 13) or calcium and vitamin D only (control group, n = 14). Subjects in the TPT group were treated with 20 µg/day teriparatide for 12 weeks. ¹⁸F‐PET scans of the proximal femur, pelvis, and lumbar spine were performed at baseline and 12 weeks. The plasma clearance of ¹⁸F‐fluoride to bone, K_i, a validated measurement of bone formation, was measured at four regions of the hip, lumbar spine, and pelvis. A significant increase in K_i was observed at all regions of interest (ROIs), including the total hip (+27%, p = 0.002), femoral neck (+25%, p = 0.040), hip trabecular ROI (+21%, p = 0.017), and hip cortical ROI (+51%, p = 0.001) in the TPT group. Significant increases in K_i in response to TPT were also observed at the lumbar spine (+18%, p = 0.001) and pelvis (+42%, p = 0.001). No significant changes in K_i were observed for the control group. Changes in BMD and bone turnover markers were consistent with previous trials of teriparatide. In conclusion, this is the first study to our knowledge to demonstrate that ¹⁸F‐PET can be used as an imaging biomarker for determining treatment efficacy at the hip as early as 12 weeks after initiation of therapy.     

A low-cost and scalable process for harvesting microalgae using commercial-grade flocculant

A low-cost and scalable harvesting process was demonstrated for Chlorella sp. FC2 IITG, which offered an improved process economy for the production of a microalgal biomass feedstock via (i) the utilization of a cheaper commercial grade chemical flocculant; (ii) the recycling of post-harvested nutrient-rich spent water for the successive growth of the FC2 cells and (iii) the modulation of the flocculant dose, resulting in the non-requirement of a pH adjustment of the spent water and separate inoculum development step. Ferrous sulphate and ferric chloride were screened from a pool of four commercial grade flocculants, resulting in high harvesting efficiencies of 99.83% and 99.93% at the lower flocculant doses (g of flocculant g of dry biomass⁻¹) of 2.5 and 3, respectively. The effect of the recycled nutrient-rich spent water and treated non-flocculated microalgal cells after harvesting was evaluated for the growth performance of the FC2 cells in six successive batches. It was found that ferrous sulphate was superior over ferric chloride in terms of the recyclability of the spent water for more number of batches, offering similar growth kinetics and nutrient recovery efficiency as compared with that of the control sample. The scale-up feasibility of the harvesting process was evaluated with a 5 L photobioreactor under indoor conditions and a 350 L open raceway pond under outdoor conditions with a modulated flocculant dose of 1.5 g ferrous sulphate. g dry biomass⁻¹. The harvesting cost of 1 kg biomass using commercial grade ferrous sulphate was estimated to be in the range of 0.17–0.3 USD and was significantly lower as compared to that of analytical grade ferrous sulphate.

A low-cost and scalable microalgal harvesting process with high harvesting efficiency has been demonstrated using a commercial flocculant and spent-water recycling.     

Terminal deletion of the long arm of chromosome 3 [46,XX,del(3)(q27→qter)]

We report on a terminal deletion of the long arm of chromosome 3 [46,XX,del(3)(q27→qter)] in a female newborn infant who died 45 hours after delivery and had multiple congenital abnormalities including bilateral anophthalmia, congenital heart disease, and abnormal genitalia. The findings are compared to those of four previously reported cases with terminal del (3q). © 1996 Wiley-Liss, Inc.     

Analgesic efficacy of inhaled morphine in patients after bunionectomy surgery

BACKGROUND: The AERx Pain Management System (Aradigm Corporation, Hayward, CA) is a novel pulmonary delivery system for the systemic administration of morphine. The authors compared the relative analgesic efficacy and safety of the AERx Pain Management System with those of placebo and intravenous morphine in an orthopedic postsurgical pain model. METHODS: Eighty-nine male and female PS-1 to PS-3 patients underwent standardized bunionectomy surgery and received multiple doses of inhaled or intravenous placebo, inhaled morphine (one inhalation [2.2 mg] or three inhalations [6.6 mg]), or intravenous morphine (4 mg) in a blinded fashion. Open-label rescue morphine (2 mg) was also available as needed. Pain intensity, pain relief, and time to pain relief were measured after the first dose. Global evaluation, morphine consumption, vital signs, and adverse events were monitored for 8 h after treatment. Blinded study personnel performed all treatment administrations and pain assessments. RESULTS: Three inhalations of morphine and 4 mg intravenous morphine provided comparable single- and multiple-dose analgesia. One inhalation of morphine was statistically indistinguishable from placebo. Three inhalations of morphine and 4 mg intravenous morphine both consistently demonstrated significantly greater analgesic efficacy than did placebo and one inhalation of morphine. CONCLUSIONS: Comparable analgesic efficacy was demonstrated between a carefully matched dose of inhaled and intravenous morphine in a postsurgical pain model.     

Risedronate reduces intracortical porosity in women with osteoporosis

Nonvertebral fractures account for 80% of all fractures and their accompanying morbidity and mortality. Despite this, the effect of drug therapy on cortical morphology has received limited attention, partly because cortical bone is believed to remodel less and decrease less with age than trabecular bone. However, the haversian canals traversing the cortex provide a surface for remodeling that produces bone loss, porosity, and cortical fragility. We developed a new method of 3D micro‐computed tomography (µCT) to quantify intracortical porosity and the effects of treatment. Women with osteoporosis randomized to risedronate (5 mg/day, n = 28) or placebo (n = 21) had paired transiliac biopsies at baseline and 5 years imaged using 3D µCT. Pores determined from 8 to 12 slices were stratified by their minor axis length into those 25 to 100 µm (closing cone of haversian canals), 100 to 300 µm (cutting cone of haversian canals), and >300 µm (coalescent cavities). Porosity was analyzed as pore area (percent bone area) and pore density (pore number/mm²). Medians are reported. Risedronate reduced pore area in the 25 to 100, 100 to 300, and 300 to 500 µm ranges over 5 years (p = .0008, .04, NS, respectively) corresponding to an 18% to 25% reduction. In the placebo group, pore area was unchanged. At 5 years, pore area and pore number/mm² in the 25 to 100 µm range were each 17% lower in the risedronate group than in the placebo group (p = .02 and .04, respectively). Risedronate is likely to maintain bone strength and reduce nonvertebral fracture risk in part by reducing remodeling and therefore the number and size of intracortical cavities. © 2010 American Society for Bone and Mineral Research     

Associations of Patient Health-Related Problem Solving with Disease Control,Emergency Department Visits,and Hospitalizations in HIV and Diabetes Clinic Samples

Background Patient problem solving and decision making are recognized as essential to effective self-management across multiple chronic diseases. However, a health-related problem-solving instrument that demonstrates sensitivity to disease control parameters in multiple diseases has not been established. Objectives To determine, in two disease samples, internal consistency and associations with disease control of the Health Problem-Solving Scale (HPSS), a 50-item measure with 7 subscales assessing effective and ineffective problem-solving approaches, learning from past experiences, and motivation/orientation. Design Cross-sectional study. Participants Outpatients from university-affiliated medical center HIV (N = 111) and diabetes mellitus (DM, N = 78) clinics. Measurements HPSS, CD4, hemoglobin A1c (HbA1c), and number of hospitalizations in the previous year and Emergency Department (ED) visits in the previous 6 months. Results Administration time for the HPSS ranged from 5 to 10 minutes. Cronbach’s alpha for the total HPSS was 0.86 and 0.89 for HIV and DM, respectively. Higher total scores (better problem solving) were associated with higher CD4 and fewer hospitalizations in HIV and lower HbA1c and fewer ED visits in DM. Health Problem-Solving Scale subscales representing negative problem-solving approaches were consistently associated with more hospitalizations (HIV, DM) and ED visits (DM). Conclusions The HPSS may identify problem-solving difficulties with disease self-management and assess effectiveness of interventions targeting patient decision making in self-care.     

Randomized evaluation of controlled-release codeine and placebo in chronic cancer pain

Codeine is widely used in combination with acetaminophen and aspirin for the management of mild to moderate pain. However, there are few controlled clinical trials of single-entity codeine in chronic cancer pain. The purpose of this study was to evaluate the clinical efficacy and safety of controlled-release codeine given every 12 hr in patients with cancer pain. Thirty-five patients with chronic cancer pain were randomized in a double-blind crossover study to controlled-release (CR) codeine or placebo, for 7 days each. Pain intensity was assessed at 0800 hr and 2000 hr using a visual analogue scale (VAS) and a five-point categorical scale, and the use of “rescue” acetaminophen-plus-codeine (300 mg/30 mg every 4 hr as needed) was recorded. Thirty patients completed the study (17 male, 13 female; mean age, 64.4 ± 9.8 years) with a mean daily CR codeine dose of 277 ± 77 mg (range, 200–400 mg). CR codeine treatment resulted in significantly lower overall VAS pain intensity scores (22 ± 0.8 mm versus 36 ± 20 mm, P = 0.0001), categorical pain intensity scores (1.2 ± 0.8 versus 1.8 ± 0.8, P = 0.0001), and pain scores when assessed by day of treatment and by time of day. Daily “rescue” analgesic consumption was significantly lower on CR codeine, compared to placebo treatment (2.2 ± 2.3 versus 4.6 ± 2.8 tablets per day, P = 0.0001). Both patients and investigators preferred CR codeine to placebo (80% versus 3%, P = 0.0014 and 73% versus 7%, P = 0.0160, respectively). These data indicate that CR codeine, given every 12 hr results in significant reductions in pain intensity and the use of “rescue” acetaminophen-plus-codeine in patients with cancer pain. CR codeine provides the benefits of a flexible single entity codeine formulation and the convenience of 12-hr duration of action, which allows patients uninterrupted sleep and improved compliance.     

Teicoplanin: a new glycopeptide antibiotic complex

The chemistry, microbiology, pharmacokinetics, clinical efficacy, and adverse effect profile of teicoplanin are reviewed and, where appropriate, compared with vancomycin. Teicoplanin is a glycopeptide antibiotic with potent bactericidal activity against a wide variety of aerobic and anaerobic gram-positive bacteria. In contrast to the structurally related vancomycin, teicoplanin has a prolonged elimination half-life of approximately 60 hours and it may be safely administered by the intramuscular route. Adverse effects of teicoplanin include ototoxicity, nephrotoxicity, skin rash, eosinophilia, neutropenia, and transient elevation of serum aminotransferases. Teicoplanin may be beneficial as an alternative to vancomycin for patients with poor vascular access and in those requiring long-term outpatient therapy. The role of teicoplanin in the treatment and prophylaxis of gram-positive infections will ultimately depend on its unfolding safety and efficacy profile.     

cAMP- and Ca²(+) /calmodulin-dependent protein kinases mediate inotropic, lusitropic and arrhythmogenic effects of urocortin 2 in mouse ventricular myocytes

BACKGROUND AND PURPOSE

Urocortin 2 is beneficial in heart failure, but the underlying cellular mechanisms are not completely understood. Here we have characterized the functional effects of urocortin 2 on mouse cardiomyocytes and elucidated the underlying signalling pathways and mechanisms.

EXPERIMENTAL APPROACH

Mouse ventricular myocytes were field-stimulated at 0.5 Hz at room temperature. Fractional shortening and [Ca²⁺]_i transients were measured by an edge detection and epifluorescence system respectively. Western blots were carried out on myocyte extracts with antibodies against total phospholamban (PLN) and PLN phosphorylated at serine-16.

KEY RESULTS

Urocortin 2 elicited time- and concentration-dependent positive inotropic and lusitropic effects (EC₅₀: 19 nM) that were abolished by antisauvagine-30 (10 nM, n = 6), a specific antagonist of corticotrophin releasing factor (CRF) CRF₂ receptors. Urocortin 2 (100 nM) increased the amplitude and decreased the time constant of decay of the underlying [Ca²⁺]_i transients. Urocortin 2 also increased PLN phosphorylation at serine-16. H89 (2 µM) or KT5720 (1 µM), two inhibitors of protein kinase A (PKA), as well as KN93 (1 µM), an inhibitor of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), suppressed the urocortin 2 effects on shortening and [Ca²⁺]_i transients. In addition, urocortin 2 also elicited arrhythmogenic events consisting of extra cell shortenings and extra [Ca²⁺]_i increases in diastole. Urocortin 2-induced arrhythmogenic events were significantly reduced in cells pretreated with KT5720 or KN93.

CONCLUSIONS AND IMPLICATIONS

Urocortin 2 enhanced contractility in mouse ventricular myocytes via activation of CRF₂ receptors in a cAMP/PKA- and Ca²⁺/CaMKII-dependent manner. This enhancement was accompanied by Ca²⁺-dependent arrhythmogenic effects mediated by PKA and CaMKII.