Modelling the value of risk-stratified skin cancer screening of asymptomatic patients by dermatologists.

BACKGROUND: Total-body skin examination (TBSE) by dermatologists detects incidental skin cancers, but there is insufficient evidence for screening guidelines. As a result, the decision to perform screening TBSE in patients presenting for a focused visit is left to the dermatologist's discretion. OBJECTIVES: To model the financial and time tradeoffs of risk-stratified skin cancer screening by dermatologists in patients presenting with unrelated focused complaints. METHODS: We performed an economic evaluation incorporating data from a previously published prospective multicentre international study in addition to US demographic data on age and skin phototype (SPT). RESULTS: The mean number needed to examine (NNE) for all US adults was 105 at an additional cost of $3796 per skin cancer detected when performing TBSE on a patient who presents for a focused exam. The NNE consistently decreased with increasing age and lighter SPT for every age and SPT screening threshold. The cost per person screened increased with higher age and lighter SPT owing to the higher likelihood of incurring diagnostic biopsies. The additional face-to-face time required per skin cancer detected by performing TBSE in patients who present for a focused visit was 4·5 h for all adults. We used a diverse cohort of international patients that did not include Americans and because of a low event rate, we combined detection of melanoma and nonmelanoma skin cancer. CONCLUSIONS: Incidental skin cancers are detected by screening TBSE and its value can be enhanced through consideration of patients' age and SPT, which are established and readily identifiable skin cancer risk factors. What is already known about this topic? Risk stratification of asymptomatic individuals using age and skin phototype (SPT) can enhance the value of total-body skin examination when performed in the clinic by a dermatologist. What does this study add? For every age and SPT screening threshold, the number needed to examine to identify one skin cancer consistently decreased with increasing age and lighter SPT. When deciding to perform a screening skin examination in patients presenting with a focused complaint, dermatologists may wish to consider a patient's risk using age and SPT to enhance the yield of this intervention. Linked Comment: Ferris. Br J Dermatol 2020; 183:417-418.

Age-dependent changes in intervertebral disc cell mitochondria and bioenergetics.

Robust cellular bioenergetics is vital in the energy-demanding process of maintaining matrix homeostasis in the intervertebral disc. Age-related decline in disc cellular bioenergetics is hypothesised to contribute to the matrix homeostatic perturbation observed in intervertebral disc degeneration. The present study aimed to measure how ageing impacted disc cell mitochondria and bioenergetics. Age-related changes measured included matrix content and cellularity in disc tissue, as well as matrix synthesis, cell proliferation and senescence markers in cell cultures derived from annulus fibrosus (AF) and nucleus pulposus (NP) isolated from the discs of young (6-9 months) and older (36-50 months) New Zealand White rabbits. Cellular bioenergetic parameters were measured using a Seahorse XFe96 Analyzer, in addition to quantitating mitochondrial morphological changes and membrane potential. Ageing reduced mitochondrial number and membrane potential in both cell types. Also, it significantly reduced glycolytic capacity, mitochondrial reserve capacity, maximum aerobic capacity and non-glucose-dependent respiration in NP. Moreover, NP cells exhibited age-related decline in matrix synthesis and reduced cellularity in older tissues. Despite a lack of changes in mitochondrial respiration with age, AF cells showed an increase in glycolysis and altered matrix production. While previous studies report age-related matrix degenerative changes in disc cells, the present study revealed, for the first time, that ageing affected mitochondrial number and function, particularly in NP cells. Consequently, age-related bioenergetic changes may contribute to the functional alterations in aged NP cells that underlie disc degeneration.

In vitro evaluation of translating and rotating plates using a robot testing system under follower load.

BACKGROUND CONTEXT: Various modifications to standard "rigid" anterior cervical plate designs (constrained plate) have been developed that allow for some degree of axial translation and/or rotation of the plate (semi-constrained plate)-theoretically promoting proper load sharing with the graft and improved fusion rates. However, previous studies about rigid and dynamic plates have not examined the influence of simulated muscle loading. PURPOSE: The objective of this study was to compare rigid, translating, and rotating plates for single-level corpectomy procedures using a robot testing system with follower load. STUDY DESIGN: In-vitro biomechanical test. METHODS: N = 15 fresh-frozen human (C3-7) cervical specimens were biomechanically tested. The follower load was applied to the specimens at the neutral position from 0 to 100 N. Specimens were randomized into a rigid plate group, a translating plate group and a rotating plate group and then tested in flexion, extension, lateral bending and axial rotation to a pure moment target of 2.0 Nm under 100N of follower load. Range of motion, load sharing, and adjacent level effects were analyzed using a repeated measures analysis of variance (ANOVA). RESULTS: No significant differences were observed between the translating plate and the rigid plate on load sharing at neutral position and C4-6 ROM, but the translating plate was able to maintain load through the graft at a desired level during flexion. The rotating plate shared less load than rigid and translating plates in the neutral position, but cannot maintain the graft load during flexion. CONCLUSIONS: This study demonstrated that, in the presence of simulated muscle loading (follower load), the translating plate demonstrated superior performance for load sharing compared to the rigid and rotating plates.

Effects of secreted factors in culture medium of annulus fibrosus cells on microvascular endothelial cells: elucidating the possible pathomechanisms of matrix degradation and nerve in-growth in disc degeneration.

OBJECTIVE: To test whether the interaction between annulus fibrosus cells (AFCs) and endothelial cells (ECs) disrupts matrix homeostasis and stimulates production of innervation mediators. METHODS: Human microvascular ECs were cultured in the conditioned media of AF cell culture derived from degenerated human surgical specimen. Matrix-metalloproteinases (MMPs) and platelet-derived growth factor (PDGF) of ECs of this culture were analyzed by qRT-PCR, Western, and immunofluorescence. Vascular endothelial growth factor (VEGF), Interleukin-8 (IL-8), and nerve growth factor (NGF) in the media of this cell culture were assayed by ELISA. To determine the effects of ECs on AFCs, qRT-PCR was performed to determine mRNA levels of collagen I, II and aggrecan in AFCs cultured in EC conditioned media. RESULTS: Compared to ECs cultured in naïve media, ECs exposed to AFC conditioned media expressed higher mRNA and protein levels of key biomarkers of invasive EC phenotype, MMP-2 (2×), MMP-13 (4×), and PDGF-B (1.5-2×), and NGF (24.9 ± 15.2 pg/mL vs 0 in naïve media). Treatment of AF cells with EC culture conditioned media decreased collagen type II expression two fold. Considerable quantities of pro-angiogenic factors IL-8 (396.7 ± 302.0 pg/mL) and VEGF (756.2 ± 375.9 pg/mL) were also detected in the conditioned media of untreated AF cell culture. DISCUSSION: AFCs from degenerated discs secreted factors which stimulated EC production of factors known to induce matrix degradation, angiogenesis, and innervation. IL-8 and VEGF maybe the secreted factors from AFCs which mediate a pro-angiogenic stimulus often implicated in the development of disc degeneration.

Statins and prostate cancer recurrence following radical prostatectomy or radiotherapy: a systematic review and meta-analysis.

BACKGROUND: In this meta-analysis, we evaluated associations between statins and recurrence-free survival (RFS) following treatment of localized prostate cancer, with attention to potential benefits among patients treated primarily with radiotherapy (RT) versus radical prostatectomy. PATIENTS AND METHODS: We identified original studies examining the effect of statins on men who received definitive treatment of localized prostate cancer using a systematic search of the PubMed and EMBASE databases through August 2012. Our search yielded 17 eligible studies from 794 references; 13 studies with hazard ratios (HRs) for RFS were included in the formal meta-analysis. RESULTS: Overall, statins did not affect RFS (HR 0.90, 95% CI 0.74-1.08). However, in RT patients (six studies), statins were associated with a statistically significant improvement in RFS (HR 0.68; 95% CI 0.49-0.93); this benefit was not observed in radical prostatectomy patients (seven studies). Sensitivity analyses suggested that primary treatment modality may impact the effect of statins on prostate cancer recurrence. CONCLUSIONS: Our meta-analysis suggests a potentially beneficial effect of statins on prostate cancer patients treated with RT but not among radical prostatectomy patients. Although limited by the lack of randomized data, these results suggest that primary treatment modality should be considered in future studies examining associations between statins and oncologic outcomes.

Outcomes of lateral retroperitoneal reservoir placement of three-piece penile prosthesis in patients following radical prostatectomy.

While placement of a three-piece inflatable penile prosthesis (IPP) with a midline reservoir can be performed with favorable outcomes after radical prostatectomy (RP), postoperative fascial scarring can introduce surgical complexity, increase intra-operative complications and/or potential obstacles for future inguinal and/or perineal surgeries. We describe the implantation of the IPP with lateral reservoir placement through a separate incision to avoid surgical complications. We obtained clinical characteristics of all patients (1998-2009) who underwent RP before IPP placement with lateral reservoir placement (cases). For comparison, patients who underwent IPP placement with midline reservoir placement were also identified (controls). Thirty-one patients with a history of RP underwent IPP placement using the lateral placement technique without intra-operative or post-operative complications. There were no significant differences in the intra-operative complication rate among 31 control patients. However, at a median follow-up of >2 years, there was a significantly higher rate of post-operative complications in controls, likely reflecting the increased co-morbidities in this group. The results of this study suggest that three-piece IPP with lateral retroperitoneal reservoir implantation is associated with comparable long-term outcomes and can be performed safely in patients who have previously undergone RP.

Dual-energy CT iodine overlay technique for characterization of renal masses as cyst or solid: a phantom feasibility study.

The aim of this study was to assess the ability of dual-energy computed tomography (DECT) to classify phantom renal lesions as cysts or enhancing masses. Six cylinders ranging in diameter from 0.5 to 3.0 cm were filled with distilled water or titrated iodinated contrast solutions with CT attenuation values at 120 kVp of 0 Hounsfield units (HU) for a cyst proxy or 10, 20, or 40 HU to represent enhancing masses. These were placed in a 12-cm-diameter renal phantom containing puréed beef mixed with iodinated contrast medium to simulate enhancing renal parenchyma of 100 and 250 HU and submerged within a 28-cm water bath. These combinations produced 48 individual phantom renal lesions of differing sizes, internal and parenchymal enhancement (12 cysts and 36 enhancing masses). DECT using 80 and 140 kVp was performed on a dual-source CT scanner. Commercial software created a color-encoded overlay indicating the location of iodine within the phantom. The lesions were individually graded as a cyst or enhancing mass by blinded, consensus interpretation of two genitourinary radiologists. Thirty-five of 36 enhancing masses and 10/12 cysts were correctly identified, equating to a sensitivity and specificity of 97% (95% CI 84-100%) and 83% (95% CI 51-97%), respectively. All lesions of 20- and 40-HU enhancement and 92% of 10-HU lesions were identified correctly. In a phantom model, the DECT iodine overlay technique is highly sensitive in detecting enhancing renal masses. Refinement of the technique remains necessary to improve specificity. If validated in patients, this may obviate the need for unenhanced acquisitions for renal mass characterization.

Long-term effects of melatonin after intracerebral hemorrhage in rats.

Free radical scavengers have been shown to improve short-term outcome after intracerebral hemorrhage (ICH). The purpose of this study was to evaluate whether melatonin (a potent free radical scavenger and an indirect antioxidant) can improve short- and/or long-term neurological function after ICH, which was induced by collagenase injection into the striatum of adult rats. Melatonin (15 mg/kg) was administered by intraperitoneal injection at 1, 24, 48, and 72 h. Neurological and behavioral testing was performed at several time points from 1 day to 8 weeks post-ICH. Neurological and behavioral deficits were observed in ICH rats at all time points, but the melatonin treatment regimen did not improve performance or level of brain injury.

Long-term behavioral characterization of a rat model of intracerebral hemorrhage.

We tested the behavioral effects of intracerebral hemorrhage (ICH) in adult male rats. ICH was induced by collagenase injection into the basal ganglia and the rats were subjected to a longitudinal behavioral test battery. Both learning and memory deficits were detected shortly after injury. Two months after injury, there were still significant short- and long-term memory deficits. Rotarod testing also revealed long-term sensorimotor coordination deficits. No differences in activity levels were detected at any time. Thus, spontaneous ICH produced detectable cognitive and motor deficits that evolved over the course of 2 months. Along with histological analysis of infarct volume, this characterization provides a suitable baseline for the analysis of therapeutic interventions.

A single day of ethanol exposure during development has persistent effects on bi-directional plasticity, N-methyl-D-aspartate receptor function and ethanol sensitivity.

To determine factors that contribute to the learning deficits observed in individuals with fetal alcohol syndrome, we examined the effects of early postnatal ethanol exposure on forms of synaptic plasticity thought to underlie memory. Treatment of rat pups with ethanol on postnatal day 7 impaired the induction of N-methyl-D-aspartate receptor-dependent long-term potentiation and abolished homosynaptic long-term depression in the CA1 region of hippocampal slices prepared at postnatal day 30. An N-methyl-D-aspartate receptor-independent form of long-term potentiation induced by very high frequency stimulation could be induced in slices from ethanol-treated rats. Defects in long-term depression correlated with a diminished contribution of ifenprodil-sensitive N-methyl-D-aspartate receptors to synaptic transmission and defects in a spontaneous alternation behavioral task. Rats exposed to ethanol on postnatal day 7 also exhibited diminished sensitivity of synaptic N-methyl-D-aspartate receptors to block by ethanol at postnatal day 30 and decreased behavioral sedation to systemic ethanol injections. These results indicate that changes in synaptic plasticity and N-methyl-D-aspartate receptor function are likely to provide a neural substrate for the cognitive and behavioral changes that follow developmental ethanol exposure.

Deletion of the N-terminus of murine map2 by gene targeting disrupts hippocampal ca1 neuron architecture and alters contextual memory.

Microtubule-associated protein-2 (MAP2) is a brain specific A-kinase anchoring protein that targets the cyclic AMP-dependent protein kinase holoenzyme (PKA) to microtubules. Phosphorylation of MAP2 by different protein kinases is crucial for neuronal growth. The N-terminus of MAP2 contains the binding site for regulatory subunit II of cAMP-dependent protein kinase (PKA-RIIbeta). Using homologous recombination, we created a mutant line of mice (delta1-158) that express truncated MAP2 lacking the N-terminal peptide and the PKA binding site. Deletion of the PKA binding site from the MAP2 gene resulted in decreased efficiency of MAP2 phosphorylation. Biochemical and immunohistochemical studies demonstrate major changes in the morphology of hippocampal neurons in delta1-158 mice. Behavioral tests indicate that delta1-158 mice were impaired (exhibited less conditioned freezing) relative to Wild-Type (WT) controls during a test of contextual, but not during auditory cue, fear conditioning when tested at 8 weeks or 8 months of age. The delta1-158 mice displayed a heightened sensitivity to shock at 8 weeks, but not at 8 months of age. We conclude that PKA binding to MAP2 and MAP2 phosphorylation is essential for the selective development of contextual memory.

Treatment of acute liver failure in pigs reduces hepatocyte function in a bioartificial liver support system.

Several different types of bioartificial liver (BAL) support systems have been developed to bridge patients suffering from acute liver failure (ALF) to transplantation or liver regeneration. In this study we assessed the effects of ALF plasma on hepatocyte function in the BAL system that has been developed in our center. Pigs (40-60 kg) were anaesthetised and a total hepatectomy was performed. Cells were isolated from the resected livers and were transferred to the bioreactor of the BAL system. Twenty hours after cell isolation, hepatocytes in the BAL were tested for cell viability and functional activity by using a recirculating test medium in which assessment of LDH leakage, ammonia clearance, urea synthesis, 7-ethoxycoumarin O-deethylase (ECOD) activity and pseudocholine esterase production was performed. Subsequently, two groups were studied. In one group (I, n=5), the cell-loaded bioreactor was used to treat the donor pig, rendered anhepatic, for 24 hours. In the second group (II, n=5) the bioreactor was cultured for 24 h and served as a control. After 24 hours treatment or culturing, the cell viability count and functional activity tests were repeated. The results show that hepatocytes in the BAL remained viable after 24 h treatment of anhepatic pigs, as shown by the LDH release and pseudocholine esterase production. However, metabolic functions such as ammonia clearance, ECOD and urea synthesis were reduced after 24 h exposure of hepatocytes to autologous ALF plasma, whereas these functions were unaltered after 24 h culturing of the cells in the bioreactor.

Polymyositis-dermatomyositis-associated interstitial lung disease.

We report findings in 70 patients with both diffuse interstitial lung disease and either polymyositis (PM) or dermatomyositis (DM). Initial presentations were most commonly either musculoskeletal (arthralgias, myalgias, and weakness) or pulmonary (cough, dyspnea, and fever) symptoms alone; in only 15 patients (21.4%) did both occur simultaneously. Pulmonary disease usually took the form of acute to subacute antibiotic-resistant community-acquired pneumonia. Chest radiographs and computed tomography most commonly demonstrated bilateral irregular linear opacities involving the lung bases; occasionally consolidation was present. Jo-1 antibody was present in 19 (38%) of 50 patients tested. Synchronous associated malignancy was present in 4 of 70 patients (5.7%). Surgical lung biopsies disclosed nonspecific interstitial pneumonia (NSIP) in 18 of 22 patients (81.8%), organizing diffuse alveolar damage (DAD) in 2, bronchiolitis obliterans organizing pneumonia (BOOP) in 1, and usual interstitial pneumonia (UIP) in 1. Treatment usually included prednisone in 40-60 mg/d dosages for initial control, followed by lower dose prednisone plus an immunosuppressive agent such as azathioprine or methotrexate for disease suppression. Survival was significantly better than that observed for historical control subjects with idiopathic UIP, and was more consistent with survival previously reported in idiopathic NSIP. There was no difference in survival between Jo-1 positive and Jo-1 negative groups.

Brain metabolic and clinical effects of rivastigmine in Alzheimer's disease.

In-vivo metabolic measures with positron emission tomography using (18)F-fluorodeoxyglucose (FDG-PET) have demonstrated hypometabolism in temporal, frontal, and hippocampal areas during the early stages of Alzheimer's disease (AD). Progression of the dementia in AD involves compromised cholinergic functioning. Cholinesterase inhibitors have demonstrated efficacy in improving cognition and behaviour in AD. In this study, we demonstrate the usefulness of FDG-PET in measuring the progression of untreated AD and its modification by treatment with rivastigmine (Exelon, Novartis Pharmaceuticals, East Hanover, New Jersey, USA), a centrally selective cholinesterase inhibitor of the carbamate type. Patients with mild to moderate probable AD (Mini-Mental Status Exam scores of 10-26, inclusive) were enrolled in a double-blind, placebo controlled comparison of three fixed daily doses of rivastigmine (3, 6, or 9 mg/d) or placebo for 26 wk. FDG-PET scans were obtained on 27 patients at baseline and following 26 wk of treatment using the Snodgrass Picture Naming activation task. A total of 71.4% of the patients treated with placebo deteriorated clinically compared to only 25.0% of the patients treated with rivastigmine (chi2 = 4.8; p & 0.03). Rivastigmine-responders (i.e. those who clinically improved or remained clinically stable as measured by the Clinicianaposs Interview-Based Impression of Change-plus) showed a marked increase in brain metabolism (p <0.01) involving, but not limited to, structures comprising the memory-related cortices and the prefrontal system. These metabolic changes were not observed in the placebo-treated patients or the rivastigmine non-responders. Of note is that responders increased hippocampal metabolism by 32.5% (p < 0.03) compared to a non-significant decrease in the non-responders (6.4%) and placebo-treated patients (4.1%). These results are consistent with the literature suggesting that FDG-PET can sensitively measure the progression of AD and its improvement with cholinesterase inhibitors. Rivastigmine prevented the expected deterioration in clinical status and dramatically increased brain metabolic activity in a majority of patients.

Inactivation of protein farnesyltransferase by active-site-targeted dicarbonyl compounds.

Upon farnesylation by protein farnesyltransferase (FTase), key proteins become compartmentalized in cells. For example, cell membrane localization is essential for the mitogenic role of mutant Ras protein, which acts as a switch for cancer cell proliferation. We report that alpha-dicarbonyl compounds derived from the isoprenoid skeleton or other hydrophobic groups potently obstruct farnesylation of a Ras model peptide by human recombinant FTase in vitro. A geranyl-derived isoprenoid diketone, 5,9-dimethyl-8-decene-2,3-dione, at 17 microM caused a 62% reduction in FTase activity after 30 minutes. A farnesyl-derived isoprenoid diketone, 5,9,13-trimethyl-8,12-tetradecadiene-2,3-dione, at 93 microM caused a 94% reduction after 30 minutes. Other dicarbonyl compounds found to be effective against FTase in vitro were (+/-)-6-(camphorquinone-10-sulfonamido)-hexanoic acid, 4,4'-biphenyldiglyoxaldehyde, dehydroascorbic acid 6-palmitate, 2-oxododecanal, and phenylglyoxal. Higher concentrations of the alpha-dicarbonyl compound resulted in more rapid and more extensive inactivation. These findings demonstrate that alpha-dicarbonyl compounds targeted to FTase interfere with protein farnesylation in vitro and may lead to derivatives that have utility as chemotherapeutic agents.

Behavioral phenotyping of GFAP-apoE3 and -apoE4 transgenic mice: apoE4 mice show profound working memory impairments in the absence of Alzheimer's-like neuropathology.

For the purpose of studying the potential neurobehavioral effects of different human apolipoprotein E (apoE) isoforms produced within the brain, transgenic (TG) mice were generated in which human apoE3 or apoE4 isoforms were under control of an astrocyte-specific, glial fibrillary acidic protein promoter and these TG mice were bred back to apoE knockout (KO) mice. Behavioral phenotypes of apoE3 and apoE4 TG mice were derived by conducting a longitudinal study in which apoE3 and apoE4 TG mice were compared with apoE KO and wild-type (WT) mice (all male) on several behavioral measures. Analysis of locomotor activity, "open-field" behaviors, acoustic startle/prepulse inhibition, and elevated plus maze data suggested that the apoE TG/KO groups were more "emotionally reactive" than WT mice, with apoE4 mice typically being the most reactive. The absence of performance differences among groups on the rotating holeboard and water navigation tasks suggested intact reference memory processing in apoE TG/KO mice. However, apoE4 mice were profoundly impaired on a working memory-based protocol in the radial arm maze (11-14 months). Nonassociative factors (sensorimotor capacities or emotionality differences) did not appear to confound interpretation of the learning/memory results. Western blot analysis revealed no alterations in the level of synaptic, neuronal, or glial markers in neocortex or hippocampus and histologic analysis revealed no evidence of Abeta deposition or neuritic plaques in the apoE KO/TG mice. Our findings suggest that apoE4 expression in the brain may have selective deleterious effects on memory function in the absence of typical Alzheimer's-like neuropathology.

Response of patients with Alzheimer disease to rivastigmine treatment is predicted by the rate of disease progression.

BACKGROUND: Evidence suggests that disease severity predicts the response of patients with Alzheimer disease (AD) to cholinesterase inhibitor treatment, raising the question of whether disease progression also predicts response to this treatment. OBJECTIVE: To evaluate retrospectively whether rate of disease progression during placebo treatment affects response to subsequent rivastigmine tartrate therapy for patients with mild to moderately severe AD. DESIGN: A 26-week, open-label extension study following a 26-week, double-blind, randomized, placebo-controlled trial. SETTING: Outpatient research centers at 22 sites in the United States. PATIENTS: We studied 187 of 235 patients originally randomized to receive placebo treatment in the double-blind phase of the trial who continued with open-label (rivastigmine) extension therapy. INTERVENTION: Placebo treatment for 26 weeks followed by rivastigmine treatment, 2 to 12 mg/d, for 26 weeks. MAIN OUTCOME MEASURES: Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), Progressive Deterioration Scale, Mini-Mental State Examination, and Global Deterioration Scale scores. RESULTS: Rivastigmine administration during open-label extension therapy benefited patients who had progressed slowly and those who had progressed rapidly during initial double-blind placebo treatment. Slowly progressive patients responded with a mean 1.03-point improvement in the week 26 (ie, start of open-label rivastigmine treatment) ADAS-Cog score at 12 weeks of rivastigmine treatment (week 38 of treatment; P =.02 vs week 26). However, more rapidly progressive patients had a significantly larger mean 4.97-point improvement from the week 26 ADAS-Cog score at 12 weeks (with respect to week 26 of treatment and slowly progressive patient scores, P<.001 for both). Thus, a more rapid disease progression rate while receiving placebo treatment was predictive of a significantly stronger patient response to rivastigmine therapy. This relation also was observed with the other 3 outcome measures and was still apparent when accounting for disease severity. CONCLUSIONS: Rate of disease progression for patients with mild to moderate AD seems to predict response to rivastigmine treatment. Patients with more rapidly progressive disease might be particularly likely to benefit from rivastigmine therapy.

A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease.

The efficacy of a centrally active cholinesterase inhibitor, rivastigmine tartrate (ENA 713; Exelon, in patients with mild to moderately severe Alzheimer's disease was evaluated in a 26-week open-label extension of a 26-week, double-blind, placebo-controlled study. By 52 weeks, patients originally treated with 6-12 mg/day rivastigmine had significantly better cognitive function than patients originally treated with placebo.

Histologic signatures of thermal injury: applications in transmyocardial laser revascularization and radiofrequency ablation.

BACKGROUND AND OBJECTIVE: Cardiac treatments such as transmyocardial laser revascularization and radiofrequency ablation cause thermal injury. We sought to provide quantitative histologic methods of assessing such injury by using the inherent birefringence of cardiac muscle and collagen; specifically, to exploit the connection between thermal injury and the loss of birefringence. STUDY DESIGN/MATERIALS AND METHODS: We quantified tissue birefringence changes in vitro for temperatures up to 130 degrees C. This information was used to assess thermal injury associated with myocardial channels made in vitro. We then measured in vivo cardiac injury 30 minutes and 3 days after radiofrequency exposure. RESULTS: Birefringence decreased above 60 degrees C for muscle and above 70 degrees C for collagen. Temperatures above 80 degrees C were associated with collagen fiber straightening and above 95 degrees C with little muscle birefringence. Injury adjacent to laser channels was greatest parallel to cell orientation. In vivo, muscle with reduced birefringence was surrounded by cells exhibiting focal birefringence increases (contraction bands). Early injury assessment marked by birefringence changes corresponded to lesion size at 3 days. CONCLUSION: Polarized light revealed histologic temperature signatures corresponding to irreversible muscle injury and collagen denaturation.

A multi-element ICP-MS survey method as an alternative to the heavy metals limit test for pharmaceutical materials.

A multi-element inductively coupled plasma-mass spectrometry (ICP-MS) survey method has been demonstrated as an alternative to the antiquated 'heavy metals limit test' prescribed by United States Pharmacopoeia (USP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP), for drug substances, intermediates, and raw materials. The survey method is simple, fast, sensitive, semi-quantitative to quantitative, and includes all the elements which can be analyzed by atomic spectroscopy.