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.

Relationship of F-actin distribution to development of polar shape in human polymorphonuclear neutrophils.

Polymerization of actin has been associated with development of polar shape in human neutrophils (PMN). To examine the relation of filamentous actin (F-actin) distribution to shape change in PMN, we developed a method using computerized video image analysis and fluorescence microscopy to quantify distribution of F-actin in single cells. PMN were labeled with fluorescent probe NBD-phallicidin to measure filamentous actin and Texas red to assess cell thickness. We show that Texas red fluorescence is a reasonable measure of cell thickness and that correction of the NBD-phallicidin image for cell thickness using the Texas red image permits assessment of focal F-actin content. Parameters were derived that quantify total F-actin content, movement of F-actin away from the center of the cell, asymmetry of F-actin distribution, and change from round to polar shape. The sequence of change in F-actin distribution and its relation to development of polar shape in PMN was determined using these parameters. After stimulation with chemotactic peptide at 25 degrees C, F-actin polymerized first at the rim of the PMN. This was followed by development of asymmetry of F-actin distribution and change to polar shape. The dominant pseudopod developed first in the region of lower F-actin concentration followed later by polymerization of actin in the end of the developed pseudopod. Asymmetric F-actin distribution was detected in round PMN before development of polar shape. Based upon these data, asymmetric distribution of F-actin is coincident with and probably precedes development of polar shape in PMN stimulated in suspension by chemotactic peptide.

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 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.

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.

Altered stress-induced anxiety in adenylyl cyclase type VIII-deficient mice.

Stress results in alterations in behavior and physiology that can be either adaptive or maladaptive. To define the molecular pathways involved in the response to stress further, we generated mice deficient (KO) in the calcium-stimulated adenylyl cyclase type VIII (AC8) by homologous recombination in embryonic stem cells. AC8 KO mice demonstrate a compromise in calcium-stimulated AC activity in the hippocampus, hypothalamus, thalamus, and brainstem. Hippocampal slices derived from AC8 KO mice fail to demonstrate CA1-region long-term depression after low-frequency stimulation, and AC8 KO mice also fail to activate CRE-binding protein in the CA1 region after restraint stress. To define the behavioral consequences of AC8 deficiency, we evaluated AC8 KO mice in the elevated plus-maze and open field. Although naive AC8 KO mice exhibit indices of anxiety comparable with that of wild-type mice, AC8 KO mice do not show normal increases in behavioral markers of anxiety when subjected to repeated stress such as repetitive testing in the plus-maze or restraint preceding plus-maze testing. These results demonstrate a novel role for AC8 in the modulation of anxiety.

Enzymatic addition of modified cytosine nucleotides to DNA. Methacrylate polymerization by an azo pyrimidine.

An azo pyrimidine that induces the polymerization of 1-glyceryl methacrylate has been prepared. 1-Glyceryl methacrylate contains substituent glycol groups for binding heavy atoms for subsequent electron microscopic studies. Oxodation of 1-methyl N4-ureidocytosine (compound 1A) with N-bromosuccinimide produced 4-aminocarbonylazo-2-pyrimidinone (compound 2A). This orange compound shows a broad peak (lambda max = 349 nm) in its ultraviolet absorption spectrum. Mixing compound 2A with mildly acidic aqueous solutions of 1-glyceryl methacrylate (pH 3.6) resulted in polymerization of the methacrylate. Under these conditions, the ester 1-glyceryl methacrylate does not hydrolyze appreciably as judged by oxidation of the glycol groups with NaIO4 and spectrophotometric analysis of the HCHO liberated using Schiff's reagent. Attachment of azo nucleotides to the 3'-terminus of DNA was achieved in two steps. First, N4-ureidocytosine deoxynucleotides were enzymatically added to single strand DNA primers using calf thymus terminal deoxynucleotidyl transferase, Co2+, and N4-ureido-2'-deoxycytidine 5'-triphosphate (prepared by the HSO3--catalyzed transamination reaction of dCTP with semicarbazide). Second, these modified nucleotides were oxidized with N-bromosuccinimide to produce DNA that contained azo pyrimidine nucleotides at its 3'-end (azoDNA). Upon adding acid to the azoDNA, the azo nucleotides decomposed. If these nucleotides induce methacrylate polymerization upon decomposition as did compound 2A, it may be possible to mark the location of DNA termini in situ for electron microscopy by attaching heavy atoms to the poly(1-glyceryl methacrylate) formed. Such studies may elucidate the nature and location of the ends of the eukaryotic chromosomal DNA molecule in both chromosomes and interphase nuclei.

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.

Pronounced and prolonged ST segment elevation: a pathognomonic sign of tumor invasion of the heart.

Electrocardiographic abnormalities are commonly seen with tumor invasion of the heart. However, most of these abnormalities are nonspecific. Pronounced and prolonged ST segment elevation. In the absence of myocardial infarction occurred in a patient with carcinoma of the lung. Noninvasive cardiac studies suggested the presence of tumor invasion of the heart, which was confirmed at autopsy. Prolonged ST segment elevation in the absence of Q waves seems to be a pathognomonic sign for tumor invasion of the heart.

Cimetidine therapy in nonsteroidal anti-inflammatory drug gastropathy. Double-blind long-term evaluation.

To assess the efficacy of cimetidine in treating and preventing gastric mucosal lesions associated with nonsteroidal anti-inflammatory drug (NSAID) therapy (NSAID gastropathy), we endoscopically studied 104 patients taking NSAIDs for a variety of rheumatic diseases. Fifty-six percent (22/43) of patients randomized to cimetidine 300 mg four times a day and 52% (22/42) of those randomized to placebo showed progression of endoscopic lesions during the eight-week short-term phase. Thirty-nine patients whose endoscopic lesions improved were then randomized to a ten-month maintenance regimen of either cimetidine 400 mg at bedtime or placebo. Fifty percent (7/14) of placebo-treated and 42% (5/12) of cimetidine-treated patients showed progression of lesions during the maintenance phase. The failure of cimetidine to offer any significant benefit under these protocol conditions reflects the fundamental difference in pathophysiologic features between classic acid-mediated ulcer disease and NSAID gastropathy.

Gamma-aminobutyric acid-A and -B receptor antagonists increase luteinizing hormone-releasing hormone neuronal responsiveness to intracerebroventricular norepinephrine in ovariectomized estrogen-treated rats.

These studies determined whether endogenous gamma-aminobutyric acid (GABA) secretion affects LHRH neuronal responsiveness to norepinephrine (NE). The intracerebroventricular (icv) infusion of either bicuculline or phaclofen (GABA-A or GABA-B receptor antagonists, respectively) into ovariectomized (OVX) estrogen-treated rats did not affect basal LH levels (95 +/- 8.5 ng/ml) obtained over the 120 min of this study. When NE was infused icv, it produced a modest rise in plasma LH, which peaked within 15 min (240 +/- 25 ng/ml) and then declined toward baseline over the next 90 min. In contrast, if bicuculline was given icv at about time zero, and NE was infused (icv) 15 min later, plasma LH secretion was markedly increased and reached a peak concentration of 723 +/- 98 ng/ml within 15 min after NE treatment. Similarly, when bicuculline was infused into the medial preoptic area (MPOA), and NE was given 15 min later (icv), a peak LH level of 726 +/- 105 ng/ml was obtained within 15 min. If phaclofen was given icv at about time zero, and NE was infused 15 min later, LH rose dramatically to reach a peak concentration of 844 +/- 126 ng/ml within 15 min; a similar amplified LH response occurred when the GABA-B antagonist was infused into the MPOA and icv NE was given 15 min later. Comparisons of the LH responses obtained over the 120 min of the study suggest that icv infusions of the GABA-B receptor antagonist were more effective in sustaining peak LH secretion than the GABA-A receptor antagonist. In other groups of rats, the MPOA was electrochemically stimulated (ECS), and the effects of icv NE alone or combined with GABA receptor antagonists were evaluated. MPOA ECS alone induced a significant rise in plasma LH, which peaked between 35-45 min and then declined to approach basal levels by 150 min. In a second group, the MPOA was ECS, and at 30 min NE was infused icv. Plasma LH levels in these rats remained significantly elevated for the next 30 min before beginning their decline. In other animals, the MPOA was stimulated, and 15 min later either bicuculline or phaclofen was infused icv. Neither drug affected the patterns or concentrations of LH obtained after MPOA ECS alone. However, when rats received MPOA ECS plus either icv bicuculline or phaclofen, and these treatments were followed 15 min later by icv infusions of NE, LH secretion patterns and levels were altered significantly.(ABSTRACT TRUNCATED AT 400 WORDS)

Endogenous opioid peptides inhibit oxytocin release in the lactating rat after dehydration and urethane.

One physiological role for endogenous opioid peptides is to attenuate the release of oxytocin (OT) from the hypothalamo-neurohypophysial system during dehydration and hemorrhage when vasopressin maintains fluid balance and blood pressure. During lactation, OT, which stimulates milk ejection, is released without vasopressin. The influence of endogenous opioid peptides on OT release during suckling has been studied primarily in animals anesthetized with urethane. In addition to anesthesia, urethane dehydrates the animal by elevating plasma osmolality and reducing cardiovascular volume. Thus, we examined in lactating rats the response of the magnocellular neuroendocrine system to dehydration and the role of endogenous opioid peptides in regulating OT release during suckling under conditions of altered fluid balance in conscious and urethane-anesthetized rats. Release of OT in response to an increase in plasma osmolality or a decrease in blood volume was attenuated during lactation in both conscious and anesthetized rats. Blockade of opiate receptors with naloxone (5 mg/kg) did not alter suckling-induced release of immunoreactive OT in conscious, normally hydrated rats, but did augment hormone release after urethane (1.1 g/kg, ip) or after osmotic stimulation with hypertonic sodium chloride (2.5%; 20 ml/kg, ip). During dehydration, the combination of decreased responsiveness of oxytocinergic neurons to osmotic stimulation and inhibition of OT release by opioid peptides may be important in the lactating rat for conserving pituitary stores of OT needed for milk ejection.

Ontogeny of opioid inhibition of vasopressin and oxytocin release in response to osmotic stimulation.

We have shown, using the opiate receptor antagonist naltrexone, that endogenous opioid peptides inhibit the release of oxytocin (OT), but not of vasopressin (AVP), from the hypothalamo-neurohypophysial system during dehydration. The stimulus for the release of neurohypophysial hormones during dehydration is both hypovolemia and increased plasma osmolality. The aims of this study were to determine whether opioid peptides inhibit OT secretion during an osmotic stimulus alone and, if so, to study the ontogeny of opiate inhibition of OT and AVP release during osmotic stimulation. Effects of endogenous opioid peptides were evaluated by injecting naloxone into immature and adult rats. Hypertonic saline was used as the osmotic stimulus. Adult male rats were injected sc with normal saline (0.85%; 1 ml/kg BW) or naloxone (5 mg/kg BW), followed 5 min later by normal or hypertonic (1 M) saline (15 ml/kg BW). After 170 min, a second injection of saline or naloxone was given; animals were decapitated 10 min later. Immature male and female rats at 2, 8, 21, and 30 days of age received 0.85% saline (1 ml/kg BW) or naloxone (5 mg/kg BW) ip 5 min before normal or hypertonic (2.5%) saline (20 ml/kg BW, ip). Pups were decapitated 15 min later. AVP and OT were measured by RIA in extracts of plasma, pituitaries, and hypothalami. In control rats, the contents of AVP and OT increased with age in both the pituitary and hypothalamus, attaining adult levels by day 21 for AVP and by day 30 for OT. In contrast, plasma concentrations of both AVP and OT were highest in 8-day-old rats and decreased thereafter to adult levels by 30 days of age. Hypertonic saline raised plasma osmolality 9-16 mosmol/kg H2O, increased AVP and OT concentrations in plasma of adults and immature rats at 2, 8, 21, and 30 days of age, and reduced pituitary stores of OT in adult animals. Blocking the action of opioid peptides with naloxone during osmotic stimulation augmented the rise in plasma OT in rats of all ages but further elevated plasma AVP only in immature rats. In adult animals, blocking opiate receptors with naloxone enhanced the depletion of OT stores from the pituitary, but did not affect the AVP content. We conclude that in the adult rat, endogenous opioid peptides inhibit OT release during osmotic stimulation, thereby allowing preferential release of AVP.(ABSTRACT TRUNCATED AT 400 WORDS)

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 polymorphism in the cystatin C gene is a novel risk factor for late-onset Alzheimer's disease.

OBJECTIVE: To investigate whether or not a coding polymorphism in the cystatin C gene (CST3) contributes risk for AD. DESIGN: A case-control genetic association study of a Caucasian dataset of 309 clinic- and community-based cases and 134 community-based controls. RESULTS: The authors find a signficant interaction between the GG genotype of CST3 and age/age of onset on risk for AD, such that in the over-80 age group the GG genotype contributes two-fold increased risk for the disease. The authors also see a trend toward interaction between APOE epsilon4-carrying genotype and age/age of onset in this dataset, but in the case of APOE the risk decreases with age. Analysis of only the community-based cases versus controls reveals a significant three-way interaction between APOE, CST3 and age/age of onset. CONCLUSION: The reduced or absent risk for AD conferred by APOE in older populations has been well reported in the literature, prompting the suggestion that additional genetic risk factors confer risk for later-onset AD. In the author's dataset the opposite effects of APOE and CST3 genotype on risk for AD with increasing age suggest that CST3 is one of the risk factors for later-onset AD. Although the functional significance of this coding polymorphism has not yet been reported, several hypotheses can be proposed as to how variation in an amyloidogenic cysteine protease inhibitor may have pathologic consequences for AD.

Vasopressin gene transcripts in mineralocorticoid hypertension: an in situ study.

OBJECTIVE: To test the hypothesis that enhanced expression of the vasopressin gene accompanies the development of deoxycorticosterone acetate (DOCA)-salt hypertension in the rat and to compare the response with those observed during chronic hypernatremia. METHODS: Transcript levels were determined by measurement of vasopressin messenger RNA (mRNA) in the supraoptic nucleus and paraventricular nucleus by in situ hybridization, autoradiography and image analysis. Plasma, urinary and pituitary vasopressin were determined by radioimmunoassay. DESIGN: High-resolution localization and measurement of specific mRNA in the supraoptic and paraventricular nuclei before and during development of DOCA-salt hypertension were compared with corresponding results in both age-matched controls and normal rats that drank hypertonic saline. RESULTS: Vasopressin mRNA levels were increased in the paraventricular nucleus during the established and chronic stages of DOCA-salt hypertension, but were unchanged in the supraoptic nucleus. Urinary excretion of vasopressin was increased in the prehypertensive, established and chronic phases of DOCA-salt hypertension, whereas plasma vasopressin levels were increased only in the chronic phase. Pituitary vasopressin levels were unchanged. In comparative studies, vasopressin mRNA levels in both the supraoptic and paraventricular nuclei and plasma vasopressin were significantly increased in normal rats drinking 2% saline. CONCLUSION: Whereas hypernatremic rats showed markedly elevated vasopressin transcripts in the supraoptic and paraventricular nuclei, DOCA-salt hypertension is associated with increased vasopressin mRNA in the paraventricular but not the supraoptic nucleus. The response in the paraventricular nucleus may explain part of the increased peripheral vasopressin levels and suggests that this nucleus makes a critical contribution to the pathogenesis of DOCA-salt hypertension.