Attributes of response in depressed patients switched to treatment with duloxetine.

BACKGROUND: This study was designed to assess clinical and functional outcomes associated with switching to duloxetine treatment in patients with major depressive disorder (MDD) experiencing emotional and painful physical symptoms in their current episode. METHODS: In this 8-week, multinational, multicentre, single-arm, open-label clinical trial, 242 MDD patients were switched to duloxetine 60 mg/day after selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) treatment. The primary analysis compared mean change from baseline in Brief Pain Inventory-Modified Short Form (BPI-SF) interference score between initial responders [≥ 50% reduction from baseline on the 17-item Hamilton Depression Rating Scale (HAMD(17)) Maier subscale] and initial non-responders after 4 weeks. Initial responders continued with duloxetine 60 mg/day. Initial non-responders received duloxetine 120 mg/day for the remaining 4 weeks. Depression, pain, anxiety and functional outcomes were also compared after 8 weeks. RESULTS: BPI-SF interference decreased from baseline in initial responders (n = 108) and initial non-responders (n = 85) after 4 weeks of duloxetine treatment, with greater reductions in initial responders [BPI-SF mean difference in reduction: 1.01 (95% CI 0.42-1.61); p < 0.001]. Reductions in pain interference favouring initial responders were also apparent after 8 weeks [0.68 (95% CI: 0.03-1.33); p = 0.042]. Depression, pain, anxiety and function improved over 8 weeks across patient groups. CONCLUSIONS: Elements of core mood and pain are important residual symptoms following poor treatment response in MDD. Early improvement in these symptoms after switching to duloxetine indicated an increased chance of functional recovery.

Simulation of paleocortex performs hierarchical clustering.

Simulations were performed of layers I and II of olfactory paleocortex, as connected to its primary input structure, olfactory bulb. Induction of synaptic long-term potentiation by means of repetitive sampling of inputs caused the simulation to organize encodings of learned cues into a hierarchical memory that uncovered statistical relationships in the cue environment, corresponding to the performance of hierarchical clustering by the biological network. Simplification led to characterization of those parts of the network responsible for the mechanism, resulting in a novel, efficient algorithm for hierarchical clustering. The hypothesis is put forward that these corticobulbar networks and circuitry of similar design in other brain regions contain computational elements sufficient to construct perceptual hierarchies for use in recognizing environmental cues.

Association between painful physical symptoms and clinical outcomes in East Asian patients with major depressive disorder: a 3-month prospective observational study.

AIMS: Reports from non-Asian populations indicate that painful physical symptoms (PPS) are associated with poorer clinical and functional outcomes in major depressive disorder (MDD). The purpose of this study is to report comparative changes in disease severity, treatment patterns and quality of life observed in East Asian patients with MDD, with and without PPS, as assessed prospectively over a 3-month observation period. METHODS: This observational study enrolled 909 patients with MDD in psychiatric care settings in China, Hong Kong, Korea, Malaysia, Singapore and Taiwan. Patients were classified as PPS positive (PPS+) or negative (PPS-) based on mean modified Somatic Symptom Inventory scores of >or= 2 or < 2 respectively. The Clinical Global Impression of Severity (CGI-S) and 17-item Hamilton Depression Rating Scale (HAMD(17)) determined depression severity; a visual analogue scale (VAS) determined pain severity; and the EuroQoL (EQ-5D) assessed well-being after 3 months observation. RESULTS: Of the 909 enrollees, 355/471 (75.4%) of PPS+ patients and 363/438 (82.9%) of PPS- patients completed the study (p = 0.006). PPS+ patients improved less than PPS- patients on depression, pain and quality of life measures during the study (HAMD(17) p < 0.001, CGI-S p < 0.001, VAS p = 0.008 and EQ-5D p = 0.004). Fewer PPS+ patients (46.5%) achieved remission compared with PPS- patients (69.4%, p < 0.001). CONCLUSION: As the presence of PPS is associated with poorer outcomes in East Asian MDD patients, clinical management should aim to address both the mental and PPS associated with MDD.

Higher olfactory processes: perceptual learning and memory.

The past year has seen several important findings emerge from studies of higher olfactory processes. The identification of synaptic long-term potentiation in the olfactory cortex, induced via repetitive burst stimulation at the theta rhythm, and physiological activity patterns associated with learning, some of which mimic long-term potentiation induction patterns, have suggested relationships between rhythmic activity, behavioral learning and synaptic plasticity. In addition, the construction of computational models of the olfactory bulb and cortex have generated testable behavioral and physiological predictions which have been supported by experimental evidence.

Injectable vaccines for preventing pneumococcal infection in patients with chronic obstructive pulmonary disease.

BACKGROUND: As chronic obstructive pulmonary disease (COPD) progresses, exacerbations can occur with increasing frequency. One goal of therapy in COPD is to try and prevent these exacerbations, thereby reducing disease morbidity and associated healthcare costs. Pneumococcal vaccinations are considered to be one strategy for reducing the risk of infective exacerbations. OBJECTIVES: To determine the safety and efficacy of pneumococcal vaccination in COPD. The primary outcome assessed was acute exacerbations. Secondary outcomes of interest included episodes of pneumonia, hospital admissions, adverse events related to treatment, disability, change in lung function, mortality, and cost effectiveness. SEARCH STRATEGY: We searched the Cochrane Airways Group COPD trials register using pre-specified terms. We also conducted additional handsearches of conference abstracts. The last round of searches were performed in April 2006. SELECTION CRITERIA: Only randomised controlled trials assessing the effects of injectable pneumococcal vaccine in people with COPD were included. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and three review authors independently assessed trial quality. MAIN RESULTS: Although 10 studies cited in 11 publications were identified that met the inclusion criteria for this review, only four of these provided data on participants with COPD. The studies which did provide data for this review consisted of two trials using a 14-valent vaccine, and two using a 23-valent injectable vaccine. Data for the primary outcome, acute exacerbation of COPD, was available from only one of the four studies. The odds ratio of 1.43 (95% confidence interval (CI) 0.31 to 6.69) between interventions was not statistically significant. Of the secondary outcomes for which data were available and could be extracted, none reached statistical significance. Three studies provided dichotomous data for persons who developed pneumonia (OR 0.89, 95% CI 0.58 to 1.37, n = 748). Rates of hospital admissions and emergency department visits came from a single study. There was no significant reduction in the odds of all-cause mortality 1 to 48 months post-vaccination (Peto odds ratio 0.94, 95% CI 0.67 to 1.33, n = 888), or for death from cardiorespiratory causes (OR 1.07, 95% CI 0.69 to 1.66). AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials that injectable pneumococcal vaccination in persons with COPD has a significant impact on morbidity or mortality. Further large randomised controlled trials would be needed to ascertain if the small benefits suggested by individual studies are real.

Origins and distribution of cholinergically induced beta rhythms in hippocampal slices.

Regional variations and substrates of high-frequency rhythmic activity induced by cholinergic stimulation were studied in hippocampal slices with 64-electrode recording arrays. (1) Carbachol triggered beta waves (17.6 +/- 5.7 Hz) in pyramidal regions of 75% of the slices. (2) The waves had phase shifts across the cell body layers and were substantially larger in the apical dendrites than in cell body layers or basal dendrites. (3) Continuous, two-dimensional current source density analyses indicated apical sinks associated with basal sources, lasting approximately 10 msec, followed by apical sources and basal sinks, lasting approximately 20 msec, in a repeating pattern with a period in the range of 15-25 Hz. (4) Carbachol-induced beta waves in the hippocampus were accompanied by 40 Hz (gamma) oscillations in deep layers of the entorhinal cortex. (5) Cholinergically elicited beta and gamma rhythms were eliminated by antagonists of either AMPA or GABA receptors. Benzodiazepines markedly enhanced beta activity and sometimes introduced a distinct gamma frequency peak. (6) Twenty Hertz activity after orthodromic activation of field CA3 was distributed in the same manner as carbachol-induced beta waves and was generated by a current source in the apical dendrites of CA3. This source was eliminated by high concentrations of GABA(A) receptor blockers. It is concluded that cholinergically driven beta rhythms arise independently in hippocampal subfields from oscillatory circuits involving (1) bursts of pyramidal cell discharges, (2) activation of a subset of feedback interneurons that project apically, and (3) production of a GABA(A)-mediated hyperpolarization in the outer portions of the apical dendrites of pyramidal neurons.

Stimulus- and cell-type-specific regulation of CCAAT-enhancer binding protein isoforms in glomerular mesangial cells by lipopolysaccharide and cytokines.

Binding sites for the CCAAT-enhancer binding protein (C/EBP) family are present in the promoter regions of several genes that are known to be expressed by mesangial cells (MC) during the pathogenesis of glomerular inflammatory diseases. The precise regulation of the C/EBP family by agents that are known to activate MC is, however, poorly understood. We report here the action of interleukin-1 (IL)-1 and, for the first time, lipopolysaccharide (LPS), platelet-derived growth factor (PDGF), IL-6, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) on the C/EBP expression profile and functional DNA binding activity in primary rat MC. Both cell-type- and stimulus-specific regulation of C/EBP mRNA expression and DNA binding activity were identified, with C/EBPalpha being induced by LPS, C/EBPbeta by LPS, IL-1, TNF-alpha and C/EBPdelta by LPS, IL-1, IFN-gamma, TNF-alpha and PDGF. Such differential regulation, particularly that of C/EBPbeta, may be responsible for the mediator-specific differences in the expression of C/EBP-regulated genes in MC. Additionally, the involvement of potential post-transcriptional mechanisms in the regulation of C/EBPdelta were identified. These studies provide novel insights into the stimulus-specific regulation of gene expression during renal diseases.

Gene, stimulus and cell-type specific regulation of activator protein-1 in mesangial cells by lipopolysaccharide and cytokines.

Activator protein-1 (AP-1) plays an important role in the regulation of gene expression in mesangial cells (MC) during the pathogenesis of glomerular inflammatory disease. The precise regulation of the AP-1 family by agents that are known to activate MC is, however, poorly understood. The action of platelet-derived growth factor (PDGF) and, for the first time, lipopolysaccharide (LPS), interleukin-6 (IL-6), interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) on AP-1 gene expression in MC was therefore studied. Whilst the expression of JunD was not affected by any of the mediators, the mRNA levels of c-fos and JunB were induced by LPS, IL-6, IFN-gamma, PDGF and TNF-alpha, and that of c-jun by LPS, IFN-gamma, PDGF and TNF-alpha. Electrophoretic mobility shift assays showed a time-dependent increase in AP-1 DNA binding activity with JunB representing the major mediator-inducible member involved in DNA-protein interactions. However, stimulus-specific changes in the kinetics and magnitude of AP-1 mRNA expression and DNA binding activity were identified and, additionally, the results showed the potential existence of cell-type-specific mechanisms in the regulation of the AP-1 family. These studies provide novel insights into the mediator-specific modulation of AP-1-regulated gene expression and the activation of MC in renal diseases.

A distinct member of the aspartic proteinase gene family from the human malaria parasite Plasmodium falciparum.

A gene (hap) transcribed during the intra-erythrocytic life cycle stages of the human malaria parasite Plasmodium falciparum was cloned and sequenced. It was found to encode a protein belonging to the aspartic proteinase family but which carried replacements of catalytically crucial residues in the hallmark sequences contributing to the active site of this type of proteinase. Consideration is given as to whether this protein is the first known parasite equivalent of the pregnancy-associated glycoproteins that have been documented in ungulate mammals. Alternatively, it may be operative as a new type of proteinase with a distinct catalytic mechanism. In this event, since no counterpart is known to exist in humans, it affords an attractive potential target against which to develop new anti-malarial drugs.

Information processing and developmental assessments in 3-month-old infants exposed prenatally to cocaine.

OBJECTIVE: To determine the effect of prenatal cocaine exposure on 3-month infant information processing and developmental assessments. METHODS: One hundred and eight infants, 61 cocaine-exposed and 47 controls, participated at 3 months of age in an infant-control habituation and novelty responsiveness procedure and in a developmental assessment using the Bayley Scales of Infant Development both administered by experimenters blind to the drug exposure status of the infant. RESULTS: Compared to the non-drug-exposed group, infants exposed prenatally to cocaine were significantly more likely to fail to start the habituation procedure and, for those who did, significantly more likely to react with irritability early in the procedure. The majority of infants in both groups reached the habituation criterion, and among those who did there were no significant differences between cocaine and non-cocaine-exposed infants in habituation or in recovery to a novel stimulus. Infants who were cocaine-exposed showed comparatively depressed performance on the motor (Psychomotor Developmental Index) but not the mental (Mental Developmental Index (MDI)) scales of the Bayley. These results obtained for habituation and Bayley MDI controlling for both perinatal and sociodemographic factors. CONCLUSIONS: Differences in reactivity to novelty but not in information processing between cocaine-exposed and non-cocaine-exposed infants suggest that the effects of prenatal cocaine exposure may be on arousal and attention regulation rather than early cognitive processes.

Neurobehavioral profiles of neonates exposed to cocaine prenatally.

This study examined the effects of maternal cocaine use on performance on the Neonatal Behavioral Assessment Scale (NBAS). Cocaine-exposed newborns (n = 56) were compared with a non-cocaine-exposed group (n = 30) born to mothers with similar sociodemographic characteristics. Cocaine-exposed newborns showed significant reduction in birth weight but did not experience greater obstetric or postnatal complications. On neurobehavioral assessments using the NBAS, cocaine-exposed newborns showed significantly depressed performance on the habituation cluster but not on other NBAS clusters when differences in birth weight were controlled. In a sample of 30 cocaine-exposed newborns matched on birth weight, gestational age, and race to the 30 non-cocaine-exposed newborns, cocaine-exposed newborns continued to show depressed habituation performance. The significance of a selective effect of cocaine exposure on early habituation performance is discussed in terms of the implications for attentional regulation in the first year of life.

A profile of the behavioral changes produced by facilitation of AMPA-type glutamate receptors.

A newly developed group of benzoylpiperidine drugs that enhance AMPA-receptor-gated currents ("ampakines") has been shown to improve memory encoding in rats across a variety of experimental paradigms. The present experiments were intended to i) provide a partial profile of the behavioral changes produced by ampakines, ii) test if two ampakines (BDP-12 and BDP-20) that differ significantly in their effects on AMPA receptor kinetics produce similar behavioral profiles, and iii) determine if physiological potency is reflected in behavioral potency. BDP-20 reduced two measures of exploratory activity in aged rats but increased speed of performance in a radial maze; the drug also caused substantially improved retention of spatial information. These results are similar to those obtained with BDP-12, an analog that differs from BDP-20 in its effects on ligand binding to the AMPA receptor and on the physiological responses of the receptors to glutamate. BDP-20 was approximately ten-fold more potent in behavioral effects than BDP-12, which agrees with the relative potencies of the two drugs as assessed with excised patches and excitatory synaptic responses. These findings indicate that ampakines, though differing in their effects on AMPA-receptor-mediated responses, have similar effects at the behavioral level.

Regulation of arousal and attention in preschool children exposed to cocaine prenatally.

Four lines of evidence suggest a plausible link between prenatal cocaine exposure (CE) and specific effects on the mechanisms subserving arousal and attention regulation in infants and preschool-aged children. These are (1) the association of prenatal CE with alterations in monoaminergic system ontogeny; (2) neurobehavioral effects of prenatal CE in animals consistent with an enduring increased level of activity in response to novelty and inhibited exploration and altered responses to stress, suggesting overarousal in the face of novel/stressful situations and disrupted attention and exploration; (3) altered norepinephrine system function in cocaine-exposed human infants; and (4) neurobehavioral findings in infants and preschool-aged children suggestive of disrupted arousal regulation in the face of novelty, increased distractibility, and consequent impaired attention to novel, structured tasks. This paper summarizes findings on response to novel challenges from a cohort of prenatally cocaine-exposed infants and preschool-aged children followed longitudinally since birth. Arousal regulation in the face of novel challenges is operationalized behaviorally as state and emotional reactivity and neurophysiologically as the startle response and heart rate variability. Across different ages and tasks, behavioral and neurophysiological findings suggest that prenatally cocaine-exposed children are more likely to exhibit disrupted arousal regulation. Because the regulation of arousal serves as a gating mechanism to optimize orientation and attention, arousal regulation has important implications for ongoing information processing, learning, and memory. Furthermore, impaired arousal regulation predisposes children to a lower threshold for activation of "stress circuits" and may increase their vulnerability to the developmentally detrimental effects of stressful conditions particularly when such children are also exposed to the chaotic environmental conditions often characterizing substance-abusing families.

Simulated dendritic spines influence reciprocal synaptic strengths and lateral inhibition in the olfactory bulb.

Whereas many theories have been proposed for the function of dendritic spines in axodendritic processing, the influence of spines on reciprocal dendrodendritic processing has received relatively little attention. Mitral cells in the olfactory bulb, for example, synapse on granule cell spines (gemmules) which are in turn presynaptic to reciprocal inhibitory synapses back onto the same mitral cells. The postulate that these synapses respond with synaptic strengths graded by presynaptic depolarization results in a sensitivity of the reciprocal response to the local depolarization in the spine head. A biophysical computer simulation was performed to study this effect and the effect of changing the spine neck diameter and cytoplasmic resistance on the reciprocal and lateral inhibitory responses given graded dendrodendritic synapses. Since spine head local potentials are larger than similar inputs on dendritic shafts, spines facilitate the graded reciprocal response even for low levels of activity. Spine heads also reduce the synaptic current, lowering the contribution to the rest of the granule dendritic tree and thus reducing lateral inhibition. In addition, an increase in the effective spine neck axial resistance further increases the reciprocal synaptic response and decreases the lateral inhibitory response. Short-term, reversible, and long-term methods of implementing this resistance-based dendrodendritic plasticity are discussed as well as the partial dependence of the reciprocal increase/lateral decrease effect on a broad synaptic gradation. Candidate memory operations by the bulb are also discussed, including a possible recognition memory pass/block function.

A novel approach to training pediatrics primary care residents.

From 1984 through 1987, 12 pediatrics residents from the Yale University School of Medicine took part in a three-year program that emphasized four areas in primary care: well-child care, developmental-behavioral pediatrics, chronic illness, and adolescent medicine. Program evaluation included a videotaped interview, an assessment of the residents' skill in the management of patients' behavioral problems, and multiple-choice examinations. The program residents improved their interviewing skills more than did the comparison residents, particularly in the process and psychosocial content areas, and also did better in the management of patients' behavioral problems. There was no difference in factual knowledge of behavioral and developmental pediatrics and adolescent medicine. While traditional residency training in primary care may provide the resident with comparable cognitive knowledge, such training may not always improve the resident's ability to apply the knowledge in the primary care setting.

Schedule-induced behavior in children as a function of interreinforcement interval length.

Two four year old twin female children were tested on fixed interval (FI) 30-, 60-, 90- and 120-sec food schedules with M&M candy reinforcers. Both subjects displayed increased drinking, gross and fine body movement, and grooming on the FI schedules as compared to Baseline conditions. Bitonic functions were noted for drinking, fine body movements and grooming for Subject J and for drinking and fine movement for Subject K, similar to those which have previously been reported in animal studies. These preliminary results demonstrated that certain behaviors may be induced by intermittent food reinforcement schedules in humans and are excessive when appropriate baselines are used for comparison. Also, these data further strengthen the species generality of schedule-induced behaviors to human subjects.

The effects of retroperitoneal carbon dioxide insufflation on hemodynamics and arterial carbon dioxide.

BACKGROUND: Laparoscopic techniques are being increasingly used for retroperitoneal surgery. However, hemodynamic and ventilatory efforts of retroperitoneal carbon dioxide (CO2) insufflation have not been studied. We hypothesized that differences in absorptive surface, anatomy, and compartment compliance could result in different hemodynamic and ventilatory effects between retroperitoneal and intraperitoneal insufflation. METHODS: Pigs (n = 7) were anesthetized and stabilized. The peritoneal cavity was incrementally insufflated with CO2 to a maximum pressure of 25 cm H2O and the gas released. Hemodynamics and arterial blood gas values were recorded initially, at each level of insufflation, and following the pneumoperitoneum release until baseline values were reached. This insufflation protocol was repeated in the retroperitoneum. RESULTS: Mean arterial pressure (111 mm Hg, 95% confidence interval 99 to 156) and cardiac output (3.7 L/min, 2.8 to 5.2) did not change with increasing insufflation pressure of either intraperitoneum or retroperitoneum. PaCO2 was directly related to insufflation pressure in both spaces, increasing from 41.2 mm Hg (37.3 to 43.4) at baseline to 57.7 mm Hg (47.6 to 82.1) at insufflation pressure of 25 cm H2O. After release of the insufflation gas, time to return to baseline PaCO2 was slightly less from the retroperitoneal space (73 minutes, 45 to 105) than the intraperitoneal (107 minutes, 35 to 175). CONCLUSIONS: The effects of CO2 insufflation on hemodynamics and PaCO2 are the same in the retroperitoneal and intraperitoneal spaces.

Psychological effects of a drug that facilitates brain AMPA receptors.

The effects of 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516), a centrally active compound that facilitates AMPA receptor-mediated synaptic responses, were tested in human subjects. Separate tests of delayed recall were given prior to and nearly 3 h after administration of placebo (n = 12) or drug (n = 36). Control subjects exhibited poorer performance in the second session than in the first while subjects given 600-1200 mg of the drug did not. There were no pre- vs post-treatment differences in immediate recall in either group. The drug did not reliably affect self-assessment scores for any of several psychological variables but did disrupt the normally present correlations for within-subject changes in the variables. These results suggest that AMPA receptor modulators may (1) improve memory under some circumstances and (2) produce psychological effects that are subtle or not related to specific mood states.

Fatal metoprolol overdose.

Metoprolol, a beta 1-adrenergic blocking agent, has been found effective in the treatment of hypertension. A death due to deliberate ingestion of metoprolol is described, including the case history, postmortem toxicologic findings, and identification and quantitation of the drug by high pressure liquid chromatography and gas chromatography/mass spectrometry. Metoprolol levels were found to be 4.7 mg/L in blood, 194 mg/L in urine, 3.3 mg/L in vitreous humor, 3.9 mg/L in pleural fluid, 254 mg/L in bile, 7.1 mg/kg in kidney, and 6.3 mg/kg in liver.

Necrotizing fasciitis in childhood.

Necrotizing fasciitis is a rare entity in the pediatric population. Five cases of this soft tissue infection were treated at the authors' institution between January and December 1993. Three of the children were profoundly neutropenic secondary to chemotherapy. All five were treated with aggressive surgical debridement, frequent dressing changes, broad-spectrum antibiotics, and nutritional support. In addition, the patients with neutropenia received a combination of granulocyte-colony stimulating factor and granulocyte transfusions. One child died of overwhelming sepsis and bone marrow graft failure. The others eventually made a complete recovery. Necrotizing fasciitis may be becoming a more common problem in children. Aggressive chemotherapeutic regimens and more frequent use of bone marrow transplantation could be a factor in this. Early diagnosis and aggressive surgical therapy is critical. However, mortality may be significant, especially in patients with neutropenia. Leukocyte response to the infection may be a prognostic marker. Pseudomonas and enteric gram-negative organisms are seen frequently in immunocompromised children with necrotizing fasciitis. Antimicrobial selection should supply adequate coverage of these organisms.