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Laura F Cavallone,1 Karen Frey,1 Michael C Montana,1 Jeremy Joyal,1 Karen J Regina,1 Karin L Petersen,2 Robert W Gereau IV11Department of Anesthesiology, Washington University in St Louis, School of Medicine, St Louis, MO, USA; 2California Pacific Medical Center Research Institute, San Francisco, CA, USAIntroduction: Heat/capsaicin skin sensitization is a well-characterized human experimental model to induce hyperalgesia and allodynia. Using this model, gabapentin, among other drugs, was shown to significantly reduce cutaneous hyperalgesia compared to placebo. Since the larger thermal probes used in the original studies to produce heat sensitization are now commercially unavailable, we decided to assess whether previous findings could be replicated with a currently available smaller probe (heated area 9 cm2 versus 12.5–15.7 cm2).Study design and methods: After Institutional Review Board approval, 15 adult healthy volunteers participated in two study sessions, scheduled 1 week apart (Part A). In both sessions, subjects were exposed to the heat/capsaicin cutaneous sensitization model. Areas of hypersensitivity to brush stroke and von Frey (VF) filament stimulation were measured at baseline and after rekindling of skin sensitization. Another group of 15 volunteers was exposed to an identical schedule and set of sensitization procedures, but, in each session, received either gabapentin or placebo (Part B).Results: Unlike previous reports, a similar reduction of areas of hyperalgesia was observed in all groups/sessions. Fading of areas of hyperalgesia over time was observed in Part A. In Part B, there was no difference in area reduction after gabapentin compared to placebo.Conclusion: When using smaller thermal probes than originally proposed, modifications of other parameters of sensitization and/or rekindling process may be needed to allow the heat/capsaicin sensitization protocol to be used as initially intended. Standardization and validation of experimental pain models is critical to the advancement of translational pain research.Keywords: experimental pain model, hyperalgesia, peripheral sensitization, central sensitization

Background:Human experimental pain models leading to development of secondary hyperalgesia are used to estimate efficacy of analgesics and antihyperalgesics. The ability to develop an area of secondary hyperalgesia varies substantially between subjects, bu

As part of a comprehensive study of the natural history of herpes zoster (HZ), 57 of 94 subjects in a cohort at elevated risk for post-herpetic neuralgia (PHN) consented to collection of 3-mm skin punch biopsies from affected, mirror-image, and distant control skin at baseline and followup visits. As cutaneous innervation is reduced in longstanding severe PHN, we tested the hypothesis that development of PHN is correlated with severity of initial neural injury and/or a failure of neural recovery. Quantitative analysis using single-label PGP9.5 immunofluorescence microscopy showed epidermal profiles were reduced in zoster skin by approximately 40% at study entry compared to control and mirror skin. The density of the subepidermal plexus was approximately 15% lower in zoster skin. Mirror skin was not denervated compared to control skin. Although not significant at all visits, correlations between epidermal nerve fiber density in HZ skin and thermal sensation, allodynia, capsaicin response, and average daily pain all associated more severe abnormalities with lower epidermal innervation. There was limited evidence that the initial neural injury was more severe in the 15 eventual PHN subjects. Overall, pain and pain-related disability resolved the fastest. Sensory abnormalities and symptom aggravation by focal capsaicin application showed partial and selective recovery over 6months. In contrast, cutaneous innervation showed no recovery at all by 6months, conclusive evidence that resolution of pain and allodynia does not require cutaneous reinnervation. A much longer period of observation is needed to determine if zoster-affected skin is ever reinnervated. [ABSTRACT FROM AUTHOR]

The natural history of sensory function in the first 6months after herpes zoster (HZ) was determined in a cohort of 94 subjects at elevated risk for developing post-herpetic neuralgia (PHN). All four visits included ratings of pain and sensory symptoms, mapping areas of altered sensation and allodynia, and quantitative thermal and mechanical sensory testing. The last three visits included the capsaicin response test. Sensory thresholds in distant control skin were stable. Mirror-image skin was persistently hyperesthetic to warming and mechanical stimuli and hyperalgesic to heat compared to distant control skin. HZ skin showed deficits in all thermal modalities. Sensory recovery was limited and selective. Allodynia area and severity, hyperalgesia to von Frey hair, and cold detection threshold improved, but deficits to warmth and heat pain did not. Capsaicin on HZ skin significantly aggravated pain and allodynia in the majority of subjects at 6-8weeks after HZ onset. At study entry, eventual PHN subjects had significantly more impairment in detecting warmth and cold, a larger area of altered sensation, a larger area of allodynia, and more severe allodynia. The results support the study hypothesis that severity of initial injury predicts PHN, especially impaired cold sensation in HZ skin. The hypothesis that PHN develops because of a failure to recover normal neural function was not supported. Sensory recovery proceeded at the same rate in eventual pain-free and eventual PHN subjects and is not a requirement for pain resolution. Early interventions that reduce neural injury or enhance recovery should be of benefit. [ABSTRACT FROM AUTHOR]

Women in the sex trade whose economic and social base are urban streets face multiple dangers of predation, isolation, and illness. A Mobile Access Project (MAP) to provide emergency medical help, peer counseling, condoms and clean needles, resource information and referral, and a place of respite and safety was initiated for sex trade workers in Vancouver, British Columbia, Canada. We conducted surveys with 100 women sex workers who accessed MAP services and reviewed MAP logbooks to document use of services. We assessed the impact of MAP through review of data from a concurrent cohort study of injection drug users and a survey of 97 women at a drop-in center in the Downtown Eastside. Over 90% of MAP clients reported that the van made them feel safer on the street. Sixteen percent of surveyed MAP clients recalled a specific incident in which the van's presence protected them from a physical assault and 10% recalled an incident when its presence had prevented a sexual assault. Distribution of needles and condoms has increased steadily since the implementation of MAP. Eighty percent of women surveyed at a drop-in center in the Downtown Eastside had received services from MAP. The peer-led Mobile Access Project has emerged as a viable harm reduction strategy for serving the immediate health and trauma-related needs of women engaged in street-level sex work. [ABSTRACT FROM AUTHOR]

BACKGROUND: We reported previously that the socio-economic status (SES) of individuals predicts variation in brain serotonergic responsivity, as assessed by neuropharmacological challenge in an adult community sample, and that this association is qualified by allelic variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR). Here we examine whether serotonergic responsivity covaries similarly with the SES of communities, as indexed by US Census data in the same study sample. METHOD: Community SES was defined by levels of income, economic disadvantage, housing costs, and educational attainment of census tracts in which 249 locally recruited study participants (54% male) resided. Serotonergic responsivity was assessed as the baseline-adjusted, peak plasma prolactin (Prl) concentration following acute administration of the serotonin-releasing agent, fenfluramine; tissue for DNA extraction and 5-HTTLPR genotyping was available on 131 participants. RESULTS: Subjects residing in census tracts of lower SES showed a blunted Prl response to fenfluramine (diminished serotonergic responsivity) relative to individuals living in more affluent neighborhoods. When adjusted for personal income and education, SES at the community level continued to predict fenfluramine-stimulated Prl responses and did so independently of 5-HTTLPR genotype. CONCLUSIONS: Area-level indices of relative social and economic disadvantage covary with individual differences in brain serotonergic responsivity, and this association is, in part, independent of individually defined SES. These findings may be relevant to reported effects of low community SES on the prevalence of psychiatric disorders or behaviors associated with dysregulation of central serotonergic function, such as depression, impulsive aggression, and suicide. [ABSTRACT FROM AUTHOR]

Abstract Background Parasite heterogeneity and within-host competition are thought to be important factors influencing the dynamics of host-parasite relationships. Yet, while there have been many theoretical investigations of how these factors may act, empirical data is more limited. We investigated the effects of parasite density and heterogeneity on parasite virulence and fitness using four strains of the entomopathogenic fungus, Metarhizium anisopliae var. anisopliae, and its leaf-cutting ant host Acromyrmex echinatior as the model system. Results The relationship between parasite density and infection was sigmoidal, with there being an invasion threshold for an infection to occur (an Allee effect). Although spore production was positively density-dependent, parasite fitness decreased with increasing parasite density, indicating within-host scramble competition. The dynamics differed little between the four strains tested. In mixed infections of three strains the infection-growth dynamics were unaffected by parasite heterogeneity. Conclusions The strength of within-host competition makes dispersal the best strategy for the parasite. Parasite heterogeneity may not have effected virulence or the infection dynamics either because the most virulent strain outcompeted the others, or because the interaction involved scramble competition that was impervious to parasite heterogeneity. The dynamics observed may be common for virulent parasites, such as Metarhizium, that produce aggregated transmission stages. Such parasites make useful models for investigating infection dynamics and the impact of parasite competition.

Background: Enuresis, also referred to as nocturnal enuresis, is characterised by discrete episodes of urinary incontinence during sleep in children aged ≥5 years in the absence of congenital or acquired neurological disorders. This guideline is an update of the 2017 version., Recommendations: The guideline provides recommendations and suggestions for various therapeutic options for enuresis available in South Africa (SA). These options include behavioural modification, urotherapy, pharmaceutical therapy, alarm therapy, alternative therapies, neuromodulation, psychological support and biofeedback. Additionally, it explores the role of a voiding diary, additional investigations and mobile phone applications (apps) in treating enuresis. The document also outlines standardised definitions for clarity., Conclusion: This is an updated guideline endorsed by relevant key opinion leaders in SA, with additional input from international experts in the field.

Mental health professionals are tasked with making difficult clinical decisions in treatment settings. In the forensic system, decision making regarding staff supervised community outings (SSCOs) provides a significant challenge due to the need to balance patient liberties, mental health recovery, and public safety. This study explored the characteristics and rehabilitative nature of SSCOs, characteristics of patients attending SSCOs, and any adverse events that occurred during the outings. Employing a cross-sectional design, 110 patients who participated in SSCOs over a one-year period from a Canadian Forensic Psychiatric Hospital were included. Clinical records were reviewed to capture patient and SSCO variables. Descriptive analyses were used to calculate participant, risk, SSCO, and adverse event characteristics. Qualitative analysis was used to explore the purpose of SSCOs and rehabilitative progress that occurred during the outings. Patients attending SSCOs were comprised of long-stay patients with over half having committed a violent index offence. Almost 75% of patients had a moderate/high risk for violence and 50% of the patients had a moderate/high risk of absconding. During the study period, 463 SSCOs were completed. Most outings focused on developing skills for daily living and staff comments suggested many patients developed skills in these areas. Despite considerable risk profiles and public concern regarding forensic patients having community access, there was a single occurrence of unauthorized leave and no instances of violence or substance use. This research can disrupt stigma, demonstrating that SSCOs support a specific rehabilitative intent, promote community reintegration, and maintain public safety., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Farrell, Petersen, Hanzouli and Nicholls.)

Background: Most medical educational programs emphasize clinical observation or clinical skill acquisition, fewer focus upon research. The Danish-American Research Exchange (DARE) program, sponsored by the Lundbeck Foundation, is unique in that the medical student initiates biomedical research collaboration between Danish and US medical institutions. To achieve this, Danish medical students (DARE students) conduct binational mentored research projects while based in the United States for 10 months. In addition, DARE students are introduced to interdisciplinary thinking about how to develop ultra-low-cost healthcare interventions through the '$10 Challenge'., Methods: We conducted a cross-sectional study of DARE alumni over five consecutive years (2015-2020, n = 24). Research metrics included completion of a research project, primary authorship, and co-authorship of publications. The number of publications, prior to and after the DARE program were enumerated. For the first four cohorts, graduation from medical school and acceptance or intention to enter a joint MD-PhD program also were assessed. Two focus groups were conducted using constructivist grounded theory. Discussions were transcribed, redacted, and coded using Dedoose software., Results: DARE Medical students were 31.2 years (range 24-35), the majority were women (67%;16/24). The majority (17/24;71%) completed a first author publication in a peer-reviewed journal with a median of 3.9 per DARE alumnus. DARE alumnus reported increased proficiency in biostatistics, epidemiology, coding and public speaking as well as stronger research qualities in creativity, critical thinking, comfort in approaching scientist in both the US and Denmark (p < 0.001 for all). Qualitative key themes included: increased confidence, a deepening of research inquiry and linkage to a research network., Conclusions: Preliminarily, this study suggests that medical students can initiate binational collaboration in medicine. Benefits include research productivity, intention to pursue academic medical careers, as well as positive impacts on motivation. This medical student-initiated research model lays the groundwork for using this model across other country pairs to promote binational collaboration., (© 2023. The Author(s).)

Neonatal AKI (NAKI) remains a challenge in low- and middle-income countries (LMICs). In this perspective, we address issues of diagnosis and risk factors particular to less well-resourced regions. The conservative management pre-kidney replacement therapy (pre-KRT) is prioritized and challenges of KRT are described with improvised dialysis techniques also included. Special emphasis is placed on ethical and palliation principles., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 McCulloch, Adabayeri, Goka, Khumalo, Lala, Leahy, Ngubane-Mwandla, Nourse, Nyann, Petersen and Levy.)

Background: Globally, very few childhood deaths have been attributed to coronavirus disease 2019 (COVID-19). We evaluated clinical, microbiologic and postmortem histopathologic findings in childhood deaths in whom severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified antemortem or postmortem., Methods: Surveillance of childhood deaths was ongoing during the initial COVID-19 outbreak in South Africa from April 14, 2020, to August 31, 2020. All children hospitalized during this time had a SARS-CoV-2 test done as part of standard of care. Postmortem sampling included minimally invasive tissue sampling (MITS) of lung, liver and heart tissue; blood and lung samples for bacterial culture and molecular detection of viruses (including SARS-CoV-2) and bacteria. The cause of death attribution was undertaken by a multidisciplinary team and reported using World Health Organization framework for cause of death attribution., Results: SARS-CoV-2 was identified on antemortem and/or postmortem sampling in 11.7% (20/171) of deceased children, including 13.2% (12/91) in whom MITS was done. Eighteen (90%) of 20 deaths with SARS-CoV-2 infection were <12 months age. COVID-19 was attributed in the causal pathway to death in 91.7% (11/12) and 87.5% (7/8) cases with and without MITS, respectively. Lung histopathologic features in COVID-19-related deaths included diffuse alveolar damage (n = 6, 54.5%), type 2 pneumocyte proliferation (n = 6, 54.5%) and hyaline membrane formation (n = 5, 36.4%). Culture-confirmed invasive bacterial disease was evident in 54.5% (6/11) of COVID-19 attributed deaths investigated with MITS., Conclusions: COVID-19 was in the causal pathway of 10.5% (18/171) of all childhood deaths under surveillance. The postmortem histopathologic features in fatal COVID-19 cases in children were consistent with reports on COVID-19 deaths in adults; although there was a high prevalence of invasive bacterial disease in the children., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: We hypothesized that the prevalence of vertebral fractures would be low and that bone mineral density (BMD) would be less severely affected in a black South African (SA) population treated with glucocorticoids (GCs) than that reported in mainly white populations., Methods: All children aged 5-17.9 years with chronic non-malignant illnesses who were on GCs (intravenous or oral) for greater than 3 months duration were evaluated. DXA scans were performed using a Hologic Discovery machine (Software version Apex 4.0.2) and the Hologic paediatric reference database. Whole body less head (WBLH) and lumbar spine (LS) bone mineral content (BMC) and density (BMD) Z-scores unadjusted and adjusted for height were calculated using the Zemel equation calculator., Results: Seventy-two patients (49% with renal, 24% with rheumatic, 14% with neurological, 11% with hepatic and 3% with respiratory conditions; mean age 11.6 ± 3.3 years, 57% boys, 92% SA black) were enrolled. The mean duration of GC treatment was 34.1 (±25.1) months. Mean WBLH and LS height adjusted BMD Z-scores were -1.2 ± 1.5 and -0.9 ± 1.0 respectively. Eleven percent of patients had a LS height adjusted BMD Z-score ≤ -2. The prevalence of vertebral fractures on lateral vertebral fracture assessment (VFA) was 15% (11 of 72 patients)., Conclusion: The prevalence of vertebral fractures (15%) in predominantly black children on GCs with chronic non-malignant illnesses is similar to that reported from North America suggesting that routine yearly DXA scans including VFA are warranted in this highly at-risk population., Competing Interests: Kebashni Thandrayen, Udai Kala, Nilesh Lala, Grace Okudo, Kiran Parbhoo, Fatima Moosa, Charl Verwey, Marc Hauptfleisch, Christina Hajinicolaou, Priya Ambaram, Bhadrish Mistry, Karen Petersen and John Pettifor declare that they have no conflict of interest., (© 2021 The Author(s).)

Background: The role of the voiding cystourethrogram (VCUG) in the follow-up of children with posterior urethral valves (PUVs) post-ablation has been considered a standard practice. The urethral ratio and gradient of change have proven to be useful., Objectives: We aimed to review the role of the 'ideal' ratio on predicting residual PUV post-ablation., Methods: A systematic review of the PubMed, SCOPUS and Web of Science databases was performed (April 2019). The search terms included 'Urethral Ratio and Posterior urethral valve ablation'. All cited reference lists were further evaluated for additional inclusive studies., Results: Eleven studies were identified, of which nine were relevant to the topic. Case reports, comments and adult and animal studies were excluded, leaving four studies for critical review. In total, 338 patients were assessed. The control group consisted of 167 age-matched, male children. Study regions included India and Australia. The ages ranged from 15 days to 3.4 years. Ablation methods included the use of a resectoscope with cutting diathermy, cold knife or Bugbee electrode. The mean urethral ratios in the control group ranged from 1.04 to 1.73. The suggested predictive urethral cut-off ratios recommended include 2.2 ( p = 0.001), 2.5-3 and 3.5., Conclusion: Although the precise cut-off ratio could not be clearly defined in this review, a urethral ratio less than a range of 2.2-3.5 has proven to be a beneficial predictor of ablation success and should thus be incorporated into standard VCUG reporting templates in the follow-up of PUVs in male children in resource-limited settings., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article., (© 2020. The Authors.)

Background: Current estimates for causes of childhood deaths are mainly premised on modeling of vital registration and limited verbal autopsy data and generally only characterize the underlying cause of death (CoD). We investigated the potential of minimally invasive tissue sampling (MITS) for ascertaining the underlying and immediate CoD in children 1 month to 14 years of age., Methods: MITS included postmortem tissue biopsies of brain, liver, and lung for histopathology examination; microbial culture of blood, cerebrospinal fluid (CSF), liver, and lung samples; and molecular microbial testing on blood, CSF, lung, and rectal swabs. Each case was individually adjudicated for underlying, antecedent, and immediate CoD by an international multidisciplinary team of medical experts and coded using the International Classification of Diseases, Tenth Revision (ICD-10)., Results: An underlying CoD was determined for 99% of 127 cases, leading causes being congenital malformations (18.9%), complications of prematurity (14.2%), human immunodeficiency virus/AIDS (12.6%), diarrheal disease (8.7%), acute respiratory infections (7.9%), injuries (7.9%), and malignancies (7.1%). The main immediate CoD was pneumonia, sepsis, and diarrhea in 33.9%, 19.7%, and 10.2% of cases, respectively. Infection-related deaths were either an underlying or immediate CoD in 78.0% of cases. Community-acquired pneumonia deaths (n = 32) were attributed to respiratory syncytial virus (21.9%), Pneumocystis jirovecii (18.8%), cytomegalovirus (15.6%), Klebsiella pneumoniae (15.6%), and Streptococcus pneumoniae (12.5%). Seventy-one percent of 24 sepsis deaths were hospital-acquired, mainly due to Acinetobacter baumannii (47.1%) and K. pneumoniae (35.3%). Sixty-two percent of cases were malnourished., Conclusions: MITS, coupled with antemortem clinical information, provides detailed insight into causes of childhood deaths that could be informative for prioritization of strategies aimed at reducing under-5 mortality., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Seawater reverse osmosis (SWRO) is becoming an increasingly important source of potable water in arid and semi-arid regions worldwide. Discharge of brine-effluent from desalination facilities has been shown to significantly impact coastal marine ecosystems ranging from seagrass meadows to microbial communities. In this study, we examined the impacts of increased salinity (10% above ambient) and presence of antiscalants (0.2 mg L -1 , polyphosphonate-based) on three reef-building coral species; Stylophora pistillata, Acropora tenuis and Pocillopora verrucosa, from the Gulf of Aqaba (northern Red-Sea). Our results indicate that the corals, as well as associated bacteria and algae, were significantly impaired by the elevated salinity and antiscalants, leading to partial bleaching. Specifically, the abundance of bacteria and symbiotic algae as well as calcification rates were typically lower (20-85%, 50-90% and 40-50%, respectively) following incubations with both amendments. However, the impact of desalination brine was often species-specific. Thus, we propose that the ecotoxicological criteria used for hard corals should be determined based on the sensitivity of key species in the community dominating the area affected by desalination discharge., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: After excision of a primary malignant melanoma (MM), treatment of stage IB or higher MM consists of sentinel lymph node biopsy (SLNB). If malignant cells are identified, a complete lymph node dissection (CLND) can be performed., Objective: To determine the natural history of pain and sensory changes after MM surgery., Methods: We prospectively followed 39 patients (29 SLNB-only, 2 CLND-only, and 8 CLND preceded by SLNB) from before inguinal or axillary surgery through 6 months after surgery on measures of pain intensity, sensory symptoms, allodynia, and questionnaires of anxiety, depression, and catastrophizing., Results: No patient had pain preoperatively. Ten days after surgery, 35% had surgical site pain after SLNB-only compared with 90% after CLND ( P < 0.003); clinically meaningful pain (Visual Analogue Scale ≥ 30 mm/100 mm) was reported by 3% of patients after SLNB-only compared with 40% after CLND ( P < 0.001). At 6 months, all SLNB-only patients were pain-free. By contrast, 4 of 7 in the SLNB + CLND group still had pain ( P < 0.002). At 6 months, symptoms of altered sensation or numbness were reported by 32% and 42% of SLNB-only patients, and by 67% and 67% of patients undergoing CLND surgery (both P > 0.05)., Conclusion: Acute pain is more common after CLND surgery. Undergoing SLNB followed by more invasive CLND surgery may increase the likelihood of pain at 6 months. Persistent sensory symptoms typical of those associated with nerve injury are more common after CLND. Surgery for MM is a good model for studying the natural history of postsurgical pain and sensory changes., Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Background: Posterior urethral valves (PUV) are a common cause of congenital obstructive nephropathy. The outcome of patients with PUV at Chris Hani Baragwanath Academic Hospital in Johannesburg, South Africa, has not been documented previously., Objectives: To describe the outcome of patients diagnosed with PUV over a 29-year period from January 1985 to December 2013, and to analyse risk factors for chronic kidney disease., Methods: This was a retrospective record review of boys aged &lt;14 years diagnosed with PUV at Chris Hani Baragwanath Academic Hospital. PUV was diagnosed by a voiding cystourethrogram (VCUG) and/or at cystoscopy. Valves were resected primarily or after vesicostomy. The glomerular filtration rate was calculated using the Schwartz formula, and stratified as normal or decreased for age at presentation and at the final visit., Results: Records of 181 patients were analysed. The diagnosis was made during the first year of life in 139 patients (76.8%). Clinical presentation included urinary tract infection (UTI) in 109 patients (60.2%), palpable bladder in 98 (54.1%), palpable kidney in 85 (46.9%), and poor urinary stream in 78 (43.1%). An ultrasound scan was reported normal in 10.9%. Vesicostomy was performed in 80 patients (44.2%) and primary valve ablation in 101 (55.8%), with vesicostomy being more prevalent in the pre-2000 era. The median duration of follow-up was 21 months (interquartile range 5 - 79) and renal outcome at last visit was normal in 117 patients (64.6%). The presence of bladder diverticula was associated with a favourable renal outcome. Thirteen patients (7.2%) died, and 102 (56.3%) defaulted from follow-up., Conclusions: PUV frequently presents with UTI and palpable bladder and/or kidneys. Findings on ultrasound were normal in 10.9% of our patients with PUV. A VCUG is indicated in the presence of palpable kidneys or bladder even if the ultrasound scan is normal. Bladder diverticula as a pressure-release mechanism are renoprotective. Vesicostomy or primary valve ablation did not affect final renal outcome. Chronic kidney disease occurred in 34.8% of patients after surgical correction. Adherence to scheduled appointments is problematic in this population. Long-term follow-up is mandatory.

Background: Posterior reversible encephalopathy syndrome (PRES) is a reversible neurological condition presenting with seizures and visual disturbances and diagnosed on magnetic resonance imaging (MRI). Little is understood about its pathogenesis, particularly in children, but it is thought to be related to hypertension., Objectives: To review the presentation, diagnosis and outcome of PRES in paediatric renal patients at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa, between 1 January 2000 and 31 January 2017 and compare these with published case reports to date., Methods: This was a retrospective analysis of five new cases and a review of the existing literature., Results: The five reported patients were all hypertensive at the time of diagnosis and presented with seizures. Most (91%) of the 64 reviewed patients were also hypertensive at initial presentation. All five of the reported and 91% of the reviewed patients presented with seizures. The most common pattern of change on MRI occurred in the parietal and occipital regions. Complete neurological recovery occurred in four of the five reported and 87.5% of the reviewed patients., Conclusion: All patients presented clinically with hypertensive crises and radiological evidence of PRES. Seizures were the most common presenting symptom. The prognosis for paediatric patients with PRES is favourable, so it is important to confirm the diagnosis in low-resource settings where intensive care is limited.

Aims/hypothesis: The aim of this randomised, crossover trial was to compare cognitive functioning and associated brain activation patterns during hypoglycaemia (plasma glucose [PG] just below 3.1 mmol/l) and euglycaemia in individuals with type 1 diabetes mellitus., Methods: In this patient-blinded, crossover study, 26 participants with type 1 diabetes mellitus attended two randomised experimental visits: one hypoglycaemic clamp (PG 2.8 ± 0.2 mmol/l, approximate duration 55 min) and one euglycaemic clamp (PG 5.5 mmol/l ± 10%). PG levels were maintained by hyperinsulinaemic glucose clamping. Cognitive functioning was assessed during hypoglycaemia and euglycaemia conditions using a modified version of the digit symbol substitution test (mDSST) and control DSST (cDSST). Simultaneously, regional cerebral blood flow (rCBF) was measured in pre-specified brain regions by six H 2 15 O-positron emission tomographies (PET) per session., Results: Working memory was impaired during hypoglycaemia as indicated by a statistically significantly lower mDSST score (estimated treatment difference [ETD] -0.63 [95% CI -1.13, -0.14], p = 0.014) and a statistically significantly longer response time (ETD 2.86 s [7%] [95% CI 0.67, 5.05], p = 0.013) compared with euglycaemia. During hypoglycaemia, mDSST task performance was associated with increased activity in the frontal lobe regions, superior parietal lobe and thalamus, and decreased activity in the temporal lobe regions (p < 0.05). Working memory activation (mDSST - cDSST) statistically significantly increased blood flow in the striatum during hypoglycaemia (ETD 0.0374% [95% CI 0.0157, 0.0590], p = 0.002)., Conclusions/interpretation: During hypoglycaemia (mean PG 2.9 mmol/l), working memory performance was impaired. Altered performance was associated with significantly increased blood flow in the striatum, a part of the basal ganglia implicated in regulating motor functions, memory, language and emotion., Trial Registration: NCT01789593, clinicaltrials.gov FUNDING: This study was funded by Novo Nordisk.

Objective: The potential influence of probiotic supplementation on cardiovascular health and stress responsivity remains largely unexplored. Some evidence suggests the possibility that probiotics may influence blood pressure. A separate body of research suggests that exaggerated cardiovascular reactions to acute psychological stress in the laboratory predict cardiovascular morbidity and mortality. The current investigation explored the effect of acute probiotic use on (1) resting cardiovascular measures in healthy young adults and (2) cardiovascular and psychological reactions to an acute psychological stressor in the laboratory., Method: Participants (N = 105, M [SD] age = 20.17 [1.26], 84.8% white) completed a 2-week, double-blind, and placebo-controlled trial of a multispecies and multistrain probiotic. Exclusion criteria included previous probiotic use, diagnosed gastrointestinal disorder, and/or current antibiotic use. At visits 1 and 2, participants completed the Paced Auditory Serial Addition Test, a widely used psychological stress task. Participants were randomly assigned to a probiotic blend or matched placebo., Results: Compared with placebo, 2-week probiotic supplementation did not affect resting measures of cardiovascular function, cardiovascular responses during or recovery from stress, or psychological reactions to acute psychological stress., Conclusions: Contrary to expectations, short-term use of a probiotic supplement in healthy participants did not influence measures of cardiovascular function or responsivity to psychological stress. Future research is needed to determine species- and strain-specific effects of probiotics in healthy participants with various degrees of stress responsiveness, as well as in diseased populations.

Emphysematous pyelonephritis is a severe necrotizing infection of the kidneys characterized by gas formation within the parenchyma, the collecting system or the perinephric tissue. To our knowledge, there have only been 4 cases of this condition reported in children. We report 2 additional cases in children managed at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.

Background: Herpes zoster (HZ) is associated with underlying immunodeficiency and may thereby predict mortality of subsequent cancer., Methods: By using Danish nationwide medical databases, we identified all cancer patients with a prior hospital-based HZ diagnosis during 1982-2011 (n=2754) and a matched cancer cohort without prior HZ (n=26 243). We computed adjusted mortality rate ratios (aMRRs) associating prior HZ with mortality following cancer., Results: Prior HZ was associated with decreased mortality within the year after cancer diagnosis (aMRR 0.87; 95% confidence interval (CI): 0.81-0.93), but not thereafter (aMRR 1.07; 95% CI: 0.99-1.15). However, prior HZ predicted increased mortality throughout the entire follow-up among patients aged <60 years (aMRR 1.39; 95% CI: 1.15-1.68) and those with disseminated HZ (aMRR 1.18; 95% CI: 1.01-1.37). The increased mortality rates were observed primarily for haematological and immune-related cancers., Conclusions: Overall, HZ was not a predictor of increased mortality following subsequent cancer.

Objectives: To examine whether preadmission use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) influenced 30-day stroke mortality., Methods: We conducted a nationwide population-based cohort study. Using medical databases, we identified all first-time stroke hospitalizations in Denmark between 2004 and 2012 (n = 100,043) and subsequent mortality. We categorized NSAID use as current (prescription redemption within 60 days before hospital admission), former, and nonuse. Current use was further classified as new or long-term use. Cox regression was used to compute hazard ratios (HRs) of death within 30 days, controlling for potential confounding through multivariable adjustment and propensity score matching., Results: The adjusted HR of death for ischemic stroke was 1.19 (95% confidence interval [CI]: 1.02-1.38) for current users of selective cyclooxygenase (COX)-2 inhibitors compared with nonusers, driven by the effect among new users (1.42, 95% CI: 1.14-1.77). Comparing the different COX-2 inhibitors, the HR was driven by new use of older traditional COX-2 inhibitors (1.42, 95% CI: 1.14-1.78) among which it was 1.53 (95% CI: 1.02-2.28) for etodolac and 1.28 (95% CI: 0.98-1.68) for diclofenac. The propensity score-matched analysis supported the association between older COX-2 inhibitors and ischemic stroke mortality. There was no association for former users. Mortality from intracerebral hemorrhage was not associated with use of nonselective NSAIDs or COX-2 inhibitors., Conclusions: Preadmission use of COX-2 inhibitors was associated with increased 30-day mortality after ischemic stroke, but not hemorrhagic stroke. Use of nonselective NSAIDs at time of admission was not associated with mortality from ischemic stroke or intracerebral hemorrhage., (© 2014 American Academy of Neurology.)

Proof-of-concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The goal of most POC trials is to determine whether a treatment is likely to be efficacious for a given indication and thus whether it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge in designing POC trials is obtaining sufficient information to make this important go/no-go decision in a cost-effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia, with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic-pharmacodynamic relationships, and minimization of missing data. Efficiency of single-dose studies for treatments with rapid onset is discussed. The trade-off between parallel-group and crossover designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs, including N-of-1 designs, enriched designs, adaptive designs, and sequential parallel comparison designs, are summarized, and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

The impact of co-morbidity on the cardiovascular risk after single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) remains unclear. We examined the association between a normal versus abnormal SPECT MPI scan on 10-year risk of myocardial infarction, stroke, and all-cause death, overall and according to co-morbidity level. We identified all patients without previous myocardial infarction or cerebrovascular disease, who had an SPECT MPI performed at Aarhus University Hospital Skejby during 1999 to 2011. We categorized the SPECT MPI scan as normal (no defects) or abnormal (reversible and/or fixed defects). Using nationwide medical registries, we obtained information on co-morbidity level (using Charlson co-morbidity index) and outcomes. We used Cox regression to compute hazard ratios with 95% confidence intervals (CIs), adjusting for gender, age, and co-morbidity level. Among 7,040 patients, 4,962 (70%) had normal scans and 2,078 (30%) abnormal scans. Patients with a normal versus abnormal scan had a 10-year risk of 5.7% versus 10.9% for myocardial infarction, 6.0% versus 7.8% for stroke, and 16.5% versus 29.0% for all-cause death. After adjustment, an abnormal scan was associated with increased risk of myocardial infarction (adjusted hazard ratio 1.73, 95% CI 1.37 to 2.18) and all-cause death (1.42, 95% CI 1.23 to 1.65) but not stroke (1.12, 95% CI 0.86 to 1.45). Co-morbidity level did not affect substantially the association between the scan result and the outcomes. In conclusion, independently of co-morbidity level, an abnormal SPECT MPI scan was associated with an increased 10-year risk of myocardial infarction and all-cause death but not stroke., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The objective of this study was to establish in healthy volunteers the maximally tolerated multiple dose (MTMD) of the ionotropic glutamate receptor 5 antagonist LY545694 (part A), and to investigate whether that dose had analgesic or antihyperalgesic effects in the brief thermal stimulation (BTS) pain model (Part B). Part A was a double-blind, placebo-controlled study in 3 groups of 10 healthy men. To simulate an extended-release formulation, study drug was administered orally over 6hours (12 equally divided aliquots at 30-minute intervals). Part B was a double-blind, placebo-controlled, double-dummy, 3-way crossover study in 27 healthy men. At each of the 3 study periods, subjects received either LY545694 (MTMD; as determined during part A) as a simulated, twice daily extended-release formulation for 4 doses over 3days, gabapentin (600mg 8hours apart; 6 doses over 3days; positive control), or matching placebo. The BTS model was induced twice with a 1-hour interval on each of the 2 study days, before drug administration and at the time of expected peak analgesia of LY545694. Plasma exposure for LY545694 was approximately linear over the 25- to 75-mg dose range. The MTMD of LY545694 was 25mg twice daily. Areas of secondary hyperalgesia were significantly smaller after administration of LY545694 and gabapentin compared with placebo (P<.0001 and P=.0004, respectively), but there was no difference between areas after administration of gabapentin and LY545694 (P=.400). Neither gabapentin nor LY545694 reduced the painfulness of skin heating during BTS model induction. The most common treatment-emergent adverse event was dizziness. The results of this study suggest that LY545694 should be explored further as a potential treatment for chronic pain involving neuronal sensitization., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Studies on complications related to chronic nerve injury following sentinel lymph node biopsy (SLNB) and complete lymph node dissection (CLND) for melanoma are sparse. This review summarizes the existing literature on pain and neuropathic complications in melanoma patients undergoing SLNB with or without CLND. The Cochrane Central Register of Controlled Trials and the Embase and PubMed databases were searched. Full-text English language articles published before June 2013 were included. Prospective and retrospective studies assessing persistent (>1 month) sensory nerve injury, postoperative pain, neuropathic pain, and sensory disturbances following SLNB with or without CLND in melanoma patients were eligible. Nine studies (six prospective and three retrospective) including data for 3632 patients met our inclusion criteria. Outcome parameters were too heterogeneous to conduct a quantitative analysis, and few studies systematically evaluated pain and sensory abnormalities. Persistent postoperative pain was reported in 1-14% of patients following SLNB and in 6-34% following CLND and sensory abnormalities in 0.1-32 and 2-82%, respectively. In the one study that assessed the type of pain, neuropathic pain was suggested to explain persistent pain in 31-66% of patients with SLNB and 82-89% of patients with CLND. Sensory-nerve-related complications in melanoma patients seem to be less pronounced following SLNB compared with CLND. Prospective observational studies are necessary to identify predictors of persistent pain, to evaluate the prevalence and impact of pain and sensory abnormalities, and to develop strategies for prevention of long-term complications.

Postherpetic neuralgia (PHN) is a common complication after herpes zoster (HZ). Subjects who completed a longitudinal observational 6-month study (4 visits) of the natural history of HZ were recontacted for 2 additional follow-up visits that included pain and sensory symptom assessment, quantitative sensory testing, capsaicin response test, and 3-mm punch skin biopsies in HZ-affected, mirror-image, and control skin sites. Forty-three subjects (14 with PHN at 6 months) of the original 94 subjects in the cohort were comprehensively assessed at a median 3.9 years after HZ onset (visit 5), and 10 subjects underwent a final assessment at a median 7.7 years after HZ onset (visit 6). At 3.9 years, none of the 29 subjects who had been pain free at 6 months had a recurrence of pain. Only 2 of the 14 subjects with PHN at 6 months still had pain at 3.9 years. One subject with PHN at 6 months was free of symptoms at 3.9 years but had very mild pain at 7.7 years. Sensory function continued on a path toward normalization, but was still abnormal in many subjects, especially those who met criteria for PHN at 6 months. Even at 7.7 years, reinnervation of HZ-affected skin was not apparent., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Objective: The objective of this study is to assess the clinical and social outcomes for a cohort of patients who were part of the redevelopment of psychiatric services in British Columbia., Method: This study used a naturalistic, quasi-experimental design, to examine the outcomes of a cohort of 189 long-stay patients at Riverview Hospital (RVH), some of whom moved into Tertiary Psychiatric Residential Facilities (TPRFs), some into the community in less structured facilities, and some remained at RVH. Data was collected from clinical files at RVH and at each participating site, semi-structured interviews and self-report measures were completed with patients. In addition, semi-structured interviews were also conducted with staff members., Results: There was very minimal evidence of transinstitutionalization to prisons or homelessness; one participant resided in a correctional facility, one resided in a forensic facility, and one participant spent some time homeless. In addition, the majority of participants remained in residences that provided 24h care. Eighty percent of our population was diagnosed with a schizophrenia spectrum disorder. Psychiatric symptoms remained fairly stable; some embarrassing social behaviors increased; however, aggressive behaviors showed no increase; neuropsychological deficits did not deteriorate, there were even some improvements. Participants demonstrated increases in several independent living skills including: money management, food preparation and storage, job skills, and transportation skills. In addition, participants experienced a significant increase in their perceived quality of life., Conclusions: This study builds on existing research demonstrating that well-planned and appropriately resourced hospital closures can lead to positive psycho-social outcomes for participants and can successfully avoid negative outcomes such as transinstitutionalization to the judiciary system and homelessness., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Human experimental pain models leading to development of secondary hyperalgesia are used to estimate efficacy of analgesics and antihyperalgesics. The ability to develop an area of secondary hyperalgesia varies substantially between subjects, but little is known about the agreement following repeated measurements. The aim of this study was to determine if the areas of secondary hyperalgesia were consistently robust to be useful for phenotyping subjects, based on their pattern of sensitization by the heat pain models., Methods: We performed post-hoc analyses of 10 completed healthy volunteer studies (n = 342 [409 repeated measurements]). Three different models were used to induce secondary hyperalgesia to monofilament stimulation: the heat/capsaicin sensitization (H/C), the brief thermal sensitization (BTS), and the burn injury (BI) models. Three studies included both the H/C and BTS models., Results: Within-subject compared to between-subject variability was low, and there was substantial strength of agreement between repeated induction-sessions in most studies. The intraclass correlation coefficient (ICC) improved little with repeated testing beyond two sessions. There was good agreement in categorizing subjects into 'small area' (1(st) quartile [<25%]) and 'large area' (4(th) quartile [>75%]) responders: 56-76% of subjects consistently fell into same 'small-area' or 'large-area' category on two consecutive study days. There was moderate to substantial agreement between the areas of secondary hyperalgesia induced on the same day using the H/C (forearm) and BTS (thigh) models., Conclusion: Secondary hyperalgesia induced by experimental heat pain models seem a consistent measure of sensitization in pharmacodynamic and physiological research. The analysis indicates that healthy volunteers can be phenotyped based on their pattern of sensitization by the heat [and heat plus capsaicin] pain models.

Background: The number of physicians providing maternity care in Canada is decreasing, and the rate of cesarean delivery is increasing. We evaluated the effect on perinatal outcomes of an interdisciplinary program designed to promote physiologic birth and encourage active involvement of women and their families in maternity care., Methods: We conducted a retrospective cohort study involving 1238 women who attended the South Community Birth Program in Vancouver, Canada, from April 2004 to October 2010. The program offers comprehensive, collaborative, interdisciplinary care from family physicians, midwives, community health nurses and doulas to a multiethnic, low-income population. A comparison group, matched for neighbourhood of residence, maternal age, parity and gestational age at delivery, comprised 1238 women receiving standard care in community-based family physician, obstetrician and midwife practices. The primary outcome was the proportion of women who underwent cesarean delivery., Results: Compared with women receiving standard care, those in the birth program were more likely to be delivered by a midwife (41.9% v. 7.4%, p < 0.001) instead of an obstetrician (35.5% v. 69.6%, p < 0.001). The program participants were less likely than the matched controls to undergo cesarean delivery (relative risk [RR] 0.76, 95% confidence interval [CI] 0.68-0.84) and, among those with a previous cesarean delivery, more likely to plan a vaginal birth (RR 3.22, 95% CI 2.25-4.62). Length of stay in hospital was shorter in the program group for both the mothers (mean ± standard deviation 50.6 ± 47.1 v. 72.7 ± 66.7 h, p < 0.001) and the newborns (47.5 ± 92.6 v. 70.6 ± 126.7 h, p < 0.001). Women in the birth program were more likely than the matched controls to be breastfeeding exclusively at discharge (RR 2.10, 95% CI 1.85-2.39)., Interpretation: Women attending a collaborative program of interdisciplinary maternity care were less likely to have a cesarean delivery, had shorter hospital stays on average and were more likely to breastfeed exclusively than women receiving standard care.

A length-dependent neuropathy with pain in the feet is a common complication of diabetes (painful diabetic neuropathy). It was hypothesized that pain may arise from sensitized-hyperactive cutaneous nociceptors, and that this abnormal signaling may be reduced by topical administration of the α(2)-adrenergic agonist, clonidine, to the painful area. This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Nociceptor function was measured by determining the painfulness of 0.1% topical capsaicin applied to the pretibial area of each subject for 30minutes during screening. Subjects were then randomized to receive 0.1% topical clonidine gel (n=89) or placebo gel (n=90) applied 3 times a day to their feet for 12weeks. The difference in foot pain at week 12 in relation to baseline, rated on a 0-10 numerical pain rating scale (NPRS), was compared between groups. Baseline NPRS was imputed for missing data for subjects who terminated the study early. The subjects treated with clonidine showed a trend toward decreased foot pain compared to the placebo-treated group (the primary endpoint; P=0.07). In subjects who felt any level of pain to capsaicin, clonidine was superior to placebo (P<0.05). In subjects with a capsaicin pain rating ⩾2 (0-10, NPRS), the mean decrease in foot pain was 2.6 for active compared to 1.4 for placebo (P=0.01). Topical clonidine gel significantly reduces the level of foot pain in painful diabetic neuropathy subjects with functional (and possibly sensitized) nociceptors in the affected skin as revealed by testing with topical capsaicin. Screening for cutaneous nociceptor function may help distinguish candidates for topical therapy for neuropathic pain., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Background: The effect of pregabalin on acute herpes zoster pain has not been previously evaluated., Methods: In a randomized, double-blind, placebo-controlled, two-session crossover study the effect of a single oral dose of pregabalin (150 mg) on pain and allodynia was evaluated in 8 subjects with herpes zoster., Results: Over 6 hours of observation, pain decreased by a mean of 33% with pregabalin and 14% with placebo (p < 0.10). Effects on allodynia and SF-MPQ were not significant., Conclusions: Compared to an earlier study of gabapentin 900 mg for acute zoster pain and allodynia that followed a nearly identical protocol, pregabalin had a similar effect on pain and was well tolerated, with no difference from placebo on sleepiness. Common side effects of light-headedness, unsteady gait, and slowed thinking were almost identical to that observed in the earlier study of gabapentin. Subject recruitment proved difficult in part due to the widespread off-label use of gabapentin and pregabalin for acute zoster pain in our region of the USA., Trial Registration: ClinicalTrials.gov Identifier: NCT00352651.

The protein complex AMP-activated protein kinase (AMPK) is believed to play an important role in the regulation of skeletal muscle glucose and lipid metabolism. Defects in the AMPK system might therefore be an important factor in the pathogenesis of type 2 diabetes. We aimed to identify genetic and environmental mechanisms involved in the regulation of AMPK expression and activity and to examine the association between AMPK protein levels and activity on the one hand, and glucose and fat metabolism on the other. We investigated skeletal muscle biopsies from 100 young and 82 older mono- and dizygotic nondiabetic twins excised during the basal and insulin-stimulated states of a physiological hyperinsulinemic-euglycemic clamp. AMPKalpha1, -alpha2, and -gamma3 mRNA expression was investigated using real-time PCR, and Western blotting was employed to measure protein levels. Multiple regression analyses indicated that skeletal muscle AMPK mRNA and protein expression as well as activity were regulated by sex, age, obesity, and aerobic capacity. Comparison of intraclass correlations on AMPK measurements from mono- and dizygotic twins suggested that skeletal muscle AMPK expression was under minor genetic influence. AMPKgamma3 protein expression and activity were negatively related to whole body glucose uptake through the nonoxidative metabolic pathway and positively related to phosphorylation of glycogen synthase. Our results suggest that skeletal muscle AMPK expression is under minor genetic control but regulated by age and sex and associated with obesity and aerobic capacity. Furthermore, our results indicate a role for gamma3-containing AMPK complexes in downregulation of insulin-stimulated nonoxidative glucose metabolism possibly through inhibition of glycogen synthase activity.

Tolerance to the anti-nociceptive effects of opioids develops rapidly in animals. In contrast, humans with chronic pain show little or no loss of pain relief in prospective opioid trials of 4-8 weeks duration. Employing the Brief Thermal Sensitization model to induce transient cutaneous secondary hyperalgesia, we tested the hypothesis that opioid analgesic tolerance would develop rapidly. In this outpatient randomized placebo-controlled study, subjects in the MMMMP group received two injections of subcutaneous morphine 6 mg (150 min apart) on Monday-Thursday (total 48 mg over 4 days) and matching saline placebo on Friday. Subjects in the PPPPM group received placebo on Monday-Thursday and morphine (total 12 mg) on Friday. Sixty-one healthy volunteers were enrolled; morphine side effects accounted for all nine non-completions. Compared to the first placebo day, the reduction in the area of secondary hyperalgesia on the first morphine day was significant and robust in both groups. Morphine suppression of the painfulness of skin heating and elevation of the heat pain detection threshold were also significant. During 4 days of twice-daily injections, the decline in anti-hyperalgesic effects of morphine did not reach statistical significance (p=0.06) compared to placebo. Morphine side effects did not correlate with anti-hyperalgesic effects and withdrawal symptoms did not emerge. As 4 days is the threshold for demonstrating analgesic tolerance to twice-daily morphine in animal models, a longer period of opioid exposure in healthy volunteers might be needed to detect analgesic tolerance.

Recent evidence suggests that individuals with certain personality traits are at elevated risk for chronic systemic inflammation. To date, this literature has focused on the related traits of hostility and negative affect (NA). In this study, we examine the covariation of trait measures of hostility and NA with the inflammatory mediators interleukin-6 and C-reactive protein. We also explore whether observed associations reflect independent contributions of cognitive, affective and behavioral components of hostile dispositions or shared trait variance with global negative affectivity. Subjects were a diverse sample of 855 relatively healthy middle-aged community volunteers (50% male) from the Adult Health and Behavior Project. The Buss and Perry Aggression Questionnaire (BPAQ) and an Abbreviated Cook-Medley Hostility Scale (ACM) were used to measure dimensions of hostility, and the Multidimensional Personality Questionnaire was used to measure trait NA. Regression analyses accounting for demographic characteristics and medical covariates showed a positive relationship of all components of hostility and trait NA with both IL-6 and CRP. After controlling for trait NA, only the behavioral component of hostility was independently associated with the inflammatory markers. The relationships of cognitive and affective components of hostility with inflammatory markers were largely explained by lifestyle factors, particularly body mass index and smoking. In contrast, lifestyle factors did not explain the covariation of hostile behavioral tendencies and inflammation. These findings suggest that unique attributes of aggressive behavioral tendencies account for much of the variability in inflammation associated with hostility and negative emotions, raising the possibility that individuals high in aggression are at increased risk of inflammatory disease.

Objective: We evaluated the association of variants in the sterol regulatory element-binding factor 1 gene (SREBF1) with type 2 diabetes. Due to the previous inconclusive quantitative trait associations, we also did studies of intermediate quantitative phenotypes., Research Design and Methods: We genotyped four variants in SREBF1 in the population-based Inter99 cohort (n = 6,070), the Danish ADDITION study (n = 8,662), and in additional type 2 diabetic patients (n = 1,002). The case-control studies involved 2,980 type 2 diabetic patients and 4,522 glucose-tolerant subjects., Results: The minor alleles of rs2297508, rs11868035, and rs1889018 (linkage disequilibrium R(2) = 0.6-0.8) associated with a modestly increased risk of type 2 diabetes (rs2297508: OR 1.17 [95% CI 1.05-1.30], P = 0.003), which was confirmed in meta-analyses of all published studies (rs2297508 G-allele: 1.08 [1.03-1.14] per allele, P = 0.001). The diabetes-associated alleles also associated strongly with a higher plasma glucose at 30 and 120 min and serum insulin at 120 min during an oral glucose tolerance test (all P < 0.006) and the minor allele of rs1889018 with a surrogate measure of insulin sensitivity (P = 0.03). Furthermore, the diabetes-associated alleles associated with a modestly increased A1C level in the population-based Inter99 of middle-aged subjects and in the ADDITION study of high-risk individuals (P = 0.006 and P = 0.008, respectively)., Conclusions: We associate sequence variation in SREBF1 with a modestly increased predisposition to type 2 diabetes. In the general population, the diabetes-associated alleles are discreetly associated with hyperglycemia presumably due to decreased insulin sensitivity. Because sterol regulatory element-binding protein-1c is a mediator of insulin action, the findings are consistent with the presence of a yet undefined subtle loss-of-function SREBF1 variant.

Objective: Three independent studies have shown that variation in the fat mass and obesity-associated (FTO) gene associates with BMI and obesity. In the present study, the effect of FTO variation on metabolic traits including obesity, type 2 diabetes, and related quantitative phenotypes was examined., Research Design and Methods: The FTO rs9939609 polymorphism was genotyped in a total of 17,508 Danes from five different study groups., Results: In studies of 3,856 type 2 diabetic case subjects and 4,861 normal glucose-tolerant control subjects, the minor A-allele of rs9939609 associated with type 2 diabetes (odds ratio 1.13 [95% CI 1.06-1.20], P = 9 x 10(-5)). This association was abolished when adjusting for BMI (1.06 [0.97-1.16], P = 0.2). Among 17,162 middle-aged Danes, the A-allele associated with overweight (1.19 [1.13-1.24], P = 1 x 10(-12)) and obesity (1.27 [1.20-1.34], P = 2 x 10(-16)). Furthermore, obesity-related quantitative traits such as body weight, waist circumference, fat mass, and fasting serum leptin levels were significantly elevated in A-allele carriers. An interaction between the FTO rs9939609 genotype and physical activity (P = 0.007) was found, where physically inactive homozygous risk A-allele carriers had a 1.95 +/- 0.3 kg/m(2) increase in BMI compared with homozygous T-allele carriers., Conclusions: We validate that variation in FTO is associated with type 2 diabetes when not adjusted for BMI and with an overall increase in body fat mass. Furthermore, low physical activity seems to accentuate the effect of FTO rs9939609 on body fat accumulation.

Surgical removal of painful skin was first attempted as a treatment for chronic intractable post-herpetic neuralgia (PHN) more than a century ago, but long-term follow-up has rarely been reported. A patient who underwent surgical excision of 294cm(2) of thoracic skin comprising the entire area of pain and allodynia in October 2000 has been followed for 5.5years post-surgery. Our initial report presented evidence of benefit in the form of reduced pain, elimination of allodynia, and reduced medication consumption during the first post-operative year. Unfortunately, pain steadily increased and now exceeds pre-surgery levels despite increased medication use. Pain topography and characteristics are different from pre-surgery and may relate to the pathophysiology of PHN. Skin resection cannot be recommended as a treatment for PHN.

In a longitudinal observational study of 94 patients (39 M:55 F, mean age 69) at elevated risk for developing post herpetic neuralgia (PHN), the natural history of pain during the first 6 months after herpes zoster (HZ) rash onset was determined. Pain severity and impact were rated using pain-VAS, SF-MPQ, and MPI. Applying a definition of PHN of average daily pain >0/100 on the pain VAS during the last 48 h, 30 subjects had PHN at 6 months. These 30 subjects reported more pain and a higher SF-MPQ score (p<0.01) at study inclusion than the 64 subjects whose pain completely resolved by 6 months. At 6 months, mean daily pain in the PHN group was 11/100 (95% CI 5,16) and only nine of these subjects were still taking prescription medication for HZ pain. The rate of recovery (pain severity over time) was the same in the PHN and no-pain groups. At study inclusion, the SF-MPQ and MPI scores in our PHN group were similar to historical controls with chronic severe PHN enrolled in clinical trials, but by 6 months the scores in our PHN subjects were significantly lower than historic controls. Only two subjects met the more stringent criteria for 'clinically meaningful' PHN at 6 months (> or = 30/100 on the pain VAS). Defining PHN as average daily pain >0/100 at 6 months after rash onset appears to substantially overestimate the number of HZ patients negatively impacted by ongoing pain and disability.

The objective of this article is to provide evidence-based recommendations for the management of patients with herpes zoster (HZ) that take into account clinical efficacy, adverse effects, impact on quality of life, and costs of treatment. Systematic literature reviews, published randomized clinical trials, existing guidelines, and the authors' clinical and research experience relevant to the management of patients with HZ were reviewed at a consensus meeting. The results of controlled trials and the clinical experience of the authors support the use of acyclovir, brivudin (where available), famciclovir, and valacyclovir as first-line antiviral therapy for the treatment of patients with HZ. Specific recommendations for the use of these medications are provided. In addition, suggestions are made for treatments that, when used in combination with antiviral therapy, may further reduce pain and other complications of HZ.