An investigation into the potential for upward range expansion in high-montane species on the roof of the world.

Climate warming is occurring in high-mountain areas at a faster rate than the global average. To escape the increasing temperatures, alpine species may shift in distribution upwards, threatening cold-adapted nival plant specialists. However, little is known about the success of seedling emergence and establishment at high altitudes outside the current range, particularly in the highest mountain areas of the Himalayas. We selected four native alpine species occurring around 4000 m a.s.l. and sowed seeds at the natural growing site (GS), at a high elevation site (HS; 5000 m a.s.l.) and at high elevation with soil from the growing site (HS-S) in the Khumbu Valley, north-eastern Nepal. We monitored seedling emergence and establishment for two consecutive years. Seedling emergence and establishment varied between species. Emergence was similar between GS and HS and improved at HS-S. Establishment was low at high elevations with all but one species having high mortality after winter. Seedling emergence of low elevation plants is possible at high elevations in the Everest region, indicating species may be able to shift their distribution range upwards. However, successful establishment may be limited by the soil and high winter mortality at high elevations, although not in all species. Climate warming will potentially lead to upward migration of some Himalayan plant species, leading to altered community composition in high-mountain areas.

Postpartum nutrition affects the insulin-like growth factor system in dominant follicles and plasma of anestrous beef cows.

Effects of nutrition on insulin-like growth factor-I (IGF-I), IGF binding proteins (IGFBP), and insulin in plasma and dominant follicles were evaluated at day 72 and 56 (Exp. 1, n = 12 and Exp. 2, n = 28, respectively) postpartum in anovulatory primiparous beef cows. Cows were stratified based on body condition score at calving and randomly assigned to nutritional treatments: maintain (M), 2.27 kg of a 40 % CP supplement per day and ad libitum hay; or gain (G), ad libitum access to a 50 % concentrate diet and ad libitum hay. Blood samples were collected twice weekly starting 30 days postpartum. Ovarian follicles were evaluated using ultrasonography commencing 42 (Exp. 1) or 30 (Exp. 2) days postpartum. Body weight and condition score were greater (P < 0.05) for cows of G than M groups and postpartum interval to luteal function was longer for cows of the M than G group. Insulin and IGF-I concentrations in follicular fluid (FF) and plasma were greater (P < 0.05) for cows of the G than M group at follicular aspiration. Plasma and FF IGFBP4 and IGFBP5 concentrations were greater (P <  0.05) in Exp. 2, and IGFBP5 was greater in Exp. 1 for cows of the G than M group. Treatment did not affect FF steroid concentrations or granulosal cell CYP19A1, PAPPA, IGFBP4, and IGFBP5 mRNA abundance. These results indicate concentrations of IGF-I, insulin, IGFBP4, and IGFBP5 in FF and plasma are affected by nutritional intake and may be related to follicular function.

1,2,3, MHC: a review of mass-spectrometry-based immunopeptidomics methods for relative and absolute quantification of pMHCs.

Quantitative mass-spectrometry-based methods to perform relative and absolute quantification of peptides in the immunopeptidome are growing in popularity as researchers aim to measure the dynamic nature of the peptide major histocompatibility complex repertoire and make copies-per-cell estimations of target antigens of interest. Multiple methods to carry out these experiments have been reported, each with unique advantages and limitations. This article describes existing methods and recent applications, offering guidance for improving quantitative accuracy and selecting an appropriate experimental set-up to maximize data quality and quantity.

Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs.

We endeavored to identify objective blood biomarkers for pain, a subjective sensation with a biological basis, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We studied psychiatric patients, a high risk group for co-morbid pain disorders and increased perception of pain. For discovery, we used a powerful within-subject longitudinal design. We were successful in identifying blood gene expression biomarkers that were predictive of pain state, and of future emergency department (ED) visits for pain, more so when personalized by gender and diagnosis. MFAP3, which had no prior evidence in the literature for involvement in pain, had the most robust empirical evidence from our discovery and validation steps, and was a strong predictor for pain in the independent cohorts, particularly in females and males with PTSD. Other biomarkers with best overall convergent functional evidence for involvement in pain were GNG7, CNTN1, LY9, CCDC144B, and GBP1. Some of the individual biomarkers identified are targets of existing drugs. Moreover, the biomarker gene expression signatures were used for bioinformatic drug repurposing analyses, yielding leads for possible new drug candidates such as SC-560 (an NSAID), and amoxapine (an antidepressant), as well as natural compounds such as pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), and apigenin (a plant flavonoid). Our work may help mitigate the diagnostic and treatment dilemmas that have contributed to the current opioid epidemic.

Hepatic Hilar Lymph Node Reactivity at Kasai Portoenterostomy for Biliary Atresia: Correlations With Age, Outcome, and Histology of Proximal Biliary Remnant.

We hypothesized that if infection is the proximate cause of congenital biliary atresia, an appropriate response to antigen would occur in lymph nodes contiguous with the biliary remnant. We compared the number of follicular germinal centers (GC) in 79 surgically excised hilar lymph nodes (LN) and 27 incidentally discovered cystic duct LNs in 84 subjects at the time of hepatic portoenterostomy (HPE) for biliary atresia (BA) to autopsy controls from the pancreaticobiliary region of non-septic infants >3 months old at death. All 27 control LN lacked GC, a sign in infants of a primary response to antigenic stimulation. GC were found in 53% of 106 LN in 56 of 84 subjects. Visible surgically excised LN contiguous with the most proximal biliary remnants had 1 or more well-formed reactive GC in only 26/51 subjects. Presence of GC and number of GC/LN was unrelated to age at onset of jaundice or to active fibroplasia in the biliary remnant but was related to older age at HPE. Absent GC in visible and incidentally removed cystic duct LNs predicted survival with the native liver at 2 and 3 years after HPE, P = .03, but significance was lost at longer intervals. The uncommon inflammatory lesions occasionally found in remnants could be secondary either to bile-induced injury or secondary infection established as obstruction evolves. The absence of consistent evidence of antigenic stimulation in LN contiguous with the biliary remnant supports existence of at least 1 major alternative to infection in the etiology of biliary atresia.

Reasons why patients referred to diabetes education programmes choose not to attend: a systematic review.

AIMS: To identify the reasons why those offered a place on diabetes education programmes declined the opportunity. BACKGROUND: It is well established that diabetes education is critical to optimum diabetes care; it improves metabolic control, prevents complications, improves quality of life and empowers people to make informed choices to manage their condition. Despite the significant clinical and personal rewards offered by diabetes education, programmes are underused, with a significant proportion of patients choosing not to attend. METHODS: A systematic search of the following databases was conducted for the period from 2005-2015: Medline; EMBASE; Scopus; CINAHL; and PsycINFO. Studies that met the inclusion criteria focusing on patient-reported reasons for non-attendance at structured diabetes education were selected. RESULTS: A total of 12 studies spanning quantitative and qualitative methodologies were included. The selected studies were published in Europe, USA, Pakistan, Canada and India, with a total sample size of 2260 people. Two broad categories of non-attender were identified: 1) those who could not attend for logistical, medical or financial reasons (e.g. timing, costs or existing comorbidities) and 2) those who would not attend because they perceived no benefit from doing so, felt they had sufficient knowledge already or had emotional and cultural reasons (e.g. no perceived problem, denial or negative feelings towards education). Diabetes education was declined for many reasons, and the range of expressed reasons was more diverse and complex than anticipated. CONCLUSION: New and innovative methods of delivering diabetes education are required which address the needs of people with diabetes whilst maintaining quality and efficiency.

The role of post-mortem MRI in the neonatal intensive care unit.

OBJECTIVE: Post-mortem examination can provide important information about the cause of death and play a significant role in the bereavement process. Autopsies reveal previous unknown medical problems approximately 20 to 30% of the time. A non-invasive magnetic resonance imaging-based post-mortem examination (PM-MRI) may provide an alternative for families who do not consent to an autopsy. STUDY DESIGN: This study was a prospective observational study of recently expired neonates and infants. Subjects underwent a full body MRI scan (brain, chest, abdomen and pelvis) followed by conventional autopsy if the family desired to have one. MRI results were compared with autopsy findings and the ante-mortem clinical diagnosis. A follow-up survey was conducted to investigate family perceptions of the PM-MRI process. RESULTS: Thirty-one infants underwent full PM-MRI. Of 31 infants, 19 (61%) had complete agreement between the clinician's impression and PM-MRI. Twenty-four infants also had conventional autopsy, with 14/24 (58%) infants having PM-MRI results consistent with autopsy findings. PM-MRI was superior at detection of free intraperitoneal/intrathoracic air and hepatic iron overload. Whole-body PM-MRI did not have the resolution to detect focal/microscopic injury, vascular remodeling and some forms of brain injury. Of those families who remembered the PM-MRI findings, the majority felt that the information was useful. CONCLUSIONS: PM-MRI studies may provide an important adjunct to conventional autopsy and a substitute when the latter is not possible for personal or religious reasons. Clinicians should be aware of, and communicate with the family, the resolution limits of the whole-body PM-MRI to detect certain types of injury.

Autosomal dominant SCN8A mutation with an unusually mild phenotype.

BACKGROUND: Mutations in SCN8A, coding for the voltage-gated sodium channel Nav 1.6, have been described in relation to infantile onset epilepsy with developmental delay and cognitive impairment, in particular early onset epileptic encephalopathy (EIEE) type 13. CASE REPORT: Here we report an infant and his father with early onset focal epileptic seizures but without cognitive or neurological impairment in whom next generation sequence analysis identified a heterozygous mutation (c.5630A > G, p. (Asn1877Ser)) in the SCN8A gene. This mutation, confirmed by Sanger sequence analysis, affects a highly conserved amino acid and in silico tools predicts that it may be pathogenic. The reported infant has a normal developmental profile at 16-month follow-up. His father also had normal development and has no cognitive impairment at 42 years. This is the second known SCN8A mutation associated with a phenotype of benign familial infantile epilepsy. Good seizure control was achieved in our patients with sodium channel blockers. CONCLUSION: Based on our proband and a recently described group of families with benign familial infantile epilepsy and SCN8A variant we suggest expanding testing to patients with infantile epilepsy and no cognitive impairment. In addition, the same SCN8A variant (c.5630A > G, p. (Asn1877Ser)) is also found in patients with epilepsy and developmental delay highlighting the phenotypic variability and the possible role of other protective genetic factors.

Complete Genome Sequence of the African Strain AXO1947 of Xanthomonas oryzae pv. oryzae.

Xanthomonas oryzae pv. oryzae is the etiological agent of bacterial rice blight. Three distinct clades of X. oryzae pv. oryzae are known. We present the complete annotated genome of the African clade strain AXO194 using long-read single-molecule PacBio sequencing technology. The genome comprises a single chromosome of 4,674,975 bp and encodes for nine transcriptional activator-like (TAL) effectors. The approach and data presented in this announcement provide information for complex bacterial genome organization and the discovery of new virulence effectors, and they facilitate target characterization of TAL effectors.

Respiratory failure in a term infant with cis and trans mutations in ABCA3.

A full-term female neonate presented with persistent respiratory failure and radiologic studies consistent with surfactant deficiency. Sequencing of the ATP-binding cassette transporter A3 gene (ABCA3) revealed three mutations: R280C, V1399M and Q1589X. The infant underwent bilateral lung transplantation at 9 months of age and is alive at 3 years of age. Parental sequencing demonstrated that two of the mutations (R280C and Q1589X) were oriented on the same allele (cis), whereas V1399M was oriented on the opposite allele (trans). As more than one mutation in ABCA3 can be present on the same allele, parental studies are needed to determine allelic orientation to inform clinical decision making and future reproductive counseling.

Unsuccessful treatment of severe pyruvate carboxylase deficiency with triheptanoin.

UNLABELLED: Pyruvate carboxylase (PC) deficiency (OMIM 266150) is an autosomal recessive disorder that usually presents with lactic acidaemia and severe neurological dysfunction, leading to death in infancy. Because the enzyme is involved in gluconeogenesis and anaplerosis of the Krebs cycle, therapeutic strategies have included avoiding fasting and attempts to correct the defect of anaplerosis. Triheptanoin is a triglyceride of C7 fatty acids. The oxidation of odd chain fatty acids leads to the production not only of acetyl-CoA but also of propionyl-CoA, which is an anaplerotic substrate for the Krebs cycle. One infant with PC deficiency has previously been treated with triheptanoin as well as citrate and 2-chloropropionate. We report two further patients with PC deficiency, who were treated with triheptanoin, continuously from 11 and 21 days of age. They were also given citrate, aspartate and dichloroacetate. Triheptanoin did not lead to any clinical or biochemical improvement. The plasma and CSF lactate concentrations remained high with episodes of severe ketoacidosis and lactic acidosis. Both patients had severe hearing loss, roving eye movements, seizures and very limited neurodevelopmental progress; they died at the ages of 7 and 8 months. CONCLUSION: Though triheptanoin did not alter the clinical course in our patients, it was well tolerated. It remains possible that less severely affected patients might benefit from this form of therapy.

Dietary practices in pyridoxine non-responsive homocystinuria: a European survey.

BACKGROUND: Within Europe, the management of pyridoxine (B6) non-responsive homocystinuria (HCU) may vary but there is limited knowledge about treatment practice. AIM: A comparison of dietetic management practices of patients with B6 non-responsive HCU in European centres. METHODS: A cross-sectional audit by questionnaire was completed by 29 inherited metabolic disorder (IMD) centres: (14 UK, 5 Germany, 3 Netherlands, 2 Switzerland, 2 Portugal, 1 France, 1 Norway, 1 Belgium). RESULTS: 181 patients (73% >16 years of age) with HCU were identified. The majority (66%; n=119) were on dietary treatment (1-10 years, 90%; 11-16 years, 82%; and >16 years, 58%) with or without betaine and 34% (n=62) were on betaine alone. The median natural protein intake (g/day) on diet only was, by age: 1-10 years, 12 g; 11-16 years, 11 g; and >16 years, 45 g. With diet and betaine, median natural protein intake (g/day) by age was: 1-10 years, 13 g; 11-16 years, 20 g; and >16 years, 38 g. Fifty-two percent (n=15) of centres allocated natural protein by calculating methionine rather than a protein exchange system. A methionine-free l-amino acid supplement was prescribed for 86% of diet treated patients. Fifty-two percent of centres recommended cystine supplements for low plasma concentrations. Target treatment concentrations for homocystine/homocysteine (free/total) and frequency of biochemical monitoring varied. CONCLUSION: In B6 non-responsive HCU the prescription of dietary restriction by IMD centres declined with age, potentially associated with poor adherence in older patients. Inconsistencies in biochemical monitoring and treatment indicate the need for international consensus guidelines.

Metabolic status, gonadotropin secretion, and ovarian function during acute nutrient restriction of beef heifers.

The effect of acute nutritional restriction on metabolic status, gonadotropin secretion, and ovarian function of heifers was determined in 2 experiments. In Exp. 1, 14-mo-old heifers were fed a diet supplying 1.2 × maintenance energy requirements (1.2M). After 10 d, heifers were fed 1.2M or were restricted to 0.4 × maintenance requirements (0.4M; d 0). Heifers received PGF2α (25 mg, intramuscularly) on d -10, 0, and 10 to synchronize ovulation. After 30 d, 1.2M and 0.4M heifers were realimented to 1.2 M for 100 d. Blood samples were collected every other day from d 0 to 14 then 3 times weekly thereafter. Heifers in Exp. 2 were managed as in Exp. 1 except that animals were fitted with an indwelling jugular catheter and blood samples were collected at 10-min intervals for 8 h on d 9, 10, and 11. Concentrations of progesterone in plasma were used to quantify ovarian luteal function. All 1.2M heifers ovulated, whereas only 30% of 0.4M heifers ovulated in Exp. 1. Concentrations of NEFA were greater and concentrations of thyroxine and IGF-I were less (P < 0.05) in plasma of 0.4M heifers compared with 1.2M heifers. The size of dominant follicles in Exp. 1 was reduced (P < 0.05) in 0.4M compared with 1.2M heifers. Concentrations of IGF-I were increased and anovulatory heifers resumed ovarian cycles an average of 35 d after realimentation. Concentrations of insulin were greater (P < 0.05) in plasma of 1.2M compared with 0.4M heifers in Exp. 2. The frequency of LH pulses was reduced (P < 0.05) in 0.4M heifers on d 9, and FSH in plasma on d 11 was not influenced by treatment. Reduced concentrations of IGF-I in plasma of nutrient-restricted heifers were associated with the reduced size of dominant follicles and indicated a local effect of growth factors on follicles. The decreased LH pulse frequency of 0.4M heifers before luteolysis indicates that restriction of nutrients decreased LH support of follicle growth. A preovulatory increase in estradiol in plasma and an ovulatory surge of LH were not detected in nutrient restricted heifers that did not ovulate. It is concluded that restricting beef heifers to 0.4 × maintenance energy requirements reduced the availability of metabolic fuel and decreased metabolic hormones, resulting in changes within the reproductive neuroendocrine-ovarian axis that compromised the ability of the dominant follicle to secrete sufficient concentrations of estrogen to stimulate an ovulatory surge of LH.

Surface-enhanced charge-density-wave instability in underdoped Bi2Sr(2-x)La(x)CuO(6+δ).

Neutron and X-ray scattering experiments have provided mounting evidence for spin and charge ordering phenomena in underdoped cuprates. These range from early work on stripe correlations in Nd-LSCO to the latest discovery of charge-density-waves in YBa2Cu3O(6+x). Both phenomena are characterized by a pronounced dependence on doping, temperature and an externally applied magnetic field. Here, we show that these electron-lattice instabilities exhibit also a previously unrecognized bulk-surface dichotomy. Surface-sensitive electronic and structural probes uncover a temperature-dependent evolution of the CuO2 plane band dispersion and apparent Fermi pockets in underdoped Bi2 Sr(2-x) La(x) CuO(6+δ) (Bi2201), which is directly associated with an hitherto-undetected strong temperature dependence of the incommensurate superstructure periodicity below 130 K. In stark contrast, the structural modulation revealed by bulk-sensitive probes is temperature-independent. These findings point to a surface-enhanced incipient charge-density-wave instability, driven by Fermi surface nesting. This discovery is of critical importance in the interpretation of single-particle spectroscopy data, and establishes the surface of cuprates and other complex oxides as a rich playground for the study of electronically soft phases.

Gender-related differences in the pathway to and characteristics of U.S. medical school deanships.

PURPOSE: To explore factors that may be involved in the persistent paucity of women leaders in U.S. academic medicine and to provide baseline gender-related data for developing strategies to promote gender equity in academic medicine leadership. METHOD: Using data sets from the Association of American Medical Colleges, the authors examined the relationship of gender to career progression and to deanship characteristics by conducting descriptive and correlation statistical analyses for 534 full and interim deans (38 women; 496 men) appointed between 1980 and November 2006 (inclusive) to serve U.S. Liaison Committee on Medical Education (LCME)-accredited medical schools. RESULTS: Although the number of women deans increased during the 27-year study period, the representation of women remains low (they constitute only 15% of deans appointed from 2000 to 2006) and has failed to keep pace with the percentages of women medical school faculty and students. On average, women deans-most with deanships at less research-intensive medical schools-obtained their initial doctorates from similarly less research-intensive schools, held more business-related advanced degrees beyond the original doctorate, took longer to be promoted to full professor, and had shorter tenures than did their men counterparts. CONCLUSIONS: Women leaders of U.S. LCME-accredited medical schools have taken longer to advance through the academic ranks, serve at less research-intensive institutions, and had shorter tenures than did men deans. These results underscore the challenges women leaders face in traditionally male-dominated organizations, and they provide baseline data to inform medical schools building inclusive senior leadership teams.

Dietary management of urea cycle disorders: UK practice.

BACKGROUND: There is no published data describing UK dietary management of urea cycle disorders (UCD). The present study describes dietary practices in UK inherited metabolic disorder (IMD) centres. METHODS: Cross-sectional data from 16 IMD centres were collected by a questionnaire describing the management of UCD patients on prescribed protein-restricted diets. RESULTS: One hundred and seventy-five patients [N-acetylglutamate synthase deficiency, n = 3; carbamoyl phosphate synthase deficiency (CPS), n = 8; ornithine transcarbamoylase deficiency (OTC), n = 75; citrullinaemia, n = 41; argininosuccinic aciduria (ASA), n = 36; arginase deficiency, n = 12] were reported; 70% (n = 123) aged 0-16 years; 30% (n = 52) >16 years. Prescribed median protein intake decreased with age (0-6 months: 2 g kg(-1) day(-1); 7-12 months: 1.6 g kg(-1) day(-1); 1-10 years: 1.3 g kg(-1) day(-1); 11-16 years: 0.9 g kg(-1) day(-1) and >16 years: 0.8 g kg(-1) day(-1)) with little variation between disorders. Adult protein prescription ranged 0.4-1.2 g kg(-1) day(-1) (40-60 g day(-1)). In the previous 2 years, 30% (n = 53) were given essential amino acid supplements (EAAs) (CPS, n = 2; OTC, n = 20; citrullinaemia, n = 15; ASA, n = 7; arginase deficiency, n = 9). EAAs were prescribed for low plasma quantitative essential amino acids (n = 13 centres); inadequate natural protein intake (n = 11) and poor metabolic control (n = 9). From diagnosis, one centre prescribed EAAs for all patients and one centre for severe defects only. Only 3% (n = 6) were given branch chain amino acid supplements. Enteral feeding tubes were used by 25% (n = 44) for feeds and 3% (n = 6) for medications. Oral energy supplements were prescribed in 17% (n = 30) of cases. CONCLUSIONS: In the UK, protein restriction based on World Health Organization 'safe intakes of protein', is the principle dietary treatment for UCD. EAA supplements are prescribed mainly on clinical need. Multicentre collaborative research is required to define optimal dietary treatments.

Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is an aggressive brain tumor for which there is no cure. Overexpression of wild-type epidermal growth factor receptor (EGFR) and loss of the tumor suppressor genes Ink4a/Arf and PTEN are salient features of this deadly cancer. Surprisingly, targeted inhibition of EGFR has been clinically disappointing, demonstrating an innate ability for GBM to develop resistance. Efforts at modeling GBM in mice using wild-type EGFR have proven unsuccessful to date, hampering endeavors at understanding molecular mechanisms of therapeutic resistance. Here, we describe a unique genetically engineered mouse model of EGFR-driven gliomagenesis that uses a somatic conditional overexpression and chronic activation of wild-type EGFR in cooperation with deletions in the Ink4a/Arf and PTEN genes in adult brains. Using this model, we establish that chronic activation of wild-type EGFR with a ligand is necessary for generating tumors with histopathological and molecular characteristics of GBMs. We show that these GBMs are resistant to EGFR kinase inhibition and we define this resistance molecularly. Inhibition of EGFR kinase activity using tyrosine kinase inhibitors in GBM tumor cells generates a cytostatic response characterized by a cell cycle arrest, which is accompanied by a substantial change in global gene expression levels. We demonstrate that an important component of this pattern is the transcriptional activation of the MET receptor tyrosine kinase and that pharmacological inhibition of MET overcomes the resistance to EGFR inhibition in these cells. These findings provide important new insights into mechanisms of resistance to EGFR inhibition and suggest that inhibition of multiple targets will be necessary to provide therapeutic benefit for GBM patients.

Sciatic nerve injury induces functional pro-nociceptive chemokine receptors in bladder-associated primary afferent neurons in the rat.

Visceral sensory afferents during disease or following injury often produce vague, diffuse body sensations, and pain referred to somatic targets. Alternatively, injury due to trauma or disease of somatic nerve targets can also lead to referred pain in visceral targets via a somatovisceral reflex. Both phenomenons are thought to be due to convergence of visceral and somatic afferents within the spinal cord. To investigate a potential peripheral influence for referred pain in visceral targets following somatic nerve injury, we examined whether a sciatic nerve injury known to produce hindpaw tactile hyperalgesia alters the frequency of micturition and the sensitivity of bladder-associated sensory neurons to pro-nociceptive chemokines. Adult female Sprague-Dawley rats received injections of cholera toxin B subunit conjugated to 555 into urinary bladder wall to retrogradely label visceral primary afferent neurons. After 7 days, the right sciatic nerve of these animals was subjected to a lysophosphatidylcholine (LPC)-induced focal demyelination injury. Pre- and post-injury tactile sensitivity in the hind paw and micturition frequency were assayed. Animals were allowed to survive for 14-28 days. Lumbosacral and lumbar dorsal root ganglia (DRG) ipsilateral to the nerve injury were acutely dissociated from sham and nerve injured animals. Bladder wall-associated sensory neurons identified via the retrograde marker were assayed for fluxes in intracellular calcium following administration of pro-nociceptive chemokines. The assayed chemokines included monocyte chemoattractant protein-1 (MCP1/CCL2) and stromal cell derived factor-1 alpha (SDF1/CXCL12). LPC nerve injured animals exhibited tactile hyperalgesia and increased micturition frequency for at least 28 days. Focal demyelination of the sciatic nerve also increased the number of injured L4L5 and non-injured L6-S2 bladder-associated sensory neurons that responded to MCP1 and SDF1 when compared with sensory neurons derived from uninjured naïve and sham-injured control animals. Taken together, these data suggest that some visceral hypersensitivity states may have a somatic origin. More importantly, nociceptive somatovisceral sensation may be mediated by upregulation of chemokine signaling in visceral sensory neurons.

Cohort analysis of directly observed treatment outcomes for tuberculosis patients in urban Pakistan.

BACKGROUND: This quasi-experimental cohort study aimed to evaluate World Health Organization (WHO) defined tuberculosis (TB) treatment outcomes for patients under directly observed treatment at a health facility (clinic DOT) or at home (family DOT) in urban Pakistan. METHODS: We enrolled 582 sputum smear-positive TB patients being treated by either clinic DOT (n = 295) or family DOT (n = 287) in 11 treatment centres. Patients and/or family members were interviewed for baseline measurements. WHO-defined treatment outcomes were evaluated at the end of treatment. Proportions of 'cured' patients were computed. A log-binomial model was used to evaluate the associations of various factors with 'cured' status. RESULTS: The proportion of 'cured' patients was respectively 66% and 34% in the clinic DOT and family DOT groups (risk difference 0.32; 95%CI 0.24-0.39). Patients on clinic DOT were more likely to achieve cure (adjusted relative risk [RR(adj)] 1.85; 95%CI 1.43-2.39) than those on family DOT, as were patients satisfied with their health care worker's attitude (RR(adj) 5.73; 95%CI 2.54-12.96). CONCLUSION: Clinic DOT nearly doubled the proportion of cured patients compared to family DOT. Efforts to improve care-provider attitudes to enhance patient satisfaction, and effective implementation of the WHO's public-private mix approach, may enhance TB control in this and similar settings.