A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes

Intercellular signaling by fibroblast growth factors plays vital roles during embryogenesis. Mice deficient for fibroblast growth factor receptors (FgfRs) show abnormalities in early gastrulation and implantation, disruptions in epithelial–mesenchymal interactions, as well as profound defects in membranous and endochondrial bone formation. Activating FGFR mutations are the underlying cause of several craniosynostoses and dwarfism syndromes in humans. Here we show that a heterozygotic abrogation of FgfR2-exon 9 (IIIc) in mice causes a splicing switch, resulting in a gain-of-function mutation. The consequences are neonatal growth retardation and death, coronal synostosis, ocular proptosis, precocious sternal fusion, and abnormalities in secondary branching in several organs that undergo branching morphogenesis. This phenotype has strong parallels to some Apert's and Pfeiffer's syndrome patients.

On signal sequence polymorphisms and diseases of distribution.

We report a previously unappreciated property of the signals that target organelle-specific proteins to their subcellular sites of action. Such targeting sequences are shown to be polymorphic. We discovered this polymorphism when we cloned the mitochondrial manganese-containing superoxide dismutase from cell lines of normal individuals and patients with genetic diseases of premature aging and compared their sequences to each other and to those previously reported. The polymorphism consists of a single nucleotide change in the region of the DNA that encodes the signal sequence such that either an alanine or valine is present. Subsequently, eight cell lines were analyzed and all three possible combinations of the two signal sequences were observed. Such signal sequence polymorphisms could result in diseases of distribution, where essential proteins are not properly targeted, thereby leading to absolute or relative deficiencies of critical enzymes within specific cellular compartments. Progeria and related syndromes may be diseases of distribution.

On the belief that arthritis pain is related to the weather.

There is a widespread and strongly held belief that arthritis pain is influenced by the weather; however, scientific studies have found no consistent association. We hypothesize that this belief results, in part at least, from people's tendency to perceive patterns where none exist. We studied patients (n = 18) for more than I year and found no statistically significant associations between their arthritis pain and the weather conditions implicated by each individual. We also found that college students (n = 97) tend to perceive correlations between uncorrelated random sequences. This departure of people's intuitive notion of association from the statistical concept of association, we suggest, contributes to the belief that arthritis pain is influenced by the weather.

Qualidade de vida relacionada à saude em mulheres com reações adversas após tratamento com quimioterapia para câncer de mama

Trata-se de estudo descritivo, exploratório, transversal, quantitativo, realizado com mulheres em tratamento quimioterápico para neoplasias de mama, em Aracaju-Sergipe-Brasil. O objetivo foi avaliar a qualidade de vida relacionada à saúde (QVRS) destas mulheres que apresentaram reações adversas pós quimioterapia. Foram utilizados instrumentos contendo dados sócio demográficos, clínicos e terapêuticos, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 e formulário de registro de toxicidades dos antineoplásicos. Na análise dos dados, foram utilizados análise descritiva, cálculos de percentual, teste de Shapiro-Wilk, coeficiente de correlação de Pearson ou de Spearman, teste de ANOVA ou Kruskal-Wallis. Os resultados mostraram dados de 206 mulheres, a partir da segunda sessão de quimioterapia, com média de idade de 53,1 anos, maioria procedente de Sergipe, com Carcinoma Ductal Infiltrante, estadiamento III. A maioria realizou cirurgia oncológica, não realizaram radioterapia devido à grande fila de espera, o protocolo de quimioterapia mais comum foi TAC (docetaxel, doxorrubicina e ciclofosfamida). Quanto às reações adversas, a maioria não apresentou alterações hematológicas e metabólicas no momento da coleta das informações, nas alterações funcionais, a fadiga foi presente em 80,8% dos casos, de forma moderada. Nas alterações gastrintestinais, diarreia, constipação, mucosite, náusea, vômito e dor abdominal foram citadas pela maioria. Nas alterações dermatológicas, a alopecia, hiperpigmentação na pele, alterações nas unhas, prurido na pele, descamação e eritema multiforme foram citadas pelas entrevistadas. Nas alterações cardiovasculares, hipotensão e HAS sobressaíram-se. Nas alterações neurológicas, neuropatia periférica, perda da audição e zumbido foram comuns. Os resultados da avaliação da QVRS foram analisadas à luz do referencial teórico de Ferrel et al. (1995) com os seguintes resultados: média do escore 76,01; escalas funcionais apresentaram escore baixo, com aspectos físico, emocional, cognitivo, funcional e social bastante afetados após o tratamento, o desempenho de papéis e função emocional foram os mais prejudicados; na escala de sintomas, os domínios mais prejudicados foram: dificuldades financeiras, fadiga e insônia. Na análise de correlação, o escore geral da QVRS apresentou correlação estatisticamente significante com a quantidade de reações adversas na medula óssea. Em todos os casos estatisticamente significantes o domínio emocional apresentou correlações positivas e o domínio dor, correlações negativas. A idade apresentou correlação estatisticamente significante e negativa com os domínios físico e dificuldades financeiras e positiva com perda de apetite. Pelo procedimento de comparações múltiplas, as diferenças ocorreram entre os estados civis casado e separado e também casado e solteiro, entre as religiões católica e evangélica, entre os ensinos fundamental e médio e entre médio e superior; para a extensão da doença os domínios dor e insônia apresentaram diferenças estatisticamente significantes entre as categorias de extensão. Para renda mensal, os domínios fisico, desempenho de papel, emocional, constipação e dificuldades financeiras apresentaram diferenças estatisticamente significantes entre as categorias de renda. Nos domínios fisico, desempenho de papel e emocional as diferenças ocorreram entre as faixas de 1 a 3 e mais de 6 salários. Concluiu-se que as reações adversas causadas pelo tratamento antineoplásico com quimioterapia afetaram de algum modo as pacientes, causando déficits em vários domínios, prejudicando assim sua QVRS

Efectos de los aminoácidos ramificados en deportes de larga duración: revisión bibliográfica

Introducción: El informe emitido por la Agencia Europea de Seguridad Alimentaria (EFSA) en 2010 sobre las declaraciones nutricionales y propiedades saludables, muestra que no existen evidencias científicas que apoyen la suplementación con aminoácidos ramificados (BCAAs). El objetivo de este estudio es analizar los efectos del consumo de suplementos de BCAAs en deportes de larga duración (DLD). Métodos: Estudio descriptivo de revisión bibliográfica sobre el estado actual del efecto del consumo de suplementos de BCAAs. Se realizó una búsqueda en la base de datos PubMed y estrategia de bola de nieve. Criterios de inclusión: Estudios realizados en humanos, ensayos clínicos controlados aleatorizados (ECCA) en castellano/inglés relacionados con el consumo de BCAAs, leucina, valina e isoleucina en DLD y sus efectos sobre el daño muscular, rendimiento deportivo, fatiga central, respuesta anabólica y sistema inmunológico publicados en cualquier país hasta mayo 2014. Resultados: De los 330 estudios identificados, 14 cumplieron los criterios de inclusión. La media de sujetos participantes en los estudio es igual a (11,36 ± 7,43). Sólo dos estudios incluyen un grupo de mujeres. Las disciplinas deportivas que se encontraron en los estudios fueron carrera a pie, ciclismo, combinación ciclismo y carrera a pie, triatlón distancia olímpica y un estudio que incluía 2 grupos de deportistas (triatlón distancia olímpica y carrera a pie). Se estudian los efectos de los BCAAs y daño muscular, rendimiento deportivo, fatiga central, respuesta anabólica en periodo de recuperación y respuesta inmunológica en periodos diferentes del entrenamiento: antes, durante y después o una combinación de éstos. Discusión: Se observa que existe un menor grado de dolor y daño muscular, menor percepción del esfuerzo y fatiga mental, mayor respuesta anabólica en periodo de recuperación y mejora de la respuesta inmunológica cuando se suplementa con BCAAs, no obstante su toma antes o durante la actividad física no mejora el rendimiento deportivo. No se ha encontrado consenso en la dosis y cronología de la toma más eficaz, aunque es más efectivo si hay una relación 2-3/1/1g, entre los aminoácidos Leucina/ Isoleucina y Valina.

Constructing the Vulvar Pain Assessment Questionnaire Inventory

The goals of this program of research were to examine the link between self-reported vulvar pain and clinical diagnoses, and to create a user-friendly assessment tool to aid in that process. These goals were undertaken through a series of four empirical studies (Chapters 2-6): one archival study, two online studies, and one study conducted in a Women’s Health clinic. In Chapter 2, the link between self-report and clinical diagnosis was confirmed by extracting data from multiple studies conducted in the Sexual Health Research Laboratory over the course of several years. We demonstrated the accuracy of diagnosis based on multiple factors, and explored the varied gynecological presentation of different diagnostic groups. Chapter 3 was based on an online study designed to create the Vulvar Pain Assessment Questionnaire (VPAQ) inventory. Following the construct validation approach, a large pool of potential items was created to capture a broad selection of vulvar pain symptoms. Nearly 300 participants completed the entire item pool, and a series of factor analyses were utilized to narrow down the items and create scales/subscales. Relationships were computed among subscales and validated scales to establish convergent and discriminant validity. Chapters 4 and 5 were conducted in the Department of Obstetrics & Gynecology at Oregon Health & Science University. The brief screening version of the VPAQ was employed with patients of the Program in Vulvar Health at the Center for Women’s Health. The accuracy and usefulness of the VPAQscreen was determined from the perspective of patients as well as their health care providers, and the treatment-seeking experiences of patients was explored. Finally, a second online study was conducted to confirm the factor structure, internal consistency, and test-retest reliability of the VPAQ inventory. The results presented in these chapters confirm the link between targeted questions and accurate diagnoses, and provide a guideline that is useful and accessible for providers and patients.

Shoulder pain in overhead athletes : a systematic review of orthopaedic causes

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Differences in analgesia in opioid naïve and tolerant patients with sciatic nerve blockade following elective foot and ankle surgery

1.1 Introduction and Purpose: Adequate postoperative analgesia in the opioid tolerant with chronic non-malignant pain is challenging. Multimodal pain relief regimens include regional anesthesia but opioid tolerant patients report increased postoperative pain and opioid consumption. This study compared analgesia in opioid naïve and tolerant patients receiving postoperative sciatic nerve blockade for foot and ankle surgery. 1.2 Method: Preoperative pain scores, trauma, maintenance and intraoperative opioid doses and following postoperative sciatic nerve blockade, patient self-reported pain scores and opioid consumption at discharge from the post-anesthesia unit and 24 hours were recorded. 1.3 Results: 191 patients enrolled. 40.3% were opioid tolerant and 33% had lower extremity trauma. Preoperative, immediate and delayed postoperative pain scores and intraoperative, immediate and 24 hour postoperative consumption of opioids were increased in opioid tolerant patients. Trauma and continuous infusion in opioid naïve and tolerant groups did not result in differences in 24 hour opioid consumption. 1.4 Limitations: Small subgroups and use of the pain score limited the accuracy of results. 1.5 Conclusion: Opioid tolerant patients require greater analgesic doses following sciatic nerve blockade for foot and ankle surgery. 24 hour opioid consumption for opioid naïve and tolerant patients is neither influenced by lower extremity injury nor continuous infusion.

An ancient neurotrophin code in zebrafish; the Runx/Cbfβ complex specifies the fate switch from TrkB+ to TrkC+ nociceptors and sensory receptor expression

Thesis (Ph.D.)--University of Washington, 2016-06

Joining forces - Combining cognition-targeted motor control training with group or individual pain physiology education: A successful treatment for chronic low back pain

Chronic unremittent low back pain (LBP) is characterised by cognitive barriers to treatment. Combining a motor control training approach with individualised education about pain physiology is effective in this group of patients. This randomized comparative trial (i) evaluates an approach to motor control acquisition and training that considers the complexities of the relationship between pain and motor output, and (ii) compares the efficacy and cost of individualized and group pain physiology education. After an "ongoing usual treatment" period, patients participated in a 4-week motor control and pain physiology education program. Patients received four one-hour individualized education sessions (IE) or one 4-hour group lecture (GE). Both groups reduced pain (numerical rating scale) and disability (Roland Morris Disability Questionnaire). IE showed bigger decreases, which were maintained at 12 months (P < 0.05 for all). The combined motor control and education approach is effective. Although group education imparts a lesser effect, it may be more cost-efficient. [ABSTRACT FROM AUTHOR]

Evidence of altered lumbopelvic muscle recruitment in the presence of sacroiliac joint pain

Study Design. Cross-sectional study of electromyographic onsets of trunk and hip muscles in subjects with a clinical diagnosis of sacroiliac joint pain and matched control subjects. Objectives. To determine whether muscle activation of the supporting leg was different between control subjects and subjects with sacroiliac joint pain during hip flexion in standing. Background. Activation of the trunk and gluteal muscles stabilize the pelvis for load transference; however, the temporal pattern of muscle activation and the effect of pelvic pain on temporal parameters has not been investigated. Methods. Fourteen men with a clinical diagnosis of sacroiliac joint pain and healthy age-matched control subjects were studied. Surface electromyographic activity was recorded from seven trunk and hip muscles of the supporting leg during hip flexion in standing. Onset of muscle activity relative to initiation of the task was compared between groups and between limbs. Results. The onset of obliquus internus abdominis (OI) and multifidus occurred before initiation of weight transfer in the control subjects. the onset of obliquus internus abdominis, multifidus, and gluteus maximus was delayed on the symptomatic side in subjects with sacroiliac joint pain compared with control subjects, and the onset of biceps femoris electromyographic activity was earlier. IN addition, electromyographic onsets were different between the symptomatic and asymptomatic sides in subjects with sacroiliac joint pain. Conclusions. The delayed onset of obliquus internus abdominis, multifidus, and gluteus maximus electromyographic activity of the supporting leg during hip flexion, in subjects with sacroiliac joint pain. suggests an alteration in the strategy for lumbopelvic stabilization that may disrupt load transference through the pelvis.

The role of morphine-6-glucuronide (M6G) in pain control

Morphine-6beta-D-glucuronide (M6G) is an analgesically active metabolite of morphine, accounting for approximate to10% of the morphine dose when administered by systemic routes to humans. Although M6G is more hydrophilic than morphine, it crosses the blood-brain barrier, albeit relatively slowly. For this reason, it is generally thought that, after chronic dosing, M6G contributes significantly to the analgesic effects of systemically administered morphine. Owing to its polar nature, M6G is cleared from the systemic circulation primarily via renal elimination. As M6G accumulates in patients with renal impairment, there is an increased risk of M6G-induced respiratory depression in renal failure patients who are being dosed chronically with systemic morphine. Consistent with its analgesic and respiratory depressant properties, M6G binds to the p-opioid receptor in a naloxone-reversible manner. Although the affinity of M6G for the mu-opioid receptor is similar to or slightly less than that of morphine, preclinical studies in rodents show that M6G is one to two orders of magnitude more potent than morphine when administered by central routes. This major discrepancy between the markedly higher intrinsic antinociceptive potency of M6G relative to morphine, despite their similar p-opioid receptor binding affinities, is difficult to reconcile. It has been proposed that M6G mediates its pain-relieving effects through a novel 'M6G opioid receptor', while others have argued that M6G may have higher efficacy than morphine for transduction of intracellular events. When administered by parenteral routes to rodents, M6G's antinociceptive potency is no more than twofold higher than morphine. In humans, the analgesic efficacy and respiratory depressant potency of M6G relative to morphine have been assessed in a number of short-term studies involving the intrathecal or intravenous routes of administration. For example, in hip replacement patients, intrathecal M6G provided excellent postoperative analgesia but the occurrence of late respiratory depression in 10% of these patients raised serious concern about safety. In postoperative patients, intravenous M6G administered by means of patient-controlled analgesia (PCA), or bolus plus PCA, produced no analgesia in one study and limited analgesia in another. Similarly, there was a lack of significant analgesia in healthy volunteers who received intravenous M6G for the alleviation of experimental pain (carbon dioxide applied to the nasal mucosa). In contrast, satisfactory analgesia was produced by bolus doses of intravenous M6G administered to patients with cancer pain, and to healthy volunteers with experimentally-induced ischaemic, electrical or thermal (ice water) pain. Studies to date in healthy volunteers suggest that intravenous M6G may be a less potent respiratory depressant and have a lower propensity for producing nausea and vomiting than morphine. However, it is unclear whether equi-analgesic doses of M6G and morphine were compared. Clearly, more extensive short-term trials, together with studies involving chronic M6G administration, are necessary before the potential clinical utility of M6G as an analgesic drug in its own right can be determined.

A randomized controlled trial of a nurse-administered educational intervention for improving cancer pain management in ambulatory settings

The persistence of negative attitudes towards cancer pain and its treatment suggests there is scope for identifying more effective pain education strategies. This randomized controlled trial involving 189 ambulatory cancer patients evaluated an educational intervention that aimed to optimize patients' ability to manage pain. One week post-intervention, patients receiving the pain management intervention (PMI) had a significantly greater increase in self-reported pain knowledge, perceived control over pain, and number of pain treatments recommended. Intervention group patients also demonstrated a greater reduction in willingness to tolerate pain, concerns about addiction and side effects, being a "good" patient, and tolerance to pain relieving medication. The results suggest that targeted educational interventions that utilize individualized instructional techniques may alter cancer patient attitudes, which can potentially act as barriers to effective pain management. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Use of complementary and alternative medicine and quality of life: changes at the end of life

The purpose of this study was to compare the physical, psychological and social dimensions associated with quality-of-life outcomes over the last year of life, between advanced cancer users and nonusers of complementary and alternative medicine. One hundred and eleven patients were identified through Queensland Cancer Registry records, and followed up every four to six weeks until close to death using standardized protocols. Outcome measures were symptom burden, psychological distress, subjective wellbeing, satisfaction with conventional medicine and need for control over treatment decisions. At the initial interview, 36 (32%) participants had used complementary/ alternative medicine the previous week; mainly vitamins, minerals and tonics and herbal remedies. Among all participants, 53 (48%) used at least one form of complementary/ alternative medicine over the study period. Only six (11%) visited alternative practitioners on a regular basis. Overall, complementary/ alternative medicine users reported higher levels of anxiety and pain, less satisfaction with conventional medicine and lower need for control over treatment decisions compared with nonusers. These differences tend to change as death approaches. A more rigorous assessment of complementary/ alternative medicine use, psychological distress, pain and subjective wellbeing among patients with advanced cancer is needed in the clinical setting.

Quality assurance experience with the randomized neuropathic bone pain trial (Trans-Tasman Radiation Oncology Group, 96.05)

Background and purpose: Trans-Tasman Radiation Oncology Group 96.05 is a prospective randomized controlled trial comparing a single 8 Gy with 20 Gy in five fractions of radiotherapy (RT) for neuropathic pain due to bone metastases. This paper summarizes the quality assurance (QA) activities for the first 234 patients (accrual target 270). Materials and methods: Independent audits to assess compliance with eligibility/exclusion criteria and appropriateness of treatment of the index site were conducted after each cohort of approximately 45 consecutive patients. Reported serious adverse events (SAEs) in the form of cord/cauda equina compression or pathological fracture developing at the index site were investigated and presented in batches to the Independent Data Monitoring Committee. Finally, source data verification of the RT prescription page and treatment records was undertaken for each of the first 234 patients to assess compliance with the protocol. Results: Only one patient was found conclusively not to have genuine neuropathic pain, and there were no detected 'geographical misses' with RT fields. The overall rate of detected infringements for other eligibility criteria over five audits (225 patients) was 8% with a dramatic improvement after the first audit. There has at no stage been a statistically significant difference in SAEs by randomization arm. There was a 22% rate of RT protocol variations involving ten of the 14 contributing centres, although the rate of major dose violations (more than +/- 10% from protocol dose) was only 6% with no statistically significant difference by randomization arm (P = 0.44). Conclusions: QA auditing is an essential but time-consuming component of RT trials, including those assessing palliative endpoints. Our experience confirms that all aspects should commence soon after study activation. Crown Copyright (C) 2003 Published by Elsevier Science Ltd. All rights reserved.