Developmental motor deficits induced by combined fetal exposure to lipopolysaccharide and early neonatal hypoxia/ischemia: a novel animal model for cerebral palsy in very premature infants.

A critical issue in animal models of perinatal brain injury is to adapt the pertinent pathophysiological scenarios to their corresponding developmental window in order to induce neuropathological and behavioral characteristics reminiscent to perinatal cerebral palsy (CP). A major problem in most of these animal models designed up to now is that they do not present motor deficits characteristic of CP. Using a unique rat paradigm of prenatal inflammation combined to an early postnatal hypoxia-ischemia pertinent to the context of very early premature human newborns, we were interested in finding out if such experimental conditions might reproduce both histological damages and behavioral deficits previously described in the human context. We showed that exposure to lipopolysaccharide (LPS) or hypoxia-ischemia (H/I) induced behavioral alterations in animals subjected to forced motor activity. When both LPS and H/I aggressions were combined, the motor deficits reached their highest intensity and affected both spontaneous and forced motor activities. LPS+H/I-exposed animals also showed extensive bilateral cortical and subcortical lesions of the motor networks affecting the frontal cortices and underlying white matters fascicles, lenticular nuclei and the substantia nigra. These neuropathological lesions and their associated motor behavioral deficits are reminiscent of those observed in very preterm human neonates affected by subsequent CP and validate the value of the present animal model to test new therapeutic strategies which might open horizons for perinatal neuroprotection.

Chemokine network in the nervous system: a new target for pain relief.

Physical insults including but not limited to nerve damage, inflammation, visceral pathologies and cancer generate long lasting pain commonly referred as chronic pain. Recently, members of the chemokine family and their receptors emerged as key modulators in nociceptive influx transmission in neuropathic and inflammatory chronic pain models. To this day, rodents defective in specific chemokine receptors have provided evidence of the implication of chemokine in pain sensitivity. In addition, up-regulation of chemokines and their receptors at multiple levels in the central nervous (CNS) and peripheral (PNS) systems is associated in the development of chronic pain. Indeed, we point out the fact that chemokines are synthesized and released by both neuronal and non-neuronal cells and act as neuromodulators. Even if their functional roles in the CNS remain largely unknown, chemokines participate in the glial activation and modulation of neuronal excitability as well as neurotransmitter release. This review focuses on three chemokines (i.e. CCL2, CXCL12, CX3CL1) recently identified as important mediators of the initiation and maintenance of pain hypersensitivity, thus broadening the panel of new strategies for the management of chronic pain.

Development and Implementation of a Registry of Patients Attending Multidisciplinary Pain Treatment Clinics: The Quebec Pain Registry.

The Quebec Pain Registry (QPR) is a large research database of patients suffering from various chronic pain (CP) syndromes who were referred to one of five tertiary care centres in the province of Quebec (Canada). Patients were monitored using common demographics, identical clinical descriptors, and uniform validated outcomes. This paper describes the development, implementation, and research potential of the QPR. Between 2008 and 2013, 6902 patients were enrolled in the QPR, and data were collected prior to their first visit at the pain clinic and six months later. More than 90% of them (mean age ± SD: 52.76 ± 4.60, females: 59.1%) consented that their QPR data be used for research purposes. The results suggest that, compared to patients with serious chronic medical disorders, CP patients referred to tertiary care clinics are more severely impaired in multiple domains including emotional and physical functioning. The QPR is also a powerful and comprehensive tool for conducting research in a "real-world" context with 27 observational studies and satellite research projects which have been completed or are underway. It contains data on the clinical evolution of thousands of patients and provides the opportunity of answering important research questions on various aspects of CP (or specific pain syndromes) and its management.

Descending nociceptive inhibition is modulated in a time-dependent manner in a double-hit model of chronic/tonic pain.

Clinical evidences suggest that an imbalance between descending inhibition and facilitation drives the development of chronic pain. However, potential mechanisms promoting the establishment of a persistent pain state and the increased pain vulnerability remain unknown. This preclinical study was designed to evaluate temporal changes in descending pain modulation at specific experimental endpoints (12, 28, 90 and 168 days) using a novel double-hit model of chronic/tonic pain (first hit: chronic constriction injury (CCI) model; second hit: tonic formalin pain in the contralateral hindpaw). Basal activity of bulbo-spinal monoaminergic systems was further assessed through liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) screening of cerebrospinal fluid (CSF). We found that CCI-operated rats exhibited a reduced nociceptive response profile, peaking on day 28, when subjected to tonic pain. This behavioral response was accompanied by a rapid increase in basal CSF serotonin and norepinephrine levels 12 days after neuropathy, followed by a return to sham levels on day 28. These molecular and behavioral adaptive changes in descending pain inhibition seemed to slowly fade over time. We therefore suggest that chronic neuropathic pain produces a transient hyperactivation of bulbo-spinal monoaminergic drive when previously primed using a tonic pain paradigm (i.e., formalin test), translating into inhibition of subsequent nociceptive behaviors. Altogether, we propose that early hyperactivation of descending pain inhibitory mechanisms, and its potential ensuing exhaustion, could be part of the temporal neurophysiological chain of events favoring chronic neuropathic pain establishment.

Tuberculosis in health care settings and the estimated benefits of engineering controls and respiratory protection.

Intra-institutional spread of tuberculosis (Tb) has re-emerged as a substantial public and occupational health threat. To characterize the person-hours and lifetime risks of Tb-related morbidity and mortality, we performed a risk assessment for health care workers (HCWs) developing Tb-related morbidity and mortality at varying levels of exposure, engineering controls, and respiratory protection. Under average conditions of exposure, one Tb skin-test conversion is estimated to occur for every 2650 person-hours of work by unprotected workers. With higher exposures, a skin-test conversion for an unprotected worker may occur in as few as 3 person-hours. Use of respiratory protection is estimated to reduce risks by the following proportions: surgical mask, 2.4-fold; disposable dust, fume, mist, or disposable high-efficiency particulate air filtering (HEPA) mask, 17.5-fold; elastomeric HEPA cartridge respirator, 45.5-fold; or powered air-purifying respirator (PAPR), 238-fold. Assuming a lifetime exposure of 250 hours, the risk of a skin-test conversion is estimated to be 9%. We conclude that HCWs are at substantial risk for Tb-related morbidity and mortality, and that administrative controls, engineering controls, and respirators offer substantial benefits in risk reduction.

[Evaluative research on the distribution of health videocassettes destined for a disadvantaged Montreal population]. / Recherche évaluative sur la distribution de vidéocassettes santé destinées à une population défavorisée de Montréal.

The present article describes the implementation and the evaluation of an intervention done in the context of a heart health community and multifactorial program. The intervention aimed to offer six videocassettes on cardiovascular health to a low-income and low-educated clientele through five video-clubs. All videoclubs (n = 5) from St. Henri/Petite Bourgogne agreed to distribute the videocassettes free of charge. Two components were examined: admissibility by videoclubs' owner and clientele's receptivity towards the intervention. Results showed that all videoclubs offered free display and service for the videocassettes. The article also presents a discussion of the feasibility and the possibilities to broaden this type of action.

[Evaluation of the implementation of an educational curriculum: optimal interventions for the adoption of an educational program of health in elementary schools]. / Evaluation de l'implantation d'un curriculum scolaire: Pistes d'interventions pour optimiser l'adoption et l'implantation de programmes d'éducation à la santé dans les écoles primaires.

A multiple case study design is used to explain the level of implementation of a "Heart Health" curriculum by grade four teachers of eight schools in a Montreal multiethnic and underprivileged district. An interview and logbook examine the following variables: 1) personal characteristics of the teachers; 2) organizational characteristics of the schools; 3) characteristics of the program; 4) collaboration between the health and educational sectors; and 5) curriculum level of use and fidelity of implementation. The results show in particular that the personal characteristics of the teachers and the characteristics of the program explain the level of implementation of the Heart Health curriculum.

Pediatric environmental health: perceptions from a survey questionnaire.

To expand the base of knowledge regarding perceptions about potential environmental threats to children's health, a survey was conducted in the Northwest United States. Samples of Head Start parents, PTA presidents, public health officials, school nurses, naturopathic physicians, family practitioners, and pediatricians were mailed a questionnaire inquiring into the nature and degree of concerns about pediatric environmental health. The response rate was 24%. Trends in the data showed disparities in perceptions regarding levels of concern and exposure concerns between respondent categories. Disparities also existed regarding information resources used for children's environmental health. Recognizing differences in perceptions of children's environmental health, as demonstrated in these results, may be useful for risk communication and resource allocation, especially in the context of the wide variety of health belief models. Such knowledge may help clarity situations with environmental health risk concerns, including clinical, public health, and educational circumstances.

Improving the selection of true incident cases of low back pain by screening retrospective administrative data.

BACKGROUND: The difficulty in identifying the onset of low back pain (LBP) limits the capacity to determine the incidence of LBP at the population level and, further, to identify risk factors. In the literature, incidence cohorts have been built with patients initially considered LBP-free for 6-12 months prior to their selection. This 'clearance period' might not be sufficient to exclude recurrent patients having experienced previous LBP episodes and might result in a misclassification bias. METHODS: Using the Canadian province of Quebec's medical administrative physicians' claims database, a cohort of prevalent claims-based recurrent LBP patients was built for 2007. The medical history of 81,329 patients was screened for a period of 11 years. Positive predictive values (PPVs), kappa statistics and a survival function were calculated to determine the optimal clearance period for capturing first-time events. RESULTS: The 2007 annual incidence of adult claims-based recurrent LBP was estimated at 242 per 100,000 persons. Men between 18 and 34 years of age were found to be 1.18 times more at risk than their counterparts. Altogether, the elderly (over 80 years) had 52% more new cases than the 18-34 age group. A very good convergence for PPV and kappa was found for a 7-year clearance period. This allowed determining the annual incidence from 2000 to 2007, showing a decrease of 26%. CONCLUSION: Screening the medical history of LBP patients can provide more accurate incidence estimates by limiting the over-ascertainment of first-time LBP patients. A 4- to 7-year clearance period should be considered.

Intrathecal administration of NTS1 agonists reverses nociceptive behaviors in a rat model of neuropathic pain.

Chronic neuropathic pain arising from peripheral nerve damage is a severe clinical issue where there is a major unmet medical need. We previously demonstrated that both neurotensin (NT) receptor subtypes 1 (NTS1) and 2 (NTS2) are involved in mediating the naloxone-insensitive antinociceptive effects of neurotensin in different analgesic tests including hotplate, tail-flick, and tonic pain. However, the role of these receptors in neuropathic pain management has been poorly investigated. In the present study, we therefore examined whether intrathecal delivery of NTS1 agonists was effective in reducing neuropathic pain symptoms in rats. Neuropathy was induced by sciatic nerve constriction (CCI model), and the development of mechanical allodynia and thermal hyperalgesia on the ipsi- and contralateral hind paws was examined 3, 7, 14, 21, and 28 days post-surgery. CCI-operated rats exhibited significant increases in thermal and mechanical hypersensitivities over a 28-day testing period. Spinal injection of NT to CCI rats alleviated the behavioral responses to radiant heat and mechanical stimuli, with a maximal reversal of 91% of allodynia at 6 µg/kg. Intrathecal administration of the NTS1-selective agonist, PD149163 (30-90 µg/kg) also produced potent anti-allodynic and anti-hyperalgesic effects in nerve-injured rats. Likewise, heat hyperalgesia and tactile allodynia produced by CCI of the sciatic nerve were fully reversed by the NTS1 agonist, NT69L (5-25 µg/kg). Altogether, these results support the idea that the NTS1 receptor subtype is involved in pain modulation, and the potential use of NTS1 agonists for the treatment of painful neuropathies.

Altered morphine-induced analgesia in neurotensin type 1 receptor null mice.

Both neurotensin (NT) and opioid agonists have been shown to induce antinociception in rodents after central administration. Besides, previous studies have revealed the existence of functional interactions between NT and opioid systems in the regulation of pain processing. We recently demonstrated that NTS1 receptors play a key role in the mediation of the analgesic effects of NT in long-lasting pain. In the present study, we therefore investigated whether NTS1 gene deletion affected the antinociceptive action of mu opioid drugs. To this end, pain behavioral responses to formalin were determined following systemic administration of morphine in both male and female NTS1 knockout mice. Acute injection of morphine (2 or 5 mg/kg) produced strong antinociceptive effects in both male and female wild-type littermates, with no significant sex differences. On the other hand, morphine analgesia was considerably reduced in NTS1-deficient mice of both sexes compared to their respective controls, indicating that the NTS1 receptor actively participates in mu opioid alleviating pain. By examining specifically the flinching, licking and biting nociceptive behaviors, we also showed that the functional crosstalk between NTS1 and mu opioid receptors influences the supraspinally-mediated behaviors. Interestingly, sexual dimorphic action of morphine-induced pain inhibition was found in NTS1 null mice in the formalin test, suggesting that the endogenous NT system interacts differently with the opioid network in male and female mice. Altogether, these results demonstrated that NTS1 receptor activation operates downstream to the opioidergic transmission and that NTS1-selective agonists combined with morphine may act synergistically to reduce persistent pain.

Involvement of NTS2 receptors in stress-induced analgesia.

Stress activates multiple neural systems that suppress pain sensation. This adaptive phenomenon referred as stress-induced analgesia (SIA) is mediated by the activation of endogenous pain inhibitory systems. Both opioid and non-opioid forms of SIA have been elicited in rodents according to stressor parameters and duration. There is accumulating evidence that the endogenous neurotensin (NT) system plays an important role in SIA. Especially, NT-deficient mice were shown to exhibit reduced SIA following water avoidance or restraint stress. Since central NT produces naloxone-insensitive analgesic effects by acting on spinal and supraspinal NTS2 receptors, we hypothesized that NT might mediate non-opioid SIA through NTS2 activation. Here, we evaluated the influence of an opioid-independent severe stress produced by a cold-water swim for 3 min at 15 degrees C on rodent offspring's pain perception. Our results demonstrated that mice lacking NTS2 exhibit significantly reduced SIA following cold-water swim stress. Indeed, NTS2 knockout mice submitted to both acute (plantar test) and tonic (formalin test) pain stimuli show a greater sensitivity to pain in comparison to wild-type littermates. Accordingly, pretreatment with the NT receptor antagonist SR142948A results in a hyperalgesic response to stress induced by cold-water swim. Endogenous NT regulates hypothalamic-pituitary-adrenal axis activity in stress condition by increasing corticosterone plasma levels. Accordingly, the plasma levels of corticosterone measured by radioimmunoassay are significantly reduced in non-stressed and stressed NTS2-deficient mice in comparison with wild-type mice. To further investigate the site of action of NT in mediating SIA, we microinjected NTS2 agonists in lumbar spinal cord and quantified post-stress sensitivity to pain in rats using the plantar test. Exogenously administered NTS2 analogs, JMV-431, beta-lactotensin and NT69L markedly enhance the magnitude and duration of stress antinociception in both 25- and 60-day-old rats. In sum, by using genetic and pharmacological approaches, we demonstrated here that NTS2 receptors mediate non-opioid SIA. Our results also revealed that the release of endogenous NT in response to stress requires the presence of NTS2 to stimulate corticotropin-releasing factor (CRF)-induced elevation of plasma corticosterone, and that NTS2 receptors localized at the lumbar spinal cord participate to the disinhibition of descending pain control pathways. Therefore, these data highlight the significance of NTS2 as a novel target for the treatment of pain and stress-related disorders.

An evaluation of factors affecting hazardous waste workers' use of respiratory protective equipment.

The purpose of this study was to describe the perceptions of a group of hazardous waste workers about their workplace hazards and to understand their beliefs and attitudes about the use of respiratory protective equipment (RPE). There were two phases of data collection: (1) interviews to identify factors that influence respirator use and (2) a written survey to evaluate the importance of these factors. This article describes the findings from the written survey completed by 255 eligible respondents (return rate = 46.5%, 255/548). Subjects used a weighting system to score 18 identified factors that influence the use of RPE. Scores were compared according to type of respirator, frequency of use, and associated health symptoms. The factors that had the most positive influence on respirator use were concern about work exposure, fit-testing, and training. The most negative influences were communication, personal comfort, effect on vision, structural environment, and fatigue. More frequent users (once per month or more) were significantly more likely to view fit-testing, health effects, and effects on vision negatively than were less frequent users. Persons who reported health symptoms associated with respirator use had more negative scores than persons without health symptoms. Workers categorized as laborers were more likely to be frequent respirator users and to wear supplied-air respirators, and were significantly more likely to view vulnerability to disease negatively, than were other worker groups. The findings from this study indicate that respiratory protection programs must extend beyond training and education; to be maximally effective, health professionals must be responsive to the specific concerns of the workers.

Barriers and solutions in implementing occupational health and safety services at a large nuclear weapons facility.

The Hanford Nuclear Reservation is one of the U.S. Department of Energy's largest nuclear weapons sites. The enormous changes experienced by Hanford over the last several years, as its mission has shifted from weapons production to cleanup, has profoundly affected its occupational health and safety services. Innovative programs and new initiatives hold promise for a safer workplace for the thousands of workers at Hanford and other DOE sites. However, occupational health and safety professionals continue to face multiple organizational, economic, and cultural challenges. A major problem identified during this review was the lack of coordination of onsite services. Because each health and safety program operates independently (albeit with the guidance of the Richland field operations office), many services are duplicative and the health and safety system is fragmented. The fragmentation is compounded by the lack of centralized data repositories for demographic and exposure data. Innovative measures such as a questionnaire-driven Employee Job Task Analysis linked to medical examinations has allowed the site to move from the inefficient and potentially dangerous administrative medical monitoring assignment to defensible risk-based assignments and could serve as a framework for improving centralized data management and service delivery.

Respiratory protective devices: rates of medical clearance and causes for work restrictions.

BACKGROUND: There are no published data on the outcomes and benefits of medical evaluations for the use of respiratory protective devices. We, therefore, conducted a retrospective database and chart review to assess the rates of medical clearance and causes for work restrictions at a Department of Energy complex. METHODS: All workers with work restrictions or denied clearance over a one-year period were identified and their medical records abstracted. RESULTS: Of the 5,569 workers who received medical evaluation, only 71 (1.3%) received limitations on respirator use documented in their medical record. Of the 65 workers with sufficient medical records for additional analysis, 9 of the 5,569 workers (0.2%) were denied medical clearance, while 56 workers (1.1%) received work restrictions. Pregnancy was the most common cause for denying medical clearance for respirator use. Lung disease, cardiovascular disease, and claustrophobia were the most common causes for work restrictions. Physical examination and spirometry added little to the detection of relevant medical conditions. CONCLUSIONS: We conclude that few workers fail medical clearance for respirator use or receive work restrictions. Data on adverse events from respirator use are needed to help design appropriate medical evaluations and uniform criteria for work restrictions or denial of medical clearance.

Medical clearance for respirator use: sensitivity and specificity of a questionnaire.

BACKGROUND: OSHA regulations require that workers receive medical clearance prior to respirator use, and recently, a detailed questionnaire has been provided to assist with this purpose. However, there are limited published data on the sensitivity and specificity of self-administered questionnaires for identifying individuals who may safely wear a respirator. METHODS: We tested 474 consecutive workers at a Department of Energy complex. After completing the self-administered questionnaire, all workers received a standardized physician evaluation including interview, physical examination, and spirometry. The outcomes of the questionnaire assessment were compared to the outcomes of physician evaluation. RESULTS: Data for analysis were available from 413 of workers (87%). All workers received medical clearance; only 10 workers (2.4%) received work restrictions. The questionnaire demonstrated 100% sensitivity in identifying workers who required work restrictions, but had specificity of only 19%. Compared to physician evaluation, the questionnaire had modest sensitivity to the detection of chronic medical conditions. CONCLUSIONS: These data suggest that the rates of medical clearance for respirator use are very high, and that a self-administered questionnaire may be appropriate for medical clearance in certain settings. It is recommended that the policy of routine physician evaluation and spirometry for respirator clearance be re-examined.