Understanding Cannabis-Based Therapeutics in Sports Medicine.

CONTEXT: With increased use of cannabis-based products by the public for both recreational and medical use, sports medicine clinicians should be informed of historical context, current legal considerations, and existing evidence with regard to efficacy, safety, and risks in the athletic community. EVIDENCE ACQUISITION: A review of ClinicalTrials.gov, MEDLINE, and CINAHL from 2015 to present was conducted with emphasis on the most recent literature using search terms, cannabis, nabiximols, cannabinoids, pain management, THC, CBD, and marijuana. Bibliographies based on original search were utilized to pursue further literature search. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 3. RESULTS: At present, limited high-quality studies exist for use of cannabinoids for acute pain, chronic pain, or concussion. None of the trials involving cannabinoids included the athletic population. Thus, results from this clinical review are extrapolated to conditions of the sports medicine population. For acute pain, 2 small-randomized double-blinded crossover trials concluded no immediate effect of cannabinoid therapy. More robust evidence exists for treatment of chronic pain conditions through meta-analysis and systemic reviews. Cannabinoid therapy exhibits moderate efficacy as a treatment for some chronic pain conditions. Investigations included a broad spectrum of chronic pain conditions, including neuropathic, musculoskeletal, inflammatory, and central pain conditions, and reveal reduction in pain and improvement of quality of life with limited adverse effects. For concussion, evidence is based on preclinical in vitro and animal models revealing possible neuroprotective effects as well as 2 clinical studies involving the presence of cannabinoids for concussion (some sports-related), but there are no high-quality trials evaluating efficacy for treatment with cannabinoids at this time. CONCLUSION: Although various biochemical explanations exist on the use of cannabinoid therapy through modulation of the endocannabinoid system for several medical issues affecting athletes, recommendations from clinicians must be extrapolated from a majority of research done in the nonathletic population. Lack of strong-quality clinical evidence, coupled with inconsistent federal and state law as well as purity issues with cannabis-based products, make it difficult for the sports medicine clinician to widely recommend cannabinoid therapeutics at present. Future larger, higher quality clinical research studies with standardized pure extracts will better guide appropriate medical use going forward. At present, evidence for a multitude of therapeutic applications is emerging for cannabinoid treatment approaches. With emphasis placed on patient-centered clinical decisions, cannabinoids hold promise of treatment for athletes with chronic pain conditions. Clinicians who treat the athletic community must consider legal and ethical issues when discussing and recommending the use of cannabinoids, with acknowledgment of inconsistencies in purity of various formulations and concerns of drug testing.

Prohibited Contaminants in Dietary Supplements.

CONTEXT: With the increasing use of unregulated dietary supplements, athletes are at continued risk from adverse medical events and inadvertent doping. EVIDENCE ACQUISITION: A review of Clinical Key, MEDLINE, and PubMed databases from 2012 to 2017 was performed using search terms, including dietary supplement, contamination, doping in athletes, inadvertent doping, and prohibited substances. The references of pertinent articles were reviewed for other relevant sources. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 3. RESULTS: Poor manufacturing processes and intentional contamination with many banned substances continue to occur in dietary supplements sold in the United States. Certain sectors, such as weight loss and muscle-building supplements, pose a greater threat because they are more likely to be contaminated. CONCLUSION: Athletes will continue to be at risk for adverse events and failed doping tests due to contaminated dietary supplements until legislation changes how they are regulated. In the interim, there are several steps that can be taken to mitigate this risk, including improved education of medical staff and athletes and use of third party-certified products.

A cardiovascular disease policy model: part 2-preparing for economic evaluation and to assess health inequalities.

OBJECTIVES: This is the second of the two papers introducing a cardiovascular disease (CVD) policy model. The first paper described the structure and statistical underpinning of the state-transition model, demonstrating how life expectancy estimates are generated for individuals defined by ASSIGN risk factors. This second paper describes how the model is prepared to undertake economic evaluation. DESIGN: To generate quality-adjusted life expectancy (QALE), the Scottish Health Survey was used to estimate background morbidity (health utilities) and the impact of CVD events (utility decrements). The SF-6D algorithm generated utilities and decrements were modelled using ordinary least squares (OLS). To generate lifetime hospital costs, the Scottish Heart Health Extended Cohort (SHHEC) was linked to the Scottish morbidity and death records (SMR) to cost each continuous inpatient stay (CIS). OLS and restricted cubic splines estimated annual costs before and after each of the first four events. A Kaplan-Meier sample average (KMSA) estimator was then used to weight expected health-related quality of life and costs by the probability of survival. RESULTS: The policy model predicts the change in QALE and lifetime hospital costs as a result of an intervention(s) modifying risk factors. Cost-effectiveness analysis and a full uncertainty analysis can be undertaken, including probabilistic sensitivity analysis. Notably, the impacts according to socioeconomic deprivation status can be made. CONCLUSIONS: The policy model can conduct cost-effectiveness analysis and decision analysis to inform approaches to primary prevention, including individually targeted and population interventions, and to assess impacts on health inequalities.

A cardiovascular disease policy model that predicts life expectancy taking into account socioeconomic deprivation.

OBJECTIVES: A policy model is a model that can evaluate the effectiveness and cost-effectiveness of interventions and inform policy decisions. In this study, we introduce a cardiovascular disease (CVD) policy model which can be used to model remaining life expectancy including a measure of socioeconomic deprivation as an independent risk factor for CVD. DESIGN: A state transition model was developed using the Scottish Heart Health Extended Cohort (SHHEC) linked to Scottish morbidity and death records. Individuals start in a CVD-free state and can transit to three CVD event states plus a non-CVD death state. Individuals who have a non-fatal first event are then followed up until death. Taking a competing risk approach, the cause-specific hazards of a first event are modelled using parametric survival analysis. Survival following a first non-fatal event is also modelled parametrically. We assessed discrimination, validation and calibration of our model. RESULTS: Our model achieved a good level of discrimination in each component (c-statistics for men (women)-non-fatal coronary heart disease (CHD): 0.70 (0.74), non-fatal cerebrovascular disease (CBVD): 0.73 (0.76), fatal CVD: 0.77 (0.80), fatal non-CVD: 0.74 (0.72), survival after non-fatal CHD: 0.68 (0.67) and survival after non-fatal CBVD: 0.65 (0.66)). In general, our model predictions were comparable with observed event rates for a Scottish randomised statin trial population which has an overlapping follow-up period with SHHEC. After applying a calibration factor, our predictions of life expectancy closely match those published in recent national life tables. CONCLUSIONS: Our model can be used to estimate the impact of primary prevention interventions on life expectancy and can assess the impact of interventions on inequalities.

The changing face of hepatitis B in greater Glasgow: epidemiological trends 1993-2007.

BACKGROUND AND AIMS: Whilst hepatitis B (HBV) is historically uncommon in Scotland, anecdotal experience suggests an increasing prevalence of chronic infection. We sought to establish whether the incidence of chronic HBV is increasing in Greater Glasgow, and whether patients are assessed in secondary care. METHODS: The regional virus centre database identified HBV surface antigen (HBsAg) positive samples. For adult patients tested in Glasgow between 1993-2007 the first positive test was identified and classified as acute or chronic infection serologically. Clinic referral and attendance data was then obtained. RESULTS: 1,672 patients tested HBsAg positive; 1051 with chronic infection, 421 acute and 200 indeterminate. New diagnoses of HBV remained stable over time, however falling numbers of acute cases were mirrored by a rise in chronic cases from 40 to 119 per annum between 2000 and 2007. Of 193 patients diagnosed in 2006 and 2007, 51% were not seen in secondary care due to non referral (43%) or non attendance (8%). CONCLUSION: Chronic HBV trebled in Glasgow between 2000 and 2007. Most patients were not assessed in secondary care. Improved levels of clinic referral and attendance are required to ensure best care for HBV patients in Glasgow.

Prevalence of genetic haemochromatosis and iron overload in patients attending rheumatology and joint replacement clinics.

BACKGROUND & AIMS: Genetic Haemochromatosis (GH) is common in North European and Celtic populations and is associated with arthropathy. We aimed to measure the frequency of the common GH mutations (C282Y and H63D), the carrier frequency of C282Y and markers of iron overload in patients who were referred to our rheumatology and joint replacement clinics. METHODS: Unselected patients attending these clinics were anonymously tested for the described mutations. Transferrin saturation and serum ferritin were also measured and if elevated, the patients had predictive counselling then named GH mutation testing. The carrier and mutation frequencies were also determined in 340 local controls. RESULTS: One hundred and sixty-one unselected patients attending these clinics were studied. The C282Y mutation carrier frequency was 1 in 5.2 in patients compared with 1 in 8.1 in controls (p < 0.005). The overall mutation frequencies were similar in patients and controls. One patient was found to be a homozygous for the C282Y mutation and eight were compound heterozygotes. Seven other patients had a raised ferritin, one of whom was a C282Y heterozygote. CONCLUSION: The C282Y carrier frequency is significantly higher in patients attending rheumatology and joint replacement clinics than in controls. Screening of these patients for GH should be considered.

Histological changes in radial forearm skin flaps in the oral cavity.

We reported previously that skin flaps transplanted to the oral cavity in reconstructive surgery for oral cancer frequently acquired the gross appearance of buccal mucosa. The changes were shown to be reactive in nature. The "changed" flaps generally had a heavier infiltration of leukocytes in the dermis and appeared to have thicker epithelium. The present study quantifies these parameters, as well as the numbers of intraepithelial leukocytes. The flaps that had acquired the gross appearance of oral mucosa had significantly thicker epithelium, larger numbers of dermal leukocytes, and more intraepidermal inflammatory cells per unit length than flaps that retained the gross appearance of thin skin. No correlation was found between these changes and radiotherapy.

Axonal cytoskeletal changes after non-disruptive axonal injury.

In animal models of human diffuse axonal injury, axonal swellings leading to secondary axotomy occur between 2 and 6 h after injury. But, analysis of cytoskeletal changes associated with secondary axotomy has not been undertaken. We have carried out a quantitative analysis of cytoskeletal changes in a model of diffuse axonal injury 4 h after stretch-injury to adult guinea-pig optic nerves. The major site of axonal damage was the middle portion of the nerve. There was a statistically significant increase in the proportion of small axons with a diameter of 0.5 micron and smaller in which there was compaction of neurofilaments. Axons with a diameter greater than 2.0 microns demonstrated an increased spacing between cytoskeletal elements throughout the length of the nerve. However, in the middle segment of the nerve these larger axons demonstrated two different types of response. Either, where periaxonal spaces occurred, there was a reduction in axonal calibre, compaction of neurofilaments but no change in their number, and a loss of microtubules. Or, where intramyelinic spaces occurred there was an increased spacing between neurofilaments and microtubules with a significant loss in the number of both. Longitudinal sections showed foci of compaction of neurofilaments interspersed between regions where axonal structure was apparently normal. Neurofilament compaction was correlated with disruption of the axolemma at these foci present some hours after injury. We suggest that the time course of these axonal cytoskeletal changes after stretch-injury to central axons is shorter than those changes documented to occur during Wallerian degeneration.

Workplace in fluency management: factoring the workplace into fluency management.

This article addresses competency-based standards and guidelines for the involvement of speech-language pathologists in the workplace of clients who stutter. It advocates broadening customary practices in stuttering treatment and suggests that speech-language pathologists should extend their scope of service delivery to the workplace. It presents a sequence for the collaborative involvement of the employer and other workplace members and proposes strategies for evaluating workplace based fluency programs. Issues of fluency management, transfer, maintenance, and efficacy are discussed in the workplace context. Also addressed is workplace communication as well as such factors as stereotypes, discrimination, and resistance to change which may impinge on workplace intervention. It is argued that structured intervention, transfer, and generalization within a collaborative workplace framework facilitates best practice for the fluency clinician and more appropriate outcomes for the diversity of clients who stutter.

A confocal microscopic survey of serotoninergic axons in the lumbar spinal cord of the rat: co-localization with glutamate decarboxylase and neuropeptides.

Patterns of co-localization of serotonin with glutamate decarboxylase (the synthetic enzyme for GABA) or each one of eight neuropeptides (calcitonin gene-related peptide, dynorphin, enkephalin, galanin, neuropeptide Y, neurotensin, substance P and somatostatin) were investigated with dual-colour confocal laser scanning microscopy in the lumbar spinal cords of three adult rats. Four regions of the gray matter were studied (laminae I-II, V, IX and X). The extent of co-localization was estimated by direct assessment of merged pairs of optical sections and by automated image analysis. Co-localization of serotonin and glutamate decarboxylase was found only in a few axons of laminae I-II but was not detected in other laminae. Peptides were not co-localized with serotonin in the superficial dorsal horn but considerable co-localization was found in motor nuclei and sparse co-localization was found in laminae V and X. Galanin and substance P frequently co-existed with serotonin in lamina IX but some co-localization with dynorphin, somatostatin, [Met]enkephalin and neuropeptide Y was also detected. Galanin, substance P and dynorphin were also co-localized with serotonin in a few axons of the deep dorsal horn and in the gray matter around the central canal. Neurotensin and calcitonin gene-related compound did not co-exist with serotonin in any of the laminae investigated. This evidence suggests that different populations of serotoninergic axons project to different regions of the spinal gray matter. Those containing glutamate decarboxylase terminate in the superficial dorsal horn and are likely to be involved in antinociception, whereas those containing peptides terminate principally in motor nuclei and are likely to modulate motor activity.

The effects of nerve growth factor on neurite outgrowth from cultured adult and aged mouse sensory neurons.

The present study demonstrated, by detailed computer image analysis, that cultured aged (2 years) as well as adult (6 months) mouse sensory neurons retained a capacity for neurite extension throughout the 9-day period investigated. Neurites arose predominantly from intermediate- and large-sized neurons. The numbers of neurites, the neurite with the major or longest length, the number of branches and the total extent of neuritogenesis were measured blindly from a total of 440 adult and 451 aged neurons, in five independent experiments for each, and data were statistically tested by ANOVA. The results demonstrated that NGF significantly enhanced neurite outgrowth from aged neurons in a low density enriched culture system as well as from adult neurons, and thereby extends the previous findings from other laboratories [7,25], which only monitored the response of young adult neurons. For total neurite lengths of adult and aged neurons differences were evident by the end of the 9-day culture period: major neurite length enhancement was predominantly responsible for the effect on adult neurons, whereas increased branch lengths contributed more in the case of aged neurons.

The relationship between glycine and gephyrin in synapses of the rat spinal cord.

In order to examine the relationship between gephyrin (the peripheral membrane protein associated with glycine receptors) and glycinergic boutons, we have carried out a post-embedding immunogold study of glycine-like immunoreactivity on sections of rat lumbar spinal cord which had previously been reacted with monoclonal antibody to gephyrin. In all three areas examined (laminae I and II, lamina III and lamina IX) the majority of profiles which were presynaptic at gephyrin-immunoreactive synapses were enriched with glycine-like immunoreactivity. It was estimated that at least 83% of profiles presynaptic to gephyrin-immunoreactive synapses in the superficial dorsal horn (laminae I and II) were glycine-immunoreactive, while for lamina III and the ventral horn (lamina IX) the proportions were at least 91% and 98% respectively. This provides strong evidence that glycine is a transmitter at those synapses where gephyrin- and glycine-like immunoreactivities are both present, but suggests that gephyrin may sometimes be expressed at non-glycinergic synapses and indicates the need for caution in using gephyrin-immunoreactivity as a marker for glycinergic synapses within the spinal cord. By reacting serial sections of dorsal horn with antisera to glycine and GABA, we have shown that many boutons in laminae I-III of the dorsal horn show both types of immunoreactivity and are therefore likely to use both amino acids as inhibitory transmitters. Many of the boutons which were presynaptic at axoaxonic synapses in the ventral part of lamina II and in lamina III were glycine- and GABA-immunoreactive and in many cases the postsynaptic element was the central axon of a type II synaptic glomerulus. Taken together with pharmacological evidence, this suggests that inhibitory interneurons in the dorsal horn which use both GABA and glycine may be important in controlling the flow of information from hair follicle afferents to other spinal neurons.

Immunocytochemical evidence that neurotensin is present in glutamatergic neurons in the superficial dorsal horn of the rat.

In order to determine whether glutamate is enriched in neurotensin-containing axons in the superficial dorsal horn of the rat spinal cord, we have carried out preembedding immunocytochemistry with an antiserum to neurotensin and then used a postembedding immunogold method with antiserum to glutamate. The immunogold label (corresponding to glutamate-like immunoreactivity) over 40 neurotensin-immunoreactive boutons in laminae I and II of the lumbar dorsal horn was compared with that over nearby axons that formed asymmetrical or symmetrical synapses. In addition, for 20 of these boutons, the labeling was compared with that over mossy and parallel fiber terminals (both of which are thought to use glutamate as a transmitter) from sections of cerebellum that had been processed together with those of spinal cord. Glutamate-like immunoreactivity was consistently high over neurotensin-immunoreactive boutons relative to most surrounding profiles. Immunostaining over these boutons was slightly (11%) lower than that over matched terminals that formed asymmetrical synapses, but considerably higher than that over the terminals that formed symmetrical synapses. The level of glutamate immunoreactivity in neurotensin-immunoreactive boutons in dorsal horn was similar to that in cerebellar parallel fiber terminals, but significantly lower than that in mossy fiber terminals. These results suggest that glutamate is a transmitter used by neurotensin-immunoreactive axons in the dorsal horn, and since these axons are thought to be largely or entirely derived from neurotensin-containing neurons in laminae I-III, they provide immunocytochemical evidence for a population of excitatory glutamatergic neurons in this region.

Sending your teenagers away. Controlled stress decreases neurotic vulnerability.

OBJECTIVE: To study the effect of a controlled stressor on the rate of personality maturity. DESIGN: Eighteen-month prospective controlled study. SETTING: General community. EXPERIMENTAL: Exposed to the stress of 12 months' intercultural experience. CONTROL: Remained in usual environment. MAIN OUTCOME MEASURE: A measure of personality vulnerability/maturity derived from a canonical correlational combination of trait anxiety, locus of control, and defense style. RESULTS: Exchange students exposed to the stressor made significantly greater gains in personality maturity (0.28 vs 0.03 SD: P < or = .01) than did the control students matched on this measure at baseline. CONCLUSION: Exchange students exposed to the stress of living abroad showed a substantial decrease in vulnerability, which should decrease the risk of future neurotic disorders in this group.

Diagnosis, personality and the long-term outcome of depression.

Patients diagnosed in the late 1960s as suffering from either endogenous or neurotic depression, or as presenting with depression but discharged with another neurotic diagnosis, were followed for 15 years. Diagnosis at index admission did not predict overall outcome, but patients with endogenous depression, an apparently stable diagnosis, had longer index admissions, were readmitted sooner, but spent less time ill than patients in either of the neurosis groups. Personality abnormality accounted for 20% of the variance in outcome in the neurotic groups and only 2% of the variance in the endogenous group. Thus there is evidence that endogenous and neurotic depression are two illnesses and that, in the neuroses particularly, prognosis will depend on the extent to which these personality abnormalities are modified by treatment.

[Estimation of severity of illness in intensive care: validation of physiologic stability index]. / Estimación de gravedad en cuidados intensivos: validación de índice de estabilidad fisiológica.

Physiological stability index (PSI) is a score proposed to evaluate the severity of different diseases in pediatric intensive care units (PICU) by giving scores to the deterioration of 34 measurable physiological variables. In order to validate PSI, it was prospectively applied to 132 patients who entered our PICU. A significant difference (p less than 0.001) was found between the average score of those patients who survived (means: 6.1) versus those who did not (means: 21); No difference was found between theoretical mortality rates obtained by logistic regression analysis and those obtained according to PSI score ranks even thought direct hemodynamic measurements like cardiac output and capillary (wedge) pulmonary pressure were not considered in this study. In conclusion, the PSI is a useful method to measure the severity of illness in pediatric intensive care and to compare results among PICU.