A proof-of-concept study comparing tinnitus and neural connectivity changes following multisensory perceptual training with and without a low-dose of fluoxetine.

Background. This proof-of-concept study investigated a method of multisensory perceptual training for tinnitus, and whether a short, low-dose administration of fluoxetine enhanced training effects and changed neural connectivity.Methods. A double-blind, randomized placebo controlled design with 20 participants (17 male, 3 female, mean age = 57.1 years) involved 30 min daily computer-based, multisensory training (matching visual, auditory and tactile stimuli to perception of tinnitus) for 20 days, and random allocation to take 20 mg fluoxetine or placebo daily. Behavioral measures of tinnitus and correlations between pairs of a priori regions of interest (ROIs), obtained using resting-state functional magnetic resonance imaging (rs-fMRI), were performed before and after the training.Results. Significant changes in ratings of tinnitus loudness, annoyance, and problem were observed with training. No statistically significant changes in Tinnitus Functional Index, Tinnitus Handicap Inventory or Depression Anxiety Stress Scales were found with training. Fluoxetine did not alter any of the behavioural outcomes of training compared to placebo. Significant changes in connectivity between ROIs were identified with training; sensory and attention neural network ROI changes correlated with significant tinnitus rating changes. Rs-fMRI results suggested that the direction of functional connectivity changes between auditory and non-auditory networks, with training and fluoxetine, were opposite to the direction of those changes with multisensory training and placebo.Conclusions. Improvements in tinnitus measures were correlated with changes in sensory and attention networks. The results provide preliminary evidence for changes in rs-fMRI accompanying a multisensory training method in persons with tinnitus.

A proof-of-principle study of the short-term effects of 3,4-methylenedioxymethamphetamine (MDMA) on tinnitus and neural connectivity.

Background: This study was conducted to investigate the short-term behavioural and neurophysiological effects of 3,4-methylenedioxymethamphetamine (MDMA) on tinnitus perception.Methods: A double-blind randomized controlled cross-over design. Part 1. Behavioural measures of tinnitus following 30 mg MDMA or placebo administration (N = 5 participants) and Part 2. Behavioural measures of tinnitus and correlations between pairs of apriori regions of interest (ROI) using resting-state functional magnetic resonance imaging (rs-fMRI) before and after 70 mg of MDMA or placebo (N = 8 participants).Results: The results to MDMA were similar to placebo. For the 70 mg dose, there was a significant reduction after 4 h in annoyance and ignore ratings. RsMRI showed decreased connectivity compared with placebo administration between the left hippocampal, right hippocampal, left amygdala and right amygdala regions, and between the right posterior parahippocampal cortex and the left amygdala after two hours of 70 mg MDMA administration. Increased connectivity compared to placebo administration was found post MDMA between the right post-central gyrus and right posterior and superior temporal gyrus, and between the thalamus and frontoparietal network.Conclusions: Following 70 mg of MDMA two tinnitus rating scales significantly improved. There was, however, a placebo effect. Compared with placebo the rsMRI following the MDMA showed reductions in connectivity between the amygdala, hippocampus and parahippocampal gyrus. There is sufficient proof of concept to support future investigation of MDMA as a treatment for tinnitus.

Circadian disruption and biomarkers of tumor progression in breast cancer patients awaiting surgery.

Psychological distress, which can begin with cancer diagnosis and continue with treatment, is linked with circadian and endocrine disruption. In turn, circadian/endocrine factors are potent modulators of cancer progression. We hypothesized that circadian rest-activity rhythm disruption, distress, and diurnal cortisol rhythms would be associated with biomarkers of tumor progression in the peripheral blood of women awaiting breast cancer surgery. Breast cancer patients (n=43) provided actigraphic data on rest-activity rhythm, cancer-specific distress (IES, POMS), saliva samples for assessment of diurnal cortisol rhythm, cortisol awakening response (CAR), and diurnal mean. Ten potential markers of tumor progression were quantified in serum samples and grouped by exploratory factor analysis. Analyses yielded three factors, which appear to include biomarkers reflecting different aspects of tumor progression. Elevated factor scores indicate both high levels and strong clustering among serum signals. Factor 1 included VEGF, MMP-9, and TGF-ß; suggesting tumor invasion/immunosuppression. Factor 2 included IL-1ß, TNF-α, IL-6R, MCP-1; suggesting inflammation/chemotaxis. Factor 3 included IL-6, IL-12, IFN-γ; suggesting inflammation/TH1-type immunity. Hierarchical regressions adjusting age, stage and socioeconomic status examined associations of circadian, distress, and endocrine variables with these three factor scores. Patients with poor circadian coordination as measured by rest-activity rhythms had higher Factor 1 scores (R(2)=.160, p=.038). Patients with elevated CAR also had higher Factor 1 scores (R(2)=.293, p=.020). These relationships appeared to be driven largely by VEGF concentrations. Distress was not related to tumor-relevant biomarkers, and no other significant relationships emerged. Women with strong circadian activity rhythms showed less evidence of tumor promotion and/or progression as indicated by peripheral blood biomarkers. The study was not equipped to discern the cause of these associations. Circadian/endocrine aberrations may be a manifestation of systemic effects of aggressive tumors. Alternatively, these results raise the possibility that, among patients with active breast tumors, disruption of circadian activity rhythms and elevated CAR may facilitate tumor promotion and progression.

Deficiencies in the availability of essential musculoskeletal surgical services at 883 health facilities in 24 low- and lower-middle-income countries.

BACKGROUND: The sequelae of acute musculoskeletal conditions, especially injuries and infections, are responsible for significant disability in low- and middle-income countries. This study characterizes the availability of selected musculoskeletal surgical services at different tiers of the health system in a convenience sample of 883 health facilities from 24 low- and lower-middle-income countries. METHODS: Selected data points from the World Health Organization's (WHO) tool of situational analysis of surgical availability were extracted from the WHO's database in December, 2013. These included infrastructure, physical resources and supplies, interventions, and human resources. For a descriptive analysis, facilities were divided into two groups based on number of beds (<100, 100-300, and >300) and level of facility (primary referral, secondary/tertiary, and Private/NGO/Mission). Statistical comparison was made between public and Private/NGO/Mission facilities based on number of beds (≤100, 100-300, and >300) using a Chi-Square analysis, with statistical significance at p < 0.05. FINDINGS: Significant deficiencies were noted in infrastructure, physical resources and supplies, and human resources for the provision of essential orthopedic surgical services at all tiers of the health system. Availability was significantly lower in public versus Private/NGO/Mission facilities for nearly all categories in facilities with ≤100 beds, and in a subset of measures in facilities with between 100 and 300 beds. INTERPRETATION: Deficiencies in the availability of orthopedic surgical services were observed at all levels of health facility and were most pronounced at facilities with ≤100 beds in the public sector. Strengthening the delivery of essential surgical services, including orthopedics, at the primary referral level must be prioritized if we are to reduce the burden of death and disability from a variety of emergent health conditions. FUNDING: There were no sources of funding.

Recombinant human erythropoietin dosing errors due to concentrated EPO.

AIMS: Recombinant human erythropoietin (rHuEPO) is widely used to treat anemia. A dialysis provider enacted a policy utilizing 20,000 U/ml multi-dose vials for rHuEPO dosing. The purpose of this study was to determine the accuracy and precision in administering small rHuEPO doses from this vial. METHODS: Ten registered nurses (RNs) were selected at random, supplied with a rHuEPO vial refilled with water, and instructed to withdraw the following amounts (1,200 U, 2,400 U, 3,600 U) using standard procedures and assuming the standard rHuEPO concentration of 20,000 U/ml. Samples were drawn up in duplicate and placed into 1.5 ml micro-centrifuge tubes. The volumes were measured using P-100 or P-200 microliter pipettes. The equivalent amount of rHuEPO was calculated by multiplying the volume by 20 U/microl. RESULTS: The rHuEPO dosing errors were large and on occasion greater than 100% at the 1,200 U dose. The variability for each RN, while large, was less than the inter-RN variability (within-RN % error 9.6% vs. 29.8% between-RN % error at the 1,200 unit dose). Errors occurred in both directions, both under- and overdosing. CONCLUSION: Utilizing concentrated rHuEPO resulted in significant dosing errors at low rHuEPO doses. The implications include inaccurate medication administration and disparity between administered and billed dosages. Policy decisions that effect medication administration need to be carefully evaluated to determine their impact on patient well-being and safety.

Retrospective review of Surgical Availability and Readiness in 8 African countries.

OBJECTIVES: The purpose of this study was to assess surgical availability and readiness in 8 African countries using the WHO's Service Availability and Readiness Assessment (SARA) tool. SETTING: We analysed data for surgical services, including basic and comprehensive surgery, comprehensive obstetric care, blood transfusion, and infection prevention, obtained from the WHO's SARA surveys in Sierra Leone, Uganda, Mauritania, Benin, Zambia, Burkina Faso, Democratic Republic of Congo and Togo. PRIMARY AND SECONDARY OUTCOME MEASURES: Among the facilities that were expected to offer surgical services (N=3492), there were wide disparities between the countries in the number of facilities per 100 000 population that reported offering basic surgery (1.0-12.1), comprehensive surgery (0.1-0.8), comprehensive obstetric care (0.1-0.8) and blood transfusion (0.1-0.8). Only 0.1-0.3 facilities per 100 000 population had all three bellwether procedures available, namely laparotomy, open fracture management and caesarean section. In all the countries, the facilities that reported offering surgical services generally had a shortage of the necessary items for offering the services and this varied greatly between the countries, with the facilities having on average 27-53% of the items necessary for offering basic surgery, 56-83% for comprehensive surgery, 49-72% for comprehensive obstetric care and 54-80% for blood transfusion. Furthermore, few facilities had all the necessary items present. However, facilities that reported offering surgical services had on average most of the necessary items for the prevention of infection. CONCLUSIONS: There are important gaps in the surgical services in the 8 African countries surveyed. Efforts are therefore urgently needed to address deficiencies in the availability and readiness to deliver surgical services in these nations, and this will require commitment from multiple stakeholders. SARA may be used to monitor availability and readiness at regular intervals, which will enable stakeholders to evaluate progress and identify gaps and areas for improvement.

Diurnal cortisol rhythm as a predictor of breast cancer survival.

BACKGROUND: : Abnormal circadian rhythms have been observed in patients with cancer, but the prognostic value of such alterations has not been confirmed. We examined the association between diurnal variation of salivary cortisol in patients with metastatic breast cancer and subsequent survival. We explored relationships between cortisol rhythms, circulating natural killer (NK) cell counts and activity, prognostic indicators, medical treatment, and psychosocial variables. METHODS: Salivary cortisol levels of 104 patients with metastatic breast cancer were assessed at study entry at 0800, 1200, 1700, and 2100 hours on each of 3 consecutive days, and the slope of diurnal cortisol variation was calculated using a regression of log-transformed cortisol concentrations on sample collection time. NK cell numbers were measured by flow cytometry, and NK cell activity was measured by the chromium release assay. The survival analysis was conducted by the Cox proportional hazards regression model with two-sided statistical testing. RESULTS: Cortisol slope predicted subsequent survival up to 7 years later. Earlier mortality occurred among patients with relatively "flat" rhythms, indicating a lack of normal diurnal variation (Cox proportional hazards, P =. 0036). Patients with chest metastases, as opposed to those with visceral or bone metastases, had more rhythmic cortisol profiles. Flattened profiles were linked with low counts and suppressed activity of NK cells. After adjustment for each of these and other factors, the cortisol slope remained a statistically significant, independent predictor of survival time. NK cell count emerged as a secondary predictor of survival. CONCLUSIONS: Patients with metastatic breast cancer whose diurnal cortisol rhythms were flattened or abnormal had earlier mortality. Suppression of NK cell count and NK function may be a mediator or a marker of more rapid disease progression.

[Clinical evaluation of the optic disc in glaucoma]. / Klinische Papillenbeurteilung bei Glaukom.

BACKGROUND: Glaucoma is defined as a progressive neuropathy of the optic nerve, characterized by specific changes of the optic disc, parapapillary region, and retinal nerve fiber layer. OBJECTIVES: Characteristic glaucomatous changes of the optic disc, parapapillary region, and retinal nerve fiber layer are discussed and their ophthalmoscopic examination is described. MATERIALS AND METHODS: A literature search in the PubMed database was conducted. RESULTS: A systematic step-by-step approach to a qualitative and quantitative ophthalmoscopic evaluation of the optic disc regarding glaucomatous damage is presented. CONCLUSION: A systematic, clinical, qualitative, and quantitative assessment of the optic disc can be performed with little effort and forms the basis for diagnosis and treatment of glaucoma.

Psychosocial outcomes of cancer: a comparative analysis of Hodgkin's disease and testicular cancer.

PURPOSE: The psychosocial outcomes of testicular cancer and Hodgkin's disease were compared to test our hypotheses that more specific dysfunction and less hiding of symptoms would be found in the former group, as cancer visibly affects a sexual organ. Since those with Hodgkin's disease could more easily deny the disease, poorer psychosocial adjustment was predicted. PATIENTS AND METHODS: The sample consists of 85 men with Hodgkin's disease and 88 men with testicular cancer (seminomatous, n = 39; or nonseminomatous, n = 49). They were interviewed once, at least 1 year following the end of treatment. Measures of sociodemographic characteristics, physical functioning, psychologic distress, and social outcomes were collected. Treatment data were collected from medical records. RESULTS: Men with testicular cancer report more focused symptoms: less sexual enjoyment and poor health habits. Men with Hodgkin's disease report more generalized symptoms: fatigue, energy loss, and work impairment. Multivariate analysis indicates that most of these differences are site-related; independent effects of treatment on outcomes were found for more generalized symptoms. Contrary to expectations, both groups reported similar levels of infertility and erectile dysfunction. CONCLUSION: The response to testicular cancer is site-specific, while the response to Hodgkin's disease is related to both site and treatment (stage-related).

Psychosocial problems among survivors of Hodgkin's disease.

The psychosocial problems that develop in long-term survivors of Hodgkin's disease were examined in a cross-sectional survey of 403 patients. The average age at treatment was 27 years and at interview was 36 years. The median time since treatment was 9 years. Sixty percent of the patients were treated for stage I or II disease and 40% for stage III or IV. Eighty-two percent of the patients had never relapsed, and 98% were free of disease at the time of interview. The study investigated the type and frequency of problems by means of a self-administered questionnaire using standard survey items to assess disruption in three areas of life: sense of well-being, family relationships, and employment. Results indicate that energy had not returned to patients' satisfaction in 37% of the cases. This was influenced by age, time since therapy, stage of disease, and type of treatment. Patients with self-reported energy loss were more likely to be depressed. Moderately high divorce rates (32%), problems with infertility (18%), and less interest in sexual activity (20%) were reported. Employment patterns favored men returning to work, and number of hours worked was highly correlated with less depression, younger age, and return of energy. Difficulties at work were reported by 42% of the cases. The interaction of treatment, biologic, psychosocial, and functional variables is described.

Group support for patients with metastatic cancer. A randomized outcome study.

The effects of weekly supportive group meetings for women with metastatic carcinoma of the breast were systematically evaluated in a one-year, randomized, prospective outcome study. The groups focused on the problems of terminal illness, including improving relationships with family, friends, and physicians and living as fully as possible in the face of death. We hypothesized that this invention would lead to improved mood, coping strategies, and self-esteem among those in the treatment group. Eighty-six patients were tested at four-month intervals. The treatment group had significantly lower mood-disturbance scores on the Profile of Mood States scale, had fewer maladaptive coping responses, and were less phobic than the control group. This study provides objective evidence that a supportive group intervention for patients with metastatic cancer results in psychological benefit. Mechanisms underlying the effectiveness of this group intervention are explored.

Supportive-expressive group therapy and distress in patients with metastatic breast cancer: a randomized clinical intervention trial.

BACKGROUND: Metastatic breast cancer carries with it considerable psychosocial morbidity. Studies have shown that some patients with metastatic breast cancer experience clinically significant anxiety and depression and traumatic stress symptoms. Supportive-expressive group psychotherapy was developed to help patients with cancer face and adjust to their existential concerns, express and manage disease-related emotions, increase social support, enhance relationships with family and physicians, and improve symptom control. METHODS: Of 125 women with metastatic breast cancer recruited into the study, 64 were randomized to the intervention and 61 to the control condition. Intervention women were offered 1 year of weekly supportive-expressive group therapy and educational materials. Control women received educational materials only. Participants were assessed at baseline and every 4 months during the first year. Data at baseline and from at least 1 assessment were collected from 102 participants during this 12-month period, and these participants compose the study population. RESULTS: Primary analyses based on all available data indicated that participants in the treatment condition showed a significantly greater decline in traumatic stress symptoms on the Impact of Event Scale (effect size, 0.25) compared with the control condition, but there was no difference in Profile of Mood States total mood disturbance. However, when the final assessment occurring within a year of death was removed, a secondary analysis showed a significantly greater decline in total mood disturbance (effect size, 0.25) and traumatic stress symptoms (effect size, 0.33) for the treatment condition compared with the control condition. CONCLUSION: Supportive-expressive therapy, with its emphasis on providing support and helping patients face and deal with their disease-related stress, can help reduce distress in patients with metastatic breast cancer.

A Snapshot of 1001 Children Presenting with Cerebral Palsy to a Children's Disability Hospital.

BACKGROUND: Cerebral palsy (CP) has largely been an unaddressed problem in low and middle income countries (LMIC's). The purpose of this retrospective study is to provide a facility-based snapshot of CP in Nepal. METHODS: A retrospective chart review of 1001 patients diagnosed as having cerebral palsy, presenting to our institution from December 2008 to December 2011, was carried out. RESULTS: Majority of cases were found to be a result of birth complications and post-natal infections. Most children with CP were born at home, presented after walking age and came from socioeconomically unstable or borderline households. Less than 20% were attending school. Spastic diplegia was the most common presentation. Children with post-natal spasticity secondary to infection seemed to retain greater ambulatory potential. CONCLUSIONS: In contrast to CP in developed countries, the etiology in LMIC's is largely related to birth-related complications and post-natal infections. There is an urgent need to address preventable causes of cerebral palsy in Nepal.

Methylglyoxal, the foe and friend of glyoxalase and Trx/TrxR systems in HT22 nerve cells.

Methylglyoxal (MGO) is a major glycating agent that reacts with basic residues of proteins and promotes the formation of advanced glycation end products (AGEs) which are believed to play key roles in a number of pathologies, such as diabetes, Alzheimer's disease, and inflammation. Here, we examined the effects of MGO on immortalized mouse hippocampal HT22 nerve cells. The endpoints analyzed were MGO and thiol status, the glyoxalase system, comprising glyoxalase 1 and 2 (GLO1/2), and the cytosolic and mitochondrial Trx/TrxR systems, as well as nuclear Nrf2 and its target genes. We found that nuclear Nrf2 is induced by MGO treatment in HT22 cells, as corroborated by induction of the Nrf2-controlled target genes and proteins glutamate cysteine ligase and heme oxygenase 1. Nrf2 knockdown prevented MGO-dependent induction of glutamate cysteine ligase and heme oxygenase 1. The cystine/glutamate antiporter, system xc(-), which is also controlled by Nrf2, was also induced. The increased cystine import (system xc(-)) activity and GCL expression promoted GSH synthesis, leading to increased levels of GSH. The data indicate that MGO can act as both a foe and a friend of the glyoxalase and the Trx/TrxR systems. At low concentrations of MGO (0.3mM), GLO2 is strongly induced, but at high MGO (0.75 mM) concentrations, GLO1 is inhibited and GLO2 is downregulated. The cytosolic Trx/TrxR system is impaired by MGO, where Trx is downregulated yet TrxR is induced, but strong MGO-dependent glycation may explain the loss in TrxR activity. We propose that Nrf2 can be the unifying element to explain the observed upregulation of GSH, GCL, HO1, TrxR1, Trx2, TrxR2, and system xc(-) system activity.

Multisensory attention training for treatment of tinnitus.

Tinnitus is the conscious perception of sound with no physical sound source. Some models of tinnitus pathophysiology suggest that networks associated with attention, memory, distress and multisensory experience are involved in tinnitus perception. The aim of this study was to evaluate whether a multisensory attention training paradigm which used audio, visual, and somatosensory stimulation would reduce tinnitus. Eighteen participants with predominantly unilateral chronic tinnitus were randomized between two groups receiving 20 daily sessions of either integration (attempting to reduce salience to tinnitus by binding with multisensory stimuli) or attention diversion (multisensory stimuli opposite side to tinnitus) training. The training resulted in small but statistically significant reductions in Tinnitus Functional Index and Tinnitus Severity Numeric Scale scores and improved attentional abilities. No statistically significant improvements in tinnitus were found between the training groups. This study demonstrated that a short period of multisensory attention training reduced unilateral tinnitus, but directing attention toward or away from the tinnitus side did not differentiate this effect.

Dissociative reactions to the San Francisco Bay Area earthquake of 1989.

OBJECTIVE: This study systematically evaluated the psychological reactions of a nonclinical population to the October 1989 earthquake in the San Francisco Bay Area. METHOD: A representative group of about 100 graduate students from two different institutions in the Bay Area volunteered to participate in the study. Within 1 week of the earthquake, the authors administered a checklist of anxiety and dissociative symptoms to the subjects, and 4 months later they conducted a follow-up study with the same checklist. RESULTS: The participants reported significantly greater numbers and frequency of dissociative symptoms, including derealization and depersonalization, distortions of time, and alterations in cognition, memory and somatic sensations, during or shortly after the earthquake than after 4 months. To a lesser degree they also reported significantly more nonsomatic anxiety symptoms and Schneider's first-rank symptoms at the earlier testing time. CONCLUSIONS: These results suggest that among nonclinical populations, extreme distress may significantly increase the prevalence and severity of transient dissociative phenomena and anxiety. They provide further evidence of the role that dissociation plays in the response to trauma and are of considerable clinical and theoretical importance in view of the lifetime prevalence of traumatic experiences in the general population.

Hysterical psychosis and hypnotizability.

The very existence of hysterical psychosis as a diagnostic entity has been questioned as part of the general difficulty in defining both hysteria and psychosis. However, several recent investigations have documented a syndrome that usually involves brief and intense periods of psychotic behavior, generally with graphic decompensation, severe environmental stress, and rapid recompensation, in individuals with other hysterical features. The authors assert that such a syndrome does exist as a clinical entity and that the differential diagnosis can be facilitated by using a standardized measure of hypnotic trance capacity. They hypothesize that patients with hysterical psychosis are highly hypnotizable, while those who are schizophrenic and psychotic have low hypnotizability. The authors review the literature and present two case examples.

Family environment as a predictor of psychiatric rehospitalization.

The Family Environment Scale scores and demographic characteristics of 108 discharged psychiatric patients were used to predict outcome at 3 months and 1 year. Higher ratings of family expressiveness predicted fewer days of rehospitalization, especially among schizophrenic patients. Higher family cohesion scores predicted better family-rated patient adjustment. The patients were more likely to rate themselves as better adjusted if they had higher incomes, lived with parents rather than a spouse, and came from families with less emphasis on independence. Family environment was a better predictor of rehospitalization than baseline ratings of clinical status, indicating the importance of family support in the community adjustment of chronic psychiatric patients.

Hypnotic alteration of somatosensory perception.

Effects of hypnotic alterations of perception on amplitude of somatosensory event-related potentials were studied in 10 highly hypnotizable subjects and 10 subjects with low hypnotizability. The highly hypnotizable individuals showed significant decreases in amplitude of the P100 and P300 waveform components during a hypnotic hallucination that blocked perception of the stimulus. When hypnosis was used to intensify attention to the stimulus, there was an increase in P100 amplitude. These findings are consistent with observations that highly hypnotizable individuals can reduce or eliminate pain by using purely cognitive methods such as hypnosis. Together with data from the visual system, these results suggest a neurophysiological basis for hypnotic sensory alteration.