Efficacy and adverse events of oral isotretinoin for acne: a systematic review.

Despite many years of clinical use of isotretinoin, a comprehensive review of evidence for isotretinoin therapy in patients with acne is lacking. We searched MEDLINE, Embase, Cochrane Central, relevant web pages and bibliographies for randomized controlled trials in acne evaluating isotretinoin vs. control (placebo or other therapy). Data were extracted and summarized descriptively. Eleven trials were identified (total 760 patients randomized), containing mostly men. Mean treatment ages ranged from 18 to 47·9 years and participants generally had moderate-to-severe acne. Across all trials, isotretinoin therapy reduced acne lesion counts by a clinically relevant amount, and always by a greater amount than control, which was either placebo (two studies), oral antibiotics (seven studies) or other control (two studies). Across trials with an overall low risk of bias, two of three demonstrated statistically significant differences between isotretinoin and control. The frequency of adverse events was twice as high with isotretinoin (751 events) than with control (388 events). More than half of all adverse events were dermatological and related to dryness. Adverse events from isotretinoin causing participant withdrawal from trials (12 patients) included Stevens-Johnson syndrome, cheilitis, xerosis, acne flare, photophobia, elevated liver enzymes, decreased appetite, headaches and depressed mood. This review suggests that isotretinoin is effective in reducing acne lesion counts, but adverse events are common. This study was registered with PROSPERO number CRD42015025080.

In vitro reconstruction of the respiratory central pattern generator of the mollusk Lymnaea.

Most rhythmic behaviors such as respiration, locomotion, and feeding are under the control of networks of neurons in the central nervous system known as central pattern generators (CPGs). The respiratory rhythm of the pond snail Lymnaea stagnalis is a relatively simple, CPG-based behavior for which the underlying neural elements have been identified. A three-neuron network capable of generating the respiratory rhythm of this air-breathing mollusk has been reconstructed in culture. The intrinsic and network properties of this neural ensemble have been studied, and the mechanism of postinhibitory rebound excitation was found to be important for the rhythm generation. This in vitro model system enables a better understanding of the neural basis of rhythm generation.

Selection of a novel connection by adult molluscan neurons.

Predictable change in neuronal connectivity can be induced in the buccal ganglia of adult Helisoma snails when neuritic growth is evoked by axotomy. Both transient and stable novel electrical connections are established between identified neurons. The breaking of inappropriate, normally transient connections is contingent on the formation of an appropriate connection.

CRNF, a molluscan neurotrophic factor that interacts with the p75 neurotrophin receptor.

A 13.1-kilodalton protein, cysteine-rich neurotrophic factor (CRNF), was purified from the mollusk Lymnaea stagnalis by use of a binding assay on the p75 neurotrophin receptor. CRNF bound to p75 with nanomolar affinity but was not similar in sequence to neurotrophins or any other known gene product. CRNF messenger RNA expression was highest in adult foot subepithelial cells; in the central nervous system, expression was regulated by lesion. The factor evoked neurite outgrowth and modulated calcium currents in pedal motor neurons. Thus, CRNF may be involved in target-derived trophic support for motor neurons and could represent the prototype of another family of p75 ligands.

Transplantation and functional integration of an identified respiratory interneuron in Lymnaea stagnalis.

The possibility that damaged neural circuitries can be repaired through grafting has raised questions regarding the cellular mechanisms required for functional integration of transplanted neurons. Invertebrate models offer the potential to examine such mechanisms at the resolution of single identified neurons within well-characterized neural networks. Here it is reported that a specific deficit in the respiratory behavior of a pulmonate mollusc, caused by the ablation of a solitary interneuron, can be restored by grafting an identical donor interneuron. The transplanted interneuron not only survives and extends neurites within the host nervous system, but under specific conditions forms synapses with appropriate target neurons and is physiologically integrated into the host's circuitry, thereby restoring normal behavior.

Patterns of association of chronic medical conditions and major depression.

AIMS: Age and sex-related patterns of association between medical conditions and major depressive episodes (MDE) are important for understanding disease burden, anticipating clinical needs and for formulating etiological hypotheses. General population estimates are especially valuable because they are not distorted by help-seeking behaviours. However, even large population surveys often deliver inadequate precision to adequately describe such patterns. In this study, data from a set of national surveys were pooled to increase precision, supporting more precise characterisation of these associations. METHODS: The data were from a series of Canadian national surveys. These surveys used comparable sampling strategies and assessment methods for MDE. Chronic medical conditions were assessed using items asking about professionally diagnosed medical conditions. Individual-level meta-analysis methods were used to generate unadjusted, stratified and adjusted prevalence odds ratios for 11 chronic medical conditions. Random effects models were used in the meta-analysis. A procedure incorporating rescaled replicate bootstrap weights was used to produce 95% confidence intervals. RESULTS: Overall, conditions characterised by pain and inflammation tended to show stronger associations with MDE. The meta-analysis uncovered two previously undescribed patterns of association. Effect modification by age was observed in varying degrees for most conditions. This effect was most prominent for high blood pressure and cancer. Stronger associations were found in younger age categories. Migraine was an exception: the strength of association increased with age, especially in men. Second, especially for conditions predominantly affecting older age groups (arthritis, diabetes, back pain, cataracts, effects of stroke and heart disease) confounding by age was evident. For each condition, age adjustment resulted in strengthening of the associations. In addition to migraine, two conditions displayed distinctive patterns of association. Age adjusted odds ratios for thyroid disease reflected a weak association that was only significant in women. In epilepsy, a similar strength of association was found irrespective of age or sex. CONCLUSIONS: The prevalence of MDE is elevated in association with most chronic conditions, but especially those characterised by inflammation and pain. Effect modification by age may reflect greater challenges or difficulties encountered by young people attempting to cope with these conditions. This pattern, however, does not apply to migraine or epilepsy. Neurobiological changes associated with these conditions may offset coping-related effects, such that the association does not weaken with age. Prominent confounding by age for several conditions suggests that age adjustments are necessary in order to avoid underestimating the strength of these associations.

Determinants and incidence of depression in multiple sclerosis: A prospective cohort study.

OBJECTIVE: To estimate the incidence and explore potential determinants of incidence of depression in MS. METHODS: A prospective cohort study used a sample of 192 patients from the southern Alberta MS clinic registry. Participants completed baseline risk factor assessment questionnaires using either online, mail or telephone surveys, and completed the Patient Health Questionnaire every 2weeks for 6months to assess depressive symptoms in real time. Risk factors assessed included biopsychosocial variables such as socioeconomic status, illness-related factors, childhood risk factors, psychosocial factors, and health behaviors. Cox proportional hazard models were fit to estimate predictors of incidence. RESULTS: 2-week incidence of depression for females was 0.019 (95% CI 0.013-0.029) and for males was 0.044 (0.026-0.074). Strongest predictor of depression incidence risk included fatigue impact, low mobility, resiliency, self-esteem, self-efficacy, and coping style. CONCLUSION: Depression in MS exhibits a risk factor profile similar to that of depression in the general population, with the additional impact of MS illness-related factors. Potentially modifiable risk factors, such as coping with stress and resiliency, present opportunities for focus of further research in depression in MS treatment and prevention efforts. Some differences in determinants of incidence were found compared to the prevalence risk factors, highlighting the danger of using cross-sectional data to make assumptions about risk. For example, the finding that depression incidence was higher for men is opposite to the higher depression prevalence estimates found for women as well as the consensus in the literature.

Seasonal variation in major depressive episode prevalence in Canada.

BACKGROUND: The purpose of this paper is to describe variation, over the months of the year, in major depressive episode (MDE) prevalence. This is an important aspect of the epidemiological description of MDE, and one that has received surprisingly little attention in the literature. Evidence of seasonal variation in MDE prevalence has been weak and contradictory. Most studies have sought to estimate the prevalence of seasonal affective disorder using cut-points applied to scales assessing mood seasonality rather than MDE. This approach does not align with modern classification in which seasonal depression is a diagnostic subtype of major depression rather than a distinct category. Also, some studies may have lacked power to detect seasonal differences. We addressed these limitations by examining the month-specific occurrence of conventionally defined MDE and by pooling data from large epidemiological surveys to enhance precision in the analysis. METHOD: Data from two national survey programmes (the National Population Health Survey and the Canadian Community Health Survey) were used, providing ten datasets collected between 1996 and 2013, together including over 500,000. These studies assessed MDE using a short form version of the Composite International Diagnostic Interview (CIDI) for major depression, with one exception being a 2012 survey that used a non-abbreviated version of the CIDI. The proportion of episodes occurring in each month was evaluated using items from the diagnostic modules and statistical methods addressing complex design features of these trials. Overall month-specific pooled estimates and associated confidence intervals were estimated using random effects meta-analysis and a gradient was assessed using a meta-regression model that included a quadratic term. RESULTS: There was considerable sampling variability when the month-specific proportions were estimated from individual survey datasets. However, across the various datasets, there was sufficient homogeneity to justify the pooling of these estimated proportions, producing large gains in precision. Seasonal variation was clearly evident in the pooled data. The highest proportion of episodes occurred in December, January and February and the lowest proportions occurred in June, July and August. The proportion of respondents reporting MDE in January was 70% higher than August, suggesting an association with implications for health policy. The pattern persisted with stratification for age group, sex and latitude. CONCLUSIONS: Seasonal effects in MDE may have been obscured by small sample sizes in prior studies. In Canada, MDE has clear seasonal variation, yet this is not addressed in the planning of services. These results suggest that availability of depression treatment should be higher in the winter than the summer months.

Reconstruction of neuronal networks in culture.

Since the 1960s, the large neurones of some invertebrates have been exploited in attempts to define the neural circuits that underlie simple behaviours. Even in the relatively 'simple' nervous systems of these animals, it is often difficult to study individual synaptic connections in detail and to rule out involvement of unidentified neurones. These limitations have been overcome by reconstruction of partial circuits of identified neurones in cell culture. This approach has provided opportunities to examine the function of small neuronal circuits in a manner that is unapproachable in the intact nervous system.

Childhood adversity and subsequent mental health status in adulthood: screening for associations using two linked surveys.

AIMS: Accumulating evidence links childhood adversity to negative health outcomes in adulthood. However, most of the available evidence is retrospective and subject to recall bias. Published reports have sometimes focused on specific childhood exposures (e.g. abuse) and/or specific outcomes (e.g. major depression). Other studies have linked childhood adversity to a large and diverse number of adult risk factors and health outcomes such as cardiovascular disease. To advance this literature, we undertook a broad examination of data from two linked surveys. The goal was to avoid retrospective distortion and to provide a descriptive overview of patterns of association. METHODS: A baseline interview for the Canadian National Longitudinal Study of Children and Youth collected information about childhood adversities affecting children aged 0-11 in 1994. The sampling procedures employed in a subsequent study called the National Population Health Survey (NPHS) made it possible to link n = 1977 of these respondents to follow-up data collected later when respondents were between the ages of 14 and 27. Outcomes included major depressive episodes (MDE), some risk factors and educational attainment. Cross-tabulations were used to examine these associations and adjusted estimates were made using the regression models. As the NPHS was a longitudinal study with multiple interviews, for most analyses generalized estimating equations (GEE) were used. As there were multiple exposures and outcomes, a statistical procedure to control the false discovery rate (Benjamini-Hochberg) was employed. RESULTS: Childhood adversities were consistently associated with a cluster of potentially related outcomes: MDE, psychotropic medication use and smoking. These outcomes may be related to one another since psychotropic medications are used in the treatment of major depression, and smoking is strongly associated with major depression. However, no consistent associations were observed for other outcomes examined: physical inactivity, excessive alcohol consumption, binge drinking or educational attainment. CONCLUSIONS: The conditions found to be the most strongly associated with childhood adversities were a cluster of outcomes that potentially share pathophysiological connections. Although prior literature has suggested that a very large number of adult outcomes, including physical inactivity and alcohol-related outcomes follow childhood adversity, this analysis suggests a degree of specificity with outcomes potentially related to depression. Some of the other reported adverse outcomes (e.g. those related to alcohol use, physical inactivity or more distal outcomes such as obesity and cardiovascular disease) may emerge later in life and in some cases may be secondary to depression, psychotropic medication use and smoking.

Lymnaea epidermal growth factor promotes axonal regeneration in CNS organ culture.

Members of the epidermal growth factor (EGF) family are frequently implicated in the injury response of the mammalian nervous system. Although this implication is supported by extensive molecular evidence, it is not underpinned by conclusive functional data. Recently, we found that expression of an EGF homolog from the pond snail Lymnaea stagnalis (L-EGF) is upregulated after axotomy in the adult CNS, suggesting a role for this molecule in the injury response of the CNS. In the present study we asked whether L-EGF can promote axonal regeneration of three types of identified neurons in organ-cultured CNS. Treatment with purified L-EGF substantially enhanced axonal regeneration of all three types of neurons, an effect inhibited by submicromolar doses of PD153035, a specific EGF receptor (EGFR) tyrosine kinase inhibitor. In addition, PD153035 and K252a, a nonspecific kinase inhibitor, also reduced the degree of axonal regeneration that occurs without L-EGF supplementation, indicating that L-EGF or other EGFR ligands synthesized in the CNS participate in the regenerative response. An intriguing aspect of these results is that axonal regeneration of different, intrinsically L-EGF responsive and unresponsive neurons occurred in a coordinated manner. This observation suggests that indirect in addition to direct actions contribute to the beneficial effect of L-EGF. In conclusion, we provide functional evidence that an EGF homolog can promote axonal regeneration, substantiating existing molecular evidence implicating the EGF family in peripheral nerve regeneration and emphasizes the therapeutic potential of these molecules.

Retrospective and prospectively assessed childhood adversity in association with major depression, alcohol consumption and painful conditions.

BACKGROUND: Considerable evidence now links childhood adversity to a variety of adult health problems. Unfortunately, almost all of these studies have relied upon retrospective assessment of childhood events, creating a vulnerability to bias. In this study, we sought to examine three associations using data sources that allowed for both prospective and retrospective assessment of childhood events. METHODS: A 1994 national survey of children between the ages of 0 and 11 collected data from a 'person most knowledgeable' (usually the mother) about a child. It was possible to link data for n = 1977 of these respondents to data collected from the same people in a subsequent adult study. The latter survey included retrospective reports of childhood adversity. We examined three adult health outcomes in relation to prospectively and retrospectively assessed childhood adversity: major depressive episodes, excessive alcohol consumption and painful conditions. RESULTS: A strong association between childhood adversities (as assessed by both retrospective and prospective methods) and major depression was identified although the association with retrospective assessment was stronger. Weaker associations were found for painful conditions, but these did not depend on the method of assessment. Associations were not found for excessive alcohol consumption irrespective of the method of assessment. CONCLUSIONS: These findings help to allay concerns that associations between childhood adversities and health outcomes during adulthood are merely artefacts of recall bias. In this study, retrospective and prospective assessment strategies produced similar results.

Ultrastructure of an identified molluscan neuron in organ culture and cell culture following axotomy.

We examined the ultrastructure of neuron 5 from the buccal ganglion of the mollusc Helisoma trivolvis after axotomy and organ culture, and after isolation of the same neuron in culture. Buccal ganglia containing axotomized neurons 5 were cultured either in host snails or in Leibovitz medium conditioned with ganglia. In addition, some neurons 5 were isolated from buccal ganglia by micro-dissection and plated into culture. Neuron 5 and its processes were identified in both whole mounts and plastic sections of buccal ganglia after intracellular injection with Lucifer Yellow or horseradish peroxidase. Five days after axotomy of neuron 5, thick sections of buccal ganglia stained with toluidine blue revealed that densely staining basophilic bodies (Nissl bodies) within the cytoplasm had dispersed, i.e., they had undergone chromatolysis. Coincident with chromatolysis was an overall increase in diffuse basophilic staining within the cytoplasm of neuron 5 when maintained in organ culture. The dispersion of Nissl bodies viewed by light microscopy correlated with a more freely arranged rough endoplasmic reticulum and associated polysomes within neuron 5 as seen by electron microscopy. Isolated neurons 5 did not possess densely staining Nissl bodies when examined after 2 days in vitro, thus indicating that chromatolysis occurred earlier in isolated neurons. Furthermore, no increase in diffuse cytoplasmic basophilia was observed within isolated neurons 5 cultured in vitro. However, isolated neurons 5 exhibited a marked increase in the number of lipid-like bodies (0.5-1.5 micron in diameter) that were particularly evident in scanning electron micrographs. Scanning and transmission electron micrographs revealed that the isolated neurons were free of associated glia, but non-neuronal cells (hemocytes) would attach themselves to the somata and neurites. Glia surrounding neuron 5 within buccal ganglia exhibited a marked hypertrophy following axotomy and organ culture. Hypertrophy of glia was absent, however, if ganglia were axotomized and left within the animal or axotomized ganglia were implanted into host animals and examined 5 days later by electron microscopy. These observations indicate that, following axotomy, a molluscan neuron may exhibit different morphological features depending on its microenvironment. In addition, the hypertrophy of glia surrounding neurons in Helisoma was not associated with axotomy per se, but with organ culture.

Evidence for the presence, synthesis, immunoreactivity, and uptake of GABA in the nervous system of the snail Helisoma trivolvis.

In the present study several techniques were employed to test the hypothesis that gamma-aminobutyric acid (GABA) is a neurotransmitter in the central nervous system (CNS) of the pond snail Helisoma trivolvis (Mollusca, Pulmonata). First, by using chromatographic techniques, the presence of GABA and its differential distribution among the ganglia constituting the CNS was demonstrated. Second, de novo synthesis of 3H-GABA from 3H-glutamate was shown by the CNS. Levels of both endogenous and newly synthesized GABA were greatest in the buccal, cerebral, and pedal ganglia. Third, indirect immunohistochemistry of wholemounts revealed a central network of GABA-like immunoreactive neurons. With the possible exceptions of two pairs of fibers in nerve trunks, all projections from GABA-immunoreactive neurons were confined to the CNS, suggesting a predominantly central role for GABA. Stained neurons were found on the dorsal surface of the buccal ganglia and throughout the cerebral and pedal ganglia. No GABA-immunoreactive cell bodies were observed in the parietal, pleural, or visceral ganglia. Finally, uptake of 3H-GABA was examined autoradiographically in sectioned ganglia. A pattern of radiolabelled cells was observed that closely resembled the distribution of GABA-immunoreactive neurons. The data described above fulfill several criteria necessary to establish GABA as a transmitter in the nervous system of Helisoma. Taken together with previously obtained pharmacological evidence demonstrating that GABA acts on Helisoma central neurons, GABA is considered to be a strong candidate for a neurotransmitter in Helisoma.

Glutamate as a putative neurotransmitter in the mollusc, Lymnaea stagnalis.

Bath-applied glutamate (10-1000 microM) produced excitatory and inhibitory responses on numerous identified neurons of the mollusc Lymnaea stagnalis. Using both in situ and in vitro preparations, glutamate or glutamate agonists produced a depolarization in identified neurons right pedal dorsal 1 and right pedal dorsal 2 and 3. However, attempts to block glutamate-evoked responses with glutamate antagonists were unsuccessful. We examined a potential glutamatergic neuron, visceral dorsal 4. Exogenous application of the peptides (GDPFLRFamide and SDPFLRFamide) could mimic the inhibitory, but not the excitatory effects of visceral dorsal 4 on its postsynaptic cells, implying the presence of a second transmitter. We tested the possibility that glutamate is this second neurotransmitter by using excitatory synapses between visceral dorsal 4 and postsynaptic cells right pedal dorsal 2 and 3, right pedal dorsal 1, visceral F group and right parietal B group neurons. Of all the putative neurotransmitters tested, only glutamate had consistent excitatory effects on these postsynaptic cells. Also, the amplitude of the right pedal dorsal 2 and 3 excitatory postsynaptic potentials was reduced in the presence of N-methyl-D-aspartate and other glutamate agonists, suggesting desensitization of the endogenous transmitter receptor. In conclusion, some identified Lymnaea neurons respond to glutamate via a receptor with novel pharmacological properties. Furthermore, a Lymnaea interneuron may employ glutamate as a transmitter at excitatory synapses.

Developmental plasticity of respiratory behavior in Lymnaea.

The authors investigated the contribution of experience to development and maintenance of pulmonary respiration in Lymnaea stagnalis. Respiration in L. stagnalis is bimodal via both the skin and the lung. Rearing snails from eggs to adulthood while preventing lung respiration (differentially reared snails) showed that L. stagnalis can develop and survive without pulmonary respiration. These snails were able to open and close their pneumostome when given the opportunity as adults. However, quantitative aspects of their respiratory behavior were significantly altered. Prevention of pulmonary respiration in adult, normally reared snails also induced behavioral changes. Comparison of these changes with those in differentially reared snails revealed specific developmental effects, which were reversible. Thus, this is a suitable model system for studying questions related to behavioral plasticity.

Functional recovery of respiratory behavior during axonal regeneration in snails (Lymnaea stagnalis) is experience dependent.

This study investigated the role of experience in recovery of pulmonary respiration during axonal regeneration in Lymnaea stagnalis. Pulmonary respiration occurs when snails break the water surface and open the lung orifice, the pneumostome. It was shown that axotomy of all the axons innervating the pneumostome and surrounding area prevents the occurrence of lung respiration in 69% of snails. In the remaining 31%, lung respiration persisted, indicating that peripheral components alone are capable of initiating pneumostome openings and closures. Five weeks postsurgery, all snails with previous nerve crushes showed opening of the pneumostome with normal latency after breaking the water surface. However, prevention of pulmonary respiration during the recovery period dramatically changed the recovered behavior. Thus, experience in pulmonary respiration during axonal regeneration plays a role in the recovery of this behavior.

Specific in vitro synaptogenesis between identified Lymnaea and Helisoma neurons.

We tested the ability of identified neurons from two different families of pulmonate molluscs to form specific connections in vitro. The presynaptic neuron chosen for this study was the giant dopamine cell of Lymnaea stagnalis and Helisoma trivolvis which is known to synapse upon specific visceral and parietal ganglion neurons in both species. Here we show that the giant dopamine cells can reform specific connections in vitro on follower neurons from both species. Thus the mechanisms that determine synapse specificity are conserved between two different families of molluscs.