Cobimetinib: inhibiting MEK1/2 in BRAF V600-mutant melanoma.

Historically, metastatic melanoma has had extremely poor survival outcomes. The outlook, however, is rapidly changing as new molecularly targeted therapies have vastly improved patient outcomes. One such therapy is the potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor cobimetinib. Recently, cobimetinib was approved for the treatment of metastatic or unresectable melanoma with serine/threonine-protein kinase B-raf (BRAF) V600E or V600K mutations when used in combination with the BRAF inhibitor vemurafenib. Currently, multiple clinical trials are investigating this drug combination for the treatment of various cancer types (e.g., breast, melanoma, colorectal). In the phase III coBRIM trial, this combination therapy showed improved melanoma response rates and patient progression-free survival when compared to vemurafenib alone. Additionally, toxicities were generally found to be manageable with dose modification or interruption. However, tumor response to BRAF/MEK inhibition, though rapid, is often short-lived as tumors develop resistance to this combination therapy. Therefore, new trials are beginning to investigate the addition of a third targeted agent or immunotherapy in order to increase the durability of treatment response. These trials are already showing promising preliminary results.

XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer.

The limitations of cancer cell lines have led to the development of direct patient-derived xenograft models. However, the interplay between the implanted human cancer cells and recruited mouse stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg(-/-) (NSG) mouse on which a patient's tumor is then transplanted (XactMice). The human HSPCs produce immune cells that home into the tumor and help replicate its natural microenvironment. Despite previous passage on nude mice, the expression of epithelial, stromal and immune genes in XactMice tumors aligns more closely to that of the patient tumor than to those grown in non-humanized mice-an effect partially facilitated by human cytokines expressed by both the HSPC progeny and the tumor cells. The human immune and stromal cells produced in the XactMice can help recapitulate the microenvironment of an implanted xenograft, reverse the initial genetic drift seen after passage on non-humanized mice and provide a more accurate tumor model to guide patient treatment.

Views of general practitioners in Grampian about undergraduate psychiatric teaching.

This paper reports the free-text responses of general practitioners (GPs) in the Grampian area to a questionnaire about their experiences of undergraduate psychiatry teaching. Most respondents were senior GPs whose undergraduate training had taken place a number of years ago. Respondents varied in their perceptions of the quality of their psychiatric teaching. However, they reported common themes such as the bias of undergraduate teaching towards disorders which are less relevant to their practice, and the benefits of postgraduate training in psychiatry. We suggest that medical schools need to bear the needs of the non-psychiatrist in mind when developing curricula in psychiatry.

Pregnancy outcomes of women with and without a history of anorexia nervosa.

BACKGROUND: When women have a history of anorexia nervosa (AN), the advice given about becoming pregnant, and about the management of pregnancies, has usually been cautious. This study compared the pregnancy outcomes of women with and without a history of AN. METHOD: Women with a confirmed diagnosis of AN who had presented to psychiatric services in North East Scotland from 1965 to 2007 were identified. Those women with a pregnancy recorded in the Aberdeen Maternal and Neonatal Databank (AMND) were each matched by age, parity and year of delivery of their first baby with five women with no history of AN. Maternal and foetal outcomes were compared between these two groups of women. Comparisons were also made between the mothers with a history of AN and all other women in the AMND. RESULTS: A total of 134 women with a history of AN delivered 230 babies and the 670 matched women delivered 1144 babies. Mothers with AN delivered lighter babies but this difference did not persist after adjusting for maternal body mass index (BMI) in early pregnancy. Standardized birthweight (SBW) scores suggested that the AN mothers were more likely to produce babies with intrauterine growth restriction (IUGR) [relative risk (RR) 1.54, 95% confidence interval (CI) 1.11-2.13]. AN mothers were more likely to experience antepartum haemorrhage (RR 1.70, 95% CI 1.09-2.65). CONCLUSIONS: Mothers with a history of AN are at increased risk of adverse pregnancy outcomes. The magnitude of these risks is relatively small and should be appraised holistically by psychiatric and obstetric services.

Changes in undergraduate clinical psychiatry teaching in Scotland since "Tomorrow's doctors".

This paper reviews the factors which have driven changes in undergraduate education in psychiatry since the 1993 publication of "Tomorrow's Doctors",' after which it describes current undergraduate curricula in the four Scottish medical schools teaching clinical psychiatry. Reasons underlying the differences between curricula are discussed. The authors suggest that research in medical education, alongside communication and debate between medical schools and across specialties, would lead to more uniform and evidence-based curricula.

Spore germination in Mortierella alpina is associated with a transient depletion of arachidonic acid and induction of fatty acid desaturase gene expression.

Mortierella alpina is an oleaginous filamentous fungus whose vegetative mycelium is known to accumulate triglyceride oil containing large amounts of arachidonic acid (ARA 20:4, n - 6). We report that the spores of Mortierella alpina also contain a large proportion of ARA, comprising 50% of total fatty acid. Fatty acid desaturase genes were not expressed in dormant spores but were induced during germination, following a significant drop in the level of ARA (down from 50% of total fatty acid to 12%) prior to germ-tube emergence. We propose that ARA serves as a reserve supply of carbon and energy that is utilised during the early stages of spore germination in Mortierella alpina.

Psychometric properties of the BASIS-24© (Behaviour and Symptom Identification Scale-Revised) Mental Health Outcome Measure.

Objective. Outcome measurement in mental health services is an area of considerable clinical interest and policy priority. This study sought to assess the Behaviour and Symptom Identification Scale-24 (BASIS-24©), a brief, patient self-reported measure of psychopathology and functioning, in a UK sample, including establishing population norms for comparative purposes. Methods. Participants were 588 adults recruited from psychiatric inpatient, outpatient and primary care settings; and 630 adults randomly sampled from primary care lists who completed the BASIS-24©, and the Brief Symptom Inventory (BSI) at two time points. Results. BASIS-24© demonstrated adequate reliability (coefficient α values for combined clinical sample across subscales ranged from 0.75 to 0.91), validity and responsiveness to change (effect size for change of the BASIS-24© was 0.56 compared with 0.48 for BSI Global Severity Index). Population norms were established for the general population and adult in-patients (at in-take). The scale proved straightforward to complete across clinical settings. Variable rates of questionnaire distribution across clinical settings highlighted the ongoing challenge of incorporating outcome measures in clinical settings. Conclusion. BASIS-24© is a brief, easily administered, self-complete measure of mental well-being and functioning that adequately meets the requirements of reliability, validity and responsiveness to change required of an outcome measure.

Seasonal affective disorder: a vestigial evolutionary advantage?

The typical symptoms of recurrent winter depression include lowered mood, lethargy, hypersomnia, social withdrawal, decreased libido, increased appetite and weight gain. Mild hypomania often occurs in spring and summer. It is argued that this pattern of attenuated hibernation constituted an adaptive evolutionary mechanism which enhanced the likelihood of reproductive success, most notably for females, among populations living at temperate latitudes. Women were more likely to become pregnant in the summer and thus to give birth at a time of year when their babies had a higher chance of survival. Winter depression symptoms also promoted healthier pregnancies and gave rise to enhanced female-male pair-bonding which improved the survival chances of both mothers and babies. Hypomania in spring and summer also served to increase the likelihood of procreation at the optimal time of year. In the modern era, it is probable that recurrent winter depression is becoming a reproductive disadvantage.

Factors associated with patients' knowledge of and attitudes towards treatment with lithium.

BACKGROUND: Treatment with lithium is often compromised by poor adherence, by side-effects and by patients' having serum levels outside the therapeutic range. These factors may be affected by patients' knowledge and attitudes towards lithium, and we set out to establish factors associated with knowledge about and attitudes towards lithium among a large representative sample of patients. METHOD: Patients known to be taking lithium in Grampian during 1995 were surveyed postally during 1998 with the Lithium Knowledge Test (LKT) and the Lithium Attitudes Questionnaire (LAQ). Scores on these measures were analysed against patients' sociodemographic and clinical characteristics by stepwise multiple regression. RESULTS: Of 742 patients, 411 (55%) completed an LKT and 362 (49%) completed an LAQ. Stepwise multiple regression established that positive attitudes towards lithium on the LAQ were associated with higher serum lithium levels (P=0.005) and with continuing to take lithium (P<0.001). Higher knowledge on the LKT was associated with positive attitudes on the LAQ (P=0.002), with younger age (P<0.001), and with shorter duration of treatment (P=0.01) LIMITATIONS: The study was retrospective and the response rate was relatively low. CONCLUSIONS: Education about lithium is likely to be of particular importance in the elderly and 'refresher courses' are advisable for those who have been on lithium for lengthy periods. Interventions which modify attitudes, rather than enhancing knowledge, are likely to be helpful in promoting adherence.

Season of birth in females with anorexia nervosa in Northeast Scotland.

OBJECTIVE: To determine whether patients with anorexia nervosa exhibit an abnormal pattern in their season of birth. METHOD: Case records of female patients presenting to secondary services in Northeast Scotland from 1965 to 1997 who received a clinical diagnosis of anorexia nervosa were examined. The months of birth of the 446 anorexic patients with a confirmed diagnosis were compared with 5,766 female control subjects born locally in 1951, 1961, 1971, and 1981. RESULTS: Patients with anorexia nervosa had an excess of births in the first 6 months of the year (p =.013). The greatest excess was from March to June. DISCUSSION: This provides further evidence that birth dates of anorexics peak in the late spring and early summer. There are parallels with the epidemiology of schizophrenia. The evidence suggests that a seasonally fluctuating factor, most plausibly an intrauterine effect of common infectious agents during the winter months, is of etiological significance.

Light therapy for seasonal affective disorder in primary care: randomised controlled trial.

BACKGROUND: Studies of light therapy have not been conducted previously in primary care. AIMS: To evaluate light therapy in primary care. METHOD: Fifty-seven participants with seasonal affective disorder were randomly allocated to 4 weeks of bright white or dim red light. Baseline expectations for treatment were assessed. Outcome was assessed with the Structured Interview Guide for the Hamilton Depression Scale, Seasonal Affective Disorder Version. RESULTS: Both groups showed decreases in symptom scores of more than 40%. There were no differences in proportions of responders in either group, regardless of the remission criteria applied, with around 60% (74% white light, 57% red light) meeting broad criteria for response and 31% (30% white light, 33% red light) meeting strict criteria. There were no differences in treatment expectations. CONCLUSIONS: Primary care patients with seasonal affective disorder improve after light therapy, but bright white light is not associated with greater improvements.

Using simulated patients in education about alcohol misuse.

It is important to educate medical students about alcohol misuse, but this process is hampered by negative attitudes and the unavailability of typical patients. However, simulated patients can describe full longitudinal histories in a characteristically defensive style and can provide direct feedback to student interviewers.

Structure and conformation of a novel genetically engineered polysaccharide P2.

A new exocellular polysaccharide (P2) has been produced by the manipulation of a glycosyl transferase gene (aceP) involved in the biosynthesis of the polysaccharide acetan by the bacterium Acetobacter xylinum strain CKE5. The P2 polysaccharide has been studied by methylation analysis, reductive cleavage, and 1H and 13C NMR spectroscopy. The data are consistent with the structure predicted when the aceP gene is deactivated: [Molecular structure: see text]. The effect of cooling on proton NMR line width indicates a coil-helix transition in P2 at about 70 degrees C.

A distinctive flavonoid chemistry for the anomalous genus Biebersteinia.

Leaf surface extracts of Biebersteinia orphanidis have yielded a complex mixture of five flavones with the unusual 5,7-dihydroxy-6,8-dimethoxy A ring substitution pattern. They are acerosin, hymenoxin, nevadensin, sudachitin and 5,7,4'-trihydroxy-6,8-dimethoxyflavone. Also present at the leaf surface are gardenin B, luteolin, apigenin, acacetin and the coumarin umbelliferone. The internal leaf flavonoids include the 7-glucosides of apigenin, luteolin and tricetin, together with the 7-rutinosides of apigenin and luteolin. This profile differs from those of B. heterostemon and B. odora. It appears that B. orphanidis is as highly distinctive in its flavonoid pattern as it is phytogeographically. The data also confirm the conclusion of other studies, including rbcL and atpB gene sequence analysis, that Biebersteinia is completely unrelated to the Geraniaceae, where it was once placed.

Comparison of consultation rates in primary care attenders with and without seasonal affective disorder.

BACKGROUND: There is a lack of published information about the consultation patterns of patients with seasonal affective disorder (SAD) in primary care, when compared with non-seasonal controls (NSCs). METHODS: Interview-confirmed SAD cases (n=90) were age- and sex-matched to two controls without significant seasonal morbidity on the Seasonal Pattern Assessment Questionnaire (SPAQ) (non-seasonal controls, NSCs). A comparison of their consultation rates was made using data abstracted from primary care records over 4 years. RESULTS: The monthly rate of general practice consultations for SAD cases was significantly higher than that for NSCs. There was a significant difference in the median number of consultations in winter and autumn between the two groups. The matched multivariate analysis revealed that February and April were the independent months in which cases of SAD had significantly more consultations than NSCs. LIMITATIONS: Optimal diagnostic criteria for SAD have not been determined and our criteria may have been over-inclusive. CONCLUSION: In addition to a marked difference in monthly consultation rates between SAD cases and NSCs, the data demonstrate a difference in the pattern of seasonality of these rates. It is possible that increased frequency of consultation, in particular during the winter months (in patients who score as a case SPAQ), could be used as an indication of SAD in primary care.

Suicide by patients: questionnaire study of its effect on consultant psychiatrists.

OBJECTIVE: To identify the effect of patients' suicide on consultant psychiatrists in Scotland. DESIGN: Confidential coded postal questionnaire survey. PARTICIPANTS: Of 315 eligible consultant psychiatrists, 247 (78%) contributed. SETTING: Scotland. MAIN OUTCOME MEASURES: Experience of patient suicide; the features and impact of "most distressing" suicide and what helped them to deal with it. RESULTS: 167 (68%) consultants had had a patient commit suicide under their care. Fifty four (33%) reported being affected personally in terms of low mood, poor sleep, or irritability. Changes in professional practice were described by 69 (42%) of the psychiatrists-for example, a more structured approach to the management of patients at risk and increased use of mental health legislation. Twenty four (15%) doctors considered taking early retirement because of a patient's suicide. Colleagues and family or friends were the best sources of help, and team and critical incident reviews were also useful. CONCLUSIONS: Suicide by patients has a substantial emotional and professional effect on consultant psychiatrists. Support from colleagues is helpful, and professional reviews provide opportunities for learning and improved management of suicide and its aftermath.

Lithium monitoring before and after the distribution of clinical practice guidelines.

OBJECTIVE: To determine whether distribution of clinical practice guidelines improves lithium monitoring and whether standards of monitoring differed between patients in psychiatric contact and those seen only in primary care. METHOD: Standards of monitoring were assessed for patients on lithium in northeast Scotland throughout 1995 and/or throughout 1996. Guidelines were circulated in January 1996 to all local general practitioners and psychiatrists. Monitoring was compared between 1995 and 1996 and for patients with and without psychiatric contact. RESULTS: Both primary care and psychiatric records were scrutinized for 422 and 403 patients prescribed lithium throughout 1995 and 1996, respectively. While monitoring was poor on several parameters during both years, frequency of measurement of both thyroid and renal function improved in 1996. Standards of monitoring were better for patients in psychiatric care. CONCLUSION: Standards of lithium monitoring require further improvement. Locally agreed practice guidelines are helpful but patients on lithium should be in continuing contact with an experienced psychiatrist.