Spatial aspects of oncogenic signalling determine the response to combination therapy in slice explants from Kras‐driven lung tumours

A key question in precision medicine is how functional heterogeneity in solid tumours informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signalling and therapy response can be modelled in precision‐cut slices from Kras‐driven non‐small‐cell lung cancer with varying histopathologies. Unexpectedly, profiling of in situ tumours demonstrated that signalling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma, and mitogen‐activated protein kinase (MAPK) activity in adenocarcinoma. In addition, high intertumour and intratumour variability was detected, particularly of MAPK and mammalian target of rapamycin (mTOR) complex 1 activity. Using short‐term treatment of slice explants, we showed that cytotoxic responses to combination MAPK and phosphoinositide 3‐kinase–mTOR inhibition correlate with the spatially defined activities of both pathways. Thus, whereas genetic drivers determine histopathology spectra, histopathology‐associated and spatially variable signalling activities determine drug sensitivity. Our study is in support of spatial aspects of signalling heterogeneity being considered in clinical diagnostic settings, particularly to guide the selection of drug combinations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Blinding decreased recruitment in a prevention trial of postmenopausal hormone therapy

PURPOSE: To compare the effect of blind design (active drug and placebo) and nonblind design (active drug and no treatment) on recruitment. SETTING: A primary prevention trial with postmenopausal hormone therapy in Estonia. METHODS: Women who were eligible and willing to participate on the basis of the questionnaire survey were randomized into blind and nonblind groups. Recruitment rates are based on record keeping, and reasons for participating were requested in the first-year follow-up. RESULTS: The recruitment was 30% higher in the nonblind group: of the 4,295 women invited, 37% (95% confidence interval CI=35-39%) in the blind group and 48% (95% CI=46-49%) in the nonblind group were recruited. In both groups, once randomized, most of the losses were women who did not attend the first clinical examination: 49% (blind; 95% CI=47-51%) and 40% (nonblind; 95% CI=38-42%). The rest were found ineligible or lost their interest during clinical examinations. The reasons for joining the trial were relatively similar in the two groups. CONCLUSIONS: Blinding decreased women's interest in joining a long-term preventive trial. Women's reasons for joining the trial were not influenced by blinding.     

Prevalence of mental disorders among adults in Finland: basic results from the Mini Finland Health Survey

The Mini Finland Health Survey was an extensive epidemiological study of the Finnish population aged 30 or over; the prevalence of mental disorders was one aspect studied. Prevalence of symptoms in the General Health Questionnaire as well as the prevalence of self-perceived and clinically assessed mental disorders was studied. The total prevalence of clinically assessed mental disorders was 17.4%, 14.8% in the men and 19.5% in the women. A definite disorder was observed for 11.7% of the subjects. About half of the subjects suffering from a mental disorder according to clinical assessment also reported a self-perceived disorder. Of various diagnoses, the most common were phobic and anxiety neurosis (6.2%) and neurotic depression (4.6%). The prevalence of schizophrenia was 1.3%. The highest prevalence was found in the ages 50 to 64 years. The prevalence of psychoses was highest in northern and eastern Finland, and that of neuroses in southern Finland.     

Neuropeptide converting enzyme activities in CSF of low back pain patients

The activity levels of a dynorphin converting enzyme (DCE), a substance P endopeptidase (SPE) and a substance P alpha-amidating enzyme (SP-GLYE) were measured in the cerebrospinal fluid (CSF) of 90 patients with chronic low back pain, sciatica and neurological signs of rhizopathy. The DCE activity was significantly higher in men than in women. Age was related to the DCE activity independent of sex, i.e., older patients had higher enzyme activity. The activities of two substance P converting enzymes were not related to sex or age. Self-reported pain experience and affective covariates (anxiety, depression, hostility, somatization) of pain, and myelography data were not found to be related to the enzyme activity levels once adjustment had been made for sex and age. The activity levels of the enzymes measured here had no predictive value for the long-term outcome of rehabilitation and therapy at the 5-year follow-up of the patients. The sex difference in DCE activity provides further evidence in favor of the role of gender in the psychoendocrine coping with pain distress.     

Long-term outcome and quality of life in patients with Charcot foot

BackgroundThere is only sparse scientific data about the long-term effects of the Charcot foot on patients’ lives and the clinical outcome. This study evaluates the long-term effects of diabetic Charcot foot.MethodsA cross-sectional follow-up study of consecutive series of patients with Charcot foot referred to the University Hospital Diabetic Foot and Ankle Clinic between 1991 and 2002.ResultsForty-one patients were referred with Charcot foot between 1991 and 2002. After an average follow-up of 8 years their overall mortality rate was 29% (12/41) and 29 patients (30 Charcot feet) have been followed more than 5 years. Sixty-seven percent of Charcot feet suffered at least one episode of ulceration and 50% (15/30) of affected feet had surgical treatment resulting in 29 operations. Simple exostectomy was successful in 62% of cases. The need for surgical management increased markedly 4 years after the diagnosis. Correct diagnosis within 3 months resulted in better functional outcome (AOFAS) and walking distance (p = 0.006 and p = 0.008, respectively). Lower SF-36 component scores in physical functioning, social functioning and general health perceptions were found when the study population was compared to the general population and chronically ill control subjects.ConclusionsDiabetic Charcot foot decreases patient's physical functioning and general health but does not usually affect mental health. Surgical management is often required with an increase 4 years post-diagnosis. A delay of diagnosis of more than 3 months was found to adversely affect the quality of life and functional outcome.     

Relationship between craniofacial and condyle path asymmetry in unilateral cross-bite patients

The aim of this work was to examine the degree and direction of asymmetry in the condyle path, and its associations with facial and dental midline asymmetry in patients with treated and untreated unilateral cross-bite. The subjects were 22 patients, 16 female and 6 male, aged from 9 to 50 years. Nine patients had a history of treated unilateral cross-bite, the mean age of this group being 11.1 years. The children had been treated with removable or fixed expansion appliances at an age of 5-8 years. Thirteen patients had untreated unilateral cross-bite, their mean age being 23.4 years. The clinical examinations were performed by two orthodontists and standard PA roentgenograms were taken in a cephalostat. The condyle path was recorded from the inversion of a face bow fixed rigidly on the anterior mandibular teeth, the positions of the bow being first recorded with the teeth in maximal intercuspation and then in protrusion with the midline unchanged. The condyle path was found to be asymmetric in both the treated and untreated lateral cross-bite groups and to be steeper on the side of the diagnosed or treated cross-bite. The degree of asymmetry was found to be twice as great in the untreated as in the treated group. The facial asymmetry parameters describing the position of the mandible showed the strongest correlation with condyle path asymmetry. The results stress the importance of early treatment of lateral cross-bites.     

Fibrotic process and drug metabolism in alcoholic liver disease

The effect of fibrosis on drug metabolism in alcoholic liver disease was evaluated in a comparison of the concentrations of serum aminoterminal propeptide of type III procollagen and basement membrane (BM; 7S domain of type IV collagen and laminin) antigens with in vitro (cytochrome P-450) and in vivo (antipyrine) drug metabolism in 67 alcoholics classified by liver histology. Alcoholics with intact or fatty liver had rapid or normal drug metabolism and normal collagen metabolism. Alcoholics with a fatty liver plus fibrosis or active cirrhosis had reduced drug metabolism and elevated levels of serum markers for collagen and BM metabolism. Alcoholics with inactive cirrhosis who had received therapy with enzyme inducers had a tendency toward normal drug and collagen metabolism parameters. Antipyrine metabolism, but not P-450 content, was related to the levels of serum type III collagen and BM markers. The fibrotic process, especially BM formation, creates a mechanical barrier that may prevent contact between blood and hepatocytes, thus delaying substrate availability.     

Intravenous insulin has no effect on myocardial contractility or heart rate in healthy subjects

Summary To evaluate the acute effects of intravenous insulin on myocardial contractility and heart rate, echocardiography was performed in 12 healthy subjects and continuous heart rate recording in 11 healthy subjects before and during eugly-caemic insulin and glucose infusion. The rate of insulin infusion was 0.5–1.0 mU·kg^–1·min^–1. Serum insulin concentration was increased from 14.1±5.5 (mean±SD) to a plateau level of 91.3±22.8 mU/l. Left ventricular end-diastolic diameter, ejection phase indices and the heart rate remained at basal levels during the intervention. Thus moderate hyperinsulinaemia, induced by euglycaemic insulin and glucose infusion, has no inotropic or chronotropic effects in healthy supine subjects.