Association between liver fibrosis and cognition in a nationally representative sample of older adults.

BACKGROUND AND PURPOSE: Liver fibrosis, a common yet often subclinical manifestation of chronic liver disease, may have an unrecognized role in cognitive impairment. We evaluated the association between a validated liver fibrosis index and cognitive measures among older adults. METHODS: We examined the association between liver fibrosis and cognitive performance among participants aged 60 years and older in the US National Health and Nutrition Examination Survey. Liver fibrosis was measured with the validated Fibrosis-4 (FIB-4) liver fibrosis score. The outcomes were performance on four standardized cognitive tests of immediate and delayed verbal learning, verbal fluency, and attention/concentration. We used linear regression to evaluate the association between FIB-4 score and performance on cognitive tests while adjusting for potential confounders. In sensitivity analyses, we examined this association in participants without known liver disease. RESULTS: Among 3217 adult participants, the mean age was 69 years, and 54% were women. Standard liver chemistries were largely in the normal range. However, 5.0% [95% confidence interval (CI) 4.0-6.0] had liver fibrosis based on a validated cut-off. In adjusted linear regression models, higher liver fibrosis scores were associated with worse immediate recall (ß -0.39; 95% CI -0.58, -0.21), language fluency (ß -0.46; 95% CI -0.72, -0.21), and attention/concentration (ß -1.34; 95% CI -2.25, -0.43), but not delayed recall (ß -0.10; 95% CI -0.20, 0.01). Results were similar when limiting the study population to participants without known clinical liver disease. CONCLUSION: Liver fibrosis, including subclinical liver fibrosis, may be an independent risk factor for cognitive impairment among older adults.

Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer.

BACKGROUND: Src has a critical role in tumor cell migration and invasion. Increased Src activity has been shown to correlate with disease progression and poor prognosis, suggesting Src could serve as a therapeutic target for kinase inhibition. Saracatinib (AZD0530) is a novel selective oral Src kinase inhibitor. METHODS: Metastatic colorectal cancer patients who had received one prior treatment and had measurable disease were enrolled in this phase 2 study. Saracatinib was administered at 175 mg by mouth daily for 28 day cycles until dose-limiting toxicity or progression as determined by staging every 2 cycles. The primary endpoint was improvement in 4 month progression-free survival. Design of Thall, Simon, and Estey was used to monitor proportion of patients that were progression free at 4 months. The trial was opened with plan to enroll maximum of 35 patients, with futility assessment every 10 patients. RESULTS: A total of 10 patients were enrolled between January and November 2007. Further enrollment was stopped due to futility. Median progression-free survival was 7.9 weeks, with all 10 patients showing disease progression following radiographic imaging. Median overall survival was 13.5 months. All patients were deceased by time of analysis. Observed adverse events were notable for a higher than expected number of patients with grade 3 hypophosphatemia (n = 5). CONCLUSION: Saracatinib is a novel oral Src kinase inhibitor that was well tolerated but failed to meet its primary endpoint of improvement in 4 month progression-free survival as a single agent in previously treated metastatic colorectal cancer patients.

Medical students and interns' knowledge about and attitude towards homosexuality.

BACKGROUND AND RATIONALE: Medical professionals' attitude towards homosexuals affects health care offered to such patients with a different sexual orientation. There is absence of literature that explores the attitudes of Indian medical students or physicians towards homosexuality. AIM: This study aimed to evaluate Indian medical students and interns' knowledge about homosexuality and attitude towards homosexuals. MATERIALS AND METHODS: After IEC approval and written informed consent, a cross-sectional study was conducted on a purposive sample of undergraduate medical students and interns studying in one Indian medical college. The response rate was 80.5%. Only completely and validly filled responses (N = 244) were analyzed. The participants filled the Sex Education and Knowledge about Homosexuality Questionnaire (SEKHQ) and the Attitudes towards Homosexuals Questionnaire (AHQ). SEKHQ consisted of 32 statements with response chosen from 'true', 'false', or 'don't know'. AHQ consisted of 20 statements scorable on a 5-point Likert scale. Multiple linear regression was used to find the predictors of knowledge and attitude. RESULTS: Medical students and interns had inadequate knowledge about homosexuality, although they endorsed a neutral stance insofar as their attitude towards homosexuals is concerned. Females had more positive attitudes towards homosexuals. Knowledge emerged as the most significant predictor of attitude; those having higher knowledge had more positive attitudes. CONCLUSION: Enhancing knowledge of medical students by incorporation of homosexuality related health issues in the curriculum could help reduce prejudice towards the sexual minority and thus impact their future clinical practice.

A phase I trial of LHC165 single agent and in combination with spartalizumab in patients with advanced solid malignancies.

BACKGROUND: LHC165 is a Toll-like receptor (TLR)-7 agonist that generates an effective tumor antigen-specific T-cell adaptive immune response as well as durable antitumor responses. We aimed to evaluate the safety, tolerability, efficacy, dose-limiting toxicities, and pharmacokinetics (PK) of LHC165 single agent (SA) ± spartalizumab [PDR001; anti-programmed cell death protein 1 (PD-1)] in adult patients with advanced solid tumors. MATERIALS AND METHODS: In this phase I/Ib, open-label, dose-escalation/expansion study, patients received LHC165 SA 100-600 µg biweekly through intratumoral (IT) injection and LHC165 600 µg biweekly + spartalizumab 400 mg Q4W through intravenous (IV) infusion. RESULTS: Forty-five patients were enrolled: 21 patients received LHC165 SA, and 24 patients received LHC165 + spartalizumab. The median duration of exposure was 8 weeks (range 2-129 weeks). No maximum tolerated dose was reached. Recommended dose expansion was established as LHC165 600 µg biweekly as SA and in combination with spartalizumab 400 mg Q4W. The most common drug-related adverse events (AEs) were pyrexia (22.2%), pruritus (13.3%), chills (11.1%), and asthenia (4.4%). The only serious AE (SAE) suspected to be related to the study drug was grade 3 pancreatitis (n = 1). Across all tumor types, overall response rate and disease control were 6.7% and 17.8%, respectively. Overall median progression-free survival (PFS) and immune-related PFS was 1.7 months. LHC165 serum PK demonstrated an initial rapid release followed by a slower release due to continued release of LHC165 from the injection site. CONCLUSIONS: LHC165 demonstrated acceptable safety and tolerability both as SA and in combination with spartalizumab, and evidence of limited antitumor activity was seen in adult patients with relapsed/refractory or metastatic solid tumors.

Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study.

STUDY QUESTION: Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study? SUMMARY ANSWER: We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry. WHAT IS KNOWN ALREADY: Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations. STUDY DESIGN, SIZE, DURATION: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM. MATERIALS, SETTING, METHODS: SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses. MAIN RESULTS AND THE ROLE OF CHANCE: We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends. LIMITATIONS, REASONS FOR CAUTION: Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings. WIDER IMPLICATIONS OF THE FINDINGS: The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.

Effect of gender and geographic location on the expression of primary hyperparathyroidism.

BACKGROUND: The effect of gender on the expression of primary hyperparathyroidism (PHPT) is not well characterized. AIM: We therefore evaluated two Caucasian populations (US and Italian) of men and women with PHPT, matched for age and body mass index (BMI), in a cross-sectional retrospective observational study. METHODS: We studied 74 US (23 men) and 126 Italian (42 men) patients evaluating main biochemical indices of the disease and bone mineral density (BMD) at the spine and proximal femur. RESULTS: Mean serum calcium levels were higher both in Italian men compared to women (11.7 ± 1.22 mg/dl and 11.1 ± 0.83, p<0.01) and in Italian compared to US patients (11.3 ± 1.01 and 10.8 ± 0.58, p<0.001), with similar results for the serum ionized calcium. Mean serum PTH levels were not different either between the genders or between the countries. After controlling for BMI, the mean BMD at both the femoral neck and total hip in females US patients was significantly higher compared with Italian female patients. CONCLUSION: Despite similar levels of circulating PTH, Italian patients have more pronounced effects of the disease as assessed by serum calcium and a more significant cortical involvement in women as assessed by BMD.

Revealing the 3D internal structure of natural polymer microcomposites using X-ray ultra microtomography.

Properties of composite materials are directly affected by the spatial arrangement of reinforcement and matrix. In this research, partially hydrolysed cellulose microcrystals were used to fabricate polycaprolactone microcomposites. The spatial distribution of cellulose microcrystals was characterized by a newly developed technique of X-ray ultra microscopy and microtomography. The phase and absorption contrast imaging of X-ray ultra microscopy revealed two-dimensional and three-dimensional information on CMC distribution in polymer matrices. The highest contrast and flux (signal-to-noise ratio) were obtained using vanadium foil targets with the accelerating voltage of 30 keV and beam current of >200 nA. The spatial distribution of cellulose microcrystals was correlated to the mechanical properties of the microcomposites. It was observed that heterogeneous distribution and clustering of cellulose microcrystals resulted in degradation of tensile strength and elastic modulus of composites. The utilization of X-ray ultra microscopy can open up new opportunities for composite researchers to explore the internal structure of microcomposites. X-ray ultra microscopy sample preparation is relatively simple in comparison to transmission electron microscopy and the spatial information is gathered at much larger scale.

Adverse effects of perinatal illness severity on neurodevelopment are partially mediated by early brain abnormalities in infants born very preterm.

BACKGROUND: We sought to determine the mediating effects of magnetic resonance imaging (MRI) biomarkers at term gestation on the relationship between perinatal illness severity and neurodevelopment. METHODS: The Clinical Risk Index for Babies-second edition (CRIB-II) was correlated with indices of brain maturation or injury and neurodevelopment at 2-year follow-up in infants born less than 32 weeks gestation. Using a counterfactual mediation analysis, associations between CRIB-II, MRI biomarkers, and neurodevelopment were confirmed, followed by an assessment of the mediating effects of MRI biomarkers on the relationship between CRIB-II and neurodevelopment. RESULTS: CRIB-II correlated significantly with neurodevelopment and MRI biomarkers of brain injury or cortical maturation. Two MRI biomarkers, cortical surface area and global injury score, were associated with neurodevelopmental scores at follow-up and included in mediation analyses. CONCLUSION: Biomarkers of cortical maturation or brain injury at term-equivalent age mediated a substantial portion of the risks conveyed by perinatal illness severity on neurodevelopmental outcomes at 2 years corrected age.

Diffusion MRI Microstructural Abnormalities at Term-Equivalent Age Are Associated with Neurodevelopmental Outcomes at 3 Years of Age in Very Preterm Infants.

BACKGROUND AND PURPOSE: Microstructural white matter abnormalities on DTI using Tract-Based Spatial Statistics at term-equivalent age are associated with cognitive and motor outcomes at 2 years of age or younger. However, neurodevelopmental tests administered at such early time points are insufficiently predictive of mild-moderate motor and cognitive impairment at school age. Our objective was to evaluate the microstructural antecedents of cognitive and motor outcomes at 3 years' corrected age in a cohort of very preterm infants. MATERIALS AND METHODS: We prospectively recruited 101 very preterm infants (<32 weeks' gestational age) and performed DTI at term-equivalent age. The Differential Ability Scales, 2nd ed, Verbal and Nonverbal subtests, and the Bayley Scales of Infant and Toddler Development, 3rd ed, Motor subtest, were administered at 3 years of age. We correlated DTI metrics from Tract-Based Spatial Statistics with the Bayley Scales of Infant and Toddler Development, 3rd ed, and the Differential Ability Scales, 2nd ed, scores with correction for multiple comparisons. RESULTS: Of the 101 subjects, 84 had high-quality DTI data, and of these, 69 returned for developmental testing (82%). Their mean (SD) gestational age was 28.4 (2.5) weeks, and birth weight was 1121.4 (394.1) g. DTI metrics were significantly associated with Nonverbal Ability in the corpus callosum, posterior thalamic radiations, fornix, and inferior longitudinal fasciculus and with Motor scores in the corpus callosum, internal and external capsules, posterior thalamic radiations, superior and inferior longitudinal fasciculi, cerebral peduncles, and corticospinal tracts. CONCLUSIONS: We identified widespread microstructural white matter abnormalities in very preterm infants at term that were significantly associated with cognitive and motor development at 3 years' corrected age.

Squamous cell carcinoma arising in a recent plaque of discoid lupus erythematous, in a sun-protected area.

Squamous cell carcinoma is a known complication reported to occur in chronic discoid lupus erythematosus in sun-exposed areas. We report a patient with systemic lupus erythematosus who developed a squamous cell carcinoma in a recent plaque of discoid lupus erythematosus in a sun-protected area. This article emphasizes the need for a very high index of suspicion for squamous cell carcinoma and repeated biopsies when discoid lupus erythematosus fails to respond to conventional therapy or there is unexplained exacerbation.

Brain Imaging of Patients with COVID-19: Findings at an Academic Institution during the Height of the Outbreak in New York City.

BACKGROUND AND PURPOSE: A large spectrum of neurologic disease has been reported in patients with coronavirus disease 2019 (COVID-19) infection. Our aim was to investigate the yield of neuroimaging in patients with COVID-19 undergoing CT or MR imaging of the brain and to describe associated imaging findings. MATERIALS AND METHODS: We performed a retrospective cohort study involving 2054 patients with laboratory-confirmed COVID-19 presenting to 2 hospitals in New York City between March 4 and May 9, 2020, of whom 278 (14%) underwent either CT or MR imaging of the brain. All images initially received a formal interpretation from a neuroradiologist within the institution and were subsequently reviewed by 2 neuroradiologists in consensus, with disputes resolved by a third neuroradiologist. RESULTS: The median age of these patients was 64 years (interquartile range, 50-75 years), and 43% were women. Among imaged patients, 58 (21%) demonstrated acute or subacute neuroimaging findings, the most common including cerebral infarctions (11%), parenchymal hematomas (3.6%), and posterior reversible encephalopathy syndrome (1.1%). Among the 51 patients with MR imaging examinations, 26 (51%) demonstrated acute or subacute findings; notable findings included 6 cases of cranial nerve abnormalities (including 4 patients with olfactory bulb abnormalities) and 3 patients with a microhemorrhage pattern compatible with critical illness-associated microbleeds. CONCLUSIONS: Our experience confirms the wide range of neurologic imaging findings in patients with COVID-19 and suggests the need for further studies to optimize management for these patients.

White Matter Injury and Structural Anomalies in Infants with Prenatal Opioid Exposure.

Previous studies have not found structural injury or brain malformations in infants and children with prenatal opioid exposure. As part of an ongoing study evaluating neuroimaging in infants with prenatal opioid exposure, we reviewed structural brain MR imaging in 20 term infants with prenatal opioid exposure and 20 term controls at 4-8 weeks of age. We found that 8 of the 20 opioid-exposed infants had punctate white matter lesions or white matter signal abnormality on structural MR imaging, and 2 of the opioid-exposed infants had a septopreoptic fusion anomaly. No controls had white matter injury or structural malformations. Our findings underscore the importance of clinical neurodevelopmental follow-up and the need for more comprehensive imaging and long-term outcomes research following prenatal opioid exposure.

Management of anesthesia for cesarean delivery in a patient with an unruptured intracranial aneurysm.

Headaches are a common symptom during pregnancy. The thunderclap headache is a sudden onset headache reaching maximal intensity within seconds to minutes. It is typically a subarachnoid hemorrhage caused by rupture of an intracranial aneurysm or arteriovenous malformation. Physiologic changes of pregnancy, such as increased cardiac output and plasma volume, may increase the risk of aneurysmal rupture. The relationship between the mode of delivery and incidence of rupture is not well defined. In this case report, we discuss the anesthetic management for cesarean delivery of a parturient with an unruptured aneurysm, located on the left ophthalmic-internal carotid artery. The delivery options and anesthetic technique used are presented, together with a review of published literature.

Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy.

BACKGROUND: Although studies suggest decreased incident hepatocellular carcinoma (HCC) after direct-acting antivirals (DAA), data are conflicting regarding HCC recurrence and aggressiveness in patients who have a history of HCC with complete response. AIM: Characterize HCC recurrence patterns after DAA therapy. METHODS: Two reviewers searched MEDLINE and SCOPUS from January 2015 to December 2017 and identified studies evaluating HCC recurrence patterns following DAA therapy. A pooled estimate was calculated using the DerSimonian and Laird method for a random effects model. The study was conducted in accordance with PRISMA guidelines. RESULTS: Among 24 studies (n = 1820 patients), the proportion of patients with HCC recurrence following DAA therapy ranged from 0% to 59% (pooled estimate 24.4%; 95% CI: 18.4%-30.4%). Among 11 full text manuscripts, pooled HCC recurrence was 21.9% (95% CI: 16.2%-28.3%). Factors associated with recurrence included history of prior HCC recurrence and a shorter interval between HCC complete response and DAA initiation. Nine studies comparing DAA-treated and interferon-treated or untreated patients found similar recurrence among DAA-treated patients. Most (77.8%) patients with HCC recurrence were detected at an early tumour stage, of whom 64.7% received curative treatment. Study limitations included heterogeneous cohorts, potential misclassification of HCC absence prior to DAA, ascertainment bias for recurrence, and short durations of follow-up. CONCLUSIONS: Current data suggest acceptable HCC recurrence rates after DAA therapy, particularly if DAA therapy is delayed at least 6 months after HCC complete response. However, data characterising HCC recurrence after DAA therapy are of limited quality, highlighting the need for high quality prospective studies.

Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis.

BACKGROUND: Abdominal ultrasound fails to detect over one-fourth of hepatocellular carcinoma (HCC) at an early stage in patients with cirrhosis. Identifying patients in whom ultrasound is of inadequate quality can inform interventions to improve surveillance effectiveness. AIM: To evaluate and identify predictors of ultrasound quality in patients with cirrhosis. METHODS: We performed a retrospective cohort study among patients who underwent ultrasound examination for a cirrhosis-related indication between April 2015 and October 2015. Three fellowship-trained abdominal radiologists collectively reviewed all ultrasound exams and categorised exam quality as definitely adequate, likely adequate, likely inadequate and definitely inadequate to exclude liver lesions. We performed multivariable logistic regression to determine characteristics associated with inadequate ultrasound quality. RESULTS: Among 941 patients, 191 (20.3%) ultrasounds were inadequate for excluding HCC- 134 definitely inadequate and 57 likely inadequate. In multivariable analysis, inadequate quality was associated with male gender (OR 1.68, 95% CI 1.14-2.48), body mass index category (OR 1.67, 95% CI 1.45-1.93), Child-Pugh B or C cirrhosis (OR 1.93, 95% CI 1.32-2.81), alcohol-related cirrhosis (OR 2.11, 95% CI 1.33-3.37), NASH cirrhosis (OR 2.87, 95% CI 1.71-4.80), and in-patient status (OR 1.55, 95% CI 1.01-2.37). Ultrasounds were inadequate in over one-third of patients with Child-Pugh C cirrhosis, BMI >35, or NASH cirrhosis. CONCLUSIONS: One in five ultrasounds in patients with cirrhosis are inadequate for exclusion of HCC, which can contribute to surveillance failure. Alternative surveillance modalities are needed in subgroups prone to inadequate ultrasounds including obese patients, those with Child Pugh B or C cirrhosis, and those with alcohol- or NASH-related cirrhosis.

The increased cost of ventral hernia recurrence: a cost analysis.

PURPOSE: Over 300,000 ventral hernia repairs (VHRs) are performed each year in the US. We sought to assess the economic burden related to ventral hernia recurrences with a focused comparison of those with the initial open versus laparoscopic surgery. METHODS: The Premier Alliance database from 2009 to 2014 was utilized to obtain patient demographics and comorbid indices, including the Charlson comorbidity index (CCI). Total hospital cost and resource expenses during index laparoscopic and open VHRs and subsequent recurrent repairs were also obtained. The sample was separated into laparoscopic and open repair groups from the initial operation. Adjusted and propensity score matched cost outcome data were then compared amongst groups. RESULTS: One thousand and seventy-seven patients were used for the analysis with a recurrence rate of 3.78 %. For the combined sample, costs were significantly higher during recurrent hernia repair hospitalization ($21,726 versus $19,484, p < 0.0001). However, for index laparoscopic repairs, both the adjusted total hospital cost and department level costs were similar during the index and the recurrent visit. The costs and resource utilization did not go up due to recurrence, even though these patients had greater severity during the recurrent visit (CCI score 0.92 versus 1.06; p = 0.0092). Using a matched sample, the total hospital recurrence cost was higher for the initial open group compared to laparoscopic group ($14,520 versus $12,649; p = 0.0454). CONCLUSIONS: Based on our analysis, need for recurrent VHR adds substantially to total hospital costs and resource utilization. Following initial laparoscopic repair, however, the total cost of recurrent repair is not significantly increased, as it is following initial open repair. When comparing the initial laparoscopic repair versus open, the cost of recurrence was higher for the prior open repair group.

Effect of herbimycin A on growth and pp60c-src activity in human colon tumor cell lines.

The effect of herbimycin A, an ansamycin antibiotic which inhibits cellular transformation by retroviral tyrosine kinases, on the monolayer growth of seven colon tumor cell lines and one cell line established from normal colonic mucosa, CCL239, was examined. Each colon tumor cell line tested showed dose-dependent growth inhibition in response to herbimycin A. A 125ng ml-1 dose of the antibiotic caused greater than 40% growth inhibition in all colon tumor cell lines after two cell doublings. In contrast, at similar herbimycin A concentrations only 12% inhibition was observed in 'normal' CCL239 cells. No major morphologic changes were observed at the light microscopic level in any of the tumor cell lines or CCL239 cells in response to treatment with herbimycin A. Studies using the HT29 colon adenocarcinoma cell line showed dose-dependent inactivation of pp60c-src by herbimycin A, resulting in decreased autophosphorylation, enolase phosphorylation and steady-state levels, which correlated with cellular growth inhibition. Herbimycin A-induced reductions in pp60c-src kinase activity preceded changes in pp60c-src steady-state levels. Growth and pp60c-src inhibition were reversible following removal of herbimycin A from cell culture media. Our results suggest that regulation of pp60c-src tyrosine kinase activity may be important in growth control of colon tumor cells.

Stimulation of the protein tyrosine kinase c-Yes but not c-Src by neurotrophins in human brain-metastatic melanoma cells.

The c-Yes proto-oncogene (pp62c-Yes) encodes a non-receptor-type protein tyrosine kinase (NRPTK) of the Src family. c-Yes activities and protein levels are elevated in human melanoma and melanocyte cell lines. Because the neurotrophins (NT) are important in the progression of melanoma to the brain-metastatic phenotype, we determined whether NT stimulate c-Yes activity in human MeWo melanoma cells and two variant sublines with opposite metastatic capabilities, 3 S 5 and 70W. The highly brain-metastatic 70W subline had an intrinsically higher c-Yes activity than parental MeWo or poorly metastatic 3 S 5 cells. c-Yes kinase was further induced by the prototypic human NT, nerve growth factor (NGF) in a dose and time-dependent manner. In contrast, c-Src activity (pp60-Src) was similar in all these cells and unaffected by NGF exposure. Additionally, human NGF and neurotrophin-3 stimulated c-Yes in brain-metastatic 70W cells. The magnitude of c-Yes activation correlated with the degree of invasion of 70 W cells following incubation of these neurotrophins. To further examine NT stimulation of c-Yes in melanoma cells, three additional cell lines were examined. Metastatic TXM-13 and TXM-18 increased c-Yes activity in response to NGF. In contrast, no increase was observed in low-metastatic TXM-40 cells. Together, these data suggest that altered c-Yes expression may play a role in the malignant progression of the human melanocyte towards the brain-metastatic phenotype and that NT enhance the activity of c-Yes in signaling penetration into the matrix of NT-rich stromal microenvironments such as the brain.

Cyclandelate in the treatment of senility: a controlled study.

Elderly patients often manifest a variety of symptoms (e.g., depression, memory loss, irritability, hostility), categorized as "senility" or "senile dementia," which are difficult to treat and represent a major therapeutic challenge to the geriatrician. This investigation was designed to assess, under double-blind conditions, a drug often prescribed for these symptoms--cyclandelate. In a 16-week study, 58 elderly patients were randomly assigned to two groups and received either 1600 mg of cyclandelate daily or identical-appearing placebo capsules. Initially, the every four weeks thereafter, the patients were examined for changes in vital signs and for adverse reactions, also, the Sandoz Clinical Assessment-Geriatric (SCAG) Scale and the Nurses Observation Scale Inpatient Evaluation (NOSIE) were completed. At the final evaluation, a physician's global rating was obtained. Our data suggest that cyclandelate is a safe and moderately effective treatment for certain symptoms of senescence in carefully selected patients.