tbuckley/cabot-search huggingface dataset:
Randomized Trial of Cognitive-Behavioral Therapy Versus Light Therapy for Seasonal Affective Disorder: Acute Outcomes
Authors: Kelly J. Rohan, Jennifer N. Mahon, Maggie Evans, Sheau-Yan Ho, Jonah Meyerhoff, Teodor T. Postolache, Pamela M. Vacek
Journal: American Journal of Psychiatry (2015)

Objective: Whereas considerable evidence supports light therapy for winter seasonal affective disorder (SAD), data on cognitive-behavioral therapy for SAD (CBT-SAD) are promising but preliminary. This study estimated the difference between CBT-SAD and light therapy outcomes in a large, more definitive test. Method: The participants were 177 adults with a current episode of major depression that was recurrent with a seasonal pattern. The randomized clinical trial compared 6 weeks of CBT-SAD (N=88) and light therapy (N=89). Light therapy consisted of 10,000-lux cool-white florescent light, initiated at 30 minutes each morning and adjusted according to a treatment algorithm based on response and side effects. CBT-SAD comprised 12 sessions of the authors’ SAD-tailored protocol in a group format and was administered by Ph.D. psychologists in two 90-minute sessions per week. Outcomes were continuous scores on the Structured Interview Guide for the Hamilton Rating Scale for Depression–SAD Version (SIGH-SAD, administered weekly) and Beck Depression Inventory–Second Edition (BDI-II, administered before treatment, at week 3, and after treatment) and posttreatment remission status based on cut points. Results: Depression severity measured with the SIGH-SAD and BDI-II improved significantly and comparably with CBT-SAD and light therapy. Having a baseline comorbid diagnosis was associated with higher depression scores across all time points in both treatments. CBT-SAD and light therapy did not differ in remission rates based on the SIGH-SAD (47.6% and 47.2%, respectively) or the BDI-II (56.0% and 63.6%). Conclusions: CBT-SAD and light therapy are comparably effective for SAD during an acute episode, and both may be considered as treatment options.
Malignant Melanoma Misdiagnosed as a Diabetic Foot Ulcer
Authors: Lee C. Rogers, David G. Armstrong, Andrew J.M. Boulton, Anthony J. Freemont, Rayaz A. Malik
Journal: Diabetes Care (2007)

A male patient aged 48 years with type 2 diabetes presented with a painless nonhealing ulcer of 18 months duration under his right first metatarsal head. The ulcer was not a typical-appearing neuropathic foot ulcer and had mushrooming granulation tissue and areas of intact epidermis in a lenticular fashion over the wound bed (Fig. 1). The patient also complained of a “knot” in his right inguinal area. An incisional biopsy was taken from the foot lesion, which revealed a poorly differentiated melanoma covered by an intact epidermis …
Z-nucleotide accumulation in erythrocytes from Lesch-Nyhan patients.
Authors: Y Sidi, B S Mitchell
Journal: Journal of Clinical Investigation (1985)

5-Amino-4-imidazolecarboxamide riboside 5'-monophosphate (ZMP) is an intermediate in the purine de novo synthetic pathway that may be further metabolized to inosine 5'-monophosphate, degraded to the corresponding nucleoside (5-amino-4-imidazole-carboxamide riboside; Z-riboside), or phosphorylated to the corresponding 5'-triphosphate (ZTP). Accumulation of ZTP in microorganisms has been associated with depletion of folate intermediates that are necessary for the conversion of ZMP to inosine 5'-monophosphate and has been postulated to play a regulatory role in cellular metabolism. We have shown the presence of Z-nucleotides in erythrocytes derived from five individuals with the Lesch-Nyhan syndrome. Erythrocyte folate levels were within the normal range, although guanosine triphosphate levels were significantly reduced below those in normal controls (P less than 0.01). A small amount of Z-nucleotide accumulation was also found in one individual with partial deficiency of the enzyme hypoxanthine guanine phosphoribosyltransferase and in two individuals with other disorders of purine overproduction. In contrast, no Z-nucleotides were detected in 13 normal controls or in three individuals with hyperuricemia on allopurinol therapy. We conclude that Z-nucleotide formation may result from markedly increased rates of de novo purine biosynthesis. It is possible that metabolites of these purine intermediates may play a role in the pathogenesis of the Lesch-Nyhan syndrome.
B-cell recovery following rituximab-based therapy is associated with perturbations in stromal derived factor-1 and granulocyte homeostasis
Authors: Kieron Dunleavy, Frances Hakim, Hyun Kyung Kim, John E. Janik, Nicole Grant, Takayuki Nakayama, Therese White, George Wright, Larry Kwak, Ronald Gress, Giovanna Tosato, Wyndham H. Wilson
Journal: Blood (2005)
Shaping Magnetic Fields to Direct Therapy to Ears and Eyes
Authors: B. Shapiro, S. Kulkarni, A. Nacev, A. Sarwar, D. Preciado, D.A. Depireux
Journal: Annual Review of Biomedical Engineering (2014)

Magnetic fields have the potential to noninvasively direct and focus therapy to disease targets. External magnets can apply forces on drug-coated magnetic nanoparticles, or on living cells that contain particles, and can be used to manipulate them in vivo. Significant progress has been made in developing and testing safe and therapeutic magnetic constructs that can be manipulated by magnetic fields. However, we do not yet have the magnet systems that can then direct those constructs to the right places, in vivo, over human patient distances. We do not yet know where to put the external magnets, how to shape them, or when to turn them on and off to direct particles or magnetized cells—in blood, through tissue, and across barriers—to disease locations. In this article, we consider ear and eye disease targets. Ear and eye targets are too deep and complex to be targeted by a single external magnet, but they are shallow enough that a combination of magnets may be able to direct therapy to them. We focus on how magnetic fields should be shaped (in space and time) to direct magnetic constructs to ear and eye targets.
UK lags behind similar countries in stroke services
Authors: Adrian O’Dowd
Journal: BMJ (2008)

Legislation to regulate the use of human embryos for research in the United Kingdom had its second reading in the House of Commons this week, but ministers face a fight to push the most contentious measures through.The Human Fertilisation and Embryology Bill, which updates 1990 legislation to take account of advances in technology, passed the second reading by 340 votes to 78, with only nine Labour MPs rebelling.
Rho Kinase–Induced Nuclear Translocation of ERK1/ERK2 in Smooth Muscle Cell Mitogenesis Caused by Serotonin
Authors: Yinglin Liu, Yuichiro J. Suzuki, Regina M. Day, Barry L. Fanburg
Journal: Circulation Research (2004)

There is now considerable evidence supporting a mitogenic action of serotonin (5-HT) on vascular smooth muscle cells (SMC) that might participate in pulmonary hypertension (PH). Our previous studies have demonstrated that 5-HT-induced proliferation depends on the generation of reactive oxygen species and activation of extracellular signal-regulated kinase (ERK) 1/ERK2. Activation of Rho kinase (ROCK) in SMC also may be important in PH. We undertook the present study to assess the role of Rho A/ROCK and its possible relation to ERK1/ERK2 in 5-HT-induced pulmonary artery SMC proliferation. We found that this stimulation of SMC proliferation requires Rho A/ROCK as inhibition with Y27632, a ROCK inhibitor, or dominant negative (DN) mutant Rho A blocks 5-HT-induced proliferation, cyclin D1 expression, phosphorylation of Elk, and the DNA binding of transcription factors, Egr-1 and GATA-4. 5-HT activated ROCK, and the activation was blocked by GR 55562 and GR127935, 5-HT 1B/1D receptor antagonists, but not by serotonin transport (SERT) inhibitors. Activation of Rho kinase by 5-HT was independent of activation of ERK1/ERK2, and 5-HT activated ERK1/ERK2 independently of ROCK. Treatment of SMC with Y27632 and expression of DNRho A in cells blocked translocation of ERK1/ERK2 to the cellular nucleus. Depolymerization of actin with cytochalasin D (CD) and latrunculin B (latB) failed to block the translocation of ERK, suggesting that the actin cytoskeleton does not participate in the translocation. The studies show for the first time to our knowledge combinational action of SERT and a 5-HT receptor in SMC growth and Rho A/ROCK participation in 5-HT receptor 1B/1D-mediated mitogenesis of vascular SMCs through an effect on cytoplasmic to nuclear translocation of ERK1/ERK2.
The malonyl CoA axis as a potential target for treating ischaemic heart disease
Authors: J. R. Ussher, G. D. Lopaschuk
Journal: Cardiovascular Research (2008)

Cardiovascular disease is the leading cause of death and disability for people living in western societies, with ischaemic heart disease accounting for the majority of this health burden. The primary treatment for ischaemic heart disease consists of either improving blood and oxygen supply to the heart or reducing the heart's oxygen demand. Unfortunately, despite recent advances with these approaches, ischaemic heart disease still remains a major health problem. Therefore, the development of new treatment strategies is still required. One exciting new approach is to optimize cardiac energy metabolism, particularly by decreasing the use of fatty acids as a fuel and by increasing the use of glucose as a fuel. This approach is beneficial in the setting of ischaemic heart disease, as it allows the heart to produce energy more efficiently and it reduces the degree of acidosis associated with ischaemia/reperfusion. Malonyl CoA is a potent endogenous inhibitor of cardiac fatty acid oxidation, secondary to inhibiting carnitine palmitoyl transferase-I, the rate-limiting enzyme in the mitochondrial uptake of fatty acids. Malonyl CoA is synthesized in the heart by acetyl CoA carboxylase, which in turn is phosphorylated and inhibited by 5'AMP-activated protein kinase. The degradation of myocardial malonyl CoA occurs via malonyl CoA decarboxylase (MCD). Previous studies have shown that inhibiting MCD will significantly increase cardiac malonyl CoA levels. This is associated with an increase in glucose oxidation, a decrease in acidosis, and an improvement in cardiac function and efficiency during and following ischaemia. Hence, the malonyl CoA axis represents an exciting new target for the treatment of ischaemic heart disease.
Calcium and the Control of Renin Secretion*
Authors: J. C. S. FRAY, C. S. PARK, A. N. D. VALENTINE
Journal: Endocrine Reviews (1987)

DURING the past few years, substantial advances have been made in our understanding of renin secretion. Chiefly responsible for the advances is the proposition by Peart (1) that Ca plays a central role in controlling renin secretion as it does in smooth muscle contraction and relaxation. This has led to the view, based mainly on indirect evidence, that cytosolic Ca is an intracellular signal which regulates renin secretion through the baroreceptor, macula densa, and neurohormonal pathways. The specific proposal is that factors which physiologically stimulate renin secretion do so by lowering cytosolic Ca, and those which inhibit secretion do so by raising Ca (2). Thus, for example, hemodynamic factors such as renal perfusion pressure and intrarenal tissue pressure, which control renin secretion through the baroreceptor pathway, regulate Ca flux in the juxtaglomerular (JG) cells (2). Increased NaCl load at the macula densa increases adenosine production at the macula densa, and this adenosine acts on the JG cells to raise cytosolic Ca and inhibit renin secretion (3–7). The neurohormonal pathway, by β-adrenergic mechanism, stimulates renin secretion through a cAMP cascade which leads to a reduced cytosolic Ca (3), and, by aadrenergic mechanism, inhibits secretion by increasing Ca inflow and thereby cytosolic Ca (8). Several reviews have appeared which point to Ca as the common signal most likely responsible for controlling renin secretion (2, 3, 8–10). Park and co-workers (11) have recently demonstrated an inverse relationship between renin secretion and cytosolic Ca, thereby providing the first direct evidence to support the proposition of Peart (1).
UVSSA and USP7: new players regulating transcription-coupled nucleotide excision repair in human cells
Authors: Alain Sarasin
Journal: Genome Medicine (2012)

Transcription-coupled nucleotide excision repair (TC-NER) specifically removes DNA damage located in actively transcribed genes. Defects in TC-NER are associated with several human disorders, including Cockayne syndrome (CS) and ultraviolet (UV)-sensitive syndrome (UVSS). Using exome sequencing, and genetic and proteomic approaches, three recent studies have identified mutations in the UVSSA gene as being responsible for UVSS-A. These findings suggest a new mechanistic model involving UV-stimulated scaffold protein A (UVSSA) and the ubiquitin-specific protease 7 (USP7) in the fate of stalled RNA polymerase II during TC-NER, and provide insights into the diverse clinical features of CS and UVSS.
Revisiting Survival Differences by Race and Ethnicity among Hemodialysis Patients
Authors: Bruce M. Robinson, Marshall M. Joffe, Ronald L. Pisoni, Friedrich K. Port, Harold I. Feldman
Journal: Journal of the American Society of Nephrology (2006)

Hemodialysis (HD) patients who are identified as belonging to racial or ethnic minority groups have longer survival than non-Hispanic white HD patients. This study sought to determine to what extent this survival difference is explained by comprehensive adjustment for measurable case-mix and treatment characteristics. A cohort analysis was conducted among 6677 patients between 1996 and 2001 in the American arm of the first phase of the Dialysis Outcomes and Practice Patterns Study, a prospective observational study. Using multivariable proportional hazards analysis, all-cause mortality by racial/ethnic category was compared before and after adjustment for other patient-level variables that are associated with mortality. Factors that influence the statistical associations of race/ethnicity with mortality were explored. The statistically significant (P < 0.001) associations of racial/ethnic minority categories with lower mortality in unadjusted analyses were attenuated or lost in the multivariable model. Compared with non-Hispanic white patients, the adjusted hazard ratio (HR) (95% confidence interval [CI]) for mortality was 0.86 (0.72 to 1.03) for Hispanic patients; among non-Hispanic patients, the HR (95% CI) were 0.97 (0.85 to 1.11) for black patients, 0.82 (0.56 to 1.20) for Asian patients, 0.95 (0.52 to 1.73) for Native American patients, and 0.95 (0.60 to 1.50) for patients of other races (overall P = 0.66). The survival advantages for racial/ethnic minority categories were explained most notably by the combined influence of unbalanced distributions of numerous demographic, morbidity, nutritional, and laboratory variables. The associations of race/ethnicity with survival varied little by duration of ESRD and were not influenced substantially by different rates of kidney transplantation among patients who were on HD. The survival advantages for racial and ethnic minority groups on HD are explained largely by measurable case-mix and treatment characteristics. Individual racial minority group or Hispanic patients should not be expected to survive longer on HD than non-Hispanic white patients with similar clinical attributes.
Mutant KRAS–Induced Expression of ICAM-1 in Pancreatic Acinar Cells Causes Attraction of Macrophages to Expedite the Formation of Precancerous Lesions
Authors: Geou-Yarh Liou, Heike Döppler, Brian Necela, Brandy Edenfield, Lizhi Zhang, David W. Dawson, Peter Storz
Journal: Cancer Discovery (2014)

Desmoplasia and an inflammatory environment are defining features of pancreatic cancer. Unclear is how pancreatic cells that undergo oncogenic transformation can cross-talk with immune cells and how this contributes to the development of pancreatic lesions. Here, we demonstrate that pancreatic acinar cells expressing mutant KRAS can expedite their transformation to a duct-like phenotype by inducing local inflammation. Specifically, we show that KRAS(G12D) induces the expression of intercellular adhesion molecule-1 (ICAM-1), which serves as chemoattractant for macrophages. Infiltrating macrophages amplify the formation of KRAS(G12D)-caused abnormal pancreatic structures by remodeling the extracellular matrix and providing cytokines such as TNF. Depletion of macrophages or treatment with a neutralizing antibody for ICAM-1 in mice expressing oncogenic Kras under an acinar cell-specific promoter resulted in both a decreased formation of abnormal structures and decreased progression of acinar-to-ductal metaplasia to pancreatic intraepithelial neoplastic lesions.We here show that oncogenic KRAS in pancreatic acinar cells upregulates the expression of ICAM-1 to attract macrophages. Hence, our results reveal a direct cooperative mechanism between oncogenic Kras mutations and the inflammatory environment to drive the initiation of pancreatic cancer.
Diagnostic Yield of Wireless Capsule Enteroscopy in Comparison with Computed Tomography Enteroclysis
Authors: W. Voderholzer, M. Ortner, P. Rogalla, J. Beinhölzl, H. Lochs
Journal: Endoscopy (2003)

Background and Study Aims: It is still difficult to visualize changes in the small intestine. Wireless capsule enteroscopy is a new method that promises to provide new insights into the small intestine. In a prospective study, the diagnostic yield of wireless enteroscopy was therefore compared with computed tomography (CT) enteroclysis. Patients and Methods: Twenty-two patients with suspected small-bowel pathology underwent CT enteroclysis and wireless capsule enteroscopy examinations, conducted by two independent blinded investigators. The results of the two investigations (diagnoses and the number, extent, and location of lesions detected) were compared by a third investigator. Results: The patients included in the study had obscure gastrointestinal bleeding (n = 8), Crohn's disease (n = 8), unexplained diarrhea (n = 5), or suspected carcinoid tumor (n = 1). Pathological lesions were detected using capsule enteroscopy in 13 patients (59 %) and using CT enteroclysis in eight (36 %; P = 0.12). In seven patients (one case each of colonic Crohn's disease, diverticulitis, Meckel's diverticulum, carcinoid tumor, mesothelioma, colonic polyps, and irritable bowel syndrome), no pathological changes were found in the small intestine using either method. The diagnosis was established by wireless capsule enteroscopy in four patients with obscure bleeding, whereas CT enteroclysis was positive in only one patient (P = 0.1). Crohn's disease was found in two patients with unexplained diarrhea. Small-bowel lesions were identified in six patients with known Crohn's disease using capsule enteroscopy or CT enteroclysis. The only side effect of wireless capsule enteroscopy observed was abdominal pain in one patient with Crohn's disease. There were no serious side effects with CT enteroclysis. Conclusions: Wireless capsule enteroscopy detects more small-bowel lesions than CT enteroclysis in patients with obscure gastrointestinal bleeding and Crohn's disease.
Independent Association Between Plasma Leptin Levels and Heart Rate in Heart Transplant Recipients
Authors: Mikolaj Winnicki, Bradley G. Phillips, Valentina Accurso, Philippe van de Borne, Abu Shamsuzzaman, Kirti Patil, Krzysztof Narkiewicz, Virend K. Somers
Journal: Circulation (2001)

Background Leptin, the protein product of the ob gene, has been linked to a faster heart rate in animal and human studies. The interaction between leptin and heart rate in the denervated heart is not known. Therefore, we studied the relationship between plasma leptin levels and heart rate in heart transplant recipients. Methods and Results We studied 32 male patients (mean age, 56.5±9.3 years; range, 41 to 74 years) after orthotopic heart transplantation. All subjects underwent a physical examination, anthropometric measurements, blood chemistry analysis, and office blood pressure measurements. A blood sample was collected from each subject while fasting. In univariate analysis, heart rate was related to leptin levels ( r =0.47, P =0.007) but heart rate was not related to systolic or diastolic blood pressure, mean arterial pressure, body mass index, or catecholamines. Leptin levels were only strongly associated with heart rate and body mass index ( r =0.73, P &lt;0.0001). In multivariate analysis, heart rate was independently and positively associated with leptin levels (F=2.61, P =0.017). We also observed a strong, independent association between leptin levels and body mass index (F=5.8, P &lt;0.00001). Conclusions We show an independent association between leptin levels and heart rate in heart transplant recipients. We speculate that this may be due, in part, to a direct effect of leptin on heart rate, conceivably mediated through cardiac leptin receptors.
First hundred cases of variant Creutzfeldt-Jakob disease: retrospective case note review of early psychiatric and neurological features
Authors: M. D Spencer
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objective:</b> To describe the early psychiatric and neurological features of variant Creutzfeldt-Jakob disease. <b>Design:</b> Cohort study. <b>Setting:</b> National surveillance system for Creutzfeldt-Jakob disease in the United Kingdom. <b>Participants:</b> The first 100 cases of variant Creutzfeldt-Jakob disease identified in the United Kingdom. <b>Main outcome measures:</b> The timing and nature of early psychiatric and neurological symptoms in variant Creutzfeldt-Jakob disease. <b>Results:</b> The early stages of variant Creutzfeldt-Jakob disease are dominated by psychiatric symptoms, but neurological symptoms precede psychiatric symptoms in 15% of cases and are present in combination with psychiatric symptoms in 22% of cases from the onset of disease. Common early psychiatric features include dysphoria, withdrawal, anxiety, insomnia, and loss of interest. No common early neurological features exist, but a significant proportion of patients do exhibit neurological symptoms within 4 months of clinical onset, including poor memory, pain, sensory symptoms, unsteadiness of gait, and dysarthria. <b>Conclusions:</b> Although the diagnosis of variant Creutzfeldt-Jakob disease may be impossible in the early stages of the illness, particular combinations of psychiatric and neurological features may allow early diagnosis in an appreciable proportion of patients.
Caveat mTOR: aberrant signaling disrupts corticogenesis
Authors: Lucy R. Osborne
Journal: Journal of Clinical Investigation (2010)

The mammalian target of rapamycin (mTOR) signaling pathway is activated in several disorders associated with benign tumors and malformations of the cerebral cortex. In this issue of the JCI, Orlova et al. have now definitively added another disorder to this group by demonstrating that activation of mTOR signaling is associated with polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE), which is characterized by severe intractable epilepsy and megalencephaly. PMSE is caused by lack of the pseudokinase STE20-related kinase adaptor alpha (STRADalpha), and Orlova et al. show that reduction of STRADalpha levels during corticogenesis in the mouse results in a cellular phenotype and neuronal migration defects similar to those observed in patients with PMSE, clearly demonstrating a pivotal role for STRADalpha in cell polarity and growth. This study helps pave the way for possible therapeutic intervention with rapamycin to control the epilepsy and learning disabilities associated with this disorder.
A Study of Sexuality and Health among Older Adults in the United States
Authors: Stacy Tessler Lindau, L. Philip Schumm, Edward O. Laumann, Wendy Levinson, Colm A. O'Muircheartaigh, Linda J. Waite
Journal: New England Journal of Medicine (2007)

Despite the aging of the population, little is known about the sexual behaviors and sexual function of older people.