tbuckley/cabot-search huggingface dataset:
Generation of the Melatonin Endocrine Message in Mammals: A Review of the Complex Regulation of Melatonin Synthesis by Norepinephrine, Peptides, and Other Pineal Transmitters
Authors: Valerie Simonneaux, Christophe Ribelayga
Journal: Pharmacological Reviews (2003)

Melatonin, the major hormone produced by the pineal gland, displays characteristic daily and seasonal patterns of secretion. These robust and predictable rhythms in circulating melatonin are strong synchronizers for the expression of numerous physiological processes in photoperiodic species. In mammals, the nighttime production of melatonin is mainly driven by the circadian clock, situated in the suprachiasmatic nucleus of the hypothalamus, which controls the release of norepinephrine from the dense pineal sympathetic afferents. The pivotal role of norepinephrine in the nocturnal stimulation of melatonin synthesis has been extensively dissected at the cellular and molecular levels. Besides the noradrenergic input, the presence of numerous other transmitters originating from various sources has been reported in the pineal gland. Many of these are neuropeptides and appear to contribute to the regulation of melatonin synthesis by modulating the effects of norepinephrine on pineal biochemistry. The aim of this review is firstly to update our knowledge of the cellular and molecular events underlying the noradrenergic control of melatonin synthesis; and secondly to gather together early and recent data on the effects of the nonadrenergic transmitters on modulation of melatonin synthesis. This information reveals the variety of inputs that can be integrated by the pineal gland; what elements are crucial to deliver the very precise timing information to the organism. This also clarifies the role of these various inputs in the seasonal variation of melatonin synthesis and their subsequent physiological function.
Cardiovascular Mortality After Androgen Deprivation Therapy for Locally Advanced Prostate Cancer: RTOG 85-31
Authors: Jason A. Efstathiou, Kyounghwa Bae, William U. Shipley, Gerald E. Hanks, Miljenko V. Pilepich, Howard M. Sandler, Matthew R. Smith
Journal: Journal of Clinical Oncology (2008)

Purpose Gonadotropin-releasing hormone (GnRH) agonists are associated with greater risk of coronary heart disease and myocardial infarction in men with prostate cancer, but little is known about potential impact on cardiovascular mortality. We assessed the relationship between GnRH agonists and cardiovascular mortality in a large randomized phase III trial of men treated with or without adjuvant goserelin after radiation therapy (RT) for locally advanced prostate cancer. Patients and Methods Between 1987 and 1992, 945 men with locally advanced prostate cancer were randomly assigned to RT and adjuvant goserelin or RT alone. Fine and Gray's regression was used to evaluate treatment effect on cardiovascular mortality. Covariates included age, prevalent cardiovascular disease (CVD), hypertension, diabetes mellitus (DM), body mass index, race, Gleason score, stage, acid phosphatase level, prostatectomy history, and nodal involvement. Results After a median follow-up of 8.1 years, there were 117 cardiovascular-related deaths but no treatment-related increase in cardiovascular mortality. At 9 years, cardiovascular mortality for men receiving adjuvant goserelin was 8.4% v 11.4% for men treated without adjuvant goserelin (Gray's P = .17). In multiple regression analyses, treatment arm was not significantly associated with increased risk of cardiovascular mortality (adjusted hazard ratio [HR] = 0.73; 95% CI, 0.47 to 1.15; P = .16; when censoring at time of salvage goserelin therapy, HR = 0.99; 95% CI, 0.58 to 1.69; P = .97). Traditional cardiac risk factors, including prevalent CVD and DM, were significantly associated with greater cardiovascular mortality. Conclusion GnRH agonists do not seem to increase cardiovascular mortality in men with locally advanced prostate cancer. Further studies are warranted to evaluate adverse effects of GnRH agonists in men with lower cancer-specific mortality.
<i>IDDM1</i> and Multiple Family History of Type 1 Diabetes Combine to Identify Neonates at High Risk for Type 1 Diabetes
Authors: Ezio Bonifacio, Michael Hummel, Markus Walter, Sandra Schmid, Anette-G. Ziegler
Journal: Diabetes Care (2004)

OBJECTIVE—Children of affected probands are at increased risk for type 1 diabetes. The objective of this study was to determine and stratify the risk for islet autoimmunity and childhood diabetes in newborn offspring of affected parents using family history and HLA genetic markers. RESEARCH DESIGN AND METHODS—Antibodies to islet autoantigens were measured at ages 9 months, 2 years, 5 years, and 8 years in 1,610 offspring of parents with type 1 diabetes participating in the German BABYDIAB study. HLA DR and DQ genetic typing was performed. Family history of type 1 diabetes was obtained from questionnaires. RESULTS—Extensive family history of type 1 diabetes and HLA DR/DQ genotyping were associated with islet autoantibody and diabetes risks. Significant contributions to the child’s risk for developing islet autoantibodies and type 1 diabetes were conferred by a multiple first-degree family history of type 1 diabetes (two parents or one parent and a sibling; adjusted hazard [HR] ratio, 6.2 for multiple islet autoantibodies and 7.8 for type 1 diabetes), high-risk HLA genotypes (adjusted HR, 11 and 10.9), and moderate-risk HLA genotypes (adjusted HR, 6.3 and 4.3) in a multivariate analysis. Combining these factors stratified the risk for islet autoantibodies from 1 to 46% and for type 1 diabetes from 0 to 19.5% by 5 years of age. CONCLUSIONS—Risk of childhood diabetes in affected families can be stratified using a combination of genetic and family history markers very early in life.
False-negative interferon-γ release assay results in active tuberculosis: a TBNET study
Authors: Veerle de Visser, Giovanni Sotgiu, Christoph Lange, Martine G. Aabye, Marleen Bakker, Filippo Bartalesi, Kristian Brat, Cynthia B.E. Chee, Keertan Dheda, Jose Dominguez, Fusun Eyuboglu, Maha Ghanem, Delia Goletti, Asli Gorek Dilektasli, Lorenzo Guglielmetti, Won-Jung Koh, Irene Latorre, Monica Losi, Monica Polanova, Pernille Ravn, Felix C. Ringshausen, Rudolf Rumetshofer, Maria Luiza de Souza-Galvão, Steven Thijsen, Graham Bothamley, Aik Bossink
Journal: European Respiratory Journal (2014)

Tuberculosis is one of the leading causes of morbidity and mortality worldwide [1]. Rapid identification of contagious tuberculosis patients and effective treatment are necessary to prevent the spread of Mycobacterium tuberculosis , the causative bacterium of the disease. Although interferon-γ release assays (IGRAs) have been developed for the diagnosis of latent infection with M. tuberculosis , these assays are sometimes used as adjunctive tests in the diagnostic workup for active tuberculosis, despite poor specificity [2]. Advanced age was the only risk factor for false-negative IGRAs in this study of active tuberculosis <http://ow.ly/Cvp5G>
Systemic mastocytosis – the importance of looking within bone marrow fragments
Authors: Barbara J. Bain, Ahmad Khoder, Dragana Milojkovic, Tanya Bernard
Journal: American Journal of Hematology (2013)

The detection of neoplastic mast cells in a bone marrow aspirate can be difficult, even when trephine biopsy sections show an abnormal infiltrate. This is the result of infiltrates being focal, often in a paratrabecular or perivascular site, with reticulin fibrosis hindering their aspiration. In addition, mast cells can remain trapped within bone marrow particles rather than spilling into the cellular trails behind them. When mastocytosis is suspected it is important to look at the trails immediately behind the particles where a few cytologically abnormal mast cells may be found. In addition, it is also important to look within the fragments, which may be found to harbour numerous mast cells, recognisable from their brightly staining granules. Some cytological abnormalities may be apparent, even in the cells within fragments. The right image shows the typical spindle shape of a neoplastic cell, which has three cytoplasmic tails. The left image shows hypogranularity, also a typical feature of neoplastic mast cells. Another useful technique is to make a squash preparation of a bone marrow particle. The International Council for Standardisation in Haematology guidelines for bone marrow examination recommend that this be done, in addition to wedge-spread films, on all bone marrow aspirates. This is good practice and will facilitate the diagnosis not only of systemic mastocytosis but also of some cases of multiple myeloma. Finally, a trephine biopsy should be performed whenever systemic mastocytosis is suspected.
The 38th David A. Karnofsky Lecture: The Paradoxical Actions of Estrogen in Breast Cancer—Survival or Death?
Authors: V. Craig Jordan
Journal: Journal of Clinical Oncology (2008)

During the first David A. Karnofsky Award lecture entitled "Thoughts on Chemical Therapy" in 1970, Sir Alexander Haddow commented about the dramatic regressions observed with estrogen in some breast cancers in postmenopausal women, but regrettably the mechanism was unknown. He was concerned that a cancer-specific target would remain elusive, without tests to predict response to therapy. At that time, I was conducting research for my PhD on an obscure group of estrogen derivatives called nonsteroidal antiestrogens. Antiestrogens had failed to fulfill their promise as postcoital contraceptives and were unlikely to be developed further by the pharmaceutical industry. In 1972, that perspective started to change and ICI 46,474 was subsequently reinvented as the first targeted therapy for breast cancer. The scientific strategy of targeting the estrogen receptor (ER) in the tumor, treating patients with long-term adjuvant therapy, examining active metabolites, and considering chemoprevention all translated through clinical trials to clinical practice during the next 35 years. Hundreds of thousands of women now have enhanced survivorship after their diagnosis of ER-positive breast cancer. However, it was the recognition of selective ER modulation (SERM) that created a new dimension in therapeutics. Nonsteroidal antiestrogens selectively turn on or turn off estrogen target tissues throughout the body. Patient care was immediately affected by the recognition in the laboratory that tamoxifen would potentially increase the growth of endometrial cancer during long-term adjuvant therapy. At that time, a failed breast cancer drug, keoxifene, was found to maintain bone density of rats (estrogenic action) while simultaneously preventing mammary carcinogenesis (antiestrogenic action). Perhaps a SERM used to prevent osteoporosis could simultaneously prevent breast cancer? Keoxifene was renamed raloxifene and became the first SERM for the treatment and prevention of osteoporosis as well as the prevention of breast cancer, but without an increase in endometrial cancer. There the story might have ended had the study of antihormone resistance not revealed a vulnerability of cancer cells that could be exploited in the clinic. The evolution of antihormone resistance over years of therapy reconfigures the survival mechanism of the breast cancer cell, so estrogen no longer is a survival signal but a death signal. Remarkably, remaining tumor tissue is again responsive to continuing antihormone therapy. This new discovery is currently being evaluated in clinical trials but it also solves the mystery mechanism of chemical therapy with estrogen noted by Haddow in the first Karnofsky lecture.
Peroxisome proliferator-activated receptor γ C161→T polymorphism and coronary artery disease
Authors: X Wang
Journal: Cardiovascular Research (1999)

Peroxisome proliferator-activated receptor gamma (PPAR gamma) as a transcription factor plays an important role in lipid metabolism, glucose homeostasis, insulin sensitivity, obesity, diabetes, foam cell formation and atherogenesis.We have studied distribution of the PPAR gamma C161-->T substitution at exon 6 in 647 Australian Caucasian patients aged < or = 65 years (484 men and 163 women) recruited consecutively, with or without angiographically documented coronary artery disease (CAD). The frequencies of the CC, CT and TT genotypes were 69.8%, 27.7% and 2.5% and the 'T' allele frequency 0.163. They were in Hardy-Weinberg equilibrium and not different between men and women. The BMI and waist to hip ratio (WHR) among patients with CC, CT + TT genotypes were not different (P = 0.878, P = 0.677). However there was a significant association between the polymorphism and CAD. The 'T' allele carriers (CT + TT) had significantly reduced CAD risk compared to the CC homozygotes (odds ratio: 0.457, 95% CI: 0.273-0.763, P = 0.0045) in a logistic regression model after controlling other known risk factors. This reduced risk was particularly evident among CT heterozygotes (odds ratio: 0.466, 95% CI: 0.291-0.746, P = 0.0015), who also had lower apo B and total cholesterol to HDL-C ratios (P < 0.05).We report that the PPAR gamma C161-->T substitution is associated with a reduced CAD risk, particularly among CT heterozygous patients, but not with obesity in Australian Caucasian patients. It implicates that the PPAR gamma may have a significant role in atherogenesis, independent of obesity and of lipid abnormalities, possibly via a direct local vascular wall effect.
Determination of the True Phase Velocity of Arterial Pressure Waves in Vivo
Authors: Robert H. Cox
Journal: Circulation Research (1971)

Results of simultaneously recorded pressure, diameter, flow, and differential pressure from an arterial segment were studied by Fourier analysis. The method was applied to pressure propagation in the femoral artery of anesthetized dogs. Experimental values of phase velocity compared favorably with values predicted from a theoretical wave propagation model. The phase velocity was generally constant for frequencies over 35 rad/sec. At frequencies below 20 rad/sec, it decreased rapidly with decreasing frequency. The frequency variations of the true and apparent phase velocities were significantly different. The characteristic impedance of the femoral artery was a weak function of frequency arid nearly independent of the mean arterial pressure. High frequency values of the local fluid impedance above 50 rad/sec were significantly lower than those of the characteristic impedance. It was concluded that the method can be used to obtain reliable values of phase velocity in the physiological frequency range from in vivo measurements.
The Public Health Impact of Alzheimer's Disease, 2000–2050: Potential Implication of Treatment Advances
Authors: Philip D. Sloane, Sheryl Zimmerman, Chirayath Suchindran, Peter Reed, Lily Wang, Malaz Boustani, S. Sudha
Journal: Annual Review of Public Health (2002)

▪ Abstract Recent developments in basic research suggest that therapeutic breakthroughs may occur in Alzheimer's disease treatment over the coming decades. To model the potential magnitude and nature of the effect of these advances, historical data from congestive heart failure and Parkinson's disease were used. Projections indicate that therapies which delay disease onset will markedly reduce overall disease prevalence, whereas therapies to treat existing disease will alter the proportion of cases that are mild as opposed to moderate/severe. The public health impact of such changes would likely involve both the amount and type of health services needed. Particularly likely to arise are new forms of outpatient services, such as disease-specific clinics and centers. None of our models predicts less than a threefold rise in the total number of persons with Alzheimer's disease between 2000 and 2050. Therefore, Alzheimer's care is likely to remain a major public health problem during the coming decades.
Cancer prevalence in European registry areas
Authors: A. Micheli, E. Mugno, V. Krogh, M.J. Quinn, M. Coleman, T. Hakulinen, G. Gatta, F. Berrino, R. Capocaccia
Journal: Annals of Oncology (2002)

Information on cancer prevalence is of major importance for health planning and resource allocation. However, systematic information on cancer prevalence is largely unavailable.Thirty-eight population-based cancer registries from 17 European countries, participating in EUROPREVAL, provided data on almost 3 million cancer patients diagnosed from 1970 to 1992. Standardised data collection and validation procedures were used and the whole data set was analysed using proven methodology. The prevalence of stomach, colon, rectum, lung, breast, cervix uteri, corpus uteri and prostate cancer, as well as of melanoma of skin, Hodgkin's disease, leukaemia and all malignant neoplasms combined, were estimated for the end of 1992.There were large differences between countries in the prevalence of all cancers combined; estimates ranged from 1170 per 100000 in the Polish cancer registration areas to 3050 per 100000 in southern Sweden. For most cancers, the Swedish, Swiss, German and Italian areas had high prevalence, and the Polish, Estonian, Slovakian and Slovenian areas had low prevalence. Of the total prevalent cases, 61% were women and 57% were 65 years of age or older. Cases diagnosed within 2 years of the reference date formed 22% of all prevalent cases. Breast cancer accounted for 34% of all prevalent cancers in females and colorectal cancer for 15% in males. Prevalence tended to be high where cancer incidence was high, but the prevalence was highest in countries where survival was also high. Prevalence was low where general mortality was high (correlation between general mortality and the prevalence of all cancers = -0.64) and high where gross domestic product was high (correlation = +0.79). Thus, the richer areas of Europe had higher prevalence, suggesting that prevalence will increase with economic development.EUROPREVAL is the largest project on prevalence conducted to date. It has provided complete and accurate estimates of cancer prevalence in Europe, constituting essential information for cancer management. The expected increases in prevalence with economic development will require more resources; allocation to primary prevention should therefore be prioritised.
Early congenital syphilis and erythema multiforme–like bullous targetoid lesions in a 1-day-old newborn: Detection of Treponema pallidum genomic DNA from the targetoid plaque using nested polymerase chain reaction
Authors: Chao-Chang Wu, Chi-Neu Tsai, Wen-Rou Wong, Hong-Shang Hong, Ya-Hui Chuang
Journal: Journal of the American Academy of Dermatology (2006)
Nanoparticle formulations in pulmonary drug delivery
Authors: Mark M. Bailey, Cory J. Berkland
Journal: Medicinal Research Reviews (2008)

The advent of nanotechnology has reignited interest in the lungs as a major route of drug delivery for both systemic and local treatments. The large surface area of the lungs and the minimal barriers impeding access to the lung periphery make this organ a suitable portal for a variety of therapeutic interventions. Nanoparticles provide new formulation options for both dispersed liquid droplet dosage forms such as metered dose inhalers and nebulizers, and dry powder formulations. Nanoparticle formulations have many advantages over traditional dosage forms, such as enhanced dissolution properties and the potential for intracellular drug delivery. Specifically, pure drug nanoparticles, polymeric nanoparticles, polyelectrolyte complexes, and drug-loaded liposomes offer some encouraging results for delivering drugs to and through the lungs. Methods are also being investigated to produce nanoparticles with properties suitable for improving access to the peripheral lung. Traditional techniques such as spray drying and grinding, and more recent advances in supercritical fluid extraction, precipitation, and solvent extraction have been employed to produce nanoparticle formulations for pulmonary delivery. Here, the benefits of nanoparticle formulations and current progress are compared in light of the practical encumbrances of producing formulations, and possible toxicological effects of these materials.
Standard-Risk Medulloblastoma Treated by Adjuvant Chemotherapy Followed by Reduced-Dose Craniospinal Radiation Therapy: A French Society of Pediatric Oncology Study
Authors: V. Oyharcabal-Bourden, C. Kalifa, J.C. Gentet, D. Frappaz, C. Edan, P. Chastagner, E. Sariban, A. Pagnier, A. Babin, F. Pichon, S. Neuenschwander, M. Vinchon, D. Bours, V. Mosseri, C. Le Gales, M. Ruchoux, C. Carrie, F. Doz
Journal: Journal of Clinical Oncology (2005)

Objective The primary objective of this study was to decrease the late effects of prophylactic radiation without reducing survival in standard-risk childhood medulloblastoma. Patients and Methods Inclusion criteria were as follows: children between the ages of 3 and 18 years with total or subtotal tumor resection, no metastasis, and negative postoperative lumbar puncture CSF cytology. Two courses of eight drugs in 1 day followed by two courses of etoposide plus carboplatin (500 and 800 mg/m 2 per course, respectively) were administered after surgery. Radiation therapy had to begin 90 days after surgery. Delivered doses were 55 Gy to the posterior fossa and 25 Gy to the brain and spinal canal. Results Between November 1991 and June 1998, 136 patients (median age, 8 years; median follow-up, 6.5 years) were included. The overall survival rate and 5-year recurrence-free survival rate were 73.8% ± 7.6% and 64.8% ± 8.1%, respectively. Radiologic review showed that 4% of patients were wrongly included. Review of radiotherapy technical files demonstrated a correlation between the presence of a major protocol deviation and treatment failure. The 5-year recurrence-free survival rate of patients included in this study with all optimal quality controls of histology, radiology, and radiotherapy was 71.8% ± 10.5%. In terms of sequelae, 31% of patients required growth hormone replacement therapy and 25% required special schooling. Conclusion Reduced-dose craniospinal radiation therapy can be proposed in standard-risk medulloblastoma provided staging and radiation therapy are performed under optimal conditions.
MEASUREMENT OF THE EFFECT ON THE PAIN THRESHOLD OF ACETYLSALICYLIC ACID, ACETANILID, ACETOPHENETIDIN, AMINOPYRINE, ETHYL ALCOHOL, TRICHLORETHYLENE, A BARBITURATE, QUININE, ERGOTAMINE TARTRATE AND CAFFEINE: AN ANALYSIS OF THEIR RELATION TO THE PAIN EXPERIENCE
Authors: H. G. Wolff, J. D. Hardy, H. Goodell
Journal: Journal of Clinical Investigation (1941)
Immunomodulation of Natural Killer Cell Activity by Flavone Acetic Acid: Occurrence Via Induction of Interferon /beta
Authors: R. L. Hornung, H. A. Young, W. J. Urba, R. H. Wiltrout
Journal: JNCI Journal of the National Cancer Institute (1988)

The investigational drug flavone acetic acid (FAA) systemically augments natural killer (NK) cell activity in normal and tumor-bearing mice and in human cancer patients. The results from the present investigation demonstrate that in vivo administration of FAA induces in a dose-dependent manner high levels of serum interferon (IFN) within 4 hours in BALB/c, C57BL/6, and BALB/c nude mice. Antibody neutralization studies indicated that FAA induced IFN of the α/β type, while molecular hybridization studies demonstrated that FAA rapidly stimulated the production of IFN a mRNA in splenic leukocytes. In vivo administration of anti-IFN α/β antibodies to FAA-treated mice inhibited the FAA-induced augmentation of splenic NK cell activity at 4 hours. These results suggest that FAA mediates its anti-tumor effects indirectly by immunomodulation as well as directly by antiproliferative or cytotoxic activity. [J Natl Cancer Inst 1988;80:1226–1231]