tbuckley/cabot-search huggingface dataset:
Red cell vacuoles: Their size and distribution under normal conditions and after splenectomy
Authors: Walter H. Reinhart, Shu Chien
Journal: American Journal of Hematology (1988)

Abstract The frequency of occurrence of vacuoles in red blood cells was studied by transmission electron microscopy. Small vacuoles were found in about 13% of the cell sections, and they had a mean diameter of 130 ± 72 nm (mean ± SD). It can be estimated that there were about 20 small vacuoles per erythrocyte. The frequency of vacuoles was similar in density‐separated cell fractions. In splenectomized patients, the small vacuoles were 4 times more frequent; there was again no difference in vacuole density between top and bottom fractions of density‐separated red blood cells. The bottom fraction of red blood cells from splenectomized patients, however, had a high incidence of large vacuoles (&gt; 300 nm in diameter) and clustering of small vacuoles. These large vacuoles were probably the result of aggregation and fusion of small vacuoles, and their size allowed detection by light microscopy. Hence, the well‐known “pocked” or “pitted” red blood cells of splenectomized individuals were more frequent in the bottom fraction. We conclude that small vacuoles occur normally in erythrocytes, that they tend to cluster and fuse during cell aging, and that the spleen is capable of removing these structures when they reach a certain size.
High Prevalence of Respiratory Ciliary Dysfunction in Congenital Heart Disease Patients With Heterotaxy
Authors: Nader Nakhleh, Richard Francis, Rachel A. Giese, Xin Tian, You Li, Maimoona A. Zariwala, Hisato Yagi, Omar Khalifa, Safina Kureshi, Bishwanath Chatterjee, Steven L. Sabol, Matthew Swisher, Patricia S. Connelly, Mathew P. Daniels, Ashok Srinivasan, Karen Kuehl, Nadav Kravitz, Kimberlie Burns, Iman Sami, Heymut Omran, Michael Barmada, Kenneth Olivier, Kunal K. Chawla, Margaret Leigh, Richard Jonas, Michael Knowles, Linda Leatherbury, Cecilia W. Lo
Journal: Circulation (2012)

Patients with congenital heart disease (CHD) and heterotaxy show high postsurgical morbidity/mortality, with some developing respiratory complications. Although this finding is often attributed to the CHD, airway clearance and left-right patterning both require motile cilia function. Thus, airway ciliary dysfunction (CD) similar to that of primary ciliary dyskinesia (PCD) may contribute to increased respiratory complications in heterotaxy patients.We assessed 43 CHD patients with heterotaxy for airway CD. Videomicrocopy was used to examine ciliary motion in nasal tissue, and nasal nitric oxide (nNO) was measured; nNO level is typically low with PCD. Eighteen patients exhibited CD characterized by abnormal ciliary motion and nNO levels below or near the PCD cutoff values. Patients with CD aged >6 years show increased respiratory symptoms similar to those seen in PCD. Sequencing of all 14 known PCD genes in 13 heterotaxy patients with CD, 12 without CD, 10 PCD disease controls, and 13 healthy controls yielded 0.769, 0.417, 1.0, and 0.077 novel variants per patient, respectively. One heterotaxy patient with CD had the PCD causing DNAI1 founder mutation. Another with hyperkinetic ciliary beat had 2 mutations in DNAH11, the only PCD gene known to cause hyperkinetic beat. Among PCD patients, 2 had known PCD causing CCDC39 and CCDC40 mutations.Our studies show that CHD patients with heterotaxy have substantial risk for CD and increased respiratory disease. Heterotaxy patients with CD were enriched for mutations in PCD genes. Future studies are needed to assess the potential benefit of prescreening and prophylactically treating heterotaxy patients for CD.
Risk of Breast Cancer by Individual Insulin Use: An International Multicenter Study
Authors: Lamiae Grimaldi-Bensouda, David Cameron, Michel Marty, Anthony H. Barnett, Frédérique Penault-Llorca, Michael Pollak, Bernard Charbonnel, Matthew Riddle, Laurent Mignot, Jean-François Boivin, Artak Khachatryan, Michel Rossignol, Jacques Bénichou, Annick Alpérovitch, Lucien Abenhaim
Journal: Diabetes Care (2013)

OBJECTIVE Several studies have been published in 2009 suggesting a possible association between insulin glargine and increased risk of malignancies, including breast cancer. The objective of this study was to assess the relation between the individual insulins (glargine, aspart, lispro, and human insulin) and development of breast cancer. RESEARCH DESIGN AND METHODS Seven hundred seventy-five incident cases of primary invasive or in situ carcinoma breast cancer occurring in women with diabetes from 92 centers in the U.K., Canada, and France were matched to a mean of 3.9 diabetic community control subjects (n = 3,050; recruited from 580 general practices) by country, age, recruitment date, and diabetes type and management. The main risk model was a multivariate conditional logistic regression model with case/control status as the dependent variable and individual insulin use, 8 years preceding the index date, as the independent variable, controlling for past use of any insulin, oral antidiabetes drugs, reproductive factors, lifestyle, education, hormone replacement therapy and history of contraceptive use, BMI, comorbidities, diabetes duration, and annual number of physician visits. Glargine was also compared with every other insulin by computing all ratios using the variance-covariance matrix of logistic model parameters. RESULTS Adjusted odds ratios of breast cancer for each type of insulin versus no use of that insulin were 1.04 (95% CI 0.76-1.44) for glargine, 1.23 (0.79-1.92) for lispro, 0.95 (0.64-1.40) for aspart, and 0.81 (0.55-1.20) for human insulin. Two-by-two comparisons found no difference between glargine and the different types of insulins. Insulin dosage or duration of use and tumor stage did not change the results. CONCLUSIONS This international study found no difference in the risk of developing breast cancer in patients with diabetes among the different types of insulin with short- to mid-term duration of use. Longer-term studies would be of interest.
SMAD4 Levels and Response to 5-Fluorouracil in Colorectal Cancer
Authors: Pia Alhopuro, Hafid Alazzouzi, Heli Sammalkorpi, Verónica Dávalos, Reijo Salovaara, Akseli Hemminki, Heikki Järvinen, Jukka-Pekka Mecklin, Simo Schwartz, Lauri A. Aaltonen, Diego Arango
Journal: Clinical Cancer Research (2005)

Abstract We have recently reported that low tumor levels of SMAD4, a key mediator of transforming growth factor-β superfamily signaling, can predict the probability of recurrence in patients with Dukes C colorectal cancer who had surgery as the only form of treatment. However, standard treatment for Dukes C colorectal cancer patients currently involves the administration of 5-fluorouracil (5-FU)–based adjuvant chemotherapy after surgery. Approximately 30% to 40% of these patients present with recurrence and die within 5 years, and there is great need for markers capable of predicting poor prognosis after the combined surgery/adjuvant treatment. In this study, we evaluate the prognostic value of SMAD4 in patients treated with surgery and 5-FU-based adjuvant therapy. We used immunohistochemistry and quantitative real-time reverse transcription-PCR to measure the levels of SMAD4 protein and mRNA expression in the primary tumors and a number of lymph node metastases from a series of 75 Dukes C colorectal cancer patients with at least 6 years of follow-up. Patients with tumors expressing low levels of SMAD4 protein or mRNA showed significantly shorted disease-free and overall survival than patients with high tumor levels of SMAD4. The median survival of patients with low SMAD4 protein or mRNA tumor levels was 1.4 and 1.2 years, respectively, whereas patients with high SMAD4 tumor level had a median survival of &amp;gt;9.3 years. In addition, the protein and mRNA levels of SMAD4 in lymph node metastases was significantly lower than in primary tumors (P = 0.006). In contrast, allelic imbalance in chromosome 18q21 was of no prognostic significance in these patients. In conclusion, low SMAD4 tumor levels identified a subset of patients with poor prognosis following surgery and 5-FU-based adjuvant therapy; therefore, these patients could be good candidates to receive combined treatment with additional chemotherapeutic agents such as CPT-11 and/or oxaliplatin.
Membrane Microvesicles as Actors in the Establishment of a Favorable Prostatic Tumoral Niche: A Role for Activated Fibroblasts and CX3CL1-CX3CR1 Axis
Authors: Donatello Castellana, Fatiha Zobairi, Maria Carmen Martinez, Maria Antonietta Panaro, Vincenzo Mitolo, Jean-Marie Freyssinet, Corinne Kunzelmann
Journal: Cancer Research (2009)

Tumor microenvironment is enriched in plasma membrane microvesicles (MV) shed from all cell types that constitute the tumor mass, reflecting the antigenic profile of the cells they originate from. Fibroblasts and tumor cells mutually communicate within tumor microenvironment. Recent evidences suggest that tumor-derived MVs (TMV) exert a broad array of biological functions in cell-to-cell communication. To elucidate their role in cancer-to-fibroblast cell communication, TMV obtained from two prostate carcinoma cell lines with high and weak metastatic potential (PC3 and LnCaP, respectively) have been characterized. TMV exhibit matrix metalloproteinases (MMP) and extracellular MMP inducer at their surface, suggesting a role in extracellular matrix degradation. Moreover, TMV not only induce the activation of fibroblasts assessed through extracellular signal-regulated kinase 1/2 phosphorylation and MMP-9 up-regulation, increase motility and resistance to apoptosis but also promote MV shedding from activated fibroblasts able in turn to increase migration and invasion of highly metastatic PC3 cells but not LnCaP cells. PC3 cell chemotaxis seems, at least partially, dependent on membrane-bound CX3CL1/fractalkine ligand for chemokine receptor CX3CR1. The present results highlight a mechanism of mutual communication attributable not only to soluble factors but also to determinants harbored by MV, possibly contributing to the constitution of a favorable niche for cancer development.
Health Practices and Cancer Mortality Among Active California Mormons
Authors: J. E. Enstrom
Journal: JNCI Journal of the National Cancer Institute (1989)

Religiously active Mormons in California are a nonsmoking population with unusually low risk for cancer. This finding is based on the results of our 1979 questionnaire survey of life-style and the 8-year (1980–1987) follow-up of mortality among 5,231 Mormon high priests and 4,613 wives 25–99 years of age. Our study, which is the first prospective cohort study of Mormons, shows low standardized mortality ratios (SMRs) for this population, relative to those for whites in the general population in the United States, which are defined as 100. The SMRs for males are 47 for all cancers, 52 for cardiovascular diseases, and 47 for all causes; the SMRs for females are 72 for all cancers, 64 for cardiovascular diseases, and 66 for all causes. For middle-aged high priests adhering to three health practices (never smoking cigarettes, engaging in regular physical activity, and getting proper sleep), the SMRs are 34 for all cancers, 14 for cardiovascular diseases, and 22 for all causes. These results have been largely replicated in an active Mormon-like subgroup (white nonsmokers attending church weekly) from a representative sample of residents of Alameda County, CA. Our findings confirm and expand on previous descriptive studies of Mormons and demonstrate how these results can be generalized. [J Natl Cancer Inst 81:1807–1814, 1989]
Malignant mesothelioma of the pleura: a study of 52 treated and 64 untreated patients.
Authors: M R Law, A Gregor, M E Hodson, H J Bloom, M Turner-Warwick
Journal: Thorax (1984)

We have carried out sequential prospective studies of treatment with surgery alone, chemotherapy, and radiotherapy in malignant mesothelioma of the pleura. The survival of treated patients was contrasted with that of 64 contemporary untreated patients whose clinical condition at presentation was comparable with that of the treated patients. Non-radical surgery alone (28 patients) was of palliative benefit, particularly for the control of recurrent pleural effusions, and may have prolonged survival in one patient with localised malignant mesothelioma. Chemotherapy with doxorubicin, vincristine, and cyclophosphamide (12 patients, with preceding surgery in eight) was without objective benefit. Megavoltage radiotherapy by an off axis beam rotational technique (12 patients, with preceding surgery in eight) abolished pain and dyspnoea and may have prolonged survival in one patient and terminated recurrent pleural effusions in three, but it was of no value in the other patients. There was no significant difference in survival between treatment groups or between treated and untreated patients, and no difference when mesotheliomas of epithelial, sarcomatous, and mixed cell types were examined separately. Treatment of this disease appeared to fail because of the unresponsiveness of the tumour to existing forms of treatment and the advanced stage of the disease at clinical presentation.
Synthesis and Turnover of Norepinephrine in the Heart of the Spontaneously Hypertensive Rat
Authors: WILLIAM J. LOUIS, SYDNEY SPECTOR, RYO TOBEI, ALBERT SJOERDSMA
Journal: Circulation Research (1969)

The kinetics of norepinephrine (NE) metabolism in the heart was studied in genetically hypertensive and normotensive control Wistar rats. Concentrations of endogenous NE were similar in the two groups. However, rates of synthesis of NE were reduced in these hypertensive rats, whether calculated from the rate of decline (fractional turnover rate) of cardiac tritiated NE ( 3 H-NE) after intravenous injection, or estimated from levels of 14 C-NE in the heart after injection of the precursor 14 C-L-tyrosine. In experiments with 3 H-NE the synthesis rate of NE was 30.2 ng/hour/g heart in control and 18.2 ng/hour/g heart in hypertensive rats. The levels of 14 C-NE found in the heart of normotensive rats given 14 C-tyrosine were up to 1.4 times those found in hypertensive rats. These findings indicate a reduced rate of release of NE in this form of hypertension and, rather than implicating NE as a primary factor, suggest a secondary, compensatory mechanism.
Orexin Receptors: Pharmacology and Therapeutic Opportunities
Authors: Thomas E. Scammell, Christopher J. Winrow
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Orexin-A and -B (also known as hypocretin-1 and -2) are neuropeptides produced in the lateral hypothalamus that promote many aspects of arousal through the OX1 and OX2 receptors. In fact, they are necessary for normal wakefulness, as loss of the orexin-producing neurons causes narcolepsy in humans and rodents. This has generated considerable interest in developing small-molecule orexin receptor antagonists as a novel therapy for the treatment of insomnia. Orexin antagonists, especially those that block OX2 or both OX1 and OX2 receptors, clearly promote sleep in animals, and clinical results are encouraging: Several compounds are in Phase III trials. As the orexin system mainly promotes arousal, these new compounds will likely improve insomnia without incurring many of the side effects encountered with current medications.
Long-Term Inhaled Corticosteroids in Preschool Children at High Risk for Asthma
Authors: Theresa W. Guilbert, Wayne J. Morgan, Robert S. Zeiger, David T. Mauger, Susan J. Boehmer, Stanley J. Szefler, Leonard B. Bacharier, Robert F. Lemanske, Robert C. Strunk, David B. Allen, Gordon R. Bloomberg, Gregory Heldt, Marzena Krawiec, Gary Larsen, Andrew H. Liu, Vernon M. Chinchilli, Christine A. Sorkness, Lynn M. Taussig, Fernando D. Martinez
Journal: New England Journal of Medicine (2006)

It is unknown whether inhaled corticosteroids can modify the subsequent development of asthma in preschool children at high risk for asthma.We randomly assigned 285 participants two or three years of age with a positive asthma predictive index to treatment with fluticasone propionate (at a dose of 88 mug twice daily) or masked placebo for two years, followed by a one-year period without study medication. The primary outcome was the proportion of episode-free days during the observation year.During the observation year, no significant differences were seen between the two groups in the proportion of episode-free days, the number of exacerbations, or lung function. During the treatment period, as compared with placebo use, use of the inhaled corticosteroid was associated with a greater proportion of episode-free days (P=0.006) and a lower rate of exacerbations (P<0.001) and of supplementary use of controller medication (P<0.001). In the inhaled-corticosteroid group, as compared with the placebo group, the mean increase in height was 1.1 cm less at 24 months (P<0.001), but by the end of the trial, the height increase was 0.7 cm less (P=0.008). During treatment, the inhaled corticosteroid reduced symptoms and exacerbations but slowed growth, albeit temporarily and not progressively.In preschool children at high risk for asthma, two years of inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third, treatment-free year. These findings do not provide support for a subsequent disease-modifying effect of inhaled corticosteroids after the treatment is discontinued. (ClinicalTrials.gov number, NCT00272441.).
Peripheral airway function in adults with sickle cell disease
Authors: Alice Chubb, Alan Lunt, Moira Dick, David Rees, Sue Height, Swee Lay Thein, Gerrard F. Rafferty, Anne Greemough
Journal: European Respiratory Journal (2011)

Aim: Impulse oscillometry (IOS) requires minimal patient co-operation and assesses peripheral airway function. Our aim was to determine whether IOS indices were useful to identify lung function abnormalities in adults with sickle cell disease (SCD).

Methods: IOS measurements were performed on 36 adults, homozygous for sickle cell haemoglobin (HbSS), mean age 40.77 (± SD 13.80) years; the controls were 10 ethnically matched subjects. Respiratory system resistance (Rrs) at oscillation frequencies of 3Hz (Rrs3), 5Hz (Rrs5), 10Hz (Rrs10), 15Hz (Rrs15) and 20Hz (Rrs20), respiratory system reactance (Xrs) at an oscillation frequency of 5Hz (Xrs5), resonant frequency (fres) and reactance area (AX) were recorded. Frequency dependence of resistance between 3 and 20Hz (f-dr) was also calculated.

Results: Rrs was raised at all oscillometry frequencies in the SCD patients. Xrs5 and AX were increased in SCD patients (p= 0.00091, p=0.0006 respectively). The slopes of the linear transformations of frequency dependence of resistance (f-dr) curves were negative in SCD patients, but not in the controls (p<0.0001).

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Conclusion: These results suggest adults with SCD have peripheral lung changes.
Is Bias Inherent in HCFA-Sponsored Research?
Authors: Robert C. Rollings
Journal: JAMA (1991)

<h3>To the Editor.</h3> —I am confused and amazed. In the Medical News &amp; Perspectives section of the January 23/30 issue of<i>JAMA</i>, three of four articles<sup>1-3</sup>were devoted to consideration of physician ethics and conflicts of interest. I share many of the concerns addressed. Yet the lead Original Contribution (regarding evaluation of neuroleptic drug use by elderly nursing home patients under proposed Medicare and Medicaid regulations) is purportedly a scientific study supported by a cooperative agreement from the Health Care Financing Administration (HCFA) Research Center at the University of Minnesota, Minneapolis, with funding from the HCFA in Baltimore, Md. The degree of inherent bias and the self-justification of regulatory agency guidelines have immediate and possibly overwhelming implications.The Journalshould be representative of the physicians who practice and who serve their patients rather than an inadvertent tool of third parties, whether pharmaceutical firms or governmental agencies, regardless of their
Hormonal Control of Immunoreactive Somatomedin Production by Cultured Human Fibroblasts
Authors: David R. Clemmons, Louis E. Underwood, Judson J. Van Wyk
Journal: Journal of Clinical Investigation (1981)

Human growth hormone (hGH) is known to be a potent stimulator of somatomedin secretion in vivo. The induction of somatomedin by growth hormone has been difficult to study in vitro, however, because no organ containing a high concentration of somatomedin has been identified. Because fetal mouse explants have been shown to produce somatomedin in vitro, we have undertaken studies to determine whether postnatal human fibroblast monolayers also produce somatomedin, and if so, whether its production is regulated by other hormones. Quiescent human fibroblasts were exposed to serum-free minimum essential medium, and the medium was assayed for somatomedin concentration using a specific radioimmunoassay for somatomedin-C. A progressive rise in immunoreactive somatomedin to 0.08 U/ml per 10(5) cells per 24 h was observed over 72 h of incubation. This was an underestimation of the actual concentration of immunoreactive somatomedin since the amount measured following acid treatment was at least fourfold higher than in the untreated medium. Growth hormone stimulated immunoreactive somatomedin production in a dose-dependent manner: 5 ng hGH/ml = 0.1 U/ml per 10(5) cells; 50 ng hGH/ml = 0.25 U/ml per 10(5) cells. Platelet-derived growth factor and fibroblast growth factor were also stimulatory, but epidermal growth factor, thyroxine, or cortisol had no effect. Media that had been exposed to human fibroblasts stimulated DNA synthesis in BALB/c 3T3 fibroblasts (a cell type that does not produce somatomedin). Medium-derived immuno-reactive somatomedin eluted from Sephacryl S-200 in two major peaks (150,000 and 8,000 mol wt). The higher molecular weight peak is similar to the one observed when whole serum was used. These studies provide a model system for studying the humoral and nonhumoral factors that control the biosynthesis of somatomedin by human tissues. Since immunoreactive somatomedin production may be a rate-limiting factor for fibroblast growth, the delineation of the hormonal control of somatomedin production should lead to a better understanding of the mechanisms controlling human fibroblast growth.
The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model
Authors: Christopher Semsarian, Imran Ahmad, Michael Giewat, Dimitrios Georgakopoulos, Joachim P. Schmitt, Bradley K. McConnell, Steven Reiken, Ulrike Mende, Andrew R. Marks, David A. Kass, Christine E. Seidman, J.G. Seidman
Journal: Journal of Clinical Investigation (2002)

Dominant mutations in sarcomere protein genes cause hypertrophic cardiomyopathy, an inherited human disorder with increased ventricular wall thickness, myocyte hypertrophy, and disarray. To understand the early consequences of mutant sarcomere proteins, we have studied mice (designated αMHC403/+) bearing an Arg403Gln missense mutation in the α cardiac myosin heavy chain. We demonstrate that Ca2+ is reduced in the sarcoplasmic reticulum of αMHC403/+ mice, and levels of the sarcoplasmic reticulum Ca2+-binding protein calsequestrin are diminished in advance of changes in cardiac histology or morphology. Further evidence for dysregulation of sarcoplasmic reticulum Ca2+ in these animals is seen in their decreased expression of the ryanodine receptor Ca2+-release channel and its associated membrane proteins and in an increase in ryanodine receptor phosphorylation. Early administration of the L-type Ca2+ channel inhibitor diltiazem restores normal levels of these sarcoplasmic reticular proteins and prevents the development of pathology in αMHC403/+ mice. We conclude that disruption of sarcoplasmic reticulum Ca2+ homeostasis is an important early event in the pathogenesis of this disorder and suggest that the use of Ca2+ channel blockers in advance of established clinical disease could prevent hypertrophic cardiomyopathy caused by sarcomere protein gene mutations.