tbuckley/cabot-search huggingface dataset:
Fetuin-A Protects against Atherosclerotic Calcification in CKD
Authors: Ralf Westenfeld, Cora Scha[Combining Diaeresis]fer, Thilo Kru[Combining Diaeresis]ger, Christian Haarmann, Leon J. Schurgers, Chris Reutelingsperger, Ognen Ivanovski, Tilman Drueke, Ziad A. Massy, Markus Ketteler, Ju[Combining Diaeresis]rgen Floege, Willi Jahnen-Dechent
Journal: Journal of the American Society of Nephrology (2009)

Reduced serum levels of the calcification inhibitor fetuin-A associate with increased cardiovascular mortality in dialysis patients. Fetuin-A-deficient mice display calcification of various tissues but notably not of the vasculature. This absence of vascular calcification may result from the protection of an intact endothelium, which becomes severely compromised in the setting of atherosclerosis. To test this hypothesis, we generated fetuin-A/apolipoprotein E (ApoE)-deficient mice and compared them with ApoE-deficient and wild-type mice with regard to atheroma formation and extraosseous calcification. We assigned mice to three treatment groups for 9 wk: (1) Standard diet, (2) high-phosphate diet, or (3) unilateral nephrectomy (causing chronic kidney disease [CKD]) plus high-phosphate diet. Serum urea, phosphate, and parathyroid hormone levels were similar in all genotypes after the interventions. Fetuin-A deficiency did not affect the extent of aortic lipid deposition, neointima formation, and coronary sclerosis observed with ApoE deficiency, but the combination of fetuin-A deficiency, hyperphosphatemia, and CKD led to a 15-fold increase in vascular calcification in this model of atherosclerosis. Fetuin-A deficiency almost exclusively promoted intimal rather than medial calcification of atheromatous lesions. High-phosphate diet and CKD also led to an increase in valvular calcification and aorta-associated apoptosis, with wild-type mice having the least, ApoE-deficient mice intermediate, and fetuin-A/ApoE-deficient mice the most. In addition, the combination of fetuin-A deficiency, high-phosphate diet, and CKD in ApoE-deficient mice greatly enhanced myocardial calcification, whereas the absence of fetuin-A did not affect the incidence of renal calcification. In conclusion, fetuin-A inhibits pathologic calcification in both the soft tissue and vasculature, even in the setting of atherosclerosis.
THE PATHOLOGIC EFFECTS OF STREPTOCOCCI FROM CASES OF POLIOMYELITIS AND OTHER SOURCES
Authors: Carroll G. Bull
Journal: The Journal of Experimental Medicine (1917)

Streptococci cultivated from the tonsils of thirty-two cases of poliomyelitis were used to inoculate various laboratory animals. In no case was a condition induced resembling poliomyelitis clinically or pathologically in guinea pigs, dogs, cats, rabbits, or monkeys. On the other hand, a considerable percentage of the rabbits and a smaller percentage of some of the other animals developed lesions due to streptococci. These lesions consisted of meningitis, meningo-encephalitis, abscess of the brain, arthritis, tenosynovitis, myositis, abscess of the kidney, endocarditis, pericarditis, and neuritis. No distinction in the character or frequency of the lesions could be determined between the streptococci derived from poliomyelitic patients and from other sources. Streptococci isolated from the poliomyelitic brain and spinal cord of monkeys which succumbed to inoculation with the filtered virus failed to induce in monkeys any paralysis or the characteristic histological changes of poliomyelitis. These streptococci are regarded as secondary bacterial invaders of the nervous organs. Monkeys which have recovered from infection with streptococci derived from cases of poliomyelitis are not protected from infection with the filtered virus, and their blood does not neutralize the filtered virus in vitro. We have failed to detect any etiologic or pathologic relationship between streptococci and epidemic poliomyelitis in man or true experimental poliomyelitis in the monkey.
Aerobic Interval Training Versus Continuous Moderate Exercise as a Treatment for the Metabolic Syndrome
Authors: Arnt Erik Tjønna, Sang Jun Lee, Øivind Rognmo, Tomas O. Stølen, Anja Bye, Per Magnus Haram, Jan Pål Loennechen, Qusai Y. Al-Share, Eirik Skogvoll, Stig A. Slørdahl, Ole J. Kemi, Sonia M. Najjar, Ulrik Wisløff
Journal: Circulation (2008)

Individuals with the metabolic syndrome are 3 times more likely to die of heart disease than healthy counterparts. Exercise training reduces several of the symptoms of the syndrome, but the exercise intensity that yields the maximal beneficial adaptations is in dispute. We compared moderate and high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with the metabolic syndrome.Thirty-two metabolic syndrome patients (age, 52.3+/-3.7 years; maximal oxygen uptake [o(2)max], 34 mL x kg(-1) x min(-1)) were randomized to equal volumes of either moderate continuous moderate exercise (CME; 70% of highest measured heart rate [Hfmax]) or aerobic interval training (AIT; 90% of Hfmax) 3 times a week for 16 weeks or to a control group. o(2)max increased more after AIT than CME (35% versus 16%; P<0.01) and was associated with removal of more risk factors that constitute the metabolic syndrome (number of factors: AIT, 5.9 before versus 4.0 after; P<0.01; CME, 5.7 before versus 5.0 after; group difference, P<0.05). AIT was superior to CME in enhancing endothelial function (9% versus 5%; P<0.001), insulin signaling in fat and skeletal muscle, skeletal muscle biogenesis, and excitation-contraction coupling and in reducing blood glucose and lipogenesis in adipose tissue. The 2 exercise programs were equally effective at lowering mean arterial blood pressure and reducing body weight (-2.3 and -3.6 kg in AIT and CME, respectively) and fat.Exercise intensity was an important factor for improving aerobic capacity and reversing the risk factors of the metabolic syndrome. These findings may have important implications for exercise training in rehabilitation programs and future studies.
Nitric Oxide Synthesis Inhibition Does Not Impair Water Immersion-Induced Renal Vasodilation in Humans
Authors: LIOE-TING DIJKHORST-OEI, PETER BOER, TON J. RABELINK, HEIN A. KOOMANS
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Nitric oxide (NO) is tonically released in the kidney to maintain renal perfusion and adequate sodium and water clearance. Little is known about the role of NO in the renal adaptation to an acute volume challenge. This is important for our understanding of pathophysiologic conditions associated with impaired NO activity. This study examined the effects of NO synthesis inhibition on neurohumoral, renal hemodynamic, and excretory responses to head-out immersion (HOI). Seven healthy men underwent four 7-h clearance studies. One study served as a time control study (placebo infusion), and in one study N G -monomethyl-L-arginine (L-NMMA; 3 mg/kg priming dose + 3 mg/kg per h) was infused during hours 2 to 5. In a third and fourth clearance study, HOI was applied from hours 3 to 5, during infusion of either placebo or L-NMMA. To assess the degree of NO synthesis inhibition, the effect of L-NMMA on [ 15 N]-arginine-to-[ 15 N]-citrulline conversion rate was studied in four others. HOI decreased mean arterial pressure (MAP) from 87 ± 3 to 76 ± 2 mmHg and renal vascular resistance (RVR) from 82 ± 6 to 70 ± 7 mmHg · min/L, and increased sodium excretion (UNaV) from 110 ± 27 to 195 ± 29 μmol/min and flow (UV) from 14.4 ± 1.4 to 15.8 ± 1.4 ml/min. L-NMMA caused profound and sustained increases in MAP and RVR and decreases in UNaV and UV. HOI superimposed on L-NMMA infusion decreased the elevated MAP from 93 ± 4 to 83 ± 2 mmHg and RVR from 111 ± 9 to 95 ± 7 mmHg · min/L, and increased UNaV from 41 ± 8 to 95 ± 15 μmol/min and UV from 10.0 ± 1.1 to 12.7 ± 1.4 ml/min. The relative changes were not significantly different from the effects of HOI without L-NMMA infusion. HOI decreased plasma renin activity and aldosterone and increased plasma atrial natriuretic peptide and urinary cGMP. L-NMMA decreased urinary cGMP, but did not affect the plasma hormones or the changes induced by HOI. L-NMMA decreased the [ 15 N]-arginine-to-[ 15 N]-citrulline conversion rate to one-third of baseline. The results indicate that in a state of NO deficiency in humans, the kidney can still respond to an acute volume challenge with vasorelaxation, diuresis, and natriuresis.
NAC-1 Controls Cell Growth and Survival by Repressing Transcription of Gadd45GIP1, a Candidate Tumor Suppressor
Authors: Kentaro Nakayama, Naomi Nakayama, Tian-Li Wang, Ie-Ming Shih
Journal: Cancer Research (2007)

Abstract Cancer mortality and morbidity are primarily related to recurrent tumors, and characterization of recurrence-associated genes should illuminate fundamental properties of tumor progression and provide new therapeutic targets. We have previously identified NAC-1, a member of the BTB/POZ gene family and a transcription repressor, as a gene associated with recurrent ovarian carcinomas after chemotherapy. We further showed that homodimerization of NAC-1 proteins is essential for tumor growth and survival. In this study, we applied serial analysis of gene expression and identified growth arrest and DNA-damage–inducible 45-γ interacting protein (Gadd45GIP1) as one of the downstream genes negatively regulated by NAC-1. NAC-1 knockdown in both SKOV3 and HeLa cells that expressed abundant endogenous NAC-1 induced Gadd45GIP1 expression transcriptionally; on the other hand, engineered expression of NAC-1 in NAC-1–negative RK3E and HEK293 cells suppressed endogenous Gadd45GIP1 expression. In NAC-1–expressing tumor cells, induction of dominant negative NAC-1 conferred a growth-inhibitory effect that can be partially reversed by Gadd45GIP1 knockdown. Induced Gadd45GIP1 expression resulted in growth arrest in SKOV3 and HeLa cells both in vitro and in vivo. In summary, NAC-1 contributes to tumor growth and survival by at least inhibiting Gadd45GIP1 expression, which has a tumor suppressor effect in cancer cells. [Cancer Res 2007;67(17):8058–64]
Association of genetic variations in the CSF2 and CSF3 genes with lung function in smoking-induced COPD
Authors: J-Q. He, K. Shumansky, J. E. Connett, N. R. Anthonisen, P. D. Paré, A. J. Sandford
Journal: European Respiratory Journal (2008)

Granulocyte-macrophage colony-stimulating factor (CSF), also known as CSF2, and granulocyte CSF, also known as CSF3, are important survival and proliferation factors for neutrophils and macrophages. The objective of the present study was to determine whether single nucleotide polymorphisms (SNPs) of CSF2 and CSF3 are associated with lung function in smoking-induced chronic obstructive pulmonary disease. In total, five SNPs of CSF2 and CSF3 were studied in 587 non-Hispanic white subjects with the fastest (n = 281) or the slowest (n = 306) decline of lung function selected from among continuous smokers in the National Heart, Lung, and Blood Institute Lung Health Study (LHS). These SNPs were also studied in 1,074 non-Hispanic white subjects with the lowest (n = 536) or the highest (n = 538) baseline lung function at the beginning of the LHS. An increase in the number of CSF3 -1719T alleles was significantly associated with protection against low lung function (odds ratio 0.73, 95% confidence interval 0.56–0.95), and was still significant after adjustment for multiple comparisons. There was also a significant association of a CSF3 haplotype with baseline levels of forced expiratory volume in one second. No association was found for CSF2 SNPs and lung function, nor was there evidence of epistasis. In conclusion, genetic variation in colony-stimulating factor 3 is associated with cross-sectionally measured lung function in smokers.
SEPARATION AND CHARACTERIZATION OF HUMAN SERUM CHYLOMICRONS
Authors: Angelo Scanu, Irvine H. Page
Journal: The Journal of Experimental Medicine (1959)

Chylomicrons were separated by low and high speed ultracentrifugation from lipemic sera of human subjects in the absorptive phase. The final chylomicron preparation was free from other serum components and contained a small constant amount of protein, approximately 2 per cent of the chylomicron fraction. Electrophoresis, immunochemical analysis, and absorption experiments identified the protein component as derived from a mixture of beta and alpha1 serum lipoproteins. Large aliquots of an emulsion of serum freed of chylomicrons and coconut oil were incubated at 37°C. for 2 hours and ultracentrifuged as in the preparation of chylomicrons. The fat particles now showed the presence of minute amounts of beta and alpha1 serum lipoproteins in almost the same proportion as found in chylomicrons. "Finger prints" of delipidized samples of chylomicrons and particles from serum-coconut oil emulsion gave similar, although not identical patterns. The data on "clearing factor" activity corroborated the finding that serum alpha1 lipoproteins are contained in chylomicrons and particles from serum-coconut oil emulsion. These two lipide particles, partially delipidized, were both able to activate a "clearing factor" system in vitro, a property exhibited only by intact or partially delipidized alpha1 serum lipoproteins. Clearing activity was satisfactorily determined by using an emulsion of coconut oil mixed in agar as a substrate to give an opaque gel, in which the diffusing enzyme showed its activity by areas of clearing. The results obtained by this technique were in agreement with those based on fall in optical density and non-esterified fatty acid production. Chemical analysis of serum chylomicrons showed a concentration of cholesterol and phospholipides higher than could be accounted for by the attached beta and alpha1 serum lipoproteins. On the basis of these results the assumption is made that in the blood stream small amounts of serum lipoproteins, by a process of adsorption, form a complex with the absorbed triglycerides, cholesterol, and phospholipides, to produce chylomicrons.
Randomized Placebo-Controlled Phase II Trial of Perifosine Plus Capecitabine As Second- or Third-Line Therapy in Patients With Metastatic Colorectal Cancer
Authors: Johanna C. Bendell, John Nemunaitis, Sasha J. Vukelja, Christopher Hagenstad, Luis T. Campos, Robert C. Hermann, Peter Sportelli, Lesa Gardner, Donald A. Richards
Journal: Journal of Clinical Oncology (2011)

Purpose In a multicenter, double-blind phase II trial, we compared the efficacy and safety of perifosine plus capecitabine (P-CAP) with placebo plus capecitabine (CAP) in patients with metastatic colorectal cancer (mCRC) who had progressed after as many as two prior therapies. Patients and Methods Patients (n = 38) not previously treated with capecitabine received P-CAP (perifosine 50 mg orally once daily, days 1 to 21 and CAP 825 mg/m 2 orally twice daily, days 1 to 14) or CAP (825 mg/m 2 orally twice daily, days 1 to 14) in 21-day cycles until disease progression. The primary end point was time to progression (TTP). Secondary end points included overall survival (OS), overall response rate (ORR), safety, and tolerability. Results Twenty patients were randomly assigned to P-CAP and 18 to CAP. Median TTP (27.5 v 10.1 weeks; P &lt; .001) and median OS (17.7 v 7.6 months; P = .0052) were improved in patients receiving P-CAP versus CAP. ORR was 20% v 7% in the P-CAP and CAP groups, respectively, and one patient in the P-CAP group had a complete response. A subset analysis of fluorouracil-refractory patients showed a median TTP of 17.6 v 9.0 weeks (P &lt; .001) and median OS of 15.1 v 6.5 months (P = .0061). Toxicities, including diarrhea, nausea, fatigue, and hand-foot syndrome, were manageable. Conclusion P-CAP showed promising clinical activity compared with CAP in previously treated patients with mCRC. A phase III trial is underway comparing P-CAP with CAP in patients with refractory mCRC.
Should We Treat Prehypertension in Diabetes?
Authors: Ehud Grossman
Journal: Diabetes Care (2009)

Elevated blood pressure (BP), even within the normal range, is associated with cardiovascular (CV) morbidity and mortality. Therefore, the Joint National Committee (JNC) VII introduced the term “prehypertension” in the general population, which is defined as BP levels of 120–139 mmHg and 80–89 mmHg for systolic and diastolic BP, respectively (1). Prehypertension includes two different categories of BP: normal (systolic of 120–129 mmHg or diastolic BP of 80–84 mmHg) and high-normal (systolic of 130–139 mmHg or diastolic BP of 85–89 mmHg). The risk of CV events is increased by two- to fourfold with the coexistence of hypertension and type 2 diabetes. Lowering BP is particularly effective in patients with type 2 diabetes. Therefore, guidelines recommend lowering BP to below 130/80 mmHg in diabetic patients. Thus, the term “prehypertension” is inadequate for patients with type 2 diabetes. It is clear from guidelines that in diabetic patients, the high-normal BP category of prehypertension should be pharmacologically treated. However, there is no evidence that drug treatment is beneficial in the normal BP category of prehypertension. Therefore, despite the devastating effect of elevated BP in type 2 diabetes, drug treatment is not always recommended for all diabetic patients with prehypertension.

Hypertension is perhaps best defined by the BP level that has a negative impact on the CV system. Thus, numerical definitions, although hotly debated by numerous guideline committees, are not helpful to practicing physicians. Recent guidelines set the target level of BP for uncomplicated hypertension to below 140/90 mmHg and in the diabetic hypertensive patient to below 130/80 mmHg (1,2). Solid evidence exists showing that the benefits of BP lowering are far more pronounced in the diabetic than in the nondiabetic hypertensive patient. In light of the benefits of BP lowering in diabetic patients, there is a dilemma as to whether diabetic …
A memorable exam
Authors: A M. Clarfield
Journal: BMJ (2003)

On moving from the primarily English speaking Canadian province of Ontario to predominantly francophone Quebec in the late 1970s, I had to pass a French language proficiency test in order to receive my medical licence. I was already bilingual (native English and reasonable Hebrew) and had studied French in high school. However, nearly 15 years had passed since I had last said “bonjour” to my teacher, and so I had to go back to night school.

In addition to my formal language studies, I watched cartoons on television, perused the French press, and studied the television news “en francais” (after learning the main facts on the English version, which came on earlier). I assiduously studied, practised in front of a mirror, and tortured my poor French speaking patients, who were both enormously kind and helpful.

We “immigrant” physicians had one year to prove our linguistic competency, with an option for another year of study should one fail the initial test. Until receiving a certificate …
Wnt signaling pathways in urological cancers: past decades and still growing
Authors: Shahana Majid, Sharanjot Saini, Rajvir Dahiya
Journal: Molecular Cancer (2012)

Abstract The Wnt signaling pathway is involved in a wide range of embryonic patterning events and maintenance of homeostasis in adult tissues. The pathological role of the Wnt pathway has emerged from studies showing a high frequency of specific human cancers associated with mutations that constitutively activate the transcriptional response of these pathways. Constitutive activation of the Wnt signaling pathway is a common feature of solid tumors and contributes to tumor development, progression and metastasis in various cancers. In this review, the Wnt pathway will be covered from the perspective of urological cancers with emphasis placed on the recent published literature. Regulation of the Wnt signaling pathway by microRNAs (miRNA), small RNA sequences that modify gene expression profiles will also be discussed. An improved understanding of the basic genetics and biology of Wnt signaling pathway will provide insights into the development of novel chemopreventive and therapeutic strategies for urological cancers.
Influences of Maternal and Paternal PTSD on Epigenetic Regulation of the Glucocorticoid Receptor Gene in Holocaust Survivor Offspring
Authors: Rachel Yehuda, Nikolaos P. Daskalakis, Amy Lehrner, Frank Desarnaud, Heather N. Bader, Iouri Makotkine, Janine D. Flory, Linda M. Bierer, Michael J. Meaney
Journal: American Journal of Psychiatry (2014)

Differential effects of maternal and paternal posttraumatic stress disorder (PTSD) have been observed in adult offspring of Holocaust survivors in both glucocorticoid receptor sensitivity and vulnerability to psychiatric disorder. The authors examined the relative influences of maternal and paternal PTSD on DNA methylation of the exon 1F promoter of the glucocorticoid receptor (GR-1F) gene (NR3C1) in peripheral blood mononuclear cells and its relationship to glucocorticoid receptor sensitivity in Holocaust offspring.Adult offspring with at least one Holocaust survivor parent (N=80) and demographically similar participants without parental Holocaust exposure or parental PTSD (N=15) completed clinical interviews, self-report measures, and biological procedures. Blood samples were collected for analysis of GR-1F promoter methylation and of cortisol levels in response to low-dose dexamethasone, and two-way analysis of covariance was performed using maternal and paternal PTSD as main effects. Hierarchical clustering analysis was used to permit visualization of maternal compared with paternal PTSD effects on clinical variables and GR-1F promoter methylation.A significant interaction demonstrated that in the absence of maternal PTSD, offspring with paternal PTSD showed higher GR-1F promoter methylation, whereas offspring with both maternal and paternal PTSD showed lower methylation. Lower GR-1F promoter methylation was significantly associated with greater postdexamethasone cortisol suppression. The clustering analysis revealed that maternal and paternal PTSD effects were differentially associated with clinical indicators and GR-1F promoter methylation.This is the first study to demonstrate alterations of GR-1F promoter methylation in relation to parental PTSD and neuroendocrine outcomes. The moderation of paternal PTSD effects by maternal PTSD suggests different mechanisms for the intergenerational transmission of trauma-related vulnerabilities.
Lost in Translation? Estrogen Receptor Status and Endocrine Responsiveness in Breast Cancer
Authors: Nadia Harbeck, Achim Rody
Journal: Journal of Clinical Oncology (2012)

this editorial and elsewhere 2-4,12,14 testify to the long arc of hormone receptor‐positive breast cancer, confirm the enduring overall safety of tamoxifen and AIs, and provide reassurance that the well-characterized major adverse events of therapy either stabilize or resolve with cessation of treatment. The substantial near-term successes of adjuvant chemotherapy and endocrine therapy have shifted both the natural history and the dialogue in ER-positive, early-stage breast cancer for oncologists and patients alike. The issue of late recurrence—deep time for clinicians and survivors— has emerged as a fundamental challenge. RCTs have shown equivalence for either 5 years of AI treatment or a sequenced regimen of tamoxifen followed by an AI for a total of 5 years. 13,18 For women who receive AI-based adjuvant treatment, it remains unclear whether a longer program of extended therapy with an AI beyond 5 years of initial adjuvant treatment will outperform a shorter 5-year course of adjuvant endocrine therapy. Progress in the deep time problem of early-stage breast cancer will depend on answering the long and the short of that question.