tbuckley/cabot-search huggingface dataset:
Breakthrough during recombinant interferon alfa therapy in patients with chronic Hepatitis C virus infection: Prevalence, etiology, and management
Authors: L ROFFI
Journal: Hepatology (1995)

Recombinant interferon alfa (r-IFN alpha 2) has been shown to normalize the aminotransferase levels in approximately 50% of patients with chronic hepatitis C virus (HCV). Few patients experience a relapse during the treatment, in spite of a complete initial response (breakthrough). We studied 191 HCV Ab-positive patients with histologically proven chronic hepatitis. All of them were treated with r-IFN alpha 2 (3 MU three times a week). A complete response was seen in 54.4%. However, 12 of 104 responders experienced a breakthrough. At the time of breakthrough, neutralizing IFN antibodies were positive in 6 of 12 patients. Binding IFN antibodies were positive in all of these 12 patients. Continued treatment with r-IFN alpha 2, even at higher doses, did not restore the previous response in any patient. All of them were then switched to natural lymphoblastoid IFN, and this rapidly restored a complete response in all of the patients.
Increased Caffeine Intake Is Associated with Reduced Risk of Basal Cell Carcinoma of the Skin
Authors: Fengju Song, Abrar A. Qureshi, Jiali Han
Journal: Cancer Research (2012)

Abstract Studies in animals suggest that caffeine administration helps prevent squamous cell skin cancer development, but there have been limited epidemiologic studies on the association between caffeine consumption and skin cancer risk. Using data from the Nurses' Health Study and the Health Professionals Follow-up Study, we prospectively examined risks of basal cell carcinoma (BCC, 22,786 cases), squamous cell carcinoma (SCC, 1,953 cases), and melanoma (741 cases) in relation to caffeine intake. Cox proportional hazard models were used to calculate relative risks (RR) and 95% confidence intervals (CI). The amount of caffeine intake from all dietary sources was inversely associated with BCC risk. Compared with the lowest quintile, the highest quintile had the lowest risk (RR, 0.82 in women; 95% CI:,0.77–0.86 and RR, 0.87 in men; 95% CI, 0.81–0.94; Ptrend &amp;lt; 0.0001 in both). A significant inverse association was also found between caffeinated coffee consumption and BCC risk. Compared with individuals who consumed caffeinated coffee less than 1 cup per month, women who consumed more than 3 cups/d had the lowest risk (RR, 0.79; 95% CI, 0.74–0.85; Ptrend &amp;lt; 0.0001) and the RR for men was 0.90 (95% CI, 0.80–1.01; Ptrend = 0.003). Caffeine from other dietary sources (tea, cola, and chocolate) was also inversely associated with BCC risk. Decaffeinated coffee consumption was not associated with a similar decrease in BCC risk. In contrast, caffeine intake was not found to be inversely associated with risks of SCC or melanoma. Our findings argue that caffeine intake in men and women is inversely associated with risk of BCC. Cancer Res; 72(13); 3282–9. ©2012 AACR.
Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD
Authors: Georg Schlieper, Ralf Westenfeld, Thilo Krüger, Ellen C. Cranenburg, Elke J. Magdeleyns, Vincent M. Brandenburg, Zivka Djuric, Tatjana Damjanovic, Markus Ketteler, Cees Vermeer, Nada Dimkovic, Jürgen Floege, Leon J. Schurgers
Journal: Journal of the American Society of Nephrology (2011)

The mechanisms for vascular calcification and its associated cardiovascular mortality in patients with ESRD are not completely understood. Dialysis patients exhibit profound vitamin K deficiency, which may impair carboxylation of the calcification inhibitor matrix gla protein (MGP). Here, we tested whether distinct circulating inactive vitamin K–dependent proteins associate with all-cause or cardiovascular mortality. We observed higher levels of both desphospho-uncarboxylated MGP (dp-ucMGP) and desphospho-carboxylated MGP (dp-cMGP) among 188 hemodialysis patients compared with 98 age-matched subjects with normal renal function. Levels of dp-ucMGP correlated with those of protein induced by vitamin K absence II (PIVKA-II; r = 0.62, P < 0.0001). We found increased PIVKA-II levels in 121 (64%) dialysis patients, indicating pronounced vitamin K deficiency. Kaplan-Meier analysis showed that patients with low levels of dp-cMGP had an increased risk for all-cause and cardiovascular mortality. Multivariable Cox regression confirmed that low levels of dp-cMGP increase mortality risk (all-cause: HR, 2.2; 95% CI, 1.1 to 4.3; cardiovascular: HR, 2.7; 95% CI, 1.2 to 6.2). Furthermore, patients with higher vascular calcification scores showed lower levels of dp-cMGP. In 17 hemodialysis patients, daily supplementation with vitamin K2 for 6 weeks reduced dp-ucMGP levels by 27% (P = 0.003) but did not affect dp-cMGP levels. In conclusion, the majority of dialysis patients exhibit pronounced vitamin K deficiency. Lower levels of circulating dp-cMGP may serve as a predictor of mortality in dialysis patients. Whether vitamin K supplementation improves outcomes requires further study.
Differentiation and transcription factor gene therapy in experimental parkinson's disease: sonic hedgehog and gli-1, but not Nurr-1, protect nigrostriatal cell bodies from 6-OHDA-induced neurodegeneration
Authors: A Hurtado-Lorenzo, E Millan, V Gonzalez-Nicolini, D Suwelack, M G Castro, P R Lowenstein
Journal: Molecular Therapy (2004)

<h2>Abstract</h2> We tested the activity of the dopaminergic neuron differentiation factor sonic hedgehog, its downstream transcription factor target Gli-1, and an orphan nuclear receptor, Nurr-1, necessary for the induction of the dopaminergic phenotype of nigrostriatal neurons, in an <i>in vivo</i> model of nigrostriatal neurodegeneration. Our preliminary experiments demonstrated that all three constructs expressed the proper molecules and that these had the predicted biological activities <i>in vitro.</i> We expressed the N-terminal of sonic hedgehog (ShhN) and the Gli-1 and Nurr-1 entire coding regions from highly purified, and quality controlled, replication-defective adenoviral vectors injected into the brains of rats and used the dopaminergic growth factor GDNF as a positive control. The neurotoxin 6-hydroxydopamine was used to lesion the nigrostriatal dopaminergic innervation; RAd-ShhN and RAd-Gli-1 protected dopaminergic neuronal cell bodies in the substantia nigra, but not axonal terminals in the striatum, from 6-OHDA-induced cell death, while RAd-Nurr-1 was ineffective in protecting either cell bodies or axons. RAd-GDNF was able to protect both the dopaminergic cell bodies and the striatal axon terminals. Our results establish for the first time, to the best of our knowledge, that gene transfer of ShhN and one of its target transcription factors can selectively protect dopaminergic nigrostriatal neuronal cell bodies from a specific neurotoxic insult. Selective protection of nigrostriatal dopaminergic cell bodies by the differentiation factor ShhN and the transcription factor Gli-1 was achieved in a neurotoxic model that eliminates more than 70% of the nigral neurons under consideration. Differentiation and transcription factors can thus be used for the treatment of neurodegeneration by gene therapy.
Targeting PBR by Hexaminolevulinate-Mediated Photodynamic Therapy Induces Apoptosis through Translocation of Apoptosis-Inducing Factor in Human Leukemia Cells
Authors: Ingegerd Eggen Furre, Susan Shahzidi, Zivile Luksiene, Michael T.N. Møller, Elin Borgen, Janet Morgan, Kinga Tkacz-Stachowska, Jahn M. Nesland, Qian Peng
Journal: Cancer Research (2005)

Abstract Photodynamic therapy (PDT) with endogenous protoporphyrin IX derived from 5-aminolevulinic acid or its derivatives has been established for treatments of several premalignancies and malignancies; however, the mechanism of the modality is not fully elucidated. The mitochondrial permeability transition pore consists mainly of the mitochondrial outer membrane voltage-dependent anion channel and the peripheral benzodiazepine receptor (PBR) and the mitochondrial inner membrane adenine nucleotide translocator (ANT). These mitochondrial proteins are responsible for the permeability transition that leads to apoptosis. In the present study, the human leukemia cell line, Reh, was treated with PDT using hexaminolevulinate (HAL). More than 80% of apoptotic Reh cells were found after HAL-mediated PDT (HAL-PDT) with high-molecular-weight (50 kbp) DNA fragmentation. Addition of PK11195 or Ro5-4864, two ligands of PBR, during HAL-PDT significantly inhibited the apoptotic effect. Bongkrekic acid, a ligand for ANT, also reduced the PDT effect. Although the mitochondrial transmembrane potential collapsed, neither cytosolic translocation of mitochondrial cytochrome c nor activation of caspase-9, caspase-8, caspase-3, and poly(ADP-ribose) polymerase were found. However, nuclear translocation of mitochondrial apoptosis-inducing factor (AIF) was shown by both immunoblotting and immunocytochemistry. Because AIF is the sole one among all proapoptotic factors involved in caspase-dependent and caspase-independent pathways that induces the high-molecular-weight DNA fragmentation, we conclude that HAL-PDT specifically targets PBR, leading to apoptosis of the Reh cells through nuclear translocation of mitochondrial AIF. This study suggests PBR as a possible novel therapeutic target for HAL-based PDT of cancer.
Cleavage of the IPS-1/Cardif/MAVS/VISA does not inhibit T cell-mediated elimination of hepatitis C virus non-structural 3/4A-expressing hepatocytes
Authors: G Ahlen, E Derk, M Weiland, J Jiao, N Rahbin, S Aleman, D L Peterson, K Pokrovskaja, D Grander, L Frelin, M Sallberg
Journal: Gut (2008)

<h3>Background:</h3> Hepatitis C virus (HCV) effectively establishes persistent infection in human livers. The non-structural (NS) 3/4A complex participates in this process by cleavage of interferon β (IFNβ) promoter stimulator-1 (IPS-1; also termed Cardif/MAVS/VISA), which inhibits responses to double stranded (ds) RNA. However, it is not known whether this effect extends beyond innate responses. <h3>Aims:</h3> To test if HCV NS3/4A affects innate and adaptive immune responses in vivo. <h3>Methods:</h3> NS3 levels were semi-quantified in human liver biopsies, transfected cells, and in transgenic (Tg) mouse livers by western blot. The effect of NS3/4A on dsRNA-mediated signalling and on the integrity of IPS-1 was analysed using in vitro translation, transfected cells and Tg mice. Cytotoxic T cell (CTL)-mediated clearance of transient firefly luciferase (FLuc)- and/or NS3/4A-Tg hepatocytes was determined using in vivo imaging and western blot. <h3>Results:</h3> NS3 protein levels were in a comparable range (0.1–49 μg/g tissue) in infected human livers and Tg mouse livers. Importantly, these levels of NS3/4A reduced murine innate responses to synthetic dsRNA in vivo, supporting the possibility that this occurs also in infected humans. The likely explanation for this was the NS3/4A-mediated cleavage of mouse IPS-1, albeit less efficiently than human IPS-1. Despite this, FLuc- and/or NS3/4A-expressing murine hepatocytes were effectively eliminated by hepatic CTLs, utilising the classical molecules for virus-infected cell lysis, including CD8, IFNγ, perforin and FasL. <h3>Conclusions:</h3> Although HCV NS3/4A inhibits the innate immunity, this does not prevent CTL-mediated clearance of NS3/4A-expressing hepatocytes in vivo. Thus, other HCV proteins are most likely responsible for interfering with the adaptive immunity.
Unexpected Roles for pRb in Mouse Skin Carcinogenesis
Authors: Sergio Ruiz, Mirentxu Santos, M. Fernanda Lara, Carmen Segrelles, Claudio Ballestín, Jesús M. Paramio
Journal: Cancer Research (2005)

Abstract The mouse skin carcinogenesis represents one of the best models for the understanding of malignant transformation, including the multistage nature of tumor development. The retinoblastoma gene product (pRb) plays a critical role in cell cycle regulation, differentiation, and inhibition of oncogenic transformation. In epidermis, Rb−/− deletion leads to proliferation and differentiation defects. Numerous evidences showed the involvement of the retinoblastoma pathway in this model. However, the actual role of pRb is still unknown. To study the possible involvement of pRb in keratinocyte malignant transformation, we have carried out two-stage chemical skin carcinogenesis on RbF19/F19 (thereafter Rb+/+) and RbF19/F19;K14Cre (thereafter Rb−/−) animals. Unexpectedly, we found that Rb−/− mice developed fewer and smaller papillomas than the Rb+/+ counterparts. Moreover, the small size of the pRb-deficient tumors is associated with an increase in the apoptotic index. Despite this, pRb-deficient tumors display an increased conversion rate to squamous cell carcinomas. Biochemical analyses revealed that these characteristics correlate with the differential expression and activity of different pathways, including E2F/p19arf/p53, PTEN/Akt, c-jun NH2-terminal kinase/p38, and nuclear factor-κB. Collectively, our findings show unexpected and hitherto nondescribed roles of pRb during the process of epidermal carcinogenesis.
Screening for hearing loss in childhood: a study of national practice.
Authors: S Stewart-Brown, M N Haslum
Journal: BMJ (1987)

A questionnaire survey of all health districts in England and Wales was carried out at the end of 1984 to document screening programmes for identifying hearing loss in childhood. The response rate was 81.3%. All districts performed distraction testing, all but nine aiming at doing so at 7-9 months of age. All districts tested children9s hearing at school, generally before 7 years of age. The number of times that children were screened both before school and at school varied considerably, from one to six times before school and one to six times at school. Few districts collected information that would allow them to make judgments about the efficiency of effectiveness of their screening programmes.
Independent Effects of Etiology of Failure and Time to Reintubation on Outcome for Patients Failing Extubation
Authors: SCOTT K. EPSTEIN, RONALD L. CIUBOTARU
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Patients requiring reintubation after failed extubation have a poor prognosis, with hospital mortality exceeding 30 to 40%, though the reason remains unclear. To examine the impact of etiology of extubation failure and time to reintubation on hospital outcome, we performed a post hoc analysis of prospectively gathered data on 74 MICU patients (47 men, 27 women), 64 +/- 2 yr of age who required reintubation within 72 h of extubation. Cause for reintubation was classified as airway (upper airway obstruction, 11; aspiration/excess pulmonary secretions, 12) or nonairway (respiratory failure, 21; congestive heart failure, 17; encephalopathy, 7; other, 6). The duration of mechanical ventilation prior to extubation was 139 +/- 19 h, and the median time to reintubation was 21 h. Thirty-one of 74 patients (42%) died, with mortality highest for patients failing from nonairway etiologies (27/51, 53% versus 4/23, 17%; p < 0.01). Patients failing from an airway cause tended to be reintubated earlier (21 +/- 4 versus 31 +/- 3 h, p = 0.07). Mortality increased with longer duration of time from extubation to reintubation (<= 12 h, 6/25 versus > 12 h, 25/49; p < 0.05). With multiple logistic regression, both cause for extubation failure and time to reintubation were independently associated with hospital mortality. In conclusion, etiology of extubation failure and time to reintubation are independent predictors of outcome in reintubated MICU patients. The high mortality for those reintubated for nonairway problems indicate that efforts should be preferentially focused on identifying these patients. The effect of time to reintubation suggests that identification of patients early after extubation and timely reinstitution of ventilatory support has the potential to reduce the increased mortality associated with extubation failure.
Long-term Outcomes in Fellow Eyes after Acute Primary Angle Closure in the Contralateral Eye
Authors: David S. Friedman, Paul T.K. Chew, Gus Gazzard, Leonard P.K. Ang, Yoke-Fong Lai, Harry A. Quigley, Steve K.L. Seah, Tin Aung
Journal: Ophthalmology (2006)
Pancytopenia due to hemophagocytic syndrome as the presenting manifestation of babesiosis
Authors: Pankaj Gupta, Randolph W. Hurley, Peter H. Helseth, Jesse L. Goodman, Dale E. Hammerschmidt
Journal: American Journal of Hematology (1995)

Abstract We present a case of hemophagocytosis during infection with the intraërythrocytic protozoan Babesia microti in a 47‐year‐old splenectomized renal allograft recipient. After therapy with clindamycin and quinine a relapse responded to atovaquone; durable remission was not achieved until trimethoprim/sulfa was added. We postulate the severity of our patient's syndrome was due to splenectomy and chronic immunosuppression. Babesiosis should be considered when immunocompromised patients develop pancytopenia.
Bilateral Parotid Gland Enlargement and Hyperlipoproteinemia
Authors: H. Benfer Kaltreider
Journal: JAMA (1969)

Sjögren's syndrome was the initial diagnosis of the physicians who referred five patients with bilateral, noninflammatory parotid gland enlargement. This diagnosis was not confirmed in any case. All five patients had elevated plasma triglyceride concentrations and mild diastolic hypertension. Increased intake of alcoholic beverages, abnormal glucose tolerance, and moderate obesity were frequently present. Massive replacement of the parotid gland tissue by fat was observed in two biopsy specimens. Restriction of calories, alcoholic beverages, and the percent of calories from carbohydrate resulted in regression of parotid gland size in three patients observed for more than three months. A modest short-term reduction in size of the parotid gland occurred in one other patient over a five-week period. Hypertriglyceridemia was also ameliorated by this dietary regimen.
Appropriateness and delay to initiate therapy in ventilator-associated pneumonia
Authors: C. M. Luna, P. Aruj, M. S. Niederman, J. Garzón, D. Violi, A. Prignoni, F. Ríos, S. Baquero, S. Gando
Journal: European Respiratory Journal (2005)

Inappropriate therapy (IT) and delayed initiation of appropriate therapy (DIAT) result in inadequate therapy in patients with ventilator-associated pneumonia (VAP). The aim of the current study was to assess the impact of DIAT in VAP. A total of 76 mechanically ventilated patients with bacteriologically confirmed VAP were prospectively evaluated in the intensive care unit of six hospitals in Buenos Aires, Argentina. Appropriate therapy was defined as coverage of all the identified pathogens by the antimicrobial therapy administered at the time of VAP clinical diagnosis. The clinical pulmonary infection score was measured during the 3 days before, at the onset and during the days which followed the onset of VAP. A total of 24 patients received adequate therapy; mortality was 29.2%. The remaining 52 patients received either IT (n = 16) or DIAT (n = 36); the mortality was 63.5% combined, and 75.0 and 58.3% for IT and DIAT, respectively (statistically significant compared with adequate therapy). Inappropriate therapy and delayed initiation of appropriate therapy increased the mortality of ventilator-associated pneumonia. Patients with inappropriate therapy and/or delayed initiation of appropriate therapy had a more gradual increase in clinical pulmonary infection score than those receiving adequate therapy, and this increase was found to occur prior to the time of the clinical diagnosis. In conclusion, these findings might provide the rationale for a trial of earlier initiation of therapy, based on clinical grounds in an effort to improve the outcome of patients with ventilator-associated pneumonia.
Tissue iodoprotein formation during the peripheral metabolism of the thyroid hormones
Authors: Martin I. Surks, Harold L. Schwartz, Jack H. Oppenheimer
Journal: Journal of Clinical Investigation (1969)

The formation of tissue iodoproteins during the peripheral metabolism of the thyroid hormones was examined by determining the concentration of nonethanol-extractable (125)I (NE(125)I) in various tissues after the intravenous injection of 3,5,3'-triiodo-L-thyronine (T3-(125)I) and L-thyroxine-(125)I (T4-(125)I) in groups of rats with iodide-blocked thyroid glands. 3 days after T3-(125)I and 7 days after T4-(125)I injection the concentration of NE(125)I in the liver and kidney was 5-10 times greater than in plasma. Smaller but nonetheless significant concentrations of NE(125)I were demonstrated in skeletal and cardiac muscle. Hepatic subcellular fractionation studies revealed that the major portion of the liver NE(125)I was in the microsomal fraction. Lower concentrations of NE(125)I were present in the nuclear, mitochondrial, and soluble fractions. When similar studies were performed in groups of rats pretreated with phenobarbital, an increase in the metabolic clearance of T3-(125)I (30%) and T4-(125)I (100%) was observed along with a highly significant increase in the NE(125)I concentration of the liver and plasma. The increase in hepatic NE(125)I in these studies was primarily due to the microsomal component. Incubation of hepatic microsomes with T3-(125)I and T4-(125)I showed that NEI formation as well as deiodination appeared to obey simple Michaelis-Menten kinetics. Moreover, the maximal rate of both deiodination and NEI formation was increased when microsomes harvested from phenobarbital-treated rats were employed. These studies indicate that thyroid hormone metabolism results in the formation of structural and soluble tissue iodoproteins in addition to circulating iodoproteins. The rate of formation of these moieties in the liver and plasma appears to be related to the rate of hormone metabolism.
CONTROLLED TRIALS IN SURGERY
Authors: DavidH. Spodick, Wilbert Aronow, Bernard Barber, Henry Blackburn, David Boyd, C.Richard Conti, JamesP. Logerfo, Bernard Lown, VirendraS. Mathur, HenryD. Mcintosh, ThomasA. Preston, Arthur Selzer, Timothy Takaro
Journal: The Lancet (1978)
New Insight Puts CRAF in Sight as a Therapeutic Target
Authors: Ana Paula Rebocho, Richard Marais
Journal: Cancer Discovery (2011)

Abstract By selectively depleting components of the RAF-MEK-ERK pathway in transgenic mice, it is now shown in 2 studies that CRAF is critical for signaling to MEK downstream of oncogenic Kras and that BRAF is not required. Cancer Discovery; 1(2); 98–9. ©2011 AACR. Commentary on Karreth et al., p. 128
Incidence of midportion Achilles tendinopathy in the general population
Authors: S de Jonge, C van den Berg, R J de Vos, H J L van der Heide, A Weir, J A N Verhaar, S M A Bierma-Zeinstra, J L Tol
Journal: British Journal of Sports Medicine (2011)

Achilles tendon disorders, like Achilles tendinopathy, are very common among athletes. In the general population, however, knowledge about the incidence of Achilles tendinopathy is lacking. Design Cross-sectional study.In a cohort of 57.725 persons registered in primary care, the number of patients visiting the general practitioner (GP) with diagnosis of mid-portion Achilles tendon problems was counted using computerised registration networks of GPs in 2009. Subsequently, the authors assessed associations of these rates with demographic characteristics.The incidence rate of Achilles tendinopathy is 1.85 per 1,000 Dutch GP registered patients. In the adult population (21-60 years), the incidence rate is 2.35 per 1,000. In 35% of the cases, a relationship with sports activity was recorded.This is the first report on incidence rates of mid-portion Achilles tendinopathy in general practice. With an incidence of 1.85 per 1,000 registered persons, Achilles tendinopathy is frequently seen by GPs. The actual incidence might even be higher due to study limitations. More research on the frequency of this injury is required.