tbuckley/cabot-search huggingface dataset:
Clinical implications of antibiotic pharmacokinetic principles in the critically ill
Authors: Andrew A. Udy, Jason A. Roberts, Jeffrey Lipman
Journal: Intensive Care Medicine (2013)

Successful antibiotic therapy in the critically ill requires sufficient drug concentrations at the site of infection that kill or suppress bacterial growth. The relationship between antibiotic exposure and achieving the above effects is referred to as pharmacokinetics/pharmacodynamics (PK/PD). The associated indices therefore provide logical targets for optimal antibiotic therapy. While dosing regimens to achieve such targets have largely been established from studies in animals and non-critically ill patients, they are often poorly validated in the ICU. Endothelial dysfunction, capillary leak, altered major organ blood flow, deranged plasma protein concentrations, extremes of body habitus, the application of extracorporeal support modalities, and a higher prevalence of intermediate susceptibility, independently, and in combination, significantly confound successful antibiotic treatment in this setting. As such, the prescription of standard doses are likely to result in sub-therapeutic concentrations, which in turn may promote treatment failure or the selection of resistant pathogens. This review article considers these issues in detail, summarizing the key changes in antibiotic PK/PD in the critically ill, and suggesting alternative dosing strategies that may improve antibiotic therapy in these challenging patients.
Authors' reply to Sholapurkar
Authors: A. S. Oberg, B. T. Bateman
Journal: BMJ (2014)

We appreciate Sholapurkar’s interest in our study and welcome the opportunity to clarify our methods and the implications of our findings.1 2

Because we studied the extent of clustering of postpartum haemorrhage (PPH) in differentially related births (within family cluster correlation), there is no traditional “control group.” Irrespective of outcome, all births (affected and unaffected) that belong to a certain type …
Abstract 1345: Bioactivation of luteolin as a prodrug by tyrosinase inhibits human glutathione S-transferase and induces toxicity in SK-MEL-28 melanoma cells
Authors: Rajiv Balyan, Shashi Kudugunti, Nikhil Vad, Majid Moridani
Journal: Cancer Research (2011)

Abstract Glutathione S-transferase (GST) play significant role in the metabolism and detoxification of drugs used in treatment of melanoma, resulting in a decrease in their efficacy against melanoma. In the present study, we investigated: i) the selective inhibition of GST by luteolin in the presence of tyrosinase, an abundant enzyme found in melanoma, and ii) the induction of apoptosis, change in mitochondrial permeability, cell viability, cell migration and GSH depletion by luteolin in human melanoma SK-MEL-28 cell culture. The inhibition of GST was investigated using CDNB method. DTNB method was used to measure GSH depletion. MTT assay, Annexin V apoptosis assay and TMRM fluorescence were used in the investigation of biochemical mechanism of luteolin toxicity in melanoma cells. Luteolin (40 µM) induced toxicity and death in 50% of cells after 48 h incubation. Cell treatment with luteolin (40 µM) resulted in apoptotic cell death in 70% of cells and caused 45% decrease in TMRM fluorescence indicating change in mitochondrial membrane permeability. At 1 h incubation, luteolin was bioactivated by tyrosinase to luteoline-quinone for 71% as measured by GSH depletion. The luteolin is effective in preventing metastasis of cancerous cells as evident by cell migration assay. At 48 h incubation, luteolin as low as 5 µM effectively prevented the cell migration. In the presence of tyrosinase, luteolin (10 µM) showed about 87% GST inhibition; whereas in the absence of tyrosinase, luteolin led to negligible GST inhibition. Both luteolin-SG conjugate and luteolin-quinone (10 µM) inhibited ≥90% of GST activity via reversible and irreversible competitive mechanisms with Ki of 0.9 and 6.4 µM with respect to GSH, respectively. The luteolin-SG conjugate inhibited GST activity reversibly and non-competitively with Ki of 1.8, whereas luteolin-quinone showed irreversible competitive inhibition of GST activity with Ki of 1.0 µM with respect to CDNB. While luteolin is not a substrate for GST, Luteolin (25 µM) non-competitively inhibited GST with Ki of 39 µM with respect to GSH and competitively with Ki of 61 µM with respect to CDNB. Luteolin, at the concentration range of 5-80 µM, exhibited 78-99% GST inhibition in human SK-MEL-28 cell homogenate. In summary, our results suggest that luteolin was bioactivated by tyrosinase to form a quinone and luteolin-glutathione conjugate, which played major role in the inhibition of GST. For the first time, we demonstrate that luteolin acts as a selective inhibitor of GST in the presence of tyrosinase. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1345. doi:10.1158/1538-7445.AM2011-1345
Antipsychotic Drug Treatment in the Prodromal Phase of Schizophrenia
Authors: Tyrone D. Cannon, Matti O. Huttunen, Minna Dahlström, Ilkka Larmo, Pirkko Räsänen, Alo Juriloo
Journal: American Journal of Psychiatry (2002)

The safety and tolerability of short-term treatment with a low dose of risperidone was evaluated in adolescents with prodromal symptoms and a family history of schizophrenia.Four prodromal high-risk adolescents and six first-episode patients with schizophrenia were treated with average doses of 1.0 and 1.8 mg/day of risperidone, respectively, in an 8- to 12-week open-label trial.No significant treatment-related adverse events were noted. Severity of thought and behavior disturbance ratings declined by about 30%; performance on a test of verbal learning improved by about 100% during treatment in both prodromal and first-episode patients, changes that achieved statistical significance despite the small group sizes.These findings are preliminary and should not be used to guide health care decisions at this time. Randomized controlled trials are needed to determine whether antipsychotic drug treatment of prodromal patients can delay or prevent onset or attenuate the clinical course of schizophrenia.
Dietary enrichment with the polyunsaturated fatty acid eicosapentaenoic acid prevents proteinuria and prolongs survival in NZB x NZW F1 mice.
Authors: J D Prickett, D R Robinson, A D Steinberg
Journal: Journal of Clinical Investigation (1981)

Prostaglandins and related compounds are active mediators of inflammation, but data concerning their role in the pathogenesis of the glomerulonephritis of New Zealand Black x New Zealand White (NZB x NZW) F1 mice are conflicting. Dietary eicosapentaenoic acid (EPA, C20:5), a fatty acid analogue of arachidonic acid (C20:4), has been shown to impair platelet aggregation in humans, apparently through inhibition of the synthesis of prostaglandins and thromboxanes from arachidonic acid. We report here the effects of a diet high in EPA on the development of renal disease and survival in female NZB x NZW F1 mice. Animals from 4--5 wk of age were fed diets containing 25% lipid, supplied either as beef tallow or menhaden oil, with fatty acid analysis of less than 0.05 and 14.4% EPA, respectively. In the first experiment, by 13.5 mo of age, mice on the beef tallow diet had all (9/9) developed proteinuria and the majority (6/9) had died, with renal histologic examination revealing severe glomerulonephritis. In contrast, none of 10 menhaden oil-fed animals had developed proteinuria, and all were alive at this time (P less than 0.005 for both proteinuria and survival). In a second experiment using 50 mice in each dietary group, 56% of the beef tallow group vs. none of the menhaden oil group had developed proteinuria at 9 mo of age (P less than 0.005). Native DNA binding at 6 mo of age was 23.9 +/- 14.7 vs. 10.1 +/- 9.7% in the beef and menhaden oil groups, respectively (P less than 0.01). Weights were similar in all groups, and there was no evidence of essential fatty acid deficiency in any group. These results demonstrate that a diet high in EPA protects NZB x NZW F1 mice from the development of glomerulonephritis.
Influence of body water distribution on skin thickness: measurements using high-frequency ultrasound
Authors: C. Eisenbeiss, J. Welzel, W. Eichler, K. Klotz
Journal: British Journal of Dermatology (2001)

Although it is known that the skin acts as a water reservoir and participates in the fluid content of the whole body, no method has been established to quantify the fluid shifts in superficial tissue.The aim of this study was to investigate changes in dermal and subcutis thickness and echodensity at the forehead and lower leg by high-frequency (20 MHz) ultrasound under various physiological conditions influencing water balance.These parameters were measured in the skin of 20 healthy male volunteers at baseline and successively at 30 min after lying down, in a head-down position, after physical activity and after infusion of 10 mL kg-1 body weight of Ringer's solution.Dermal thickness at the forehead showed a significant increase from baseline to a horizontal position and a further increase in the head-down position. Physical activity did not lead to further changes, whereas after fluid infusion the dermal thickness also increased markedly. The echodensity showed inverse changes, with decreasing values. The thickness of the subcutis increased slightly from baseline to a lying position and decreased in the head-down position and after fluid infusion. At the lower leg, skin thickness decreased slightly in the head-down position with elevated legs, and increased after fluid infusion.Our results show that slight changes in the water distribution of the body influence the thickness and the echodensity of the dermis. Changes are more pronounced at the forehead than on the lower legs. Further, the fluid storage takes place mainly in the dermis and not in the subcutis. High-frequency ultrasound is able to quantify these effects and is a sensitive method for measuring fluid intake and balance during anaesthesia and therapy.
Evidence for Functional Sympathetic Reinnervation of Left Ventricle and Coronary Arteries After Orthotopic Cardiac Transplantation in Humans
Authors: M. Nicholas Burke, Andrew L. McGinn, David C. Homans, Betsy V. Christensen, Spencer H. Kubo, Robert F. Wilson
Journal: Circulation (1995)

Structural sympathetic reinnervation of the transplanted human heart is believed to occur > 1 year after cardiac transplantation. The functional effects of reinnervating neurons, however, are undefined.To test directly for functional sympathetic reinnervation, we measured left ventricular or coronary hemodynamics in 11 patients < or = 4 months after transplantation, in 45 patients > or = 1 year after transplantation, and in 13 untransplanted, normally innervated patients. Sympathetic neurons were stimulated with left coronary injection of tyramine (10 micrograms/kg), which causes norepinephrine release from intact sympathetic nerve terminals. Reinnervation was defined as a measure of cardiac norepinephrine release after intracoronary tyramine injection. Left ventricular pressure was measured before and at 1-minute intervals after tyramine with a micromanometer-tipped catheter (Millar Instruments). Coronary blood flow velocity (CBFV) was measured with a 3F Doppler catheter (Numed), and coronary artery cross-sectional area was calculated using quantitative coronary angiography. In both early patients and patients studied > or = 4 months after transplantation without reinnervation (late denervated), there was no change in left ventricular function in response to tyramine (delta dP/dt = 31 +/- 61 and 49 +/- 54 mm Hg/s, respectively; P = NS). In transplant recipients with reinnervation (late reinnervated), left ventricular dP/dt rose significantly (delta dP/dt = 210 +/- 97 mm Hg/s; P < .05) but less than in healthy patients (delta dP/dt = 577 +/- 66 mm Hg/s; P < .05). In both early and late denervated patients, there was no change in CBFV in response to tyramine (CBFV = 1.02 +/- 0.1 and 1.0 +/- 0.1 x basal, respectively; P = NS). In late reinnervated patients, CBFV fell significantly (CBFV = 0.94 +/- 0.1 x basal; P < .05). In healthy patients, CBFV fell even more (CBFV = 0.88 +/- 0.1 x basal; P < .05).Stimulation of reinnervating sympathetic neurons with tyramine in transplant recipients causes a significant but subnormal increase in dP/dt and a transient decrease in CBFV, suggesting that reinnervating sympathetic neurons can produce physiologically meaningful changes in left ventricular function and coronary artery tone.
Paternity by a seemingly infertile vasectomised man.
Authors: J A Thomson, P J Lincoln, P Mortimer
Journal: BMJ (1993)

A case of failed vasectomy in a patient whose semen repeatedly showed no or only scant, nonmobile spermatozoa, was confirmed by paternity testing. The patient was vasectomized in December 1987. His semen tested negative for sperm 12 and 18 weeks afterwards. 28 months after surgery his wife's pregnancy was confirmed. His semen again tested negative for spermatozoa 2.5, 3. 3.5, and 5 years after surgery, and showed only a few nonmobile sperm from the spun deposit. Paternity tests included DNA profiling with 6 single locus DNA probes on the parents and child, as well as 19 conventional protein polymorphisms. These tests defined the probability of paternity as 99.999%. The patient's brother was excluded by 2 of the 5 DNA probes. Thus this is a highly improbable case of paternity by a man deemed infertile by normally accepted criteria.
Overview of exercise induced lower leg pain
Authors: Mike Allen
Journal: British Journal of Sports Medicine (2011)

Lecture 8 This paper discusses the common causes of exercise induced lower leg pain, including chronic compartment syndrome (CCS), medial tibial stress syndrome (MTSS) and chronic calf tears (CCT). The pathogenesis, clinical presentation, diagnosis and treatment of the more popular conditions are discussed. CCSs are due to an increased pressure in one or more of the four compartments of the lower leg, brought on by exercise and relieved by rest. Clinical examination of the limb is normal. Diagnosis is made by measuring the compartment pressures during exercise. Treatment is by a subcutaneous fasciotomy of the affected compartments. MTSS is thought to be due to abnormal biomechanics leading to a periostalgia of the inner tibial border both during and after exercise, with symptoms lasting up to 24–48 h postexercise. Patients always locate their pain to the inner tibial border. Examination of the limb shows the lower and often the middle inner tibial border to be tender. Diagnosis is largely clinical but may be helped by MRI scans. Treatment is initially by physiotherapy in the form of flexibility and strengthening exercises and the fitting of orthotics. If this fails then major surgery is the only other alternative. CCT occur as a result of scar tissue in the muscle or adhesions developing between the fascia and the muscle causing pain in the posterior aspect of the calf. Often there is a past history of an acute calf tear. The pain presents during a run and often the athlete will describe pain in the posterior aspect of the calf which will increase with the intensity of exercise and if they try to run through the pain they experience a tearing sensation in the calf muscle sufficient to stop them exercising and cause them to limp up to a period of 3 days. Clinical examination often reveals tenderness over the medial head of gastrocnemius. An MRI scan may or may not aide in the diagnosis. Treatment initially is in the form of physiotherapy and if this fails then operative surgery which carries an 80% success rate. Finally other rarer causes of exercise induced leg pain are discussed, namely muscle hernia, popliteal artery entrapment syndrome, nerve entrapments and metabolic disorders.
Zinc Deficiency and Intestinal Bypass Procedures
Authors: JOHN A. GAROFALO
Journal: Annals of Internal Medicine (1979)

Letters and Corrections1 June 1979Zinc Deficiency and Intestinal Bypass ProceduresJOHN A. GAROFALO, M.D., ELLIOT STRONG, M.D., ROBERT A. GOOD, PH.D., M.D.JOHN A. GAROFALO, M.D., ELLIOT STRONG, M.D., ROBERT A. GOOD, PH.D., M.D.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-90-6-990_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: In the October 1978 issue, Atkinson and associates (1) indicate that zinc deficiency may be a common finding after intestinal bypass procedures. Meyer (2) further suggests that zinc deficiency should be sought in those patients with markedly depressed appetites, especially when associated with dysgeusia. However, the reports by Hambridge and co-workers (3) on apparent zinc deficiency in children from middle- and upper-income families in the Denver area, as well as the review by Sandstead (4), strongly suggest that zinc deficiency may be commoner than previously suspected in otherwise healthy persons.We have observed that surgery in itself...References1. ATKINSONDAHMSBRAYJACOBSANDSTEAD RWGRH: Plasma zinc and copper in obesity and after intestinal bypass. Ann Intern Med 89:491-493, 1978 LinkGoogle Scholar2. MEYER G: Intestinal bypass and zinc (letter). Ann Intern Med 90:278, 1979 LinkGoogle Scholar3. HAMBIDGEHAMBIDGEJACOBSBAUM KCMJ: LOW levels of zinc in hair, anorexia, poor growth, and hypogeusia in children. Pediatr Res 6:868-874, 1972 CrossrefMedlineGoogle Scholar4. SANSTEAD H: Zinc nutrition in the United States. Am J Clin Nutr 26:1251-1260, 1973 CrossrefMedlineGoogle Scholar5. FERNANDESNAIRONOETANAKAFLOYDGOOD GMKTRR: Impairment of cell-mediated immunity functions by dietary zinc deficiency in mice. Proc Natl Acad Sci USA 76:457-461, 1979 CrossrefMedlineGoogle Scholar6. FRAKERHAASLUECKE PSR: Effect of zinc deficiency on the immune response of the young adult A/J mouse. J Nutr 107:1889-1895, 1977 CrossrefMedlineGoogle Scholar7. LUECKESIMONELFRAKER RCP: The effect of restricted dietary intake on the antibody mediated response of the zinc deficient A/J mouse. J Nutr 108:881-887, 1978 CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Memorial Sloan-Kettering Cancer Center New York, NY 10021 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByTuberculosis after laparoscopic Roux-en-Y gastric bypass for morbid obesityHair and plasma zinc levels following exclusion of biliopancreatic secretions from functioning gastrointestinal tract in humansJejunoileal Bypass for ObesityNutrition and immunitySerum zinc, serum copper, and the Cu/Zn ratio in patients with epidermoid cancers of the head and neck 1 June 1979Volume 90, Issue 6Page: 990-990KeywordsChild healthChildrenSurgeryZinc Issue Published: 1 June 1979 PDF DownloadLoading ...
ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation
Authors: Elizabeth S. Gold, Stephen A. Ramsey, Mark J. Sartain, Jyrki Selinummi, Irina Podolsky, David J. Rodriguez, Robert L. Moritz, Alan Aderem
Journal: The Journal of Experimental Medicine (2012)

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-loaded macrophages in the arterial wall. We demonstrate that macrophage lipid body formation can be induced by modified lipoproteins or by inflammatory Toll-like receptor agonists. We used an unbiased approach to study the overlap in these pathways to identify regulators that control foam cell formation and atherogenesis. An analysis method integrating epigenomic and transcriptomic datasets with a transcription factor (TF) binding site prediction algorithm suggested that the TF ATF3 may regulate macrophage foam cell formation. Indeed, we found that deletion of this TF results in increased lipid body accumulation, and that ATF3 directly regulates transcription of the gene encoding cholesterol 25-hydroxylase. We further showed that production of 25-hydroxycholesterol (25-HC) promotes macrophage foam cell formation. Finally, deletion of ATF3 in Apoe−/− mice led to in vivo increases in foam cell formation, aortic 25-HC levels, and disease progression. These results define a previously unknown role for ATF3 in controlling macrophage lipid metabolism and demonstrate that ATF3 is a key intersection point for lipid metabolic and inflammatory pathways in these cells.
Angiotensins and the failing heart. Enhanced positive inotropic response to angiotensin I in cardiomyopathic hamster heart in the presence of captopril.
Authors: H Hirakata, F M Fouad-Tarazi, F M Bumpus, M Khosla, B Healy, A Husain, H Urata, H Kumagai
Journal: Circulation Research (1990)

We examined the hypothesis that the positive inotropic effect of angiotensin I (Ang I) may be retained in the presence of angiotensin converting enzyme inhibitors so that it may have a direct beneficial effect on the heart. Accordingly, isolated perfused hearts (Langendorff preparation) of 300-day-old cardiomyopathic hamsters (a model of spontaneous cardiomyopathy) and age-matched normal hamsters (controls) were infused with Ang I in the presence of captopril; propranolol was added to the perfusing medium to block catecholamine-mediated effects of angiotensins on the heart. Left ventricular developed pressure and the rate of increase in left ventricular developed pressure increased significantly (p less than 0.001) in both the cardiomyopathic and the normal hamster heart despite concomitant reduction in myocardial flow rate favoring a direct inotropic effect of Ang I in both normal and myopathic hearts; these changes were significantly higher by almost threefold in the cardiomyopathic than in the normal hamsters (p less than 0.01) and were blocked by the angiotensin II (Ang II) antagonist [Sar1,Thr8]Ang II. Comparing dose-left ventricular contractility response curves for Ang I and Ang II, ED50 for responses was identical in both normal and myopathic hearts, whereas peak responses to Ang II were double those to Ang I in normal hearts but were almost identical in the myopathic hearts. Binding of [125I]Ang II in six cardiomyopathic and four normal hamster hearts was of high affinity, but there was no evidence for Ang I-saturable high-affinity binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)