tbuckley/cabot-search huggingface dataset:
Peptidomimetics derived from natural products
Authors: Robert A. Wiley, Daniel H. Rich
Journal: Medicinal Research Reviews (1993)

Although much has been written in recent years about rational drug design, no drug has been designed de novo, that is, without using a natural substrate or inhibitor or screening lead as a starting point. Instead, as we have seen, medicinal chemists continue to depend upon serendipitous discovery of novel biological activities and novel chemical entities for structures on which to begin work. What rational drug design really means at present is rational drug discovery and rational optimization. These result from the application of modern structural and mechanistic biochemistry, and good synthetic chemistry, to obtain structures with the desired spectrum of biological activities. Traditionally, lead compounds were discovered in plant and animal extracts, and more recently in microorganisms and chemical libraries. These traditional approaches continue, but are augmented by advances in molecular biology, which now provide pure proteins in quantity for screening and structure determination, as well as for characterization by modern biophysical methods. Remarkably, x-ray and NMR methods can now provide the most important information needed to design new drugs, that is, the conformations of ligands bound to target proteins. Approaches to identifying possible ligands based only on the knowledge of the enzyme active site are being developed. Some of these, such as CAVEAT, have been recently reviewed. In spite of these impressive gains, de novo design of new drugs will not be achieved until we learn how to logically build specific inhibitors of a target enzyme knowing only the protein sequence of the enzyme or the amino acid sequence of the messenger substances. We have a long way to go, because by this very rigorous definition, even the successful design of a new nonpeptide drug beginning with enzyme-ligand NMR or x-ray structure constitutes rational optimization. However, as this article has illustrated, we have made great progress. Some of the current and futuristic approaches to drug design are shown in Fig. 8. Development of useful enzyme inhibitors, designed by knowing the enzyme catalytic mechanism or discovered by screening for natural inhibitors, is a very successful rational method. Discovery of receptor antagonists by screening protocols is also productive.(ABSTRACT TRUNCATED AT 400 WORDS)
Parenteral nutrition is given inappropriately in almost a third of adult cases, report says
Authors: A. Gulland
Journal: BMJ (2010)

A national inquiry into the way hospitals administer parenteral nutrition to adults and premature babies has found major deficiencies, with good practice present in less than a quarter of cases.

The study, from the National Confidential Enquiry into Patient Outcome and Death, reviewed the hospital care of 877 adults and 264 neonates given such nutrition. It found good practice in just 19% of adult cases and 23% of neonatal cases. The inquiry also found poor care and documentation when central venous catheters were inserted.

James Stewart, consultant gastroenterologist at Leicester Royal Infirmary and lead author of the report, said that although …
miR-221 Silencing Blocks Hepatocellular Carcinoma and Promotes Survival
Authors: Jong-Kook Park, Takayuki Kogure, Gerard J. Nuovo, Jinmai Jiang, Lei He, Ji Hye Kim, Mitch A. Phelps, Tracey L. Papenfuss, Carlo M. Croce, Tushar Patel, Thomas D. Schmittgen
Journal: Cancer Research (2011)

Patients with advanced hepatocellular carcinoma (HCC) face a dismal prognosis because of a lack of any effective therapies. To address this situation, we conducted a preclinical investigation of the therapeutic efficacy of oligonucleotides directed against the oncogenic microRNA miR-221, which has been implicated in HCC. Of 9 chemistries evaluated, we determined that a 2'-O-methyl phosphorothioate-modified anti-miR-221 oligonucleotide was most effective at reducing proliferation in vitro. A cholesterol-modified isoform of anti-miR-221 (chol-anti-miR-221) exhibited improved pharmacokinetics and liver tissue distribution compared with unmodified oligonucleotide. Chol-anti-miR-221 significantly reduced miR-221 levels in liver within a week of intravenous administration and in situ hybridization studies confirmed accumulation of the oligonucleotide in tumor cells in vivo. Within the same period, chol-anti-miR-221 reduced tumor cell proliferation and increased markers of apoptosis and cell-cycle arrest, elevating the tumor doubling time and increasing mouse survival. Taken together, our findings offer a preclinical proof of efficacy for chol-anti-miR-221 in a valid orthotopic mouse model of HCC, suggesting that this targeted agent could benefit treatment for patients with advanced HCC.
TREATMENT OF GONORRHOEA IN WOMEN BY SWABBING WITH MERCUROCHROME AND FLAVINE
Authors: R. S. S. Statham
Journal: BMJ (1928)

sort of plastic operation seemed out of the question1, so nlephlectomy was performed.The lumen at the uretero-pelvic junictioni was found to be very small.Recovery was rapid.The history in this case was typical of that of initer- mittent hydronephr osis.There was presuimably a coni- geniital stricture at the uretero-pelvic junictioni.Wlhen secretion of urine was free the pelvis woul(d becomiie dis- tended, with consequent valve formation at the orifice and increased obstruction to the passage of urine.Had the condition occurred oni the right side a diagnosis of appendicitis would probably have been made soonier or later.The previous negative cystoscopic findings were presumably due to the fact that the examinationi was made when the attack was over.A pyelogram miglht have settled the diagnlosis.CASE IT.A married woman, aged 53, was seen in consultation on account of haematuria.She stated that she had passed blood on one occasion seven years previously.When recovering from inifluenza in February, 1927, she had profuse haematuria lasting several days, accompanied by pain in the right loin.She was a very thin woman, and the right kidney was palpable anid tender.Slhe was admitted to hospital.Cystoscopy on February 4th, 1927, after injectioni of indigo-carmine, showed active excretion of dye by the left kidney.The right ureter excreted a little turbid urine, but no dye.The patient was then anaesthetized, and the right kidney exposed by a lumbar incision.The kidney was found but little enlarged, the cortex was thin and its surface lobulated, the renal pelvis was dilated.The kidney was removed and found to be full of blood clot.No cause for the bleeding or for the dilatation of the pelvis could be found.The patient made a rapid recovery.
Coccidioidal Meningitis and Intrathecal Corticosteroids
Authors: MAURICE L. SIEVERS
Journal: Annals of Internal Medicine (1981)

Letters and Corrections1 August 1981Coccidioidal Meningitis and Intrathecal CorticosteroidsMAURICE L. SIEVERS, M.D., JEFFREY R. FISHER, M.D.MAURICE L. SIEVERS, M.D.Search for more papers by this author, JEFFREY R. FISHER, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-95-2-242_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: Intrathecal amphotericin B therapy is required to treat coccidioidal meningits because intravenous amphotericin administration does not produce therapeutic concentrations in the cerebrospinal fluid. Most authorities recommend that the intrathecal treatment be continued until coccidioidal complement-fixing antibodies are no longer detectable in the cerebrospinal fluid (1, 2). Prolonged amphotericin therapy, however, has resulted in both transient and permanent drug-related neurologic deficits (3). Concurrent use of intrathecal corticosteroids ameliorates amphotericin-induced inflammation, but guideline for such combined treatment are vague. Our patient received amphotericin B intrathecally for 6 years because complement-fixing antibodies in the cerbrospinal fluid persisted in low titer....References1. KELLEYSIEVERSTHOMPSONECHOLS PMRC. Coccidioidal meningitis: results of treatment in 22 patients. In: AJELLO L, ed. Coccidioidomycosis. Current Clinical and Diagnostic Status. Miami, Florida: Symposia Specialists; 1977:239-51. Google Scholar2. DRUTZCATANZARO DA. Coccidioidomycosis. Am Rev Resp Dis. 1978;117:559-85, 727-71. MedlineGoogle Scholar3. CARNEVALEGALGIANISTEVENSHERRICKLANGSTON NJDMJ. Amphotericin B-induced myelopathy. Arch Intern Med. 1980;140:1189-92. CrossrefMedlineGoogle Scholar4. CRADDOCK C. Corticosteroid-induced lymphopenia, immunosuppression, and body defense. Ann Intern Med. 1978;88:564-6. LinkGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: MAURICE L. SIEVERS, M.D.; JEFFREY R. FISHER, M.D.Affiliations: Phoenix Indian Medical Center Phoenix, AZ 85016 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byThe Impact of Corticosteroids on the Outcome of Fungal Disease: a Systematic Review and Meta-analysisHost–Pathogen Interactions in Coccidioidomycosis: Prognostic Clues and Opportunities for Novel TherapiesCoccidioidal Meningitis: A Review on Diagnosis, Treatment, and Management of ComplicationsIntrathecal Amphotericin B: A 60-Year Experience in Treating Coccidioidal MeningitisInfectious diseases and immunization 1 August 1981Volume 95, Issue 2Page: 242-243KeywordsAmphotericinAntibodiesAttentionCerebrospinal fluidCorticosteroid therapyInflammationMeningitisNeurological drug therapyTreatment guidelines ePublished: 1 December 2008 Issue Published: 1 August 1981 PDF downloadLoading ...
Pathology Underrates Colon Cancer Extranodal and Nodal Metastases; <i>Ex vivo</i> Radioimmunodetection Helps Staging
Authors: A. Sézeur, F.P. Châtelet, Ch. Cywiner, Cl. de Labriolle-Vaylet, C. Chastang, Cl. Billotey, M. Malafosse, D. Gallot, P. Betton, F. Montravers, S. Carvajal-Gonzalez, S. Askienazy, J.N. Talbot, J.D. Rain, G. Milhaud, G. Saumon, J. Barbet, A. Gruaz-Guyon
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Colorectal carcinoma is frequently accompanied by small lymph nodes metastases that often escape pathologic examination. We evaluated whether ex vivo radioimmunodetection with the Affinity Enhancement System (AES) could improve detection of mesocolonic metastases. Experimental Design: A bivalent 111In-labeled hapten was injected (16 patients) 4 days after a bispecific antibody (anticarcinoembryonic antigen, antihapten). Surgery was done 1 to 3 days later, and radioactive uptake in the mesocolon was recorded. Extensive pathologic examination of the mesocolon (reference method) was done after fat dissolution. This method visualizes all lymph nodes but is not in routine use. Results: The reference method disclosed 705 nodes. There was no significant difference between the number of node metastases detected by AES or by the reference method (16 versus 17). Better detection would have been obtained by AES than by routine pathology (P &amp;lt; 0.01). In addition 12 extranodal metastases were found in this study of which eight were detected by AES. The prognostic importance of such extranodal metastases has been underlined in the literature. Routine pathology combined with AES would have disclosed all node metastases and 86% of total metastases versus 35% by routine pathology alone. Conclusions: Ex vivo radioimmunodetection could improve nodal and extranodal metastases detection in patients with colorectal cancer. Its value for improving pathologic analysis, together with the effect of these small metastases on prognosis, should be further evaluated. The benefit of adjuvant chemotherapy for patients upstaged with radioimmunodection should also be assessed because adjuvant chemotherapy improves the 5-year survival of stage III patients.
A Mass Vaccination Program in Taiwan Against Hepatitis B Virus Infection in Infants of Hepatitis B Surface Antigen—Carrier Mothers
Authors: Ding-Shinn Chen
Journal: JAMA (1987)

To combat hepatitis B virus (HBV) infection in Taiwan, a mass immunoprophylaxis program was launched on July 1,1984, aiming first at prevention of chronic HBV carriage from perinatal mother-to-infant infection. In the first 15-month period, 352 721 (78%) of 450 585 pregnant women were screened for hepatitis B surface antigen (HBsAg); HBsAg was present in 62 359 (18%), with 50% of them categorized as highly infectious. Infants born to HBsAg-positive women were given 5 μg of a plasma-derived hepatitis B vaccine at ages 1,5, and 9 weeks, with a booster at age 12 months. Infants of highly infectious carrier mothers received an additional 0.5 mL of hepatitis B immune globulin within 24 hours after birth. The coverage rate of the hepatitis B immune globulin was 77% in 27375 infants born to highly infectious mothers, and that of the first, second, third, and the fourth doses of vaccine was 88%, 86%, 84%, and 71%, respectively, in infants of 55620 carrier mothers. The reported untoward reactions to immunization were negligible. We conclude that a mass hepatitis B vaccination program is feasible in hyperendemic areas such as Taiwan; this should be a significant step toward the effective control of HBV infection in these areas. (<i>JAMA</i>1987;257:2597-2603)
Veterinary and industrial high pressure injection injuries
Authors: F. Burke, O. Brady
Journal: BMJ (1996)

<h3>ABSTRACT</h3> <h3>Introduction</h3> Optimal outcomes in total hip arthroplasty are dependent on appropriate placement of femoral and acetabular components, with technological advances providing a platform for guiding component placement to reduce the risk of malpositioned components during surgery. This study will validate the intraoperative data captured using a handheld imageless THA navigation system against postoperative measurements of acetabular inclination, anteversion, leg length, and femoral offset on CT radiographs. <h3>Methods and analysis</h3> This is a prospective observational cohort study conducted within a single-centre, single-surgeon private practice. Data will be collected for 35 consecutive patients (&gt;18years) undergoing elective THA surgery, from the research registry established at the surgeon’s practice. The primary outcome is the agreement between intraoperative component positioning data captured by the navigation system compared to postoperative measurements using computed tomography (CT). A total of ten CT scans will be re-assessed for inter- and intra-observer reliability. The influence of patient and surgical factors on the accuracy of component position will also be examined with multivariable linear regression. <h3>Ethics and dissemination</h3> Ethics approval for this study was provided through a certified ethics committee (Bellberry HREC approval number 2017-07-499). The results of this study will be disseminated through peer-reviewed journals and conference presentations. <h3>Strengths and limitations of this study</h3> This study will assess the accuracy of an imageless THA navigation system for measurement of component positioning against postoperative computed tomography analysis as gold standard. A sample size of n=35 participants will ensure adequate power to detect differences between intraoperative navigation results and postoperative CT measurements. A sample size of n=10 will provide adequate confidence to establish intra and inter-observer reliability of postoperative measurements of component positioning via CT analysis. This study will enable a mechanism to detect potential discrepancies between the component positioning measurement methods intrinsic to the Naviswiss™ device and postoperative CT analysis method and identify any corrective factors required for direct comparison of the two methods.
Culpable control or moral concepts?
Authors: Mark Alicke, David Rose
Journal: Behavioral and Brain Sciences (2010)

Abstract Knobe argues in his target article that asymmetries in intentionality judgments can be explained by the view that concepts such as intentionality are suffused with moral considerations. We believe that the “culpable control” model of blame can account both for Knobe's side effect findings and for findings that do not involve side effects.
Foxo1 mediates insulin action on apoC-III and triglyceride metabolism
Authors: Jennifer Altomonte, Lin Cong, Sonal Harbaran, Anja Richter, Jing Xu, Marcia Meseck, Hengjiang Henry Dong
Journal: Journal of Clinical Investigation (2004)

The apolipoprotein apoC-III plays an important role in plasma triglyceride metabolism. It is predominantly produced in liver, and its hepatic expression is inhibited by insulin. To elucidate the inhibitory mechanism of insulin in apoC-III expression, we delivered forkhead box O1 (Foxo1) cDNA to hepatocytes by adenovirus-mediated gene transfer. Foxo1 stimulated hepatic apoC-III expression and correlated with the ability of Foxo1 to bind to its consensus site in the apoC-III promoter. Deletion or mutation of the Foxo1 binding site abolished insulin response and Foxo1-mediated stimulation. Likewise, Foxo1 also mediated insulin action on intestinal apoC-III expression in enterocytes. Furthermore, elevated Foxo1 production in liver augmented hepatic apoC-III expression, resulting in increased plasma triglyceride levels and impaired fat tolerance in mice. Transgenic mice expressing a constitutively active Foxo1 allele exhibited hypertriglyceridemia. Moreover, we show that hepatic Foxo1 expression becomes deregulated as a result of insulin deficiency or insulin resistance, culminating in significantly elevated Foxo1 production, along with its skewed nuclear distribution, in livers of diabetic NOD or db/db mice. While loss of insulin response is associated with unrestrained apoC-III production and impaired triglyceride metabolism, these data suggest that Foxo1 provides a molecular link between insulin deficiency or resistance and aberrant apoC-III production in the pathogenesis of diabetic hypertriglyceridemia.
Vascular-Directed Tissue Factor Pathway Inhibitor Overexpression Regulates Plasma Cholesterol and Reduces Atherosclerotic Plaque Development
Authors: Shuchong Pan, Thomas A. White, Tyra A. Witt, Anca Chiriac, Cheri S. Mueske, Robert D. Simari
Journal: Circulation Research (2009)

Tissue factor pathway inhibitor (TFPI) is a potent regulator of the tissue factor pathway and is found in plasma in association with lipoproteins.To determine the role of TFPI in the development of atherosclerosis, we bred mice which overexpress TFPI into the apolipoprotein E-deficient (apoE(-/-)) background.On a high-fat diet, smooth muscle 22alpha (SM22alpha)-TFPI/apoE(-/-) mice were shown to have less aortic plaque burden compared to apoE(-/-) mice. Unexpectedly, SM22alpha-TFPI/apoE(-/-) had lower plasma cholesterol levels compared to apoE(-/-) mice. Furthermore, SM22alpha-TFPI mice fed a high-fat diet had lower cholesterol levels than did wild-type mice. Because TFPI is associated with lipoproteins and its carboxyl terminus (TFPIct) has been shown to be a ligand for the very-low-density lipoprotein (VLDL) receptor, we hypothesized that TFPI overexpression may regulate lipoprotein distribution. We quantified VLDL binding and uptake in vitro in mouse aortic smooth muscle cells from SM22alpha-TFPI and wild-type mice. Mouse aortic smooth muscle cells from SM22alpha-TFPI mice demonstrated higher VLDL binding and internalization compared to those from wild-type mice. Because SM22alpha-TFPI mice have increased circulating levels of TFPI antigen, we examined whether TFPIct may act to alter lipoprotein distribution. In vitro, TFPIct increased VLDL binding, uptake, and degradation in murine embryonic fibroblasts. Furthermore, this effect was blocked by heparinase treatment. In vivo, systemic administration of TFPIct reduced plasma cholesterol levels in apoE(-/-) mice.These studies suggest that overexpression of TFPI lowers plasma cholesterol through the interaction of its carboxyl terminus with lipoproteins and heparan sulfate proteoglycans.
A piece of my mind. Healing arts
Authors: L. M. Lanzarone
Journal: JAMA (1991)

The ritual that gets me through the day starts with a jolt from REM sleep. First sound of the day: static from the clock-radio. First thought: another day of this dehumanizing internship. First sight: a whitewashed, empty face in the mirror. This is me. My mind has abandoned its search for meaning in my work on the medical wards. The Fraternity that is Medicine, like all the others, requires that members must survive rituals of pain before they can enter the fold. But the human organism knows that repeated trauma causes the skin to lose sensation; the only protection is respite, which is not my privilege this morning. I cannot recall exactly when I gave up the search and wonder if numbness has begun to shape my thoughts. Still, internship is only a year, almost half over; residency will be an improvement. By then I might enjoy leading everyone on
Oklahoma doctor faces prison after billing for abortions when patients were not pregnant
Authors: O. Dyer
Journal: BMJ (2014)

An Oklahoma abortion doctor falsely diagnosed pregnancy in women so that he could bill them for abortion pills, charges filed by the state’s attorney general have stated.

Nareshkumar Patel, 62, faces as long as three years in prison if convicted on three counts of obtaining money under a false pretense for false diagnoses he gave to three undercover female agents—one from the state medical licensure board, one a police detective, and one from the attorney general’s office. He gave them pregnancy tests and ultrasounds, told them that they were pregnant, which they were not, …
Effects of ipratropium bromide on hypertonic saline provocations in human nasal mucosa
Authors: Uyenphuong H Le, James N Baraniuk, Mustaq Ali, Kristina Naranch, Dan Clauw, Atsushi Yuta, Sheen-Yie Fang, Yong-Jin Park, Ana Velarde, Abby Pheiffer
Journal: Journal of Allergy and Clinical Immunology (2002)
The ciliary transportability of sputum is slow on the mucus-depleted bovine trachea.
Authors: P J Wills, M J Garcia Suarez, A Rutman, R Wilson, P J Cole
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Mucus retention in the lungs is a feature of several chest diseases. It is unclear to what extent suboptimal mucus transportability is responsible for the poor clearance of lung secretions. We described a new model, the mucus-depleted bovine trachea, for measurement of the ciliary transportability of respiratory mucus. Mucus depletion was demonstrated microscopically and functionally, and it was accomplished by simple physical means without impairing ciliary action. Control mucus from the tracheas of humans and animals was transported rapidly on this system. However, sputum from 54 patients with bronchiectasis was transported slowly, at a mean of 15% of the rate of control mucus. There was no correlation between sputum transportability and either purulence or the presence of Pseudomonas aeruginosa. This work suggests that there is a serious defect in the ciliary transportability of sputum that is unrelated to the presence of infection. The model should allow in vitro assessment of agents designed to aid mucociliary clearance.