tbuckley/cabot-search huggingface dataset:
Phage Display-directed Discovery of LEDGF/p75 Binding Cyclic Peptide Inhibitors of HIV Replication
Authors: Belete A Desimmie, Michael Humbert, Eveline Lescrinier, Jelle Hendrix, Sofie Vets, Rik Gijsbers, Ruth M Ruprecht, Ursula Dietrich, Zeger Debyser, Frauke Christ
Journal: Molecular Therapy (2012)

The interaction between the human immunodeficiency virus (HIV) integrase (IN) and its cellular cofactor lens epithelium-derived growth factor (LEDGF/p75) is crucial for HIV replication. While recently discovered LEDGINs inhibit HIV-1 replication by occupying the LEDGF/p75 pocket in IN, it remained to be demonstrated whether LEDGF/p75 by itself can be targeted. By phage display we identified cyclic peptides (CPs) as the first LEDGF/p75 ligands that inhibit the LEDGF/p75–IN interaction. The CPs inhibit HIV replication in different cell lines without overt toxicity. In accord with the role of LEDGF/p75 in HIV integration and its inhibition by LEDGINs, CP64, and CP65 block HIV replication primarily by inhibiting the integration step. The CPs retained activity against HIV strains resistant to raltegravir or LEDGINs. Saturation transfer difference (STD) NMR showed residues in CP64 that strongly interact with LEDGF/p75 but not with HIV IN. Mutational analysis identified tryptophan as an important residue responsible for the activity of the peptides. Serial passaging of virus in the presence of CPs did not yield resistant strains. Our work provides proof-of-concept for direct targeting of LEDGF/p75 as novel therapeutic strategy and the CPs thereby serve as scaffold for future development of new HIV therapeutics. The interaction between the human immunodeficiency virus (HIV) integrase (IN) and its cellular cofactor lens epithelium-derived growth factor (LEDGF/p75) is crucial for HIV replication. While recently discovered LEDGINs inhibit HIV-1 replication by occupying the LEDGF/p75 pocket in IN, it remained to be demonstrated whether LEDGF/p75 by itself can be targeted. By phage display we identified cyclic peptides (CPs) as the first LEDGF/p75 ligands that inhibit the LEDGF/p75–IN interaction. The CPs inhibit HIV replication in different cell lines without overt toxicity. In accord with the role of LEDGF/p75 in HIV integration and its inhibition by LEDGINs, CP64, and CP65 block HIV replication primarily by inhibiting the integration step. The CPs retained activity against HIV strains resistant to raltegravir or LEDGINs. Saturation transfer difference (STD) NMR showed residues in CP64 that strongly interact with LEDGF/p75 but not with HIV IN. Mutational analysis identified tryptophan as an important residue responsible for the activity of the peptides. Serial passaging of virus in the presence of CPs did not yield resistant strains. Our work provides proof-of-concept for direct targeting of LEDGF/p75 as novel therapeutic strategy and the CPs thereby serve as scaffold for future development of new HIV therapeutics.
ED-18 * PRIMARY INTRACRANIAL SOFT TISSUE SARCOMA IN CHILDREN AND YOUNG ADULTS: RETROSPECTIVE ANALYSIS - MD ANDERSON CANCER CENTER EXPERIENCE
Authors: O. M. Maher, S. Khatua, W. Zaky
Journal: Neuro-Oncology (2014)

INTRODUCTION: Primary intracranial sarcoma (ISTS) is rare with unknown origin and ill-defined incidence in pediatric population. There is paucity of literature reporting outcomes of ISTS for children and young adults. Multimodality approach is used in most of the studies to treat this tumor with no well-defined treatment consensus. PATIENTS AND METHODS: A retrospective analysis of pediatric patients with primary diagnosis of ISTS treated at MD Anderson Cancer Center was conducted using descriptive measures, to describe clinical findings, treatment and long-term outcomes of children and adolescents with ISTS. RESULTS: Eleven patients (median age 6 years, range 1-20 year) with primary diagnosis of ISTS treated at our center between 2000 and 2014. Six patients were male, primary diagnosis as follows: Undifferentiated sarcoma (n = 5), Primitive neuroectodermal tumor (n = 2), Hemangiopericytoma (n = 1), Chondrosarcoma (n = 1), Aggressive mesenchymal tumor (n = 1), Neurofibrosarcoma (n = 1). Two patients had extraneural spread to the bone and the spine. Nine patients underwent gross total resection at time of diagnosis. Six cycles of the 3 drug regimens (Etoposide/ifosfamide/ Carboplatin) was the most common chemotherapy given at primary diagnosis or recurrence. Local radiation therapy with/without temozolomide were given to nine patients either after primary surgery or following surgery and adjuvant chemotherapy. Second look surgery was pursued in two patients before starting radiation and microscopic disease was found at site of the primary tumor despite of no radiologic evidence of residual disease. Five patients had disease progression, of whom four died of their disease. CONCLUSION: ISTS is rare neoplasm with dismal outcome. Despite Multimodality therapy, ISTS remains a challenge to treat with high rate of recurrence or treatment failure. Primary surgery followed by systemic chemotherapy and second look surgery at time of local control along with radiation therapy are associated with best chance for complete cure.
GMC bans doctors from signing contracts containing "gagging" clauses on issues of public interest
Authors: C. Dyer
Journal: BMJ (2012)

Doctors will have to boycott “gagging” clauses in agreements with employers or contracting bodies that try to stop them raising concerns about patients’ safety or poor quality care, under new guidance from the General Medical Council.

Mirror guidance for doctors in management roles will put them under a corresponding duty not to propose or condone contracts or agreements containing such clauses.

Gagging clauses still appear, despite NHS guidance as far back as 1999 that all trusts should “prohibit confidentiality ‘gagging’ clauses in contracts of employment and compromise agreements which seek to prevent the …
MONEY LEFT OVER AT THE END OF THE MONTH AND OUTCOMES AFTER MYOCARDIAL INFARCTION
Authors: Aditya Mandawat, Saif S. Rathore, Sachin J. Shah, Emily M. Bucholz, Kimberly J. Reid, Oliver J. Wang, Joseph S. Ross, John A. Spertus, Harlan M. Krumholz
Journal: Journal of the American College of Cardiology (2010)
Dyspepsia in general practice.
Authors: M A Sampson, C Record
Journal: BMJ (1990)

It is true that the Priory Hospitals Group is the largest provider of private psychiatric care in Britain.The authors fail to make it clear, however, that this group is the "encouraging exception"2 that they refer to.Thus the exception becomes the rule.Following the example set by the Priory group there is reason to be optimistic that private psychiatric hospitals in the United Kingdom will take a different approach to their American counterparts.Responsibilities to research and training are taken seriously.A recently held Priory Fellows Day, devoted entirely to projects associated with this hospital and attended by 120 psychiatrists, provides further evidence.In arguing that private care is elitist the authors again overlook the fact that 71 NHS patients have been successfully cared for in the Priory Hospital over the past three years.These were very disturbed patients who would otherwise have been admitted to a locked ward.They were mostly patients of social class V from the deprived inner city area in which Professor Marks and Dr Thorni- croft work.Surely the future lies in close cooperation between the private, academic, and NHS sectors.To achieve this we need to be fair minded, not prejudiced.
GlaxoSmithKline takes legal action to block new controls on its smoking cessation drug
Authors: M. Sweet
Journal: BMJ (2003)

Leading researchers have attacked the pharmaceutical giant GlaxoSmithKline for trying to block proposed new controls on the smoking cessation treatment bupropion (Zyban) in Australia.

The plan, which requires that patients have a second GP consultation to get a full prescription, was developed in response to concerns about costly waste of the treatment.

But the company has taken legal action, arguing that the Pharmaceutical Benefits Advisory Committee does not have the authority to make changes once drugs have been listed for subsidy. The company also claims that the committee's procedures denied it natural justice.

Prominent researchers, including Professor Simon …
Duodenal Ischaemia Complicating Acute Pancreatitis
Authors: H. Sheikh
Journal: BMJ (1965)

CommunicationsB 1539 time varied from four to eight hours, with a maximum inci- dence of five to six hours (Fig. 3).Emptying is considerably slower after vagotomy and faster after gastrectomy.SUMMARY A technique is described in which the gastric emptying-time is measured by radiographic observation of enteric-coated granules of barium.These are taken with a meal and become dispersed in the food within the stomach.Serial radiographs are taken to assess the emptying-time, which is found to range from four to eight hours, with a maximum incidence of five to six hours.
CUTANEOUS PORPHYRIA IN THE ADULT.
Authors: M. BOLGERT, J. CANIVET
Journal: British Journal of Dermatology (1954)

Journal Article CUTANEOUS PORPHYRIA IN THE ADULT. Get access M. BOLGERT, M. BOLGERT Hôpital Saint‐Louis, Paris Search for other works by this author on: Oxford Academic Google Scholar J. CANIVET J. CANIVET Hôpital Saint‐Louis, Paris Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 66, Issue 8-9, 1 August 1954, Pages 312–317, https://doi.org/10.1111/j.1365-2133.1954.tb12641.x Published: 01 August 1954
Are there excess Sharons in genitourinary clinics?
Authors: E. Foley, F. Willmott, D. Rowen, R. Patel, J L Low
Journal: BMJ (1999)

Most doctors believe that they can determine the age and social class of a patient merely from hearing their name-but this has not been proved.In the 1990s, paediatricians seldom encounter Hildas or Ethels, and Kylies and Bradleys are yet to call on the services of elderly medicine.Stereotypes abound, but is it true that Camillas are more likely to have private medical insurance than Paulines?Above all, are those "Essex girls" Tracey, Sandra, and Sharon really women of easy virtue?With this in mind we set out to establish whether these names are overrepresented among attenders in departments of genitourinary medicine.
Three Divergent rDNA Clusters Predate the Species Divergence in Quercus petraea (Matt.) Liebl. and Quercus robur L
Authors: Graham Muir, Colin C. Fleming, Christian Schlötterer
Journal: Molecular Biology and Evolution (2001)

Quercus petraea and Quercus robur are two closely related oak species that frequently hybridize. We sequenced 70 clones containing the 5.8S and ITS2 regions of ribosomal DNA (rDNA) from these two species and did not detect a species-specific difference. Surprisingly, three divergent (up to 12.6%) rDNA families were identified in both species, indicating that they predate the speciation event. Despite a large between-rDNA-families divergence, rDNA sequences were very similar within families, suggesting ongoing concerted evolution. Expression analysis, relative-rate tests, and mutation spectrum analyses indicated that only a single rDNA family is functional. We propose that past hybridization events, combined with nucleolar dominance, were the evolutionary processes underlying the contemporary rDNA variability in Q. petraea and Q. robur.
Lack of Clinical Utility of Cytomegalovirus Blood and Urine Cultures in Patients with HIV Infection
Authors: John J. Zurlo
Journal: Annals of Internal Medicine (1993)

Objective: To determine the clinical significance of cytomegalovirus (CMV) blood and urine cultures in patients with human immunodeficiency virus (HIV) infection. Design: Inception cohort of patients with HIV infection and CMV culture data. Setting: Government referral-based research hospital. Patients: A total of 322 HIV-infected patients who had a CMV blood culture and 293 HIV-infected patients who had a CMV urine culture within 7 days of a CD4 determination. Measurements: Cytomegalovirus blood and urine culture results; circulating CD4 lymphocyte counts; pathologic or retinopathic findings of CMV disease. Results: Nine of 26 patients (34.6%) with CMV viremia subsequently developed CMV end-organ disease compared with 11 of 74 (14.9%) patients without viremia, (difference, 19.7%; 95% CI, −0.3% to 39.7%). Fifteen of 47 patients (31.9%) with CMV viruria developed end-organ disease compared with 4 of 43 (9.3%) patients without viruria, (difference, 22.6%; CI, 6.7% to 38.5%). Cytomegalovirus culture positivity had poor predictive value for the subsequent development of end-organ disease (35% for viremia and 28% for viruria). Further, patients with proven end-organ disease were often not viremic (45%), but most were viruric (88%). Cytomegalovirus viremia did not correlate with the presence of either fever or weight loss in this patient group. Both blood culture positivity and urine culture positivity varied inversely with the CD4 count (P = 0.0001 for both associations). Conclusions: The likelihood that a blood or urine culture will be positive in a patient with HIV infection correlates better with immunologic status than with current or future clinical status. Although the absence of CMV viruria may suggest that CMV disease is not present, CMV blood and urine cultures have poor diagnostic and predictive value and therefore should be used primarily for research purposes or drug susceptibility testing and not for making clinical decisions.
Clinical Practice and Economics
Authors: Lester S. King
Journal: JAMA (1978)

The title does not do justice to the contents, for this collection of loosely related essays is both interesting and highly significant for the medical profession. The editors held the underlying premise that in the use of medical resources greater economy and efficiency were both possible and desirable. To explore this concept, they called on various clinicians to discuss their specialties while keeping this basic context in mind. With two exceptions the contributors are British, and the discussions strongly relate to the National Health Service. The lessons, however, are largely applicable to this country. The subject matter is so varied that only a few of the essays can be mentioned individually. Ederer, the sole contributor from the United States, discusses random distribution in clinical experiments, emphasizing the difficulty and the staggering expense in achieving true randomization. Whitby analyzes the enormous growth of clinical chemistry and the correlative vast increase in
Calcium dependence of serotonin-induced changes in rabbit ileal electrolyte transport.
Authors: M Donowitz, N Asarkof, G Pike
Journal: Journal of Clinical Investigation (1980)

These studies describe the calcium dependence of the serotonin-induced changes in active electrolyte transport in rabbit ileum in vitro. In the presence of a standard calcium concentration (1.2 mM) in the serosal bathing fluid, serosal serotonin caused a transient increase in short-circuit current and a prolonged decrease in net Na and Cl fluxes. Removing calcium from the serosal (no calcium plus 1 mM EGTA) but not the mucosal bathing fluid inhibited the serotoin-induced increase in ileal short-circuit current, and also completely blocked the serotonin effects on net Na and net Cl fluxes. This inhibition was rapidly reversed by readding calcium. Removing serosal calcium did not inhibit all active electrolyte transport processes, as the effect of a maximum concentration of theophylline (10 mM) was not altered. Similarly, d,l-verapamil, a calcium channel blocker, inhibited the serotonin-induced changes in short-circuit current and in net Na and net Cl fluxes, but did not alter the theophylline effects. In contrast, d-verapamil, a stereoisomer which does not block calcium channels, did not inhibit the serotonin-induced changes. The calcium dependence of these serotonin effects was associated with increased uptake of 45Ca into rabbit ileum, including increaed 45Ca uptake from the serosal surface. Serotonin also increased the rate of 45Ca efflux from rabbit ileum into a calcium-free solution, compatible with serotonin increasing the ileal plasma membrane permeability to calcium. It is postulated that serotonin affects active intestinal electrolyte transport by a mechanism dependent on serosal but not mucosal calcium that involves an increase in the intestinal plasma membrane permeability to calcium, and perhaps an increase in intracellular calcium.
Possible Problems of Large Intakes of Ascorbic Acid
Authors: R. G. Brown
Journal: JAMA (1973)

<h3>To the Editor.—</h3> In recent years the suggestion has come forth that large doses (1 to 5 gm) of ascorbic acid may be effective in reducing the incidence or severity of the common cold. This claim was disputed,<sup>1</sup>but in recent months results of clinical experiments have been published that suggest that ascorbic acid may be reasonably prophylactic for the common cold.<sup>2</sup> The use of large doses of water-soluble vitamins has not come into criticism in the same way as has the use of heroic doses of fat-soluble vitamins since the body has the capacity to excrete the water-soluble vitamins readily. It is a general interpretation that large doses of water soluble vitamins are relatively harmless. This note points to evidence from the literature that would suggest that this may not be so in the case of ascorbic acid. The function of ascorbic acids in the metabolism of
PERCUSSION OF THE CHEST IN INFANTS AND CHILDREN.
Authors: SAMUEL McC. HAMILL
Journal: JAMA (1907)

It seems to be a tendency of the present day to neglect percussion of the chest in early life. This is rather natural, since we find that more valuable, or at least more easily obtainable, results can be secured by auscultation. Furthermore, percussion of the chest in early life is a more difficult procedure and, unless properly done, less satisfactory in its results than is percussion of the adult chest. But, appreciating the valuable assistance one can obtain in the determination of obscure conditions in the thorax by means of properly carried out percussion, I am stimulated to offer this communication as a sort of protest against the neglect of so valuable a procedure. Successful results from percussion depend on a full knowledge of the subject and its limitations. One must realize the importance of the position of the patient and the necessity of a proper technic and be capable
Vulvar cancers in women with vulvar lichen planus: A clinicopathological study
Authors: Sigrid Regauer, Olaf Reich, Barbara Eberz
Journal: Journal of the American Academy of Dermatology (2014)

Vulvar squamous cell carcinomas (SCCs) arising in association with vulvar lichen planus (LP) are poorly documented.We sought to present clinicopathological features of 38 patients (median age 61 years, range 39-90 years) with LP-associated vulvar SCCs.Evaluated were location of vulvar SCC and metastases at presentation, recurrences, survival, precursor lesions, presence of human papillomavirus DNA, p16ink4a, and p53 expression.In all, 32 solitary (5 pT1a, 20 pT1b, 7 pT2) and 6 multifocal SCCs, located in the vestibulum (n=20) and in nonhair-bearing modified and glycogenated mucosa (n=18), arose in erosive (n=13) and nonerosive (n=25) LP. All SCCs were human papillomavirus DNA and p16ink4a negative. Sixteen of 38 (42%) women had inguinal metastases at presentation. Treatment was surgery with clear margins (36/38) and chemoradiation (2/38). Fourteen of 36 (39%) surgically treated patients developed between 1 and 5 new SCCs in the residual diseased mucosa. Of all recurrences, 68% developed within 12 months via precursors revealing various histologic features including elongated, but also flat rete ridges, basaloid and hypertrophic differentiation with inconsistent p53 expression. Fourteen of 38 (37%) patients died of SCCs.Retrospective study and lack of a standardized treatment protocols are limitations.LP-associated SCCs were located in nonhair-bearing vulvar mucosa. Patients had a high rate of inguinal metastases, recurrent vulvar cancers in diseased mucosa, and disease-related death.
Blood and neoplastic diseases. Management of solid tumours-surgery, radiotherapy, and chemotherapy.
Authors: T J McElwain, M J Peckham
Journal: BMJ (1974)

should be less pronounced than those seen in a normal postovulatory endometrium.Nonetheless, the endometrium does undergo cyclical changes resembling normal ones, and these changes are probably sufficiently different from the normal to prevent nidation should "escape" ovulation and fertilization occur.We thank Wyeth, Belgium, and Schering, Berlin, for supplying the contraceptive preparation for this trial.The laboratory facilities are supported in part by grant No. 20.035 from the Belgian Research Council.We are indebted to Miss M. R.
Lung cancer: the importance of seeing a respiratory physician
Authors: R.J. Fergusson, C.S. Thomson, D.H. Brewster, P.H. Brown, R. Milroy
Journal: European Respiratory Journal (2003)

Patients with lung cancer present to and are managed by a variety of clinicians. In this study the effect of involvement by a respiratory physician on the diagnosis, staging, treatment and survival of a large unselected group of lung cancer patients was investigated The study population was derived from the Scottish Cancer Registry. A total of 3,855 patients diagnosed during 1995 with lung cancer were studied. The data were validated and supplemented by references to medical records. The study found that a respiratory physician had been involved in the initial management of 2,901 (75.3%) patients. These patients were found more likely to have had the cancer diagnosis confirmed by histological methods and to have received active treatment with surgery, radiotherapy or chemotherapy. Survival, 1 yr after diagnosis was higher in patients who saw a respiratory physician (24.4 versus 11.1%) and benefit was found to have remained 3 yrs after diagnosis (8.1 versus 3.7%). Although the patients who had not seen a respiratory physician were generally older, and had more extensive disease, after correcting for age, stage and other prognostic factors, the relative hazard ratio of death for those not managed by a respiratory physician was 1.44. The data from this study supports the recommendations of recent lung cancer guidelines for the early involvement by a respiratory physician.
Liver transplantation for sclerosing cholangitis
Authors: Shunji Narumi, John P. Roberts, Jean C. Emond, John Lake, Nancy L. Ascher
Journal: Hepatology (1995)

The clinical course of 37 patients who underwent 46 liver transplantations for primary (n = 33) and secondary (n = 4) sclerosing cholangitis was reviewed. The median follow-up was 37 months. The patient and graft survivals for patients with primary sclerosing cholangitis at 1, 2, and 5 years were 96.9%, 91.6%, 87.9%, and 83.1%, 74.2%, 65.2%, respectively. In the patients with primary sclerosing cholangitis (PSC), prior surgery except for simple cholecystectomy was associated with significantly greater operative time and blood loss. No cholangiocarcinoma was identified at the time of transplantation. Human leukocyte antigen typing for PSC patients was heavily weighed toward B8 (58.8%) compared with control (11.8%). Sixty-two percent of patients with PSC also had inflammatory bowel disease. Moderate or severe rejection requiring OKT3, "rescue therapy" with FK506, or retransplantation was relatively higher in patients with inflammatory bowel disease (70%) versus patients without inflammatory bowel disease (36.4%) and a matched control group (37.5%). Progressive inflammatory bowel disease was seen in 6 of 19 patients, with 3 developing cancer and a dysplasia. Two patients in the entire group died of sepsis and 3 of colon cancer (2 recurrent and 1 primary). These data demonstrate that excellent survival results can be achieved in this group of patients. Rejection is frequent and often severe and steroid refractory. Colon cancer represents the most frequent cause of death in PSC patients after liver transplantation and demands constant attention.