Human papillomavirus detection and comorbidity: critical issues in selection of patients with oropharyngeal cancer for treatment De-escalation trials.

BACKGROUND: The presence of human papillomavirus (HPV)-infection in oropharyngeal squamous cell carcinoma (OPSCC) is a major determinant in prognostic risk modeling. However, most risk models are based on clinical trials which only include a selected patient population. The clinical significance of HPV and other prognostic factors in patients with OPSCC remains to be evaluated in a large, unselected cohort, which also includes patients with stage I/II disease and patients with severe comorbidity. PATIENTS AND METHODS: All patients diagnosed with OPSCC in 2000-2006 in two Dutch university hospitals were included. The presence of an oncogenic HPV infection was determined by p16-immunostaining, followed by a high-risk HPV general primer 5+/6+ DNA PCR on the p16-positive cases. Cox regression analysis was carried out to compare survival rates between HPV-positive and HPV-negative patients and a prognostic model was generated by recursive partitioning. RESULTS: In total, 163 of 841 (19.4%) tumors were HPV-positive. Patients with HPV-positive OPSCC had a more favorable overall survival [73.5% versus 40.9% after 5 years; P < 0.001; hazard ratio = 0.34, 95% confidence interval (CI) 0.25-0.48] compared with patients with HPV-negative OPSCC. Patients with p16-positive but HPV DNA-negative tumors showed a significantly less favorable survival than patients with p16-positive and HPV DNA-positive tumors (P < 0.001). A prognostic model was developed in which patients were classified into three risk groups according to HPV status, nodal stage and comorbidity. [Harrell's concordance index of 0.68 (95% CI 0.65-0.71)]. CONCLUSIONS: Tumor HPV status is a strong and independent prognostic factor for survival among patients with OPSCC. A prognostic risk model was proposed, based on our large, unselected cohort of patients with HPV status, comorbidity and nodal stage being the important prognostic factors. In addition, this study emphasizes the importance of performing an HPV DNA-specific test besides p16-immunostaining.

Diversity of hepatitis C virus infection among HIV-infected people who inject drugs in India.

The availability of generic direct acting antivirals (DAAs) for hepatitis C virus (HCV) treatment has prompted many low-and-middle-income countries to launch HCV elimination programs. Because the efficacy of some of these generic DAAs varies by HCV viral subtype, information on subtype distribution can contribute important information to these elimination programs. We conducted a cross-sectional serosurvey to characterize HCV subtype diversity among HIV positive people who inject drugs (PWID) across 14 cities in India. Of 801 HIV positive PWID sampled, 639 tested HCV antibody positive (78.9%). Among 105 samples sequenced, genotype 3 (58.1%) was the most commonly observed followed by genotype 1 (36.2%) and genotype 6 (5.7%). Of the genotype 3 infections, 65% were subtype 3a and 35% were subtype 3b. Of the genotype 1 infections, 94% were subtype 1a and 6% were subtype 1b. All genotype 6 samples were subtype 6n. There was some variability in genotype diversity depending on geographic region and PWID epidemic stage with greater diversity observed in older PWID epidemics. One sequence, HY018, did not cluster with any known reference sequences in phylogenetic analysis. Nearly 80% of HIV infected PWID across India are co-infected with HCV, and subtype prevalence and genetic diversity varied by region and PWID epidemic stage. HCV elimination programs in India will need to consider HCV subtype.

Next-generation muscle-directed gene therapy by in silico vector design.

There is an urgent need to develop the next-generation vectors for gene therapy of muscle disorders, given the relatively modest advances in clinical trials. These vectors should express substantially higher levels of the therapeutic transgene, enabling the use of lower and safer vector doses. In the current study, we identify potent muscle-specific transcriptional cis-regulatory modules (CRMs), containing clusters of transcription factor binding sites, using a genome-wide data-mining strategy. These novel muscle-specific CRMs result in a substantial increase in muscle-specific gene transcription (up to 400-fold) when delivered using adeno-associated viral vectors in mice. Significantly higher and sustained human micro-dystrophin and follistatin expression levels are attained than when conventional promoters are used. This results in robust phenotypic correction in dystrophic mice, without triggering apoptosis or evoking an immune response. This multidisciplinary approach has potentially broad implications for augmenting the efficacy and safety of muscle-directed gene therapy.

The Derriford twelve commandments of emergency medicine: a model for good practice in a changing world, or a survival guide for new medical staff.

Time is a precious commodity and with more junior doctors coming through our departments for shorter periods of time it has been useful to lay down some ground rules to facilitate their induction. These are presented in the form of the twelve commandments of emergency medicine.

Silent ischaemia and hypertension.

For many years now, silent ischaemia has been recognized as a distinct clinical entity, and its relevance in different patient groups has been established. However, a number of basic questions have not been answered. In explaining the pathophysiology of silent ischaemia, factors affecting both the demand and the supply side are now being recognized. With the exception of certain well-defined groups, it is not clear why some patients are mostly symptomatic, while other patients are predominantly asymptomatic. There appear to be many factors influencing the ischaemic pain threshold. Studies investigating the prevalence of silent ischaemia show a remarkably high prevalence of silent ischaemia in different patient groups. Patients with hypertension but without coronary artery disease form a specific and vulnerable high-risk population that is particularly prone to silent ischaemia. Since changes at the macrovascular level are not responsible, various factors negatively influencing either cardiac supply or demand have been investigated. A reduced coronary reserve is central in explaining the increased prevalence of silent ischaemia in hypertensives. Left ventricular hypertrophy renders meaningful detection of ST segment changes difficult, but a possible solution dealing with this problem is offered by applying more stringent criteria in terms of minimal ST depression in the definition of ischaemia. The treatment of silent ischaemia is largely the same as for angina pectoris, but whether therapy should be directed at elimination of all ischaemic episodes or only of symptomatic episodes depends on further prospective work addressing this question.

Structure-activity studies on narcotic antagonists. 2. N-substituted ethyl 3-(m- or p-hydroxyphenyl) nipecotates.

A number of N-substituted ethyl 3-(n- or p-hydroxyphenyl)nipecotates were synthesized to evaluate the role of a m- or p-hydroxy substituted beta-phenethylamine moiety in narcotic antagonist action. Ethyl m- or p-methoxy-phenylcyanoacetate was alkylated with 1-bromo-3-chloropropane. The resultant chloronitriles were hydrogenated (Raney Ni) to amines and cyclized to yield the N-substituted ethyl 3-(m- or p-methoxyphenyl)nipecotates. These were N-benzylated, O-demethylated using BBr3, N-debenzylated, and then N-alkylated. The following N-substituted derivatives were prepared: methyl, allyl, cyclopropylmethyl, and n-propyl. No significant morphine-like analgesic activity was found in mice by the tail-flick method. The acetic writhing assay showed several compounds to possess analgesic activity. N-n-Propyl and N-(cyclopropylmethyl) m-hydroxy derivatives were marginally active antagonists by the mouse tail-flick method. Surprisingly, the N-methyl m-hydroxy derivative, 11m, was found to be an antagonist.

The kinin peptide family in invertebrates.

Kinins comprise a family of peptides that were first found in the central nervous system of insects and recently also in mollusks and crustaceans. After the isolation of the first members of the kinin family, the leukokinins from Leucophaea maderae, leukokinin-related peptides were found in the cricket Acheta domesticus and the locust Locusta migratoria, all through their ability to induce Leucophaea maderae hindgut contraction. Subsequently, kinins were found in the mosquitoes Culex salinarius and Aedes aegypti and in the earworm Helicoverpa zea. The first noninsect member of this family was isolated from a mollusk, the pond snail Lymnaea stagnalis. Most recently our group has isolated the first kinins from crustaceans. Six kinins were isolated from the white shrimp Penaeus vannamei. To date, 35 members of this family have been isolated. The first relatively small family of insect kinins has grown into an expanding and rather large family with members in insects, crustaceans, and mollusks. In this paper we discuss the kinin family in terms of method of isolation, structure, in vitro and in vivo activity, distribution, receptors, and signal transduction. We will compare the crustacean and insect members of the kinin family, using the data available on crustacea.

Testosterone production by XYY subjects.

A study of plasma concentration (P1T, ng/ml), metabolic clearance rate (MCRT, L/day) and blood production rate (PBT, mg/day) was done on seven XYY subjects of various ages and four pair-matched control XY subjects by a radioinfusion technique of 1,2-3H-testosterone. Although MCRT showed no significant difference between the groups, P1T and PBT were significantly lower (P less than 0.05) in XYY subjects. Therefore, increased aggressive behavior of the XYY subjects can not be attributed to increased levels or production rates of testosterone.

Heparin-induced thrombocytopenia and thrombosis: a potential fatal complication in a routine treatment.

Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy. Life-threatening thromboembolism (HITT) may occur in a large number of patients with HIT. In this article diagnostic problems and the clinical course of 4 typical patients are described. Diagnosis was based on the occurrence of thrombocytopenia during heparin therapy and was confirmed in vitro by an ELISA to heparin-platelet factor 4 antibodies, heparin-induced platelet activation assay (HIPAA) or the platelet aggregation assay (PAA). Thrombotic complications developed in 2 patients, one of whom suffered a fatal embolism after accidentally rechallenging with low-dose heparin which was used to maintain the patency of an intravascular catheter. After discontinuation of heparin the thrombocyte count rapidly increased to normal values during treatment with the heparinoid danaparoid (Orgaran) without complications.

Acute effects of peritoneal dialysis on hemodynamics.

OBJECTIVES: To investigate the acute hemodynamic effects of peritoneal dialysis (PD) using the noninvasive Portapres technique [TNO Biomedical Instrumentation (TNO BMI); Amsterdam, The Netherlands]. DESIGN AND METHODS: Blood pressure was measured in 21 consecutive patients on continuous ambulatory PD during a standard peritoneal permeability analysis (SPA). Blood pressure, stroke volume, cardiac output, and total peripheral resistance were recorded and calculated using continuous finger pressure recordings with Portapres and Modelflow software (TNO BMI). The SPA consists of four phases: (1) drainage of night dwell dialysate, (2) instillation of a rinsing solution (1.36% glucose), (3) drainage of rinsing solution, and (4) instillation of the test solution (3.86% glucose to which dextran 70 has been added). RESULTS: Both systolic blood pressure (SBP) (7 +/- 9 mmHg, p < 0.005) and diastolic blood pressure (DBP) (5 +/- 6 mmHg, p < 0.01) increased during phase 2. Systolic BP and DBP increased further during phase 4 (SBP 8 +/- 14 mmHg, p < 0.05; DBP 6 +/- 8 mmHg, p < 0.005). These BP increases were caused by a rise in total peripheral resistance of 10% +/- 18% (p< 0.05) during phase 1, and 15% +/- 21% (p < 0.005) during phase 2. CONCLUSIONS: Instillation and dwell of a dialysis solution during PD causes a rise in blood pressure. This is caused by an increase in total peripheral resistance. Factors influencing total peripheral resistance could be a direct mechanical effect of dialysate on mesenteric resistance vessels or a temperature-related effect.

Heparin-induced thrombocytopenia with multiple cerebral infarctions simulating thrombotic thrombocytopenic purpura. A case report.

The authors describe a patient with stroke, treated with heparin for unstable angina, whose clinical features mimicked those of thrombotic thrombocytopenic purpura (TTP). His condition eventually proved to be caused by heparin-induced thrombocytopenia (HIT), complicated by thrombosis (HITT). The absence of microangiopathic hemolytic anemia should question the diagnosis in a presumed TTP patient. Early diagnosis of HITT is possible since recently two highly sensitive and specific tests have become available. Heparin treatment has to be stopped immediately if HITT is diagnosed. First-choice antithrombotic treatment in HITT patients is danaparoid.

[Disseminated lupus erythematosus induced by carbamazepine (Tegretol)]. / Lupus erythematosus disseminatus geïnduceerd door carbamazepine (Tegretol).

A 20-year-old man is described with drug-induced lupus erythematosus (DILE) induced by carbamazepine prescribed for epilepsy. The symptoms consisted mainly of arthritis and largely disappeared when carbamazepine was replaced by oxcarbazepine. With a simple decision scheme based on serological findings, differentiation between (idiopathic) systemic lupus erythematosus and DILE is possible.

Primary care guidelines from an organizational point of view.

Guidelines in primary health care have been developed to reduce assumed and undesired variation in certain aspects of care delivery by professionals. If systematically applied guidelines no doubt effect the quality of care. It is argued however that taking an organizational point of view on quality management yields new requirements with respect to development and application of guidelines. It is considered to be essential for managerial control purposes that guidelines have simple and valid indicators to monitor the actual application and to measure the preferred outcome. It is essential that the choice of guidelines to be implemented in an organization is determined in the context of an explicit plan for quality management.

[Big spleen, big problems]. / Grote milt, grote problemen.

The history of a Moroccan girl is described with splenomegaly, lymphadenopathy and pancytopenia after a holiday in her native country. Bone marrow smears were considered negative for Leishmaniasis in four different laboratories. All other diagnostic options could also not be confirmed. Reexamination of the bone marrow smears in a laboratory for tropical diseases revealed Leishmania donovani organisms. Treatment with sodium antimony gluconate was successful. Epidemiology, symptoms and diagnostic problems are discussed.