Evaluation of a comprehensive diabetic foot ulcer care quality model.

AIMS: Diabetes-related amputations are typically preceded by a diabetic foot ulcer (DFU) but models to assess the quality of care are lacking. We investigated a model to measure inpatient and outpatient quality. METHODS: Cohort study among adults hospitalized with a DFU to a safety-net hospital during 2016. We measured adherence to DFU-related quality metrics based on guidelines during and 12 months following hospitalization. Inpatient metrics included ankle-brachial index measurement during or 6 months prior to hospitalization, receiving diabetes education and a wound offloading device prior to discharge. Outpatient metrics included wound care ≤30 days of discharge, in addition to hemoglobin A1c (HbA1c) ≤8%, tobacco cessation, and retention in care (≥2 clinic visits ≥90 days apart) 12 months following discharge. RESULTS: 323 patients were included. Regarding inpatient metrics, 8% had an ankle brachial index measurement, 37% received diabetes education, and 20% received offloading prior to discharge. Regarding outpatient metrics, 33% received wound care ≤30 days of discharge. Twelve months following discharge, 34% achieved a HbA1c ≤8%, 13% quit tobacco, and 52% were retained in care. Twelve-month amputation-free survival was 71%. CONCLUSIONS: Our model demonstrated large gaps in DFU guideline-adherent care. Implementing measures to close these gaps could prevent amputations.

An improved treatment planning and quality assurance process for Collaborative Ocular Melanoma Study eye plaque brachytherapy.

PURPOSE: To develop a treatment planning platform for episcleral Collaborative Ocular Melanoma Study plaque therapy in an established treatment planning software and to improve an existing quality assurance (QA) process for nonuniformly loaded plaques that measures air kerma strengths (AKSs) and loading profile. MATERIALS AND METHODS: Treatment planning is performed in Pinnacle using scripts that let the planner choose plaque size and notching. Scripts load seed positions for each plaque and five source groups corresponding to available stock seeds that can be placed into each seed position. Contours are loaded that display the model eye and the plaque itself. Plaque QA is performed using a modification of our previous pinhole apparatus by replacing x-ray film exposure with an optical camera and scintillating film system. The captured image is processed to remove background and to correct the intensity of seeds on the plaque periphery. Measured total optical counts provide an estimate of total plaque AKS. RESULTS: Treatment planning of eye plaques using Pinnacle, in conjunction with our stock inventory of seeds, is established as standard practice at our center. Planned plaques can vary from uniformly loaded to asymmetrically loaded notched plaques. Using the optical camera system for assessment of the seed loadings has decreased QA time from 40 min/plaque to 10 min/plaque. Total AKS of each plaque can be measured using the optical camera with an accuracy of 10%. CONCLUSIONS: Treatment planning is performed on a Health Canada-approved software that accommodates nonuniform plaque loading. Optical imaging of the plaque provides absolute total AKS and the relative seed arrangement in the plaque.

A systematic review and meta-analysis of the post-operative adverse effects associated with mosquito net mesh in comparison to commercial hernia mesh for inguinal hernia repair in low income countries.

PURPOSE: Abdominal wall hernia is a common surgical condition, with more than 20 million estimated to be repaired each year. Mesh repair is the standard for most repairs; however, the mesh material itself may be a barrier to care, the cost prohibitively high for some populations and healthcare systems. The aim of this systematic review and meta-analysis was to produce a pooled comparison between the adverse event rate associated with mosquito net mesh and commercial hernia mesh. METHODS: A systematic review was carried out in accordance with PRISMA guidelines. PubMed, Ovid Embase/Medline, SCOPUS, Web of Science and the Cochrane library were searched. In addition, the ISRCTN register, ClinicalTrials.gov, ICTR Platform and EU Clinical Trials Register were searched. RESULTS: Five randomised controlled trials (RCTs) were identified. The RCTs were deemed to have similar sample populations after inspection of their sample parameters. Therefore, the adverse effects were compared individually (reoccurrence, haematoma, seroma, infection, and serous discharge) and pooled. A total of 313 mosquito net meshes were included in the study, there was no significant difference between the intervention and control groups for pooled adverse effects or individually. CONCLUSIONS: There is not a significant difference between the commercial mesh group and the mosquito net mesh group for pooled [odds ratio 0.93 (0.63, 1.35)] and individual adverse event rates. However, the 95% confidence intervals of these results are still wide. To reduce this uncertainty sample sizes must increase in future studies.

Strain-dependent and distinctive T-cell responses to HIV antigens following immunisation of mice with differing chimpanzee adenovirus vaccine vectors.

In vivo vaccination studies are conventionally conducted in a single mouse strain with results, only reflecting responses to a single immunogenetic background. We decided to examine the immune response to an HIV transgene (gag, pol and nef fusion protein) in 3 strains of mice (CBA, C57BL/6 and BALB/c) to determine the spectrum of responses and in addition to determine whether the serotype of the adenoviral vector used (ChAd3 and ChAd63) impacted the outcome of response. Our results demonstrated that all three strains of mice responded to the transgene and that the magnitude of responses were different between the strains. The C57BL/6 strain showed the lowest range of responses compared to the other strains and, very few responses were seen to the same peptide pool in all three strains of mice. In CBA and BALB/c mice there were significant differences in IFNγ production dependent on the adenoviral vector used. Our results suggest that employing a single strain of mouse may underestimate the efficacy and efficiency of vaccine products.

Analysis of T cell responses to chimpanzee adenovirus vectors encoding HIV gag-pol-nef antigen.

Adenoviruses have been shown to be both immunogenic and efficient at presenting HIV proteins but recent trials have suggested that they may play a role in increasing the risk of HIV acquisition. This risk may be associated with the presence of pre-existing immunity to the viral vectors. Chimpanzee adenoviruses (chAd) have low seroprevalence in human populations and so reduce this risk. ChAd3 and chAd63 were used to deliver an HIV gag, pol and nef transgene. ELISpot analysis of T cell responses in mice showed that both chAd vectors were able to induce an immune response to Gag and Pol peptides but that only the chAd3 vector induced responses to Nef peptides. Although the route of injection did not influence the magnitude of immune responses to either chAd vector, the dose of vector did. Taken together these results demonstrate that chimpanzee adenoviruses are suitable vector candidates for the delivery of HIV proteins and could be used for an HIV vaccine and furthermore the chAd3 vector produces a broader response to the HIV transgene.

Pharmacological characterization and antidiabetic activity of a long-acting glucagon-like peptide-1 analogue conjugated to an antithrombin III-binding pentasaccharide.

AIMS: To examine the biological characteristics of a novel glucagon-like peptide-1 (GLP-1) conjugate, in which an antithrombin III (ATIII)-binding pentasaccharide is conjugated to d-Ala(8) GLP-1 using a tetraethylene glycol linker. METHODS: We assessed GLP-1 receptor binding, cAMP generation and insulin secretory activity of the GLP-1 conjugate in vitro. Circulating half-life, glucose homeostatic and subchronic therapeutic effectiveness were then examined in vivo. RESULTS: The half-life of the GLP-1 conjugate in mice was ∼11 h. In vitro insulin secretion from clonal ß cells and islets was increased (p < 0.001) by the conjugate. The conjugate had half maximum effective concentration values of 1.3 × 10(-7) and 9.9 × 10(-8) M for displacement of (125) I-GLP-1 in competitive GLP-1 receptor binding and cAMP generation, respectively. Glucose tolerance in normal mice, immediately and 4 h after conjugate injection, resulted in significant (p < 0.001) improvements in blood glucose. These effects persisted for >48 h after administration. Daily treatment (21 days) of high-fat-fed and ob/ob mice with 25 nmol/kg conjugate resulted in significant improvement in glucose tolerance (p < 0.001) and reductions in glycated haemoglobin (HbA1c; p < 0.01) equivalent to or better than with exenatide or liraglutide. Treatment of C57BL/KsJ db/db mice for 15 days with 100 nmol/kg conjugate significantly (p < 0.001) reduced glucose and raised plasma insulin. Oral glucose tolerance was significantly (p < 0.001) improved and both 24-h glucose profile (p < 0.001) and HbA1c levels (p < 0.001) were reduced. Islet size (p < 0.001) and pancreatic insulin content were increased without change of islet cell proliferation or apoptosis. CONCLUSION: These data show that d-Ala(8) GLP-1(Lys(37) ) pentasaccharide exerts significant antidiabetic actions and has a projected pharmacokinetic/pharmacodynamic profile that merits further evaluation in humans for a possible once-weekly dosing regimen.

Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain.

One of the symptoms of diabetes is the progressive development of neuropathies. One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells. We have tested the effects of the novel GLP-1 mimetics exenatide (exendin-4; Byetta) and liraglutide (NN2211; Victoza), which are already on the market as treatments for type 2 diabetes, on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes. GLP-1 analogues were injected subcutaneously for 4, 6, or 10 weeks once daily in three mouse models of diabetes: ob/ob mice, db/db mice, or high-fat-diet-fed mice. Twenty-four hours before perfusion, animals were injected with 5'-bromo-2'-deoxyuridine (BrdU) to mark dividing progenitor cells. By using immunohistochemistry and stereological methods, the number of progenitor cells or doublecortin-positive young neurons in the dentate gyrus was estimated. We found that, in all three mouse models, progenitor cell division was enhanced compared with nondiabetic controls after chronic i.p. injection of either liraglutide or exendin-4 by 100-150% (P < 0.001). We also found an increase in young neurons in the DG of high-fat-diet-fed mice after drug treatment (P < 0.001). The GLP-1 receptor antagonist exendin(9-36) reduced progenitor cell proliferation in these mice. The results demonstrate that GLP-1 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer's disease, because these novel drugs cross the blood-brain barrier and increase neuroneogenesis.

Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC).

BACKGROUND: Histone deacetylase blockade can promote heat shock protein 90 (HSP90) acetylation, abrogating androgen receptor signaling. A phase II trial of the histone deacetylase inhibitor (HDACi) romidepsin was conducted in patients with progressing, metastatic, castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: A dose of 13 mg/m(2) was administered i.v. over 4 h on days 1, 8 and 15 every 28 days. The primary end point was rate of disease control defined as no evidence of radiological progression at 6 months. A sample size of 16 assessable patients in stage 1 and nine assessable patients in stage 2 was selected; progression to stage 2 required one or more patients with disease control in stage 1 (H(o) = 0.10, H(a) = 0.30; alpha and beta = 0.10). RESULTS: Thirty-five patients were enrolled. Two patients achieved a confirmed radiological partial response (RECIST) lasting > or = 6 months, along with a confirmed prostate-specific antigen decline of > or = 50%. Eleven patients experienced toxicity necessitating early discontinuation. The commonest adverse events were nausea (30 patients; 85.7%), fatigue (28 patients; 80.0%), vomiting (23 patients; 65.7%) and anorexia (20 patients; 57.1%). There was no significant cardiac toxicity. CONCLUSIONS: At the dose and schedule selected, romidepsin demonstrated minimal antitumor activity in chemonaive patients with CRPC. Further studies of improved HDACi, alone and in combination with other therapies, should nevertheless be investigated.

Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and glucose-dependent insulinotropic polypeptide degradation.

BACKGROUND: Nateglinide restores early-phase insulin secretion to feeding and reduces postprandial hyperglycaemia in type 2 diabetes. This study evaluated the effects of nateglinide on dipeptidyl peptidase-IV (DPP-IV) activity and glucose-dependent insulinotropic polypeptide (GIP) degradation. Research design and methods Blood samples were collected from type 2 diabetic subjects (n=10, fasting glucose 9.36+/-1.2 mmol/l) following administration of oral nateglinide (120 mg) 10 min prior to a 75 g oral glucose load in a randomised crossover design. RESULTS: Plasma glucose reached 18.2+/-1.7 and 16.7+/-1.7 mmol/l at 90 min in control and placebo groups (P<0.001). These effects were accompanied by prompt 32% inhibition of DPP-IV activity after 10 min (19.9+/-1.6 nmol/ml per min, P<0.05), reaching a minimum of 1.9+/-0.1 nmol/ml per min at 120 min (P<0.001) after nateglinide. Insulin and C-peptide levels increased significantly compared with placebo, to peak after 90 min at 637.6+/-163.9 pmol/l (P<0.05) and 11.8+/-1.4 mg/l (P<0.01) respectively. DPP-IV-mediated degradation of GIP was significantly less in patients receiving nateglinide compared with placebo. Inhibition of DPP-IV activity corresponded with a time- and concentration-dependent inhibitory effect of nateglinide on DPP-IV-mediated truncation of GIP(1-42) to GIP(3-42) in vitro. Comparison of in vitro inhibition of DPP-IV by nateglinide and vildagliptin revealed IC(50) values of 17.1 and 2.1 microM respectively. CONCLUSIONS: Although considerably less potent than specified DPP-IV inhibitors, the possibility that some of the beneficial actions of nateglinide are indirectly mediated through DPP-IV inhibition and increased bioavailability of GIP and other incretins merits consideration.

Antileishmanial and antimalarial chalcones: synthesis, efficacy and cytotoxicity of pyridinyl and naphthalenyl analogs.

The antileishmanial and antimalarial activity of methoxy-substituted chalcones (1,3-diphenyl-2-propen-1-ones) is well established. The few analogs prepared to date where the 3-phenyl group is replaced by either a pyridine or naphthalene suggest these modifications are potency enhancing. To explore this hypothesis, sixteen 3-naphthalenyl-1-phenyl-2-prop-1-enones and ten 1-phenyl-3-pyridinyl-2-prop-1-enones were synthesized and their in vitro efficacies against Leishmania donovani and Plasmodium falciparum determined. One inhibitor with submicromolar efficacy against L. donovani was identified (IC50 = 0.95 microM), along with three other potent compounds (IC50 < 5 microM), all of which were 3-pyridin-2-yl derivatives. No inhibitors with submicromolar efficacy against P. falciparum were identified, though several potent compounds were found (IC50 < 5 microM). The cytotoxicity of the five most active L. donovani inhibitors was assessed. At best the IC50 against a primary kidney cell line was around two-fold higher than against L. donovani. Being more active than pentamidine, the 1-phenyl-3-pyridin-2-yl-2-propen-1-ones have potential for further development against leishmaniasis; however it will be essential in such a program to address not only efficacy but also their potential for toxicity.

Does the serum peptidome reveal hemostatic dysregulation?

There is a significant need for markers that are diagnostic of disease, particularly cancer. For these biomarkers to be useful they would need to be able to detect disease early in its progression with high sensitivity and specificity. Many approaches are being undertaken to attempt to find such biomarkers using the tools of systems biology, i.e., parallel measurement techniques including proteomics (parallel protein measurements). Often the premise behind such an approach was to cast a wide net and then design an assay for specific elements that were found to be diagnostic. One such approach has utilized matrix-assisted laser desorption/ionization-mass spectrometry to interrogate the low-molecular-weight component of serum (the fluid component of blood following clotting), the serum peptidome. This approach has the appealing characteristic of speed of analysis but has a number of shortcomings mostly due to signal:noise and mass resolution in some instruments, making peak analysis difficult. Of course, experimental design and statistical analysis have to be conducted with the system limitations in mind. These points have been addressed by others, but few have focused on a potentially larger issue with serum peptidome analysis - are the signals being measured informing us about the disease state directly or indirectly through measurement of another physiological process such as hemostatic dysregulation? This article will present evidence that points to careful measures of the serum peptidome revealing differences in clotting time in disease states and not direct measures of tumor proteolytic activity on blood proteins.

The nutritional vulnerability of older Guyanese in residential homes / Vulnerabilidad nutricional de los ancianos guyaneses en los hogares de ancianos

OBJECTIVE: To assess the nutritional status, functional ability and food intake of older Guyanese in residential care. METHODS: Eighty-four residents of one public and two private homes underwent an anthropometric and functional ability assessment including height, weight, armspan, arm and calf circumferences and handgrip strength. Food intake in two private homes was measured over seven days by direct weighing and the use of consumption units. RESULTS: The overall prevalence of underweight was 26.2% and of overweight was 17.8% but the prevalence of underweight was higher in the public home (29.3% underweight and 17.2% overweight in the public home, and 19.2% underweight and 19.2% overweight in the private home). Mean handgrip strength was 26 kg in males and 17.7 kg in females. The nutritional adequacy of the diet provided by one of the homes was poor with the food providing less than 50% of the required amount of zinc and vitamins A, D and C. Neither home met the requirement for energy. CONCLUSION: A high prevalence of malnutrition exists in a public home for the elderly and, to a lesser degree, in two private homes. In the context of a rapidly ageing population and tight financial constraints, the challenge of providing an adequate diet must be given priority.

Objetivo: Evaluar el estatus nutricional, la capacidad funcional, y la ingestión de alimentos de ancianos guyaneses en el cuidado residencial. Métodos: Ochenta y cuatro residentes de dos hogares privados y uno público fueron sometidos a una evaluación antropométrica y de su capacidad funcional, que incluyó altura, peso, medida de la distancia de los brazos abiertos, brazos, circunferencias de la pantorrilla, y fuerza del puño. La ingestión de alimentos en dos hogares privados fue medida durante siete días mediante el peso directo y el uso de unidades de consumo. Resultados: La prevalencia general del bajo peso corporal fue de 26.2% y la del peso corporal excesivo de 17.8%, pero la prevalencia del bajo peso fue más alta en el hogar público (29.3% de bajo peso frente a 17.2% de peso excesivo en el hogar público, y 19.2% de bajo peso frente a 19.2% de peso excesivo en el hogar público). La fuerza media del puño fue 26 kg en los hombres y 17.7 kg en las mujeres. La adecuación nutricional de la dieta suministrada por uno de los hogares fue pobre, formada por alimentos que proveían menos del 50% de las cantidades requeridas de zinc y vitaminas A, D, y C. Ninguno de los hogares satisfacía los requerimientos energéticos. . Conclusion: En el hogar público para los ancianos, la prevalencia de la malnutrición es alta en grado alarmante, y lo mismo ocurre, en menor grado, en los dos hogares privados. En el contexto de una población que se avejenta rápidamente y que experimenta serias limitaciones financieras, hay que dar prioridad al reto de suministrar una dieta adecuada.

Novel role of Stat1 in the development of docetaxel resistance in prostate tumor cells.

A major obstacle for clinicians in the treatment of advanced prostate cancer is the inevitable progression to chemoresistance, especially to docetaxel. It is essential to understand the molecular events that lead to docetaxel resistance in order to identify means to prevent or interfere with chemoresistance. In initial attempts to detect these events, we analysed genomic differences between non-resistant and docetaxel-resistant prostate tumor cells and, of the genes modulated by docetaxel treatment, we observed Stat1 and clusterin gene expression heightened in the resistant phenotype. In this study, we provide biochemical and biological evidence that these two gene products are related. Stat1 and clusterin protein expression was induced upon docetaxel treatment of DU145 cells and highly overexpressed in the docetaxel-resistant DU145 cells (DU145-DR). The increase in total Stat1 corresponded to an increase in phosphorylated Stat1. Interestingly, there was no detectable difference between DU145 and DU145-DR cells expression of total Stat3 and phosphorylated Stat3. Treatment of DU145-DR cells with small interfering RNA targeted for Stat1 not only resulted in the knockdown of Stat1 expression, but it also caused the inhibition of clusterin expression. Thus, Stat1 appears to play a key role in the regulation of clusterin. Remarkably, inhibition of Stat1 or clusterin expression resulted in the re-sensitization of DU145-DR cells to docetaxel. These results offer the first evidence that Stat1, and its subsequent regulation of clusterin, are essential for docetaxel resistance in prostate cancer. Targeting this pathway could be a potential therapeutic means for intervention of docetaxel resistance.

Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic beta-cell glucose metabolism and insulin secretion.

Elevated plasma homocysteine has been reported in individuals with diseases of the metabolic syndrome including vascular disease and insulin resistance. As homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on beta-cell function and insulin secretion using clonal BRIN-BD11 beta-cells. Acute insulin release studies in the presence of various test reagents were performed using monolayers of BRIN-BD11 cells and samples assayed by insulin radioimmunoassay. Cellular glucose metabolism was assessed by nuclear magnetic resonance (NMR) analysis following 60-min exposure of BRIN-BD11 cell monolayers to glucose in either the absence or presence of homocysteine. Homocysteine dose-dependently inhibited insulin release at moderate and stimulatory glucose concentrations. This inhibitory effect was reversible at all but the highest concentration of homocysteine. 13C-glucose NMR demonstrated decreased labelling of glutamate from glucose at positions C2, C3 and C4, indicating that the tricarboxylic acid (TCA) cycle-dependent glucose metabolism was reduced in the presence of homocysteine. Homocysteine also dose-dependently inhibited insulinotropic responses to a range of glucose-dependent secretagogues including nutrients (alanine, arginine, 2-ketoisocaproate), hormones (glucagon-like peptide-1 (7-36)amide, gastric inhibitory polypeptide and cholecystokinin-8), neurotransmitter (carbachol), drug (tolbutamide) as well as a depolarising concentration of KCl or elevated Ca2+. Insulin secretion induced by activation of adenylate cyclase and protein kinase C pathways with forskolin and phorbol 12-myristate 13-acetate were also inhibited by homocysteine. These effects were not associated with any adverse action on cellular insulin content or cell viability, and there was no increase in apoptosis/necrosis following exposure to homocysteine. These data indicate that homocysteine impairs insulin secretion through alterations in beta-cell glucose metabolism and generation of key stimulus-secretion coupling factors. The participation of homocysteine in possible beta-cell demise merits further investigation.

Blood pressure and cerebral oxygenation responses to skeletal muscle tension: a comparison of two physical maneuvers to prevent vasovagal reactions.

AIM: The present study compared blood pressure, heart rate, and cerebral oxygenation responses to two manipulations used to prevent vasovagal reaction -- skeletal muscle tensing alone and skeletal muscle tensing with leg crossing. METHODS AND RESULTS: Using a repeated measures within-subjects design, healthy young adults engaged in a brief laboratory protocol that included an initial 3 min resting baseline, 3 min of muscle tensing (or no-tensing control), and a 1 min orthostatic challenge. This sequence was repeated three times for each participant to allow for a direct comparison of physiological responses to two different muscle-tensing manipulations as compared to the no-tensing control condition. Results indicated that, relative to the no-tensing, both muscle tensing manipulations elicited significant increases in systolic blood pressure (8.7 +/- 1.1 mmHg), diastolic blood pressure (4.9 +/- 0.6 mmHg), and heart rate (10.9 +/- 0.9 bpm), while a significant increase in cerebral oxygenation was only observed in response to muscle tensing with legs crossed (0.8 +/- 0.2%). Blood pressure and heart rate responses to orthostatic challenge did not differ between the two tensing manipulations, although muscle tensing with legs crossed was followed by a more rapid recovery of cerebral oxygenation levels. CONCLUSION: These findings suggest that muscle tensing elicits physiological adaptations that may help reduce the risk of vasovagal reactions; however, the combination of lower body tension with the legs crossed is likely to be most effective as it was uniquely associated with significant increases in the flow of oxygenated blood to the brain.

The detection of loose bodies in the elbow: the value of MRI and CT arthrography.

Our aim was to determine the clinical value of MRI and CT arthrography in predicting the presence of loose bodies in the elbow. A series of 26 patients with mechanical symptoms in the elbow had plain radiography, MRI and CT arthrography, followed by routine arthroscopy of the elbow. The location and number of loose bodies determined by MRI and CT arthrography were recorded. Pre-operative plain radiography, MRI and CT arthrography were compared with arthroscopy. Both MRI and CT arthrography had excellent sensitivity (92% to 100%) but low to moderate specificity (15% to 77%) in identifying posteriorly-based loose bodies. Neither MRI nor CT arthrography was consistently sensitive (46% to 91%) or specific (13% to 73%) in predicting the presence or absence of loose bodies anteriorly. The overall sensitivity for the detection of loose bodies in either compartment was 88% to 100% and the specificity 20% to 70%. Pre-operative radiography had a similar sensitivity and specificity of 84% and 71%, respectively. Our results suggest that neither CT arthrography nor MRI is reliable or accurate enough to be any more effective than plain radiography alone in patients presenting with mechanical symptoms in the elbow.

Model-based inference of recombination hotspots in a highly variable oncogene [corrected].

An emergent problem in the study of pathogen evolution is our ability to determine the extent to which their rapidly evolving genomes recombine. Such information is necessary and essential for locating pathogenicity loci using association studies, and it also directs future screening, therapeutic and vaccination strategies. Recombination also complicates the use of phylogenetic approaches to infer evolutionary parameters including selection pressures. Reliable methods that identify the presence of regions of recombination are therefore vital. We illustrate the use of an integrated model-based approach to inferring recombination structure using all available sequences of the highly variable, transforming Kaposi's sarcoma-associated herpesviral gene, ORF-K1. This technique learns the parameters of a statistical model that takes recombination hotspots, population genetic effects, and variable rates of mutation into account. As there are no known mechanisms to explain the high mutation rate in this DNA viral gene, recombination may account for some of the variability observed. We infer recombination hotspots in conserved sites such as the tyrosine kinase signaling motif, referred to here as recombination drift, as well as in nonconserved sites, a process described as recombination shift.

Paclitaxel for anthracycline-resistant AIDS-related Kaposi's sarcoma: clinical and angiogenic correlations.

BACKGROUND: Murine data indicate that angiogenesis is central to the aetiopathogenesis of Kaposi's sarcoma (KS). Therefore, we measured angiogenic cytokines and growth factors in patients with AIDS-related KS during treatment with both antiretrovirals and second-line paclitaxel chemotherapy. Cytokines measured included tumour necrosis factor-alpha (TNF-alpha), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and the interleukins IL-2, -6 and -12. PATIENTS AND METHODS: Enzyme-linked immunosorbent assays (ELISAs) were carried out to measure plasma cytokine levels in 17 patients with AIDS-related KS who had progressed within 6 months of receiving liposomal anthracyclines and were treated with paclitaxel 100 mg/m(2) every 2 weeks. Measurements were carried out before progression, at commencement and at the completion of paclitaxel. RESULTS: The objective response rate to paclitaxel was 71% (95% confidence interval 60% to 81%). In 17 patients with AIDS-related KS, we observed eight partial responses and four complete responses. Patients with AIDS Clinical Trial Group stage T1 disease had higher plasma VEGF (P = 0.05) and lower plasma TNF-alpha levels (P = 0.05) than patients with earlier stage T0 KS. There were no correlations between plasma cytokines (bFGF, VEGF, TNF-alpha, and IL-2,-6 and -12) and the CD4 and CD8 cell counts or HIV-1 RNA viral load. Response to paclitaxel was associated with a fall in plasma IL-6 levels (P = 0.04) but no change in other cytokines. There were no significant changes in CD4, CD8, CD16/56, CD19 cell counts and HIV-1 viral loads during chemotherapy. CONCLUSIONS: Angiogenic cytokines may correlate with KS disease extent but not with cellular immune function or HIV viraemia. Response to paclitaxel therapy correlates with a fall in plasma IL-6 levels and recent data indicate this may be a surrogate marker of KS-associated herpesvirus viral load. Overall, clinical response in KS correlates poorly with known angiogenic cytokines.

Osteoblastoma of the clavicle.

A 14-year-old female with a 1-year history of a painful clavicle mass underwent resection and reconstruction with an intercalated autograft and rigid plate fixation. The histopathology was diagnostic for osteoblastoma. Although a clavicle mass is a common entity following clavicle trauma, less common disorders such as bone tumors need to be considered in the differential diagnosis. Osteoblastoma is an uncommon, benign bone tumor representing 1% of all primary bone tumors. An extensive review of the literature reveals only one reported case of clavicular osteoblastoma.