Temporal bone histopathology in chronically infected ears with intact and perforated tympanic membranes.

Chronic suppurative otitis media has been clinically defined as a chronic discharge from the middle ear in the presence of a perforation of the tympanic membrane. However, irreversible tissue pathology in the middle ear or mastoid can occur behind an intact tympanic membrane. One hundred forty-four human temporal bones with chronic otitis media were divided into two groups: those with perforated (28) and those with nonperforated (116) tympanic membranes. The histopathological findings of their middle ears were compared. Granulation tissue in various degrees was the most prominent pathological feature. It was observed in 96% of temporal bones with perforation of the tympanic membrane, and in 97% of those without perforation. Also found were ossicular bony changes (96% with perforation; 90.5% without), middle ear effusion (93% with perforation; 89% without), cholesterol granuloma (21% with perforation; 12% without), cholesteatoma (36% with perforation; 4% without), and tympanosclerosis (43% with perforation; 20% without). This study shows that the histopathological changes of the middle ear are similar in temporal bones with and without perforation of the tympanic membrane. The clinician should, therefore, be aware that an intact tympanic membrane does not necessarily preclude the presence of gross pathological changes of the middle ear cleft.     

The female sexual pain disorders: genital pain or sexual dysfunction?

Vaginismus and dyspareunia have been typically classified as sexual dysfunctions. In practice and research, this conceptualization has led to a focus on sexual and interpersonal issues after biological causes were excluded. Although this approach has been very useful, it has not led to significant theoretical or therapeutic progress in the last 20 years. We propose a reconceptualization of vaginismus and dyspareunia as pain disorders that interfere with sexuality rather than as sexual disorders characterized by pain. This reconceptualization focuses the clinician and researcher on the central phenomenon—pain. It also suggests new approaches to research and treatment. Data from diagnostic, etiologic, and therapeutic studies will be presented to illustrate these points.     

High-level expression of receptor tyrosine kinase Ret and responsiveness to Ret-activating ligands in pheochromocytoma cell lines from neurofibromatosis knockout mice

Pheochromocytoma cell lines derived from neurofibromatosis knockout mice express high levels of the receptor tyrosine kinase Ret, which is involved in the pathogenesis of human pheochromocytomas in hereditary multiple endocrine neoplasia syndrome type 2 (MEN2). Mouse pheochromocytoma (MPC) cells respond to the Ret-activating ligand GDNF by exhibiting Ret phosphorylation, neurite outgrowth, decreased proliferation, and altered expression of catecholamine biosynthetic enzymes. GDNF exerts similar effects on human pheochromocytoma cells in primary cultures. Ret is minimally expressed by normal mouse chromaffin cells, from which pheochromocytomas are derived. Its expression at high levels by MPC cells suggests possible relationships between two previously unrelated tumor syndromes, neurofibromatosis, and MEN2. The responsiveness of these cells to GDNF suggests that they may be a valuable new model for neurobiology.     

Acute infectious purpura fulminans associated with asplenism or hyposplenism

Acute infectious purpura fulminans is a rapidly progressive syndrome of hemorrhagic skin necrosis associated with acute infection and disseminated intravascular coagulation. We report 5 cases of purpura fulminans and briefly review the literature. All cases were associated with encapsulated organisms (Streptococcus pneumoniae or Group A streptococcus), and 4 of the 5 patients had asplenism or functional hyposplenism.     

Preclinical characterization of AEG35156/GEM 640, a second-generation antisense oligonucleotide targeting X-linked inhibitor of apoptosis.

PURPOSE: Cancer cells can use X-linked inhibitor of apoptosis (XIAP) to evade apoptotic cues, including chemotherapy. The antitumor potential of AEG35156, a novel second-generation antisense oligonucleotide directed toward XIAP, was assessed in human cancer models when given as a single agent and in combination with clinically relevant chemotherapeutics. EXPERIMENTAL DESIGN: AEG35156 was characterized for its ability to cause dose-dependent reductions of XIAP mRNA and protein in vitro and in vivo, to sensitize cancer cell lines to death stimuli, and to exhibit antitumor activity in multiple human cancer xenograft models as a single agent or in combination with chemotherapy. RESULTS: AEG35156 reduced XIAP mRNA levels with an EC50 of 8 to 32 nmol/L and decreased XIAP protein levels by >80%. Loss of XIAP protein correlated with increased sensitization to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in Panc-1 pancreatic carcinoma cells. AEG35156 exhibited potent antitumor activity relative to control oligonucleotides in three human cancer xenograft models (prostate, colon, and lung) and was capable of inducing complete tumor regression when combined with taxanes. Antitumor effects of AEG35156 correlated with suppression of tumor XIAP levels. CONCLUSIONS: AEG35156 reduces XIAP levels and sensitizes tumors to chemotherapy. AEG35156 is presently under clinical assessment in multiple phase I trials in cancer patients as a single agent and in combination with docetaxel in solid tumors or cytarabine/idarubicin in leukemia.     

Duplex scanning in renovascular disease

This review describes our experience with renal duplex sonography (RDS) in the elderly as a screening study for renovascular disease and as an intraoperative completion study to define technical error after operative renal artery repair. Methods of patient preparation, technical aspects of renal duplex interrogation and the comparison of RDS results with angiography in the elderly are presented in detail. In the hands of an experienced sonologist, RDS examination performed according to these methods and techniques correlates highly with angiography. We believe renal duplex sonography is the preferred screening test for main renal artery stenosis and occlusion in the elderly population.     

Renovascular disease in children and adolescents

PURPOSE: This retrospective review describes the surgical management of renovascular disease in 25 consecutive children and adolescents with severe hypertension. METHODS: Patients 95 th percentile systolic or diastolic pressure adjusted for gender, age, and height). RA repair comprised 25 bypasses (73%) consisting of 28% saphenous vein, 60% hypogastric artery, and 12% polytetrafluoroethylene; 2 patch angioplasties (6%), and 7 reimplantations (21%). Branch RA exposure was required in 28 kidneys (88%), and branch reconstruction was required in 61%. Warm in situ repair was used in 53%, in situ cold perfusion in 24%, and ex vivo cold perfusion in 23%. Of six bilateral RA repairs, one was staged and two patients are awaiting a staged repair. Combined aortic reconstruction was required in three patients. No unplanned nephrectomy was performed. There were no perioperative deaths. Hypertension was cured in 36%, improved in 56%, and failed in 8% at mean follow-up of 46.4 +/- 7.8 months. The mean calculated glomerular filtration rate increased from 82.0 mL/min/1.73 m 2 preoperatively to 98.2 mL/min/1.73 m 2 postoperatively. The postoperative patency of 30 RA reconstructions was evaluated by angiography, RDS scanning, or both. At mean follow-up of 32.8 months (median, 21.2 months), primary RA patency was 91%. No failures were observed after 2 months follow-up. Estimated survival was 100% at 60 months, with one death 9 years after surgery. CONCLUSIONS: Renovascular hypertension in children and adolescents was caused by a heterogeneous group of lesions. All patients had RA repair, with arterial autografts in most of the RA bypasses. Cold perfusion preservation was used in half of the complex branch RA repairs. These strategies provided 91% primary patency at mean follow-up of 32.8 months, with beneficial blood pressure response in 92%. Surgical repair of clinically significant renovascular disease in children and adolescents is supported by these results.     

Workplace-Based Return-to-Work Interventions: A Systematic Review of the Quantitative Literature

Introduction: A systematic review was conducted to review the effectiveness of workplace-based return-to-work (RTW) interventions. Method: Seven databases were searched, in English and French, between January 1990 and December 2003 for peer-reviewed studies of RTW interventions provided at the workplace to workers with work disability associated with musculoskeletal or other pain-related conditions. Methodological quality appraisal and data extraction were conducted by pairs of reviewers. Results: Of a total of 4124 papers identified by the search, 10 studies were of sufficient quality to be included in the review. There was strong evidence that work disability duration is significantly reduced by work accommodation offers and contact between healthcare provider and workplace; and moderate evidence that it is reduced by interventions which include early contact with worker by workplace, ergonomic work site visits, and presence of a RTW coordinator. For these five intervention components, there was moderate evidence that they reduce costs associated with work disability duration. Evidence for sustainability of these effects was insufficient or limited. Evidence regarding the impact of supernumerary replacements was insufficient. Evidence levels regarding the impact of the intervention components on quality-of-life was insufficient or mixed. Conclusions: Our systematic review provides the evidence base supporting that workplace-based RTW interventions can reduce work disability duration and associated costs, however the evidence regarding their impact on quality-of-life outcomes was much weaker. Donald Cole, Jeremy Dacombe, Jaime Guzman, Sheilah Hogg-Johnson, Ellen MacEachen, Victoria Pennick, Anusha Raj, Rhoda Reardon, Dwayne Van Eerd.     

Mode of action and biochemical characterization of REP8839, a novel inhibitor of methionyl-tRNA synthetase

Aminoacyl-tRNA synthetases have attracted interest as essential and novel targets involved in bacterial protein synthesis. REP8839 is a potent inhibitor of MetS, the methionyl-tRNA synthetase in Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), and in Streptococcus pyogenes. The biochemical activity of REP8839 was shown by specific inhibition of purified S. aureus MetS (50% inhibitory concentration, <1.9 nM). Target specificity was confirmed by overexpression of the metS gene in S. aureus, resulting in an eightfold increase in the MIC for REP8839. Macromolecular synthesis assays in the presence of REP8839 demonstrated a dose-dependent inhibition of protein synthesis and RNA synthesis in S. pneumoniae R6, but only protein synthesis was affected in an isogenic rel mutant deficient in the stringent response. Strains with reduced susceptibility to REP8839 were generated by selection of strains with spontaneous mutations and through serial passages. Point mutations within the metS gene were mapped, leading to a total of 23 different amino acid substitutions within MetS that were located around the modeled active site. The most frequent MetS mutations were I57N, leading to a shift in the MIC from 0.06 microg/ml to 4 microg/ml, and G54S, resulting in a MIC of 32 microg/ml that was associated with a reduced growth rate. The mutation prevention concentration was 32 microg/ml in four S. aureus strains (methicillin-sensitive S. aureus and MRSA), which is well below the drug concentration of 2% (20,000 microg/ml) in a topical formulation. In conclusion, we demonstrate by biochemical, physiologic, and genetic mode-of-action studies that REP8839 exerts its antibacterial activity through specific inhibition of MetS, a novel target.