Acute hypoxia simultaneously induces the expression of gp91phox and endothelial nitric oxide synthase in the porcine pulmonary artery

BACKGROUND: The effect of hypoxia on the formation of superoxide (O2-), the expression of gp91phox and endothelial NO synthase (eNOS) were studied in pig intact pulmonary artery (PA) segments and PA vascular smooth muscle cells (PAVSMCs) and PA endothelial cells (PAECs). METHODS: Segments and cells were incubated under hypoxic conditions for 2 hours (with or without enzyme inhibitors) and the formation of O2- measured spectrophotometrically. Protein expression was assessed using Western blotting and immunocytochemistry. RESULTS: Hypoxia promoted the formation of O2- in PA segments, PAVSMCs and PAECs, an effect inhibited by diphenylene iodonium and apocynin (NAD[P]H oxidase inhibitors). Hypoxia induced O2- formation was enhanced by inhibition of eNOS and augmented by endotoxin and cytokines and re-oxygenation. Hypoxia also promoted the expression of gp91phox and eNOS. In intact PA segments hypoxia induced the expression of nitrotyrosine and eNOS in the endothelium. CONCLUSIONS: The simultaneous upregulation of NAD[P]H oxidase and eNOS in response to hypoxia in the PA results in the simultaneous formation of O2-, NO, and ONOO-. This may represent either a protective mechanism designed to counter the pro-oxidant effect of hypoxia or a novel pathological mechanism underlying the progression of acute respiratory distress syndrome (ARDS).     

Reoperative pancreaticoduodenectomy for periampullary carcinoma

BACKGROUND: Potentially resectable periampullary tumours may not be treated appropriately due to lack of local expertise in both assessment of resectability and resection in referring centres. Tata Memorial Hospital is a major referral centre for oncology and these patients are finally referred to this institution. In carefully selected patients, resection can be accomplished. The purpose of the present paper was to determine the perioperative morbidity and mortality for patients undergoing reoperative pancreaticoduodenectomy at a major comprehensive cancer centre. METHODS: Between January 1991 and December 2001 15 patients, who had undergone previous non-resectional surgery for operable periampullary carcinoma, underwent re-exploration. The perioperative morbidity and mortality were analysed and compared with that of the group of patients undergoing primary pancreaticoduodenectomy (143 patients) in the same period. RESULTS: All the 15 patients undergoing re-exploration had a successful resection by pancreaticoduodenectomy. In the reoperative group eight patients (53%) underwent classic pancreaticoduodenectomy and seven patients (46%) had a pylorus-preserving pancreaticoduodenectomy, as compared to 102 (71%) and 41 (29%) patients in the primary surgery group, respectively. Although the mean operative time and the estimated blood loss were higher in the reoperative group, the morbidity and mortality rates were similar in the two groups. The overall 30-day mortality rate was 6.6% and 6.9% in the reoperative and the primary surgery group, respectively. Major morbidity occurred in two of the 15 patients (13.3%), and one patient (6.6%) died following surgery in the reoperative group. CONCLUSION: Reoperative pancreaticoduodenectomy can be performed safely in carefully selected patients with resectable, localized periampullary tumours with similar morbidity and mortality to patients undergoing primary surgery.     

Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial

Pratik P. Pandharipande, MD, MSCI; Brenda T. Pun, RN, MSN, ACNP; Daniel L. Herr, MD; Mervyn Maze, MB, ChB; Timothy D. Girard, MD, MSCI; Russell R. Miller, MD, MPH; Ayumi K. Shintani, MPH, PhD; Jennifer L. Thompson, MPH; James C. Jackson, PsyD; Stephen A. Deppen, MA, MS; Renee A. Stiles, PhD; Robert S. Dittus, MD, MPH; Gordon R. Bernard, MD; E. Wesley Ely, MD, MPH

JAMA. 2007;298(22):2644-2653.

Context  Lorazepam is currently recommended for sustained sedation of mechanically ventilated intensive care unit (ICU) patients, but this and other benzodiazepine drugs may contribute to acute brain dysfunction, ie, delirium and coma, associated with prolonged hospital stays, costs, and increased mortality. Dexmedetomidine induces sedation via different central nervous system receptors than the benzodiazepine drugs and may lower the risk of acute brain dysfunction.

Objective  To determine whether dexmedetomidine reduces the duration of delirium and coma in mechanically ventilated ICU patients while providing adequate sedation as compared with lorazepam.

Design, Setting, Patients, and Intervention  Double-blind, randomized controlled trial of 106 adult mechanically ventilated medical and surgical ICU patients at 2 tertiary care centers between August 2004 and April 2006. Patients were sedated with dexmedetomidine or lorazepam for as many as 120 hours. Study drugs were titrated to achieve the desired level of sedation, measured using the Richmond Agitation-Sedation Scale (RASS). Patients were monitored twice daily for delirium using the Confusion Assessment Method for the ICU (CAM-ICU).

Main Outcome Measures  Days alive without delirium or coma and percentage of days spent within 1 RASS point of the sedation goal.

Results  Sedation with dexmedetomidine resulted in more days alive without delirium or coma (median days, 7.0 vs 3.0; P = .01) and a lower prevalence of coma (63% vs 92%; P < .001) than sedation with lorazepam. Patients sedated with dexmedetomidine spent more time within 1 RASS point of their sedation goal compared with patients sedated with lorazepam (median percentage of days, 80% vs 67%; P = .04). The 28-day mortality in the dexmedetomidine group was 17% vs 27% in the lorazepam group (P = .18) and cost of care was similar between groups. More patients in the dexmedetomidine group (42% vs 31%; P = .61) were able to complete post-ICU neuropsychological testing, with similar scores in the tests evaluating global cognitive, motor speed, and attention functions. The 12-month time to death was 363 days in the dexmedetomidine group vs 188 days in the lorazepam group (P = .48).

Conclusion  In mechanically ventilated ICU patients managed with individualized targeted sedation, use of a dexmedetomidine infusion resulted in more days alive without delirium or coma and more time at the targeted level of sedation than with a lorazepam infusion.

Trial Registration  clinicaltrials.gov Identifier: NCT00095251

     

Incidence and impact of previous orthodontic treatment in patients attending orthognathic combined clinics: a survey

This prospective questionnaire-based study was designed to determine the incidence of patients attending orthognathic combined clinics who have previously had orthodontic treatment, and to assess the impact, if any, this has had on their proposed surgical treatment. Contemporaneous and historical data from consecutive patients at different stages of treatment who were attending clinics at two London hospitals during a three-month period were included. In total 22/56 patients (39%) had previously had orthodontic treatment, and of those, it had had an undesirable effect on the current management of 10 (45%). The effects included a reduced range of dental movements available to orthodontists (8/23, 35%), undesirable extractions (5/23, 22%), and a prolonging of preoperative orthodontics (5/23, 22%). The median age at which previous orthodontic treatment had been started was 13.5 (range 11-26). Nearly a third of patients reported that they had not been advised by their referring practitioner that a combined orthodontic and surgical approach might be required. The study suggests that preliminary assessment should be improved. Patients should be informed about and prevented from undergoing orthodontic treatment that may limit future surgical management, otherwise they may have to face repeated and prolonged orthodontic treatment, unexpected operations, and potential limitations to the outcome of surgical treatment. This could be achieved through the training and education of all practitioners and the development of referral guidelines.     

Barrage laser photocoagulation for macula-sparing asymptomatic clinical rhegmatogenous retinal detachments

PURPOSE: To evaluate the efficacy of barrage laser photocoagulation in containing macula-sparing asymptomatic clinical retinal detachments (RD). METHODS: Consecutive patients presenting with asymptomatic clinical RD were prospectively treated with barrage photocoagulation in 2-3 confluent rows, using frequency-doubled Nd:YAG (532 nm) laser on an indirect-ophthalmoscopic delivery system. The patients were reviewed at 0.5, 1.5, 3, and 6 months, and yearly thereafter. Best-corrected visual acuity (BCVA), and stability/progression of rhegmatous retinal detachment beyond the barrage were noted at each visit. RESULTS: Nineteen phakic eyes of 17 patients (nine female patients), aged 12-58 years (average: 26 years), underwent barrage laser treatment. Two women had bilateral RD. Most detachments were caused by atrophic holes, and involved at least a quadrant of retina. Seven (37%) extended superiorly with breaks above the horizontal raphe. Three eyes had partial demarcation lines, and five had posterior vitreous detachment at presentation. The minimum follow-up was 6 months (mean: 21 months; range: 6-108 months). Pretreatment anatomical and functional status was maintained in 18 (95%) eyes till the final visit. One superotemporal RD progressed across the laser barrier into macula 5 months after photocoagulation, and BCVA dropped to 6/18. Scleral buckling was performed successfully, with visual recovery to 6/6. CONCLUSIONS: Barrage photocoagulation may have a place in management of asymptomatic clinical detachments, as an effective and less morbid alternative to scleral buckling.     

Spontaneous regression of extramedullary plasmacytoma —A case report

A case of extramedullary plasmacytoma in the soft tissues of the posterior chest wall of an 80-year old man is reported herein. Immunofluorescence study showed that the tumor cells produced IgGλ. An M-component was also detected in the patient’s serum by paper electrophoresis. Two months following the open biopsy done to establish diagnosis, the tumor underwent spontaneous regression and the M-component in the serum also disappeared. This is the first case report of spontaneous regression of an extramedullary plasmacytoma and the probable reasons for this spontaneous regression are discussed herein.     

Platelet glycoprotein IIb/IIIa inhibition using eptifibatide with primary coronary stenting for acute myocardial infarction: a 30-day follow-up study.

The results of primary coronary stenting for acute myocardial infarction (AMI) have been reported to improve significantly with the concomitant administration of platelet glycoprotein IIb/IIIa inhibitor abciximab. There are, however, no data available with the use of eptifibatide, a more cost-effective, small-molecule GP IIb/IIIa blocker with a shorter half-life. In a prospective multicenter feasibility and efficacy study, we assigned 55 consecutive patients with AMI being taken up for primary stenting to receive eptifibatide just before the procedure (two boluses of 180 microg/kg 10 min apart and a 24-hr infusion of 2 microg/kg/min). Clinical outcomes were evaluated at 30 days after the procedure. The angiographic patency of the vessel with TIMI flow rates, TIMI myocardial perfusion (TMP) grade, and corrected TIMI frame counts were assessed at the end of procedure and before hospital discharge. At 30 days, the primary endpoint, a composite of death, myocardial infarction, and urgent target vessel revascularization (TVR) was seen in 12.7% of patients. The TIMI 3 and TMP grade 3 flow, which was seen in 93% and 86% of patient, respectively, at the end of the procedure, declined to 86% and 78%, respectively (P < 0.05) before hospital discharge. Corrected TIMI frame counts also decreased from 25.7 +/- 7.2 to 22.9 +/- 6.8 (P < 0.05). There were five (9.1%) instances of subacute thrombosis (SAT) presenting as AMI, needing urgent TVR in all, within 3-5 days of the primary procedure. No excessive bleeding complication, directly attributable to the use of eptifibatide, was observed. The study was terminated prematurely because of an unacceptable SAT rate. Administration of eptifibatide along with primary stenting for AMI is associated with a high TIMI 3 and TMP grade 3 flow acutely. However, these flows decline significantly before hospital discharge and lead to a high rate of SAT. The dosage and duration of infusion of eptifibatide in this setting needs further evaluation.     

NMR based CSF metabolomics in tuberculous meningitis: correlation with clinical and MRI findings

Metabolic Brain Disease - We report the potential role of 1H Nuclear Magnetic Resonance (NMR) based metabolomics in tuberculous meningitis (TBM). We also correlate the significant metabolites with...     

Genes in one megabase of the HLA class I region.

To define the gene content of the HLA class I region, cDNA selection was applied to three overlapping yeast artificial chromosomes (YACs) that spanned 1 megabase (Mb) of this region of the human major histocompatibility complex. These YACs extended from the region centromeric to HLA-E to the region telomeric to HLA-F. In addition to the recognized class I genes and pseudogenes and the anonymous non-class-I genes described recently by us and others, 20 additional anonymous cDNA clones were identified from this 1-Mb region. We also identified a long repetitive DNA element in the region between HLA-B and HLA-E. Homologues of this element were located at several sites in the human genome outside of the HLA complex. The portion of the HLA class I region represented by these YACs shows an average gene density as high as the class II and class III regions. Thus, the high gene density portion of the HLA complex is extended to more than 3 Mb.     

New Insights into Understanding the Mechanisms,Pathogenesis, and Management of Malignant Mesotheliomas

Malignant mesothelioma (MM) is a relatively rare but devastating tumor that is increasing worldwide. Yet, because of difficulties in early diagnosis and resistance to conventional therapies, MM remains a challenge for pathologists and clinicians to treat. In recent years, much has been revealed regarding the mechanisms of interactions of pathogenic fibers with mesothelial cells, crucial signaling pathways, and genetic and epigenetic events that may occur during the pathogenesis of these unusual, pleiomorphic tumors. These observations support a scenario whereby mesothelial cells undergo a series of chronic injury, inflammation, and proliferation in the long latency period of MM development that may be perpetuated by durable fibers, the tumor microenvironment, and inflammatory stimuli. One culprit in sustained inflammation is the activated inflammasome, a component of macrophages or mesothelial cells that leads to production of chemotactic, growth-promoting, and angiogenic cytokines. This information has been vital to designing novel therapeutic approaches for patients with MM that focus on immunotherapy, targeting growth factor receptors and pathways, overcoming resistance to apoptosis, and modifying epigenetic changes.CME Accreditation Statement: This activity (“ASIP 2013 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2013 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.Malignant mesotheliomas (MMs), among the most aggressive tumors, arise most often from the mesothelial cells that line the pleura, peritoneum, and, occasionally, the pericardium. Because of the multifaceted properties of mesothelium that maintain a protective barrier but also produce components of the extracellular matrix, hyaluronan and other lubricants, chemokines and cytokines, and fibrinolytic and procoagulant factors, understanding its complex biology is a challenge. The intermediate filament pattern of mesothelial cells, suggesting an epithelial–mesodermal hybrid morphology, and their several patterns of differentiation during the neoplastic process suggest their transformation to malignancy is complicated and raises the question of whether one is studying a single tumor type or multiple subgroups of tumors.MMs are most commonly attributed to occupational exposures to asbestos, a regulatory term for a group of fibrous silicates that occur as needle-like amphiboles (crocidolite, amosite tremolite, anthophyllite, and antigorite) or curly serpentine (chrysotile) fibers. Although each of these fibers has its own distinctive properties, the fibrous nature and biopersistance of these inhaled fibers may be key to carcinogenic events that occur during the long latency periods (mean, 30 to 45 years) of most MMs. Most intensely investigated are chrysotile, the most commonly used type of asbestos historically (>90% use worldwide), and crocidolite, the asbestos type associated most often with MMs in humans^1,2 (Figures 1 and 2). The morphology of crocidolite asbestos is similar to nonasbestos fibers of erionite or Libby amphibole, other naturally occurring minerals associated with the development of MMs.^5,6 However, 20% to 25% of individuals with MM have no documented exposure to asbestos or other fibers, suggesting familial susceptibility (sporadic or idiopathic MM), unknown exposure to in-place or naturally occurring asbestos, or other causative agents, such as chemicals, radiation, and viruses.⁷Open in a separate windowFigure 1Properties of chrysotile (white) asbestos. A: Image of bundle of curly chrysotile fibers before processing. B: Scanning electron micrograph of chrysotile fibers (arrows) causing deformation of red blood cells. Chrysotile is positively charged, hemolytic, and cytolytic, primarily due to its magnesium content. Leaching of magnesium renders chrysotile less toxic and also results in chrysotile fiber dissolution over time. C: Scanning electron micrograph of interaction of long chrysotile fiber with the respiratory epithelium of the alveolar duct junction after inhalation by rats. Arrowheads show points of contact with and between epithelial cells. Subsequent penetration into and between cells leads to fiber deposition in the lung interstitum and access to the visceral pleura and pleural space. D: Polarized microscopy showing chrysotile fibers and fibrils.Photomicrograph is a courtesy of Lee Poye (J3 Resources, Inc., Houston, TX) Original magnification, ×100.Open in a separate windowFigure 2Properties of crocidolite, or blue, asbestos. A: Riebeckito ore showing veins of crocidolite asbestos fibers (arrow) before processing. B: Scanning electron micrograph showing morphology of needle-like fibers. C: Early penetration of a crocidolite fiber into the differentiated tracheobronchial epithelium in tracheal organ culture. D: Growth of metaplastic cells over long fibers of crocidolite observed at 1 month in this model.³ These events have not been captured in the pleura in animal inhalation models or in clinical specimens in humans, but mesothelial cells undergo proliferation, as measured by cell counts, or immunochemical markers have been observed in response to crocidolite asbestos in vitro and after inhalation by rats.⁴Because asbestos fibers neither appear to be metabolized nor directly interact with DNA, they are unlike most chemical carcinogens. The sensitivity of human mesothelial cells to fibers of high aspect (length to diameter) ratio is also perplexing, as are the phenomena governing fiber transport to the parietal pleura where most MMs are thought to develop. Although much insight exists on understanding how fibers (particularly high iron-containing amphibole asbestos types) generate reactive oxygen and nitrogen species to induce inflammation and cell signaling pathways important in proliferation and transformation, how these cellular events converge in the pathogenesis of MM remains enigmatic. This review amalgamates current observations in the field and their implications in strategies to prevent and manage MMs in patients.