Age-related changes in salivary antioxidant profile: possible implications for oral cancer

Oral cancer's much higher prevalence among older people may be due to an age-related reduction in protective salivary antioxidant mechanisms and/or an age-related increase in the magnitude of oral carcinogen attack, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), causing DNA aberrations. This study found a significantly reduced total value of salivary antioxidant capacity in elderly persons (as measured by overall antioxidant capacity [ImAnOx] assay), (46% of healthy individuals, p =.004), increased oxidative stress (86% increase in carbonyl concentrations--indicators of enhanced ROS attack, p =.001), and increased salivary concentrations and total values of RNS (7-fold and 3-fold higher respectively, p =.001), all contributing to increased DNA oxidation of oral epithelial cells. Salivary oxidative stress-related changes in the intimately related saliva and oral epithelium compounded with higher viscosity of saliva may explain the higher prevalence of oral cancer in the elderly population. Administration of local therapeutic agents (i.e., antioxidants) to the oral cavity should be considered.     

Should ileoanal pouch surgery be staged for patients with mucosal ulcerative colitis on immunosuppressives?

Introduction and objective Much debate has revolved around whether patients with mucosal ulcerative colitis (MUC) receiving immunosuppression should be weaned off immunosuppressives before undergoing ileal pouch surgery. Therefore, the aim of this study was to assess the affect of immunosuppressive drugs on postoperative complications after ileoanal pouch surgery. Materials and methods A retrospective medical record review of patients with MUC who underwent ileal pouch surgery while taking immunosuppressive drugs such as azathioprine, 6-mercaptopurine (6-MP), methotrexate, and cyclosporin A was performed. Postoperative complications in the study group were compared to three matched groups: patients with MUC who had ileoanal pouch surgery while taking systemic steroids, patients with MUC not receiving any immunosuppressive drugs, and patients with familial adenomatous polyposis. Results Twenty-two patients with MUC who underwent ileoanal pouch surgery while taking immunosuppressive drugs were identified from a prospectively entered database of patients who had this surgery between 1988 and 2005. All but two patients underwent temporary fecal diversion. Fifteen patients were taking 6-MP or azathioprine; six were on cyclosporine A, and one both on azathioprine and cyclosporine A. Fifteen patients were also taking steroids at the time of ileoanal pouch surgery. Early (within 30 days of surgery) and late complications occurred in 36 and 50% of the study group patients, respectively, but did not significantly differ from a matched group of patients with MUC who did not take immunosuppressive drugs. Patients with familial adenomatous polyposis had a significantly lower long-term complication rate. Conclusion This retrospective case-matched study suggests that the use of immunosuppressive drugs and cyclosporine A may not be associated with an increased rate of complications after ileoanal pouch surgery. This paper was presented at the annual meeting of the American Society of Colon and Rectal Surgeons, June 2–7, 2001, San Diego, CA and at the biennial meeting of the International Society of University Colon and Rectal Surgeons, April 10–14, 2002, Osaka, Japan.     

Semaphorin3A accelerates neuronal polarity in vitro and in its absence the orientation of DRG neuronal polarity in vivo is distorted

Axon guidance cues are critical for neuronal circuitry formation. Guidance molecules may repel or attract axons directly by effecting growth cone motility, or by impinging on neuronal polarity. In Semaphorin3A null mice, many axonal errors are detected, most prominently in DRG neurons. It has been generally assumed the repellent properties of Semaphorin3A are the cause of these erroneous axonal projections. Here we show that, in semaphorin3A-null mice, the initial trajectory of neurons in the DRG is abnormal, suggesting that Semaphorin3A may instruct neuronal polarity. In corroboration, in vitro Semaphorin3A dramatically increases neuronal polarization, as indicated by GSK3beta and Rac1 sub-cellular localization in DRG neurons. Polarization effects of Semaphorin3A are regulated by activated MAPK, as indicated by p-MAPK 42/44 polarization and the need for its activity for Rac1 and GSK3beta polarization. Taken together, our findings suggest that Semaphorin3A plays a role in the formation of neuronal polarity, in addition to its classic repellent role.     

Dysferlin Deficiency and the Development of Cardiomyopathy in a Mouse Model of Limb-Girdle Muscular Dystrophy 2B

Limb-girdle muscular dystrophy 2B, Miyoshi myopathy, and distal myopathy of anterior tibialis are severely debilitating muscular dystrophies caused by genetically determined dysferlin deficiency. In these muscular dystrophies, it is the repair, not the structure, of the plasma membrane that is impaired. Though much is known about the effects of dysferlin deficiency in skeletal muscle, little is known about the role of dysferlin in maintenance of cardiomyocytes. Recent evidence suggests that dysferlin deficiency affects cardiac muscle, leading to cardiomyopathy when stressed. However, neither the morphological location of dysferlin in the cardiomyocyte nor the progression of the disease with age are known. In this study, we examined a mouse model of dysferlinopathy using light and electron microscopy as well as echocardiography and conscious electrocardiography. We determined that dysferlin is normally localized to the intercalated disk and sarcoplasm of the cardiomyocytes. In the absence of dysferlin, cardiomyocyte membrane damage occurs and is localized to the intercalated disk and sarcoplasm. This damage results in transient functional deficits at 10 months of age, but, unlike in skeletal muscle, the cell injury is sublethal and causes only mild cardiomyopathy even at advanced ages.Plasma membrane damage in mechanically active cells such as the myocyte is inevitable even under normal physiological conditions.^1,2 Since membranes are not self-sealing, effective and efficient repair mechanisms are necessary to maintain cell viability. Dysferlin plays a central role in this active repair mechanism in skeletal muscle. In the absence of dysferlin disruptions of the skeletal muscle plasma membrane are not repaired leading to cell death.³ Skeletal muscle can regenerate new cells from satellite cells but eventually even this response is exhausted, and lost myocytes are replaced by fat and fibrosis resulting in debilitating muscular dystrophy.Limb-girdle muscular dystrophy type 2 B (LGMD2B), Miyoshi myopathy, and distal myopathy of anterior tibialis are three clinically distinct forms of muscular dystrophy that are caused by mutations within the dysferlin (DYSF) gene resulting in severe to complete deficiency of dysferlin expression.^4,5 Clinically, these dysferlinopathies start in young adulthood with progressive muscle weakness and atrophy that advances to severe disability in older adulthood.Dysferlin is a 273 kDa membrane-spanning protein with multiple C2 domains that bind calcium, phospholipids, and proteins to then trigger signaling events, vesicle trafficking, and membrane fusion.^6,7 The name “dysferlin” reflects the homology with FER-1, the Caenorhabditis elegans spermatogenesis factor involved in the fusion of vesicles with the plasma membrane, as well as the dystrophic phenotype associated with its deficiency.⁵ Dysferlin is crucial to calcium dependent membrane repair in muscle cells.^3,8 In normal skeletal muscle, sarcolemma injuries lead to the accumulation of dysferlin-enriched membrane patches and resealing of the membrane in the presence of Ca²⁺.^3,9While the profound effect of dysferlin deficiency in skeletal muscle has been the subject of much investigation, the effect of dysferlin deficiency in cardiac muscle has largely been ignored. However, in 2004, Kuru et al¹⁰ reported on a 57-year-old Japanese woman with LGMD2B and dilated cardiomyopathy; more recently, Wenzel et al¹¹ described dilated cardiomyopathy in two out of seven patients with LGMD2B and other cardiac abnormalities in three of the others. These observations suggest that dysferlin deficiency can lead to cardiomyopathy as well as to muscular dystrophy. However, neither the morphological location of dysferlin in the cardiomyocyte nor the progression of the disease with age are known.Spontaneous mutations in the mouse are valuable resources in understanding human disease processes. Genetically defined mice develop dysferlinopathies closely resembling LGMD2B, Miyoshi myopathy, and distal myopathy of anterior tibialis.¹² In 2004, Ho et al¹² identified A/J mice as dysferlin deficient. A retrotransposon insertion in the dysferlin gene was found to result in a null allele, resulting in skeletal muscle dystrophy that shows histopathological and ultrastructural features that closely resemble the human dysferlinopathies of LGMD2B, Miyoshi myopathy, and distal myopathy of anterior tibialis.¹² The onset of dystrophic features in A/J mice begins in proximal limb muscles at 4 to 5 months of age and progresses to severe debilitating muscular dystrophy over several months. Ho et al¹² also found that human and murine dysferlin share very similar (approximately 90% identity) amino acid sequences. Cardiac muscle was not included in their study.Recently, Han et al,⁸ using sucrose gradient membrane fractionation on homogenates of wild-type C57BL/6J mouse heart muscle, showed that dysferlin is present in the cardiomyocyte plasma membrane and intracellular vesicle fractions. It was proposed that dysferlin is localized to the cardiomyocyte sarcolemma and some unidentified type of vesicles.⁸ Han et al⁸ in one study and Wenzel et al¹¹ in another study showed that the induction of significant cardiac stress lead to cardiac dysfunction in dysferlin-deficient mice, but to what extent dysferlin deficiency causes cardiomyopathy by aging alone in patients clinically affected with the debilitating effects of LGMD2B, Miyoshi myopathy, or distal myopathy of anterior tibialis is unknown.In this study, we used the A/J mouse model to study the effects of aging in mice affected by genetically determined dysferlin deficiency by using echocardiography and conscious electrocardiography to determine functional changes in vivo, followed postmortem by light and electron microscopy to determine associated morphological changes. We have determined that the normal primary location for dysferlin in the cardiomyocyte of control A/HeJ mice is the intercalated disk (ID), and to a lesser extent, to a distinctive transverse banding pattern within the sarcoplasm of the cardiomyocyte. We have also determined that in the dysferlin-deficient cardiomyocyte there is evidence of membrane damage at these locations. We also present data that show functional cardiac deficits were present in vivo at around 10 months of age then recovered by 12 months. Histopathology showed that under normal laboratory conditions dysferlin deficiency causes only a mild cardiomyopathy even at advanced ages, suggesting the possibility of dysferlin-independent membrane repair mechanisms in cardiac muscle that do not exist in skeletal muscle.     

Reliability of exercise testing and functional activity questionnaires in children with juvenile arthritis

OBJECTIVE: To determine the reliability of formal exercise testing and the reliability of functional and activity questionnaires in children with juvenile idiopathic arthritis (JIA). METHODS: Children with JIA of any subtype ages 8-16 years who were recruited to a randomized trial comparing different exercise therapies participated in 2 preintervention sessions of exercise testing 2-6 weeks apart. Exercise testing included 1) submaximal oxygen uptake (VO(2submax)), 2) peak VO(2) (VO(2peak)), and 3) anaerobic power using modified Wingate tests (W(ant)). Two physical function questionnaires (the Childhood Health Assessment Questionnaire [C-HAQ] and Revised Activity Scale for Kids [ASK]) and 1 daily physical activity questionnaire (the Habitual Activity Estimation Scale [HAES]) were also completed at these times. Test-retest reliability was assessed using type 3, intrarater intraclass correlation coefficient (ICC(3,1)) and Bland and Altman plots were used to determine limits of agreement. RESULTS: Data were available for 74 patients (58 girls). VO(2submax), VO(2peak), and W(ant) demonstrated high reliability (ICC(3,1) 0.82, 0.91, and 0.94, respectively). C-HAQ and ASK questionnaires also had very high reliability (ICC(3,1) 0.82 and 0.91, respectively). The HAES demonstrated low reliability for total activity score (ICC(3,1) 0.15) and moderate reliability when the number of very active hours was analyzed separately (ICC(3,1) 0.59). CONCLUSION: Results of this investigation suggest that exercise testing and functional questionnaires in children with JIA are consistent and reliable. Reliability of the HAES total score was poor, but moderate when the very active hours subscale score was used.     

Reliability of Cardiac Output Calculation by the Fick Principle and Central Venous Oxygen Saturation in Emergency Conditions

Background  For many years thermodilution has been the gold standard for determining cardiac output in the critically ill patients. Less invasive methods have recently been introduced. This study aimed at evaluating the agreement between cardiac output (CO) measured by a new Fick method, using central venous saturation (Scvo₂), and that measured by the classic thermodilution technique, in patients requiring emergent CO evaluation. Settings  Prospective clinical study in a university-affiliated, tertiary hospital, at surgical and general intensive care units. Patients and methods  Fifteen mechanically ventilated patients arriving in the emergency department in hemodynamic shock, had immediately a pulmonary artery catheter introduced under fluoroscopy upon arrival into the ICU. Cardiac output (CO) was obtained in each patient via both thermodilution and the Fick method, using oxygen consumption, SpO₂ and Scvo₂. Results  COs ranged between 2 and 2.3 (in the Fick and thermodilution methods, respectively) and 19 or 19.5 l/min (respectively). Mean thermodilution-derived CO was 6.2 ± 4.2 l/min whereas the Fick’s was 7.0 ± 4.3 l/min. There was statistical significant correlation between the two modalities of measurements, with an r ² = 0.9 (P < 0.001). Conclusions  The new method of Fick assessed emergent CO as reliably as the thermodilution, regardless of whether it was low or high. The use of Scvo₂ allows for prompt bedside calculation for most emergency patients. Avi A. Weinbroum and Philippe Biderman concurred equally to the present investigation. Weinbroum AA, Biderman P, Soffer D, Klausner JM, Szold O. Reliability of cardiac output calculation by the Fick principle and central venous oxygen saturation in emergency conditions.     

Natural course and pathogenesis of transient focal neurologic symptoms during pregnancy

OBJECTIVES: To determine the pathogenesis and course of transient focal neurologic symptoms in pregnant women and to identify prognostic variables that will enable targeted workup. DESIGN: Case-control series. SETTING: Tertiary care university hospital. PATIENTS: Pregnant patients with acute transient focal neurologic symptoms. Women with histories of migraine, recurrent thromboembolism, or cerebrovascular disease were excluded. INTERVENTIONS: Diffusion-weighted imaging (DWI), perfusion-weighted imaging, fluid-attenuated inversion recovery (FLAIR) imaging, gradient-recalled echo imaging, and magnetic resonance venography (MRV) and angiography to determine the presence of brain ischemia and venous thrombosis. Patients underwent echocardiography, duplex ultrasonography, and a battery of hypercoagulability tests and were followed up a mean of 12 months after the event. RESULTS: Twenty-eight controls and 14 patients were enrolled from 23 773 pregnancies. Mean age was 31.2 (range, 24-41) years and mean gestational age at symptom onset was 28 (range, 17-44) weeks. No controls reported transient focal neurologic symptoms, migraine aura, or headache. Presenting symptoms included dysphasia (6 patients) and hemisensory (5) and hemimotor (7) syndrome. In 4 patients, these symptoms were preceded by scintillating scotoma; in 9 patients, focal symptoms were followed by a first-ever, throbbing, migraine-like headache. Only 1 patient had evidence of frank infarction on magnetic resonance imaging (MRI); 2 patients had single, small, hyperintense bright foci on FLAIR imaging without accompanying lesions on DWI, and 11 patients had normal MRI and MRV results. Echocardiography, carotid duplex ultrasonography, and hypercoagulability results were negative in all patients. None of the patients had ischemic events and 4 (29%) developed migraines with aura headaches during follow-up. CONCLUSIONS: Focal neurologic symptoms in healthy pregnant women are frequently preceded by aural visual phenomena and can usually be attributed to a first-ever migraine attack. Cerebral ischemia is less common than migraine and can be reliably diagnosed with MRI. Extensive evaluations to assess a putative hypercoagulable state and cardiocerebrovascular pathology may not be warranted in all such patients.     

Acute disseminating encephalomyelitis in neuromyelitis optica: closing the floodgates

OBJECTIVE: To report the clinical and radiological features of 2 patients with neuromyelitis optica (NMO) associated with severe acute disseminating encephalomyelitis. The first patient had anti-aquaporin 4 antibodies (NMO-IgG) but no lesion enhancement, in contrast to the second patient who was seronegative for NMO-IgG but had clear lesion enhancement on magnetic resonance imaging. DESIGN: Clinical, laboratory, and radiological analysis of 10 patients presenting with features compatible with an NMO-spectrum disorder, 2 of whom developed acute disseminating encephalomyelitis. SETTING: Inpatient ward at the Department of Neurology, Hadassah University. PATIENTS: Patients admitted during a 1-year period with features compatible with an NMO-spectrum disorder. INTERVENTIONS: Medical histories and imaging data were reviewed and serum samples were analyzed for the presence of NMO-IgG. MAIN OUTCOME MEASURES: Clinical and paraclinical evidence of brain involvement. RESULTS: Of 10 patients tested, 5 were positive for NMO-IgG. One seropositive and 1 seronegative patient had an acute disseminating encephalomyelitis-like episode. In both cases, the clinical, laboratory, and electroencephalographic findings supported a diagnosis of acute disseminating encephalomyelitis. Magnetic resonance imaging demonstrated extensive bilateral white matter lesions in both patients. Lesions in the seropositive patient were notably lacking in enhancement following gadolinium injection, whereas robust lesion enhancement was observed in the seronegative patient. CONCLUSIONS: Acute disseminating encephalomyelitis without lesion enhancement on magnetic resonance imaging may represent a childhood manifestation of seropositive NMO. The lack of enhancement suggests an intact blood-brain barrier and supports a unique mechanism of edema induction due to dysfunction of water channels.