Laminin-binding integrin alpha7 is required for contractile phenotype expression by human airway myocytes

Contractile airway smooth muscle (ASM) cells retain the ability for phenotype plasticity in response to multiple stimuli, which equips them with capacity to direct modeling and remodeling during development, and in disease states such as asthma. We have shown that endogenously expressed laminin is required for maturation of human ASM cells to a contractile phenotype, as occurs during ASM thickening in asthma. In this study, we profiled the expression of laminin-binding integrins alpha3beta1, alpha6beta1, and alpha7beta1, and tested whether they are required for laminin-induced myocyte maturation. Immunoblotting revealed that myocyte maturation induced by prolonged serum withdrawal, which was marked by the accumulation of contractile phenotype marker protein desmin, was also associated with the accumulation of alpha3A, alpha6A, and alpha7B. Flow cytometry revealed that alpha7B expression was a distinct feature of individual myocytes that acquired a contractile phenotype. siRNA knockdown of alpha7, but not alpha3 or alpha6, suppressed myocyte maturation. Thus, alpha7B is a novel marker of the contractile phenotype, and alpha7 expression is essential for human ASM cell maturation, which is a laminin-dependent process. These observations provide new insight into mechanisms that likely underpin normal development and remodeling associated with airways disease.     

Field Survey and Comparative Study of Pteris Vittata and Pityrogramma Calomelanos Grown on Arsenic Contaminated Lands with Different Soil pH

Bulletin of Environmental Contamination and Toxicology - In field survey, Pteris vittata and Pityrogramma calomelanos were only found in arsenic (As) contaminated areas with soil pH 7.2–8.8...     

Angiotensin subtype 1 rReceptor (AT1) blockade improves vasorelaxation in heart failure by up-regulation of endothelial nitric-oxide synthase via activation of the AT2 receptor

To determine whether angiotensin receptor blockade decreases vascular tone in heart failure by improving endothelial-dependent vasorelaxation and increasing nitric oxide (NO) bioavailability, we treated infarcted adult male Sprague-Dawley rats with candesartan for 7 days or 8 weeks (10 mg/kg/day in drinking water). Candesartan, at both time points, lowered left ventricular (LV) systolic pressure (P < 0.05) (122 +/- 22 versus 74 +/- 16 and 73 +/- 10 mm Hg) and LV dP/dt (5914 +/- 1294 versus 2857 +/- 1672 versus 3175 +/- 769 mm Hg/s), but lowered LV end-diastolic pressure only at 8 weeks (16.9 +/- 9.7 versus 11.2 +/- 5.7 versus 6.9 +/- 5.3 mm Hg). The vasorelaxation response to acetylcholine (ACh) in thoracic aortic segments was decreased with infarction (P < 0.05), remained unchanged with 1 week of candesartan, but increased 84 and 86% at 10-4 and 10-5 M ACh (P < 0.05) at 8 weeks. The enhanced candesartan-induced vasorelaxation at 8 weeks was abolished with NG-nitro-l-arginine methyl ester (200 microM). In bovine pulmonary endothelial cells, 20 microM candesartan increased endothelial nitric-oxide synthase (eNOS) protein levels (P < 0.05) (28.9 +/- 2.6 versus 16.1 +/- 3.7 intensity units/microg of protein); the increased eNOS was abolished by a specific angiotensin subtype 2 (AT2) receptor antagonist, PD 123319. These data suggest that AT1 receptor blockade enhances vasorelaxation in heart failure by increasing NO bioavailability, in part via an AT2 receptor-mediated up-regulation of eNOS protein.     

Topographic recordings of auditory evoked potentials to speech: Subcortical and cortical responses

Topographies of speech auditory brainstem response (speech ABR), a fine electrophysiological marker of speech encoding, have never been described. Yet, they could provide useful information to assess speech ABR generators and better characterize populations of interest (e.g., musicians, dyslexics). We present here a novel methodology of topographic speech ABR recording, using a 32‐channel low sampling rate (5 kHz) EEG system. Quality of speech ABRs obtained with this conventional multichannel EEG system were compared to that of signals simultaneously recorded with a high sampling rate (13.3 kHz) EEG system. Correlations between speech ABRs recorded with the two systems revealed highly similar signals, without any significant difference between their signal‐to‐noise ratios (SNRs). Moreover, an advanced denoising method for multichannel data (denoising source separation) significantly improved SNR and allowed topography of speech ABR to be recovered.     

eNOS Deficiency Predisposes Podocytes to Injury in Diabetes

Endothelial nitric oxide synthase (eNOS) deficiency may contribute to the pathogenesis of diabetic nephropathy in both experimental models and humans, but the underlying mechanism is not fully understood. Here, we studied two common sequelae of endothelial dysfunction in diabetes: glomerular capillary growth and effects on neighboring podocytes. Streptozotocin-induced diabetes increased glomerular capillary volume in both C57BL/6 and eNOS^−/− mice. Inhibiting the vascular endothelial growth factor receptor attenuated albuminuria in diabetic C57BL/6 mice but not in diabetic eNOS^−/− mice, even though it inhibited glomerular capillary enlargement in both. In eNOS^−/− mice, an acute podocytopathy and heavy albuminuria occurred as early as 2 weeks after inducing diabetes, but treatment with either captopril or losartan prevented these effects. In vitro, serum derived from diabetic eNOS^−/− mice augmented actin filament rearrangement in cultured podocytes. Furthermore, conditioned medium derived from eNOS^−/− glomerular endothelial cells exposed to both high glucose and angiotensin II activated podocyte RhoA. Taken together, these results suggest that the combined effects of eNOS deficiency and hyperglycemia contribute to podocyte injury, highlighting the importance of communication between endothelial cells and podocytes in diabetes. Identifying mediators of this communication may lead to the future development of therapies targeting endothelial dysfunction in albuminuric individuals with diabetes.One of the earliest features of kidney disease in diabetes is an alteration in the size- and/or charge-selective properties of the glomerular filtration barrier, a trilaminar structure that normally prevents the free passage of macromolecules into the urinary space. Manifested clinically as albuminuria, this disruption in the filtration barrier may result from structural or molecular changes in the fenestrated glomerular endothelial cells, podocytes, and/or the interpositioned glomerular basement membrane (GBM). High glucose-mediated molecular events¹ and flow-mediated stress forces induce endothelial dysfunction in diabetes² and diabetic nephropathy in particular.³ However, the mechanism by which such injury may translate to loss of glomerular permselectivity remains incompletely understood.Endothelial dysfunction in diabetic nephropathy is perhaps most readily observed as “neoangiogenesis” of the glomerular capillaries.^4,5 A number of experimental studies exploiting antiangiogenic therapies would appear, at first glance, to endorse a role for abnormal angiogenesis in the development of diabetic nephropathy.⁶ The proangiogenic growth factor, vascular endothelial growth factor (VEGF), for example, is abundantly expressed by podocytes within the diabetic glomerulus⁷ and strategies to block the activity of VEGF have been reported to attenuate albuminuria,^8–10 despite evidence to the contrary in the nondiabetic setting.^11,12 Podocytes act as the final barrier to macromolecular flow and, over recent years, injury to this specialized epithelial cell type has been acknowledged as playing a pivotal role in the pathogenesis of albuminuria in diabetes. Bidirectional crosstalk between glomerular endothelial cells and neighboring podocytes, accordingly, represents an alternative route via which endothelial injury may translate to urinary leakage of albumin.^13,14One of the major obstacles to the study of pathogenetic mechanisms in diabetic nephropathy has been the lack of an animal model that develops disease analogous to that seen in humans.¹⁵ However, augmented renal injury has recently been described in diabetic mice genetically deficient in endothelial nitric oxide synthase (eNOS), the major NOS isoform responsible for NO generation within the micro- and macrovasculature.^16–20 In this study, we sought to establish the role that eNOS plays in glomerular capillary growth in diabetes and in the paradoxical response to anti-VEGF therapy, as well as the effects of eNOS deficiency on communication with neighboring podocytes and its response to “standard of care” with renin-angiotensin-aldosterone system (RAAS) blockade.     

Unusual Combination of Holt‐Oram Syndrome and Persistent Left Superior Vena Cava

Holt‐Oram (HO) is a syndrome characterized by congenital cardiovascular malformations, specifically atrial and ventricular septal defects, and skeletal abnormalities of the upper limbs bones. Associations of HO cardiac disorders with other congenital cardiac malformations, specifically persistent left superior vena cava (PLSVC) are rarely reported and its real incidence is unknown. We present a case of this unusual combination in a patient undergoing cardiac resynchronization therapy (CRT) device implant. Methods and Results. A 63‐year‐old male with HO and a history of repaired atrial septal defect was presented for implantable cardioverter defibrillator (ICD) upgrade to CRT. The old implant was located in the right prepectoral area. The old device pocket in the right was accessed and a venous access to the right subclavian vein was obtained. The coronary sinus (CS) was easily cannulated and a long sheath advanced into the CS. A contrast injection revealed an unusually big‐sized CS, with a diameter 2.5 times the fully deployed balloon. A 0.035 wire was advanced retrograde reaching the confluence of the innominate and left subclavian veins. The outer sheath was advanced to this location and contrast venography through the sheath allowed visualization of the left jugular and subclavian veins and visualization of the PLSVC draining into the CS. No target veins for lead implant were identified. The patient was referred for surgical implant of an epicardial lead. Transesophageal echocardiogram showed a CS identified as an unusually big vascular structure located between the left atrium and the left atrial appendage. Conclusion. We report an uncommon association of HO and PLSVC. This association was only reported twice in the past and this is the first one that constitutes a casual finding during the attempt of CRT device implant. This is a combination that may complicate a device implant and recognition of it in advance may avoid performing potentially unsuccessful procedures.     

Cutaneous pseudolymphoma: an unusual eyelid presentation

Pseudolymphoma is an inflammatory response to known or unknown stimuli that results in a lymphomatous-appearing but benign accumulation of inflammatory cells. Resemblance to lymphoma is usually most apparent histologically. Most cases are idiopathic. Approximately three-quarters of cases of cutaneous pseudolymphoma are localized with the most common site on the face (70%), chest, and upper extremities. We would like to report an unusual eyelid presentation of cutaneous pseudolymphoma, not previously reported. It is therefore important to consider cutaneous pseudolymphoma as a differential diagnosis of eyelid lesions.     

A recessive major gene controls the mitsuda reaction in a region endemic for leprosy

BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae. The Mitsuda reaction is a delayed granulomatous skin reaction elicited by intradermal injection of heat-killed M. leprae. Interestingly, results of the Mitsuda test are positive in the majority of individuals, even in areas not endemic for M. leprae. Like leprosy, the Mitsuda reaction is thought to be genetically controlled, but its mode of inheritance is unknown, although the role of the NRAMP1 gene has previously been reported. METHODS: We conducted a segregation analysis of quantitative Mitsuda reactivity in 168 Vietnamese nuclear families ascertained through patients with leprosy. RESULTS: We found strong evidence (P<10-9) for a major gene controlling the Mitsuda reaction independently of leprosy clinical status. Subsequent linkage analysis showed that this major gene was distinct from NRAMP1. Under the major-gene model, approximately 12% of individuals are homozygous for the recessive predisposing allele and are predicted to display high levels of Mitsuda reactivity (mean, approximately 10 mm, versus 5 mm in other individuals). CONCLUSION: We provide evidence that the Mitsuda reaction is controlled by a major gene. Our study paves the way for the identification of this gene and should provide novel insight into the mechanisms involved in granuloma formation, especially in M. leprae infection.     

Safety and immunogenicity of an HIV subtype B and E prime-boost vaccine combination in HIV-negative Thai adults

ALVAC-HIV (vCP1521) and AIDSVAX B/E were evaluated in a phase 1/2 trial of human immunodeficiency virus (HIV)-negative Thai adults. Of 133 volunteers enrolled, 122 completed the trial. There were no serious vaccine-related adverse events, nor were there intercurrent HIV infections. Lymphoproliferative responses to glycoprotein 120 E were induced in 63% of the volunteers, and HIV-specific CD8 cytotoxic T lymphocyte responses were induced in 24%. Antibody responses increased in frequency and magnitude in association with the dose level of AIDSVAX B/E. Binding and neutralizing antibodies to the MN strain were induced in 100% and 98%, respectively, of the volunteers receiving 600 microg of AIDSVAX B/E, and such antibodies to E strains were induced in 96% and 71%, respectively, of these volunteers. This vaccine combination was well tolerated and was immunogenic, meeting milestones for advancement to phase 3 evaluation.     

Anti-GAD antibodies in Chinese patients with youth and adult-onset IDDM and NIDDM

Summary An autoimmune basis for the pathogenesis of insulin-dependent diabetes mellitus (IDDM) is supported by the frequent presence of autoantibodies – islet cell antibodies (ICAs) and GAD antibodies (GADab). However, in Chinese patients with clinical IDDM, a low prevalence of ICAs was observed. In non-insulin-dependent diabetic (NIDDM) patients, it has been suggested that the presence of GADab may identify a subset of latent autoimmune diabetes in adults (LADA). We determined the frequency of GADab in a large group of 134 IDDM and 168 NIDDM Chinese patients, and assessed the relation with ICAs status. Results showed that 39.6 % IDDM and 16.1 % NIDDM patients had GADab, and 20.1 % and 4.8 %, respectively had detectable ICAs. Frequency of GADab positivity was not influenced by whether the patients had youth or adult-onset IDDM or NIDDM, or by duration of diabetes. NIDDM patients seropositive for GADab shared similar clinical characteristics and fasting C-peptide levels with those who were GADab negative. Presence of GADab therefore did not serve to identify a sub-group of patients with latent or slow-onset IDDM. Half (53 %) of our IDDM patients had neither GADab nor ICAs. The reason for this observation is unclear. One theory is that other autoantigens yet to be identified may be contributory. Alternatively, in the Chinese, autoimmunity may not be the major factor in the pathogenesis of IDDM. [Diabetologia (1997) 40: 1425–1430] Received: 11 March 1997 and in revised form: 13 May 1997