Relative permeability of nasal, tracheal, and bronchoalveolar mucosa to macromolecules in rats exposed to ozone

Nasal, tracheal and bronchoalveolar injuries resulting from acute ozone exposure of rats were investigated by permeability changes. 99mTc-labeled diethylenetriaminepentaacetate (DPTA) and 125I-labeled bovine serum albumin (BSA) were selectively instilled into localized airway regions of anesthetized rats exposed to 0.8 ppm 03 or clean air for 2 h. Transmucosal transfer of the radiolabeled tracers was detected by counting the radioactivity in blood samples collected at short postinstillation time intervals. Permeability measurements were made on d 0, 1, and 2 after O3 exposure to analyze the extent and persistence of tissue injury in the nasal, tracheal, and bronchoalveolar regions. Normal mucosal permeability was low in nose, intermediate in bronchoalveolar zone, and high in trachea. The O3-related injury, reflected by elevated permeability, was substantial in the trachea and bronchoalveolar zone but was minimal in the nose immediately after the exposure. Abnormal permeability persisted for less than 24 h in the trachea but for more than 24 h in the bronchoalveolar zone. The results are consistent with the properties of O3 of causing greater injury in the smaller airways and the alveolar zone than in the trachea.     

Comparative evaluation of commonly used laboratory tests for post-mortem diagnosis of rabies

Animal brain samples received at WHO Collaborating Centre laboratory at National Institute of Communicable Diseases (NICD) during the years 1991-2002 were tested by Seller's stain, Fluorescent Antibody Test (FAT) and Mouse Innoculation Test (MIT) as methods of rabies diagnosis. Negri bodies on Seller's staining could be detected in 52.5% of MIT positive brains, the concordance of this test with MIT was found to be 77.8%. FAT was positive in 91.5% of MIT positive brains, though it showed concordance of 95.7% with MIT results in the total samples. 12.2% of the samples were found positive by FAT of which 1/3rd also showed the presence of Negri bodies when MIT was negative i.e. showing that the virus is present in inactivated form. Thus emphasizing the need for timely and proper collection and transportation of specimens for testing. Seller's stain and FAT give reliable diagnosis of rabies in the brain samples in majority of the cases. MIT being time-intensive test, is of academic value only in decision making as regards initiation of Post Exposure Treatment (PET), it is recommended that in cases where Seller's stain and FAT have yielded negative results the decision to initiate PET should give due consideration to the nature and circumstances of the animal bite and other epidemiological features.     

Cytokines: the yin and yang of vitiligo pathogenesis

Introduction: Dysregulation of melanocyte function is associated with vitiligo, an idiopathic autoimmune hypopigmentary skin disorder, caused by the selective destruction of melanocytes. Cytokines, the key mediators of immune response, which are pivotal in maintaining immune homeostasis, are crucial in vitiligo pathogenesis. Several studies indicate that there is an imbalance between pro- and anti-inflammatory cytokines in the skin and serum of vitiligo patients.

Areas covered: In this comprehensive review, we have summarized the correlation of cytokine imbalance and vitiligo pathogenesis, its role in melanocyte biology, and its impact on vitiligo treatment. We have integrated various published reports on the levels of major cytokines from skin and serum samples of vitiligo patients. We have also discussed the role of endoplasmic reticulum and oxidative stress on cytokine imbalance and vice versa leading to destruction of melanocytes.

Expert commentary: The review reflects that dysregulation of cytokines is multifactorial, ranging from genetic predisposition to altered protein expression relevant to vitiligo pathogenesis. We emphasize that cytokine imbalance in systemic and skin microenvironment plays a crucial role in vitiligo pathogenesis and has promising potential as therapeutic targets for vitiligo.     

Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies.

Epigenetic regulation of gene expression is mediated through alterations in the DNA methylation status, covalent modifications of core nucleosomal histones, rearrangement of histones, and by RNA interference. It is now abundantly clear that deregulation of epigenetic mechanisms cooperates with genetic alterations in the development and progression of cancer and leukemia. Epigenetic deregulation affects several aspects of tumor cell biology, including cell growth, cell cycle control, differentiation, DNA repair, and cell death. This raises the strong possibility that reversing deregulated epigenetic mechanisms may be an effective treatment strategy for leukemia and cancer. This treatment strategy may either be designed to separately or collectively target the specific perturbations in the epigenetic mechanisms found in human hematologic malignancies. The following review describes our current understanding of the important deregulated epigenetic mechanisms and the preclinical and clinical development of epigenetic and chromatin modifiers in the therapy of these disorders.     

Lack of efficacy of two consecutive treatments of radioimmunotherapy with 131I-cG250 in patients with metastasized clear cell renal cell carcinoma.

PURPOSE: A previous activity dose-escalation study using 131I-labeled chimeric monoclonal antibody cG250 in patients with progressive metastatic renal cell carcinoma (RCC) resulted in occasional therapeutic responses. The present study was designed to determine the safety and therapeutic efficacy of two sequential high-dose treatments with 131I-cG250. PATIENTS AND METHODS: Patients (n = 29) with progressive metastatic RCC received a low dose of (131)I-cG250 for assessment of preferential targeting of metastatic lesions, followed by the first radioimmunotherapy (RIT) with 2220 MBq/m2 131I-cG250 (n = 27) 1 week later. If no grade 4 hematologic toxicity was observed, a second low-dose 131I-cG250 (n = 20) was given 3 months later. When blood clearance was not accelerated, a second RIT of 131I-cG250 was administered at an activity-dose of 1110 MBq/m2 (n = 3) or 1665 MBq/m2 (n = 16). Patients were monitored weekly for toxicity, and tumor size was evaluated by computed tomography once every 3 months intervals. RESULTS: The maximum-tolerated dose (MTD) of the second RIT was 1,665 MBq/m2 because of dose-limiting hematological toxicity. Based on an intention-to-treat analysis, after two RIT treatments, the disease stabilized in five of 29 patients, whereas it remained progressive in 14 of 29 patients. Two patients received no RIT, and eight of 29 received only one 131I-cG250 RIT because of grade 4 hematologic toxicity, formation of human antichimeric antibodies, or disease progression. CONCLUSION: In patients with progressive end-stage RCC, the MTD of the second treatment was 75% of the MTD of the first RIT. In the majority of patients, two cycles of 131I-cG250 could be safely administered without severe toxicity. No objective responses were observed, but occasionally two RIT doses resulted in stabilization of previously progressive disease.     

Cryoablation of liver tumours -- a review of mechanisms, techniques and clinical outcome.

Several techniques exist for in situ destruction or ablation of liver tumours not eligible for resection. Cryoablation, i.e. the use of low temperatures to induce local tissue necrosis, was among the first of the thermal ablative techniques widely used. The procedures have typically been performed by surgeons during laparotomy, but recently minimally invasive cryoablation has been reported feasible. The present review focuses on mechanisms of tissue destruction, techniques of ablation including procedural monitoring, and clinical outcome following cryoablation of liver tumours. Plausible causes of tumour persistence at the site of ablation, i.e. local treatment failure, are discussed. Shortcomings exist in monitoring of the freezing process and may be a main cause. The evidence for the long-term outcome following liver tumour cryoablation needs to be improved. Cryoablation has been challenged by other techniques of tumour ablation such as radiofrequency ablation. Randomised trials against these modern techniques may define the role of cryoablation in the treatment of liver tumours. With improved imaging technology and patient selection, cryoablation of liver tumours may hold promise for selected patients.