Constrained analogues of tocainide as potent skeletal muscle sodium channel blockers towards the development of antimyotonic agents

1-Benzyl-N-(2,6-dimethylphenyl)piperidine-3-carboxamide and 4-benzyl-N-(2,6-dimethylphenyl)piperazine-2-carboxamide, two conformationally restricted analogues of tocainide, were designed and synthesized as voltage-gated skeletal muscle sodium channel blockers. They showed, with respect to tocainide, a marked increase in both potency and use-dependent block.     

Epitope mapping and protective immunity elicited by adenovirus expressing the Leishmania amastigote specific A2 antigen: correlation with IFN-gamma and cytolytic activity by CD8+ T cells

A2 was identified as an amastigote virulence factor of Leishmania (Leishmania) donovani and as a candidate antigen for vaccine development against visceral leishmaniasis. Here, predicted hydrophilic, class I and II MHC-binding synthetic peptides were used to define epitopes recognized by A2-specific antibodies, CD8+ T and CD4+ T cells, respectively. Immunization of BALB/c mice with adenovirus expressing A2 (AdA2) resulted in low antibody response, contrasting with high levels of IFN-gamma producing CD4+ T and CD8+ T cells specific for A2. Further, A2-specific CD8+ T cells from immunized mice were capable of lysing sensitized target cells in vivo. Finally, we demonstrated an association of A2-specific T cell responses and reduced parasitism in both liver and spleen from mice immunized with AdA2 and challenged with L. (L.) chagasi.     

Randomized phase III clinical trial of five different arms of treatment for patients with cancer cachexia: interim results

OBJECTIVE: In April 2005 a phase III randomized study was started to establish which was the most effective and safest treatment of cancer-related anorexia/cachexia syndrome and oxidative stress in improving identified primary endpoints: increase of lean body mass, decrease of resting energy expenditure (REE), increase of total daily physical activity, decrease of interleukin-6 and tumor necrosis factor-alpha, and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). METHODS: All patients were given as basic treatment polyphenols plus antioxidant agents alpha-lipoic acid, carbocysteine, and vitamins A, C, and E, all orally. Patients were then randomized to one of the following five arms: 1) medroxyprogesterone acetate/megestrol acetate; 2) pharmacologic nutritional support containing eicosapentaenoic acid; 3) L-carnitine; 4) thalidomide; or 5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. Treatment duration was 4 mo. The sample comprised 475 patients. RESULTS: By January 2007, 125 patients, well balanced for all clinical characteristics, were included. No severe side effects were observed. As for efficacy, an interim analysis on 125 patients showed an improvement of at least one primary endpoint in arms 3, 4, and 5, whereas arm 2 showed a significant worsening of lean body mass, REE, and MFSI-SF. Analysis of variance comparing the change of primary endpoints between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1, 3, and 5 versus arm 2. A significant inferiority of arm 2 versus arms 3, 4, and 5 for the primary endpoints lean body mass, REE, and MFSI-SF was observed on the basis of t test for changes. CONCLUSION: The interim results obtained thus far seem to suggest that the most effective treatment for cancer-related anorexia/cachexia syndrome and oxidative stress should be a combination regimen. The study is still in progress and the final results should confirm these data.     

Scrotal ulcers revealing pulmonary and genitourinary tuberculosis

A 76-year-old male patient with an angioimmunoblastic T-cell lymphoma under treatment with fludarabine was referred because of scrotal ulcers, evolving for several months. Respiratory, gastrointestinal, and urinary symptoms were denied. Histopathological examination showed the presence of a chronic inflammatory process with epithelioid granulomas. Ziehl-Neelsen stain was positive for acid-fast bacilli. PCR analysis allowed the identification of a mycobacteria strain belonging to the Mycobaterium tuberculosis complex. Skin biopsy was repeated and culture revealed M. tuberculosis sensitive to traditional tuberculostatic drugs. This bacteria was also isolated in bronchial and urinary specimens. Although no abnormal findings were detected on chest radiography or abdominal ultrasonography, scrotal ultrasound showed areas of nodular thickening in the lower part of the epididymis. The diagnosis of cutaneous, lung, and genitourinary tuberculosis was made and the patient was treated with multidrug therapy (rifampicin 600 mg/day, isoniazid 250 mg/day, pyrazinamide 1500 mg/day, and ethambutol 1200 mg/day for the first 2 months, followed by rifampicin and isoniazid with the same dosages for the subsequent 7 months). Complete resolution of skin lesions was observed after two months of treatment. Diagnosis and treatment modalities are discussed. This case emphasizes the importance of considering tuberculosis in the differential diagnosis of genital ulcer.     

Uncommon causes of leg ulcers: investigative approach and therapeutics

Chronic wounds of the lower limbs are a major public healthcare problem affecting 1 percent of the adult population and 3 to 5 percent of people older than 65 years. These numbers are rising in the western population as a result of increased life expectancy and increased risk factors for atherosclerotic occlusion, such as smoking, obesity, and diabetes mellitus. This very debilitating condition, which reduces significantly the quality of life, causes social discomfort and generates considerable cost, not only to the patient but also to the society. Treating chronic leg ulcers is always a challenge. Over the last years, the treatment of this condition has been given more attention because of the frequent ineffectiveness of the methods used, the awareness of the psychological and social impact, and the recognition of the risks of malignancy in these wounds. Determining the etiology is an essential factor for directed and more effective wound care. Although 90 percent of ulcers are of vascular origin, the list of other possible causes responsible for the other 10 percent is extremely long. In this review, the authors focus on the differential diagnosis of chronic leg ulcers and the impact of directed treatment in the prognosis of this condition.     

Vascular Ehlers-Danlos syndrome: a case with fatal outcome

A 13-year-old boy, born prematurely and hypotonic, from non-consanguineous healthy parents, was referred to our department because of easy bruising. A slightly extensible, thin and translucent skin, associated with dysmorphic facies, acrogeria, multiple ecchymoses, hypermobility of the small joints, dorsal kyphosis, genu valgum, flat feet, elongated upper limbs, and low muscle tone were all evident. A history of learning disability and bilateral inguinal hernia was present. Blood and imaging studies were unremarkable. A skin biopsy disclosed an unremarkable dermis; electron microscopy showed abnormalities in the diameter, contour, and shape of collagen fibrils/fibers. Genetic analysis revealed heterozygosity for a novel mutation in COL3A1 gene (c.3527G>A), confirming the diagnosis of vascular Ehlers-Danlos syndrome (VEDS). The patient died at 15 years of age because of aortic dissection. Vascular Ehlers-Danlos syndrome is a rare, life-threatening, autosomal dominant variant of EDS, resulting from mutations in COL3A1 gene. Affected individuals are prone to serious and potentially fatal complications, especially vascular, intestinal, and uterine ruptures. Delay in diagnosis is common, even when the clinical presentation is typical. Therefore, dermatologists should be familiar with VEDS features because the skin findings may be the first signs. Early diagnosis will improve management of visceral complications and allow early genetic counseling.     

Functional outcome and health status of injured patients with peripheral nerve lesions

Background

Peripheral nerve lesions (PNLs) can complicate the clinical course and outcome of multiply injured patients. Since this often impedes recovery, it can be a significant burden for both patients and clinicians. The objective of the present study was to investigate the long-term outcome and health status of patients with PNL.

Subjects and methods

Multiply injured patients admitted to an intensive rehabilitation setting were identified. The Barthel and modified Rankin scales (mRS) were administered to all patients at admission, discharge and follow-up. The short form (SF)-36 questionnaire was used at follow-up (mean: 25.3 ± 6.5 months).

Results

Seventy-seven multiply injured patients were identified, and 45 (22 male, 23 female; mean age: 59.7 ± 21.7 years; range: 19-83 years) were enrolled. Of the injured patients, 22 subjects (10 male and 12 female) had no PNL, while 23 (12 male, 11 female) did. In the PLN group, the mean Barthel scores at admission, discharge and follow-up, respectively, were 33.4 ± 17.9, 85.3 ± 3.8 and 93.0 ± 6.9 (p < 0.001) and the median mRS scores were 4 (interquartile range (IQR): 3-5), 3 (IQR: 1-3) and 1 (IQR: 0-2), respectively. In the group without PLN, the mean Barthel scores at admission, discharge and follow-up, respectively, were 30.4 ± 14.5, 86.6 ± 9.8 and 96.6 ± 4.9 (p < 0.001) and the median mRS scores were 4 (IQR: 3-5), 2 (IQR: 1-3) and 0.5 (IQR: 0-2). The mean length of hospital stay was 86.7 ± 10.8 and 65.6 ± 14.6 days in patients with and without PNL, respectively. The SF-36 did not show significant differences between the groups, but the patients with and without PNL reported significant lower mean scores on all items compared to national population norms.

Conclusion

Multiply injured patients with and without PNL showed significant improvement and a good long-term outcome after rehabilitation. However, those with PNL had a longer hospital stay and needed more rehabilitation than patients without PNL. Both the groups of patients experienced significant difficulties in the health status.