Synthesis and adrenolytic activity of 1-(1H-indol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amino}propan-2-ol and its enantiomers. Part 1

The synthesis of (2RS)-1-(1H-indol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amino}propan-2-ol ((RS)-9) and its enantiomers has been described and tested for electrocardiographic, antiarrhythmic, hypotensive and spasmolytic activities as well as for alpha(1)-, alpha(2)- and beta(1)-adrenoceptors' binding affinities. All compounds significantly decrease systolic and diastolic blood pressure, and possess antiarrhythmic activity and affinity to alpha(1)-, alpha(2)- and beta(1)-adrenoceptors. The results suggest that the antiarrhythmic and hypotensive effects of these compounds are related to their adrenolytic but not spasmolytic properties.     

Cytostatic and Antiviral Activity Evaluations of Hydroxamic Derivatives of Some Non‐steroidal Anti‐inflammatory Drugs

Non‐steroidal anti‐inflammatory drugs (NSAID) pharmacophores are interesting in designing potential anticancer drugs. Indeed, numerous experimental, epidemiologic and clinical studies suggest that NSAIDs are promising anticancer drugs. Herein, NSAID hydroxamic acids 3a‐i were prepared by a new synthetic procedure and evaluated for their antiviral and cytostatic activity against malignant tumor cell lines and normal human fibroblasts (WI38). Antiviral activity evaluation results indicated that 3f had only a minor activity against the influenza virus A/H1N1 subtype with a selectivity index of 7–10. On the other hand, the results of the in vitro cytostatic activity evaluations revealed that the majority of NSAID hydroxamic acid derivatives 3a – i exhibited a strong non‐specific antiproliferative effect at the highest concentration (100 μm ) on the tested cell line panel. Only compounds 3b , 3e and 3i exerted a differential dose‐dependent inhibitory activity against the growth of HeLa cells (p < 0.05) at concentration 10 μm . Among those three compounds, only compound 3b showed a selective cytostatic effect on HeLa in comparison with normal fibroblasts.     

Primary central nervous system vasculitis imitating a brain tumour--a case report

Primary central nervous system vasculitis (PCNSV) is a rare disease with an annual incidence rate of 2.4 cases per 1,000,000 person-years. PCNSV causes various neurological symptoms dominated by headache as well as consciousness and mental disturbances. The disease sometimes imitates a brain tumour on CT and rarely presents as stroke. The diagnosis of PCNSV is difficult and frequently requires a brain biopsy in which transmural vascular inflammation involving leptomeningeal or parenchymal vessels is typically found. Angiographic changes indicating an irregular course of vessels with characteristic segmental narrowing can be observed but sometimes the angiogram is normal. The authors present a 57-year-old man in whom PCNSV was diagnosed in brain biopsy. The patient was treated with corticosteroid pulses for 18 months with good effect lasting for 2.5 years. After one year of ending glucocorticoid therapy the symptoms had occurred again and in spite of combined therapy of glucocorticoids with cyclophosphamide the patient died.     

Avian influenza and poultry workers, Peru, 2006

Background Currently numerous countries in Asia, Africa and Europe are encountering highly pathogenic avian influenza (AI) infections in poultry and humans. In the Americas, home of the world’s largest poultry exporters, contingency plans are being developed and evaluated in preparation for the arrival of these viral strains. Objectives With this cross‐sectional study, to our knowledge the first in its kind in Central or South America, we sought to learn whether Peruvian poultry workers had evidence of previous AI infection and if so, to determine the risk factors for infection. Methods We performed a cross‐sectional seroprevalence study among 149 workers on a Peruvian poultry farm (132 exposed to poultry and 17 non‐exposed controls), serum samples were tested for human influenza virus exposure using a hemagglutination inhibition (HI) assay. Microneutralization assays were performed on all serum samples to detect antibodies against prototypic AI strains H4 through H12. Results Using multivariate proportional odds modeling we found that the prevalence of elevated titers against AI viruses was low in both groups, exposed and non‐exposed controls. Conclusions No evidence of previous AI infection among Peruvian poultry workers was found in this first cross‐sectional study performed in South America. This first occupational study of AI in Latin America was encouraging, but it likely reflects the sector of poultry production with higher biosecurity.     

Baseline psychosocial predictors of survival in localized melanoma

OBJECTIVE: There is no certainty about the contributing factors or the psychological processes involved in cancer progression. Many studies have suffered from poor theoretical basis, methodological flaws, and only one or few psychosocial factors investigated at a time. We examined the simultaneous contribution of several theory-based psychosocial elements to survival time in melanoma. METHODS: A consecutive sample of patients with localized (Clarke II-IV) melanoma (N=59) were evaluated with validated questionnaires on coping with cancer, anger expression, perceived social support, noncancer life stresses, and domains of quality of life (QOL) 3-4 months after diagnosis. Cox regression analyses were used to determine the predictors of survival time from the date of diagnosis to the date of death or the last follow-up. RESULTS: After controlling for age, gender, and Breslow depth for the tumor, the baseline psychological variables related to the cancer-prone Type C response pattern, namely, anger nonexpression (repression), hopelessness, and better single-item self-reported QOL predicted shorter survival. Before hopelessness was added to the model, the amount of depressive symptoms and heavy perceived impact of diagnosis were also predictive. In addition, longer survival was strongly predicted by Cognitive Escape-Avoidance coping, which included items close to the concept of denial/minimizing. CONCLUSION: Anger nonexpression, hopelessness, and overpositive reporting of QOL--all proposed to include in the Type C response style or reflect emotional nonexpression--seem to comprise a set of factors that reduce survival, whereas denial/minimizing response to the diagnosis as such predicts longer survival.     

Merkel cell carcinoma in a patient with B-cell chronic lymphocytic leukemia treated with cladribine and rituximab.

Merkel cell carcinoma (MCC) is an uncommon, neuroendocrine skin tumor with an aggressive clinical course. The etiology of the disease is unknown, although sun exposure and immunosuppression may play a role in its development. Coexistence of MCC with chronic lymphocytic leukemia (CLL) is extremely rare and to our knowledge it has been previously described in only 8 patients. We report a 51-year-old woman who presented with a red lump on the right cheek diagnosed as MCC. She had been diagnosed as having CLL 3 years earlier and was treated with 4 courses of cladribine (2-CdA) and subsequently with 4 courses of 2-CdA combined with rituximab. MCC was diagnosed on the basis of histological and immunohistochemical evaluation 2 months after the last course of 2-CdA and rituximab. Surgical excision with tumor-free margins was performed and local adjuvant radiotherapy was applied. Histopathological and immunohistochemical evaluation of the cervical lymph node specimens showed monotonous and diffuse infiltrate of small CD5+, CD20+, CD23+ lymphocytes and no MCC cells were present. To our knowledge, this is the first reported case of MCC occurring in CLL patients soon after treatment with 2-CdA and/or rituximab. The development of MCC in our patient may suggest that this complication rarely observed in CLL patients may have a link with strongly immunosuppressive therapy with 2-CdA and rituximab.     

Mortality in a long‐term follow‐up after treatment of CIN

After treatment of the cervical intraepithelial neoplasia (CIN) cervical cancer incidence remains elevated at least for 20 years. Whether the overall or cervical cancer mortality after treatment of CIN is elevated is unknown. The aim of this study was to determine the long‐term survival and cause‐specific mortality among women treated for CIN. The study population consisted of 7,104 women treated for CIN between 1974 and 2001 and 35,437 individually matched controls. The follow‐up of mortality was based on nationwide registries and closed at death, emigration or December 31, 2005. The possible differences in mortality were assessed using Cox proportional hazard model. With follow‐up time of approximately 630,000 woman‐years, overall 2,781 deaths were observed, 530 among women treated for CIN and 2,251 among reference population (HR 1.1, 95% CI 1.0–1.3). Mortality from any cancer (HR 1.4, 95% CI 1.2–1.7), lung cancer (HR 2.7, 95% CI 1.8–4.1) and HPV‐related anogenital cancer (HR 3.1, 95% CI 1.1–8.6) was higher among CIN patients, but mortality from cervical cancer was not (HR 1.0, 95% CI 0.3–4.0). Elevated cervical cancer incidence after treatment of CIN, documented earlier, did not predict elevation in cervical cancer mortality. This suggests high effectiveness of CIN management. Most of the excess mortality observed among CIN patients was due to increased risk of other cancers. These long‐term mortality patterns should be considered when planning and evaluating the management of CIN lesions and related cervical or other cancer prevention activity.     

Multi-drug transporter MDR1 gene polymorphism and prognosis in adult acute lymphoblastic leukemia

P-glycoprotein (P-gp), a membrane transporter encoded by MDR1 gene, influences pharmacokinetics of anti-cancer drugs and contributes to multi-drug resistance phenotype in adult acute lymphoblastic leukemia (ALL). In this study, we explored prognostic and functional role of single nucleotide polymorphism C3435T in MDR1 gene in 44 adult Caucasian patients with ALL. We found that the outcome of chemotherapy as well as MDR1 gene expression, P-gp expression and P-gp activity in isolated ALL blast cells were comparable among the patients carrying different MDR1 genotypes. Our results suggest that C3435T polymorphism in MDR1 gene is not a major prognosticator in adult ALL.     

Extragonadal teratoma in a domestic turkey (Meleagris gallopavo domestica)

This is the first report of a primary, spontaneous and, most probably, congenital teratoma in a domestic turkey, localized in front of the left eyeball. The unique localization allowed surgical excision of the tumour. The histopathological examination revealed that the tumour included structures derived from all three germ cell layers: ectoderm, mesoderm and endoderm (e.g. cartilaginous, osseous, haematopoietic, fibrous, nervous, glandular, squamous epithelial and smooth muscle tissues). The presence of epithelial cells as well as smooth muscle cells was confirmed using anti-cytokeratin and anti-desmin antibodies, respectively. The proliferative activity of the tumour cells was confirmed using proliferating cell nuclear antigen immunostaining. The other cases of teratoma in wild and domestic birds are reviewed briefly.     

Selective sparing of hippocampal CA3 cells following in vitro ischemia is due to selective inhibition by acidosis

A brief global ischemic insult to the brain leads to a selective degeneration of the pyramidal neurons in the hippocampal CA1 region while the neurons in the neighbouring CA3 region are spared. The reason for this difference is not known. The selective vulnerability of CA1 neurons to ischemia can be reproduced in vitro in murine organotypic slice cultures, if the ion concentrations in the medium during the anoxic/aglycemic insult are similar to that in the brain extracellular fluid during ischemia in vivo. As acidosis develops during ischemia, we studied the importance of extracellular pH for selective vulnerability. We found that cell death in the CA1 and CA3 regions was equally prevented by removal of calcium from the medium or following blockade of the N-methyl-D-aspartate (NMDA) receptor by D-2 amino-5-phosphonopentanoic-acid (D-APV). On the other hand, damage to the CA3 neurons markedly decreased with decreasing pH following in vitro ischemia, while the degeneration of CA1 neurons was less pH dependent. Patch-clamp recordings from pyramidal neurons in the CA1 and CA3 regions, respectively, revealed a pronounced inhibition of NMDA-receptor mediated excitatory postsynaptic currents (EPSCs) at pH 6.5 that was equally pronounced in the two regions. However, when changing pH from 6.5 to 7.4 the recovery of the EPSCs was significantly slower in the CA3 region. We conclude that acidosis selectively protects CA3 pyramidal neurons during in vitro ischemia, and differentially affects the kinetics of NMDA receptor activation, which may explain the difference in vulnerability between CA1 and CA3 pyramidal neurons to an ischemic insult.