Lymphocyte T helper-specific reactivity in sustained responders to interferon and ribavirin with negativation (seroreversion) of anti-hepatitis C virus.

BACKGROUND: Seroreversion, negativation of anti-hepatitis C virus previously positive, is sometimes found in some chronic hepatitis C-sustained responders (SRs) to antiviral therapy. AIMS: To determine the probability of seroreversion in SR treatment with Interferon and Ribavirin, and lymphocyte T helper (CD4+) reactivity to HCV antigens. METHODS: Thirty SR were followed on average for 54.8 months. Anti-HCV was tested by third generation test. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood and cultured to evaluate CD4+ proliferation in response to 2 microg/ml of eight HCV recombinant antigens from core, NS3, NS4, NS5 regions. RESULTS: Seroreversion was verified in 23% of patients (7/30), appearing at 47.5+/-24.0 months. The probability of anti-HCV loss in this group was 25% at 56 months after ending therapy. In 57% (4/7), anti-HCV returned to positive. These 7 SR patients with seroreversion also showed weaker CD4+ reactivity in 5% of tests (3/56) than the remaining 23 anti-HCV-positive SRs who showed stronger reactivity in 18% of tests (33/184), P=0.036. CONCLUSIONS: One-quarter of the SR showed seroreversion of anti-HCV and weaker CD4+ specific HCV proliferation than those who remained anti-HCV positive. The data suggest that complete viral eradication is a possible and achievable clinical objective.     

Carvedilol protects ischemic cardiac mitochondria by preventing oxidative stress.

Ischemia negatively affects mitochondrial function by inducing the mitochondrial permeability transition (MPT). The MPT is triggered by oxidative stress, which occurs in mitochondria during ischemia as a result of diminished antioxidant defenses and increased reactive oxygen species production. It causes mitochondrial dysfunction and can ultimately lead to cell death. Therefore, drugs able to minimize mitochondrial damage induced by ischemia may prove to be clinically effective. We analyzed the effect of carvedilol, a beta-blocker with antioxidant properties, on mitochondrial dysfunction. Carvedilol decreased levels of TBARS (thiobarbituric acid reactive substances), an indicator of oxidative stress, which is consistent with its antioxidant properties. Regarding cell death by apoptosis, although ischemia did increase caspase-8-like activity, there were no changes in caspase-3-like activity, which is activated downstream of caspase-8; this may indicate that the apoptotic cascade is not activated by 60 minutes of ischemia. We conclude that carvedilol protects ischemic mitochondria by preventing oxidative mitochondrial damage, and, by so doing, it may also inhibit the formation of the MPT pore.     

Telomerase activity in prognostic histopathologic features of melanoma.

BACKGROUND: Telomerase activity (TA) is believed to play a role in the regulation of senescence and to limit the number of cell divisions. The deregulation of telomerase appears to contribute to oncogenesis and the formation of immortal cell lines. As a result, it is believed that it could be used as a prognostic marker in melanoma. METHODS: TA was assayed by the polymerase chain reaction PCR-ELISA-based telomeric repeat amplification protocol (TRAP assay). One hundred and eight samples were distributed in four histological groups: 30 samples from primary cutaneous melanomas, 24 from peritumoural skin sites, 28 from benign melanocytic lesions, and 26 from normal skin sites as a control. RESULTS: TA was different among the four tested groups (Kruskall-Wallis test p<0.001), and increasing values of TA were observed progressing from normal skin to benign and then to malignant lesions. Among melanoma samples, there was a significant association between TA and ulceration (p=0.025), TA and vascular invasion (p=0.018) and TA and mitotic rate (p=0.029) (Mann-Whitney test). A linear regression analysis showed significant associations between the increase of TA with Breslow thickness (p=0.004) and the presence of satellites (p=0.002). CONCLUSIONS: We observed that TA had increased from control skin to peritumoural skin, and then to benign melanocytic lesions and finally to melanoma, suggesting tumour progression. TA showed higher values in the presence of some important histopathologic parameters related to poor prognosis in cutaneous melanoma such as ulceration, vascular invasion, satellites, high rates of mitosis, and in thicker tumours.     

Improving emergency obstetric care in Mozambique: the story of Sofala.

OBJECTIVE: The 5-year project in the province of Sofala was designed to improve access, quality and utilization of emergency obstetric care (EmOC) by strengthening rural hospitals and health centers and ultimately the health system's capacity to respond to emergencies more quickly and effectively. METHODS: Implementation consisted of attention to infrastructure, human resource development, transportation and communication systems, and management. Specific management aspects that were targeted for improvement included: supportive supervision, logistics for supplies, equipment and drugs, record keeping, monitoring and evaluation, and quality improvement techniques such as maternal death audits. RESULTS: Access to EmOC improved with an increase in the number of fully functional EmOC facilities from 4 to 18. The number of women with obstetric complications who were admitted for treatment in participating facilities tripled, and the proportion of those women dying declined by half. CONCLUSIONS: Close collaboration and partnership with the provincial health directorate make the sustainability of many results likely while the replication of much of the Sofala model to other provinces is promising for the national strategy to reduce maternal mortality.     

A review of the effects of external pressure on skin blood flow

The human foot is a complex mechanical structure consisting of bones, ligaments and joints. They act together to provide a robust system capable of absorbing and dissipating the intermitted pressure that is subjected to its plantar surface during walking to prevent soft tissue breakdown. Current studies suggest that plantar foot pressure may lead to soft tissue breakdown (e.g. neuropathic ulceration) and hence research has so far concentrated on investigating the mechanical effects of plantar foot pressure on the foot’s integrity. This has been possible through the widely available pressure and force platforms as well as in-shoe pressure systems. However, to understand how plantar foot pressure causes soft tissue breakdown it is vital to investigate both the physiological–mechanical interactions between the skin and plantar foot pressure. This review suggests that with the current advances in technology, the physiological response of skin blood flow to mechanical plantar foot pressure should be investigated and correlated further, both during static and dynamic loading, by developing a new system capable of either measuring both variables simultaneously or by synchronising two systems in real time.     

Solitary thyroid nodule: diagnosis and management

Thyroid nodules are common. Most are benign lesions since clinically important thyroid carcinoma is a relatively rare disease. The most sensitive and specific test for the diagnosis of thyroid cancer is fine-needle aspiration biopsy, but its diagnostic accuracy depends upon whether or not one excises all suspicious nodules, thus including them as correctly diagnosed. Nevertheless, fine-needle aspiration biopsy is the most sensitive, specific, and cost-effective test for thyroid cancer. Therapy depends upon the cause of the thyroid nodule.     

Metabolic expression of intrinsic developmental programs for dentine and enamel biomineralization in serumless,chemically-defined,organotypic culture

Summary Biomineralization was investigated using embryonic mouse mandibular first molars (M₁) cultured in the presence or absence of fetal calf serum. Metabolic features including cell division and Ca²⁺ and phosphate incorporation into dentine and enamel extracellular matrices were analyzed. The relative timing and magnitude of DNA synthesis for serumless cultures was comparable toin vivo controls. Isotopic calcium and phosphate incorporation into the mineral phase of dentine and enamel matrices, in the absence of serum, fluctuated during development. Molar tooth morphogenesis, cytodifferentiation, and extracellular matrix formation approximated late crown-stage development in serumless cultures. Von Kossa histochemical staining indicated calcium phosphate salt formation in serumless cultures. Analysis of anhydrous fixation-prepared enamel and dentine representing serumless cultured explants indicated that crystal size and orientation were comparable toin vivo enamel and dentine. In contrast, serum-supplemented cultures showed atypical crystal size and orientation. Calcium/phosphorous (Ca/P) ratio values for serumless cultures after 21 days showed Ca/P enamel values of 2.03 (SD±0.04, p<0.025) and dentine values of 1.89 (SD±0.01, p<0.025). Electron diffraction patterns of enamel and dentine formed in serumless cultures were principally those of highly-ordered crystalline hydroxyapatite. Our results suggest that tissue-specific dentine and enamel biomineralization is regulated by endogenous factors intrinsic to the developmental program of embryonic tooth organs during serumless culture.     

Main alkaloids from the Brazilian dendrobatidae frog Epipedobates flavopictus: pumiliotoxin 251D, histrionicotoxin and decahydroquinolines.

Epipedobates flavopictus, Dendrobatidae, is a small aposematic frog found in Brazilian Cerrado bioma. In the present work, we isolated and characterized chemically the most abundant alkaloids present in the cutaneous extract of E. flavopictus. The specimens were collected in Pirenópolis (Goiás, Brazil), their skins were removed and extracted with methanol, and submitted to purification by HPLC and identification by gas chromatography and mass spectrometry. Pumiliotoxin 251D, histrionicotoxin 285Da and two decahydroquinolines, 219A and 243A, were identified. The pumiliotoxin 251D was tested on isolated frog sciatic nerve and on isolated guinea pig ileum muscle. The pumiliotoxin 251D slightly reduced the action potentials amplitude of frog sciatic nerve. The crude skin extract of E. flavopictus and the pumiliotoxin 251D produced rhythmic contractions and increased the muscular tension on isolated guinea pig ileum.     

Oral leiomyosarcomas: report of two cases with immunohistochemical profile.

Leiomyosarcoma of the oral cavity is a very rare tumor associated with aggressive clinical behavior and low survival. In this paper, we report 2 cases of leiomyosarcoma, affecting the gingival mucosa of a 54-year-old female and the maxillary bone of a 63-year-old male. Histologically, the tumors were composed of variably oriented fascicles of spindle-shaped cells with cigar-shaped nuclei and eosinophilic cytoplasm. The lesions were treated by surgical resection. Immunoreactivity to anti-vimentin, anti-smooth muscle actin, anti-desmin, anti-laminin, and anti-muscle-specific actin antibodies were found; conversely, the tumor cells were negative for anti-S100 and AE1/AE3 proteins. This report emphasizes the role of immunohistochemical study for correct diagnosis of leiomyosarcoma.     

Cyclooxygenase-2 inhibition increases gastric tone and delays gastric emptying in rats.

We evaluated the effects of cyclooxygenase-2 (COX-2) selective inhibitors, COX-1 selective inhibitor, or COX non-selective inhibitor on gastric emptying and intestinal transit of liquids, and evaluated the effect of a COX-2 selective inhibitor on gastric tonus (GT). Male Wistar rats were treated per os with saline (control), rofecoxib, celecoxib, ketorolac, rofecoxib + ketorolac, celecoxib + ketorolac, or indomethacin. After 1 h, rats were gavage-fed (1.5 mL) with the test meal (5% glucose solution with 0.05 g mL(-1) phenol red) and killed 10, 20 or 30 min later. Gastric, proximal, medial or distal small intestine dye recovery (GDR and IDR, respectively) were measured by spectrophotometry. The animals of the other group were treated with i.v. valdecoxib or saline, and GT was continuously observed for 120 min using a pletismomether system. Compared with the control group, treatment with COX-2 inhibitors, alone or with ketocolac, as well as with indomethacin increased GDR (P < 0.05) at 10-, 20- or 30-min postprandial intervals. Ketorolac alone did not change the GDR, but increased the proximal IDR (P < 0.05) at 10 min, and decreased medial IDR (P < 0.05) at 10 and 20 min. Valdecoxib increased (P < 0.01) GT 60, 80 and 100 min after administration. In conclusion, COX-2 inhibition delayed the gastric emptying of liquids and increased GT in rats.