IL‐28B (IFN‐λ3) and IFN‐α synergistically inhibit HCV replication

Genetic variation in the IL‐28B (interleukin‐28B; interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C treated with peginterferon‐α and ribavirin. However, the mechanisms by which polymorphisms in the IL‐28B gene region affect host antiviral responses are not well understood. Using the HCV 1b and 2a replicon system, we compared the effects of IFN‐λs and IFN‐α on HCV RNA replication. The anti‐HCV effect of IFN‐λ3 and IFN‐α in combination was also assessed. Changes in gene expression induced by IFN‐λ3 and IFN‐α were compared using cDNA microarray analysis. IFN‐λs at concentrations of 1 ng/mL or more exhibited concentration‐ and time‐dependent HCV inhibition. In combination, IFN‐λ3 and IFN‐α had a synergistic anti‐HCV effect; however , no synergistic enhancement was observed for interferon‐stimulated response element (ISRE) activity or upregulation of interferon ‐ stimulated genes (ISGs). With respect to the time course of ISG upregulation, the peak of IFN‐λ3‐induced gene expression occurred later and lasted longer than that induced by IFN‐α. In addition, although the genes upregulated by IFN‐α and IFN‐λ3 were similar to microarray analysis, interferon‐stimulated gene expression appeared early and was prolonged by combined administration of these two IFNs. In conclusion, IFN‐α and IFN‐λ3 in combination showed synergistic anti‐HCV activity in vitro. Differences in time‐dependent upregulation of these genes might contribute to the synergistic antiviral activity.     

Morphology of the tongue in a newborn Stejneger's beaked whale (Mesoplodon stejnegeri)

This light and scanning electron microscopic (SEM) study on the tongue of a newborn Stejneger's beaked whale (Mesoplodon stejnegeri) demonstrated a clear difference in its form from than that of other cetacean and adult Stejneger's beaked whales. This newborn Stejneger's beaked whale had a spoon-like shaped tongue. The dorsal surface in the center part of the tongue was flat and did not have papillae, but there were marginal papillae and small papillae on the anterior part of the tongue. In the posterior of the tongue, hillock-shaped papillae with taste buds on the epithelium were observed.     

Geriatric voice and laryngeal dysfunction

Vocal disorders are a common dysfunction associated with aging that can have a significant effect on the quality of life. An appreciation for the many causes of vocal dysfunction in the elderly is a first step to providing better care for the geriatric patient with complaints about voice dysfunction.     

Management of traumatic hypopharyngeal injuries

Violation of the hypopharynx by external penetrating trauma is an uncommon occurrence that may lead to life-threatening infectious complications if not recognized promptly and treated appropriately. A retrospective review of 48 such injuries seen during a 10-year period showed that flexible fiberoptic endoscopic examination is the best screening tool for recognition of a possible hypopharyngeal mucosal violation. Direct laryngopharyngoscopy is the best method of definitively diagnosing the injury. Size of the visualized mucosal violation alone is not sufficient information on which to base the decision for medical management versus surgical intervention (i.e., immediate exploration and drainage). Rather, the size, exact site of injury, and mechanism of the injury must be considered to have equal importance. Associated vertebral body fractures may negatively influence acute outcome if diagnosis and treatment of the hypopharyngeal injury are delayed by the cervical spine injury.     

Nonsecretory primary plasma cell leukemia successfully treated with VAD and MP therapy

A 78-year-old woman was admitted to our hospital because of lumbago and appetite loss. Blood analysis revealed anemia, hypercalcemia and circulating plasma cells. Bone marrow aspiration showed an elevated ratio (43%) of plasma cells, which expressed CD38 in the absence of CD19 and CD56 expression. Spinal MR imaging revealed multiple compression fractures and suggested diffuse invasion of plasma cells into the spinal bodies. No M-protein was detectable in serum or urine by immunoelectrophoresis and immunofixation, but cytoplasmic M-protein (IgG-kappa) was detected by enzyme antibody staining. On the basis of the history and data, nonsecretory primary plasma cell leukemia was diagnosed. First, the patient was given modified VAD therapy (vincristine, doxorubicin, and prednisolone) and complete remission was obtained. Then MP therapy (melphalan and prednisolone) was instituted, and remission has since been maintained for 11 months. Like many other cases of primary plasma cell leukemia, this case suggests that CD56 may act as an adhesion molecule between neoplastic plasma cells and bone marrow stromal cells. Our experience with this exceedingly rare case suggests the superiority of combination chemotherapy as an induction therapy and the effectiveness of MP therapy as maintenance therapy for this disease.     

Cyclotheonamide E4 and E5, new potent tryptase inhibitors from an Ircinia species of sponge

Tryptase is a protease released from mast cells and is believed to contribute to the inflammatory process in allergic diseases including asthma. In the course of screening to find tryptase inhibitors, we isolated two new tryptase inhibitors, cyclotheonamide E4 (3) and E5 (4), from a marine sponge of the genus Ircinia. The structures of these molecules were determined by interpretation of 1H and 13C NMR spectra, and they were shown to be closely related to the previously reported cyclotheonamides E (1), E2, and E3 (2). These molecules contain two unusual amino acids, vinylogous tyrosine and alpha-ketohomoarginine, which are involved in strong activities against serine proteases. Cyclotheonamide E4 showed potent inhibitory activity against human tryptase (IC50 5.1 nM). Therefore, cyclotheonamide E4 may be useful as a therapeutic agent in the treatment of allergic diseases including asthma.     

A seasonal model to simulate influenza oscillation in Tokyo

The purpose of our study was to establish a seasonal model to simulate the oscillation of the number of influenza cases with weather conditions and calendar months in Tokyo, Japan, during the winter season. Surveillance data for influenza in Tokyo was retrieved from the Infectious Agents Surveillance Report, published by the National Institute of Infectious Diseases in Japan. We obtained data for 86 parameters of weather conditions from the Meteorological Agency. The best-fit model was built by multiple regression with stepwise analysis. The reported number of patients with influenza per week was significantly increased with fewer days of maximum temperature 10 per week (T10) and more days of relative humidity <60% per week (S60), adjusted by calendar month, average temperature, and vapor pressure. Annual oscillation of the number of reported influenza cases at the start, peak, and end weeks almost exactly matched the model, although peak levels for each oscillation did not always match. However, this model showed that 81% of the variation among the observed number of influenza cases was explained by a linear relationship with the seasonal parameters utilized. The validity of this model applied to data from 1999 to 2002, showing a 75% correlation. Using this model, if the number of days with both T10 and S60 increased by one per week, the number of influenza cases was simulated to decrease by approximately half. These results suggest that most of the oscillation in the number of influenza cases may be explained using a seasonal model that can simulate the impact of global warming.     

Tramadol inhibits norepinephrine transporter function at desipramine-binding sites in cultured bovine adrenal medullary cells

Tramadol is a widely used analgesic, but its mode of action is not well understood. To study the effects of tramadol on norepinephrine transporter (NET) function, we assayed the effect of tramadol on [3H]-norepinephrine ([3H]-NE) uptake and [3H]-desipramine binding to plasma membranes isolated from bovine adrenal medulla. We then characterized [14C]-tramadol binding in cultured bovine adrenal medullary cells. Tramadol inhibited the desipramine-sensitive uptake of [3H]-NE by the cells in a concentration-dependent manner (50% inhibitory concentration = 21.5 +/- 6.0 microM). Saturation analysis revealed that tramadol increased the apparent Michaelis constant of [3H]-NE uptake without changing the maximal velocity, indicating that inhibition occurred via competition for the NET (inhibition constant, K(i) = 13.7 microM). Tramadol inhibited the specific binding of [3H]-desipramine to plasma membranes. Scatchard analysis of [3H]-desipramine binding revealed that tramadol increased the apparent dissociation constant (K(d)) for binding without altering maximal binding, indicating competitive inhibition (K(i) = 11.2 microM). The binding of [14C]-tramadol to the cells was specific and saturable, with a K(d) of 18.1 +/- 2.4 microM. These findings indicate that tramadol competitively inhibits NET function at desipramine-binding sites. IMPLICATIONS: Tramadol competitively inhibits norepinephrine transporter function at desipramine-binding sites in the adrenal medullary cells and probably the noradrenergic neurons of the descending inhibitory system.