Pharmacological evaluation of a selective bradykinin B1 antagonist in a canine model of arthritis.

The effects of a selective bradykinin 1 receptor antagonist, compound A, were evaluated in a canine model of acute inflammatory model of arthritis. Despite detection of the B1 receptor in canine type B synoviocytes using a fluorescent ligand, oral administration of compound A (9 and 27 mg/kg) did not improve weight bearing of dogs injected intra-articularly with IL-1ß in a force plate analysis. Analysis of the synovial fluid of IL-1ß-treated dogs indicated high levels of bradykinin postchallenge. Excellent exposure, coupled with evidence of the presence of the B1 receptor during an acute inflammatory model of pain, indicates an inability of the receptor to mediate inflammatory pain in canines.

Assessing coughing-induced influenza droplet transmission and implications for infection risk control.

Indoor transmission of respiratory droplets bearing influenza within humans poses high risks to respiratory function deterioration and death. Therefore, we aimed to develop a framework for quantifying the influenza infection risk based on the relationships between inhaled/exhaled respiratory droplets and airborne transmission dynamics in a ventilated airspace. An experiment was conducted to measure the size distribution of influenza-containing droplets produced by coughing for a better understanding of potential influenza spread. Here we integrated influenza population transmission dynamics, a human respiratory tract model, and a control measure approach to examine the indoor environment-virus-host interactions. A probabilistic risk model was implemented to assess size-specific infection risk for potentially transmissible influenza droplets indoors. Our results found that there was a 50% probability of the basic reproduction number (R0) exceeding 1 for small-size influenza droplets of 0·3-0·4 µm, implicating a potentially high indoor infection risk to humans. However, a combination of public health interventions with enhanced ventilation could substantially contain indoor influenza infection. Moreover, the present dynamic simulation and control measure assessment provide insights into why indoor transmissible influenza droplet-induced infection is occurring not only in upper lung regions but also in the lower respiratory tract, not normally considered at infection risk.

Assessing dengue infection risk in the southern region of Taiwan: implications for control.

Dengue, one of the most important mosquito-borne diseases, is a major international public health concern. This study aimed to assess potential dengue infection risk from Aedes aegypti in Kaohsiung and the implications for vector control. Here we investigated the impact of dengue transmission on human infection risk using a well-established dengue-mosquito-human transmission dynamics model. A basic reproduction number (R 0)-based probabilistic risk model was also developed to estimate dengue infection risk. Our findings confirm that the effect of biting rate plays a crucial role in shaping R 0 estimates. We demonstrated that there was 50% risk probability for increased dengue incidence rates exceeding 0.5-0.8 wk-1 for temperatures ranging from 26°C to 32°C. We further demonstrated that the weekly increased dengue incidence rate can be decreased to zero if vector control efficiencies reach 30-80% at temperatures of 19-32°C. We conclude that our analysis on dengue infection risk and control implications in Kaohsiung provide crucial information for policy-making on disease control.

Using experimental human influenza infections to validate a viral dynamic model and the implications for prediction.

The aim of this work was to use experimental infection data of human influenza to assess a simple viral dynamics model in epithelial cells and better understand the underlying complex factors governing the infection process. The developed study model expands on previous reports of a target cell-limited model with delayed virus production. Data from 10 published experimental infection studies of human influenza was used to validate the model. Our results elucidate, mechanistically, the associations between epithelial cells, human immune responses, and viral titres and were supported by the experimental infection data. We report that the maximum total number of free virions following infection is 10(3)-fold higher than the initial introduced titre. Our results indicated that the infection rates of unprotected epithelial cells probably play an important role in affecting viral dynamics. By simulating an advanced model of viral dynamics and applying it to experimental infection data of human influenza, we obtained important estimates of the infection rate. This work provides epidemiologically meaningful results, meriting further efforts to understand the causes and consequences of influenza A infection.

Understanding influenza virus-specific epidemiological properties by analysis of experimental human infections.

This study aimed to estimate the natural history and transmission parameters based on experimental viral shedding and symptom dynamics in order to understand the key epidemiological factors that characterize influenza (sub)type epidemics. A simple statistical algorithm was developed by combining a well-defined mathematical scheme of epidemiological determinants and experimental human influenza infection. Here we showed that (i) the observed viral shedding dynamics mapped successfully the estimated time-profile of infectiousness and (ii) the profile of asymptomatic probability was obtained based on observed temporal variation of symptom scores. Our derived estimates permitted evaluation of relationships between various model-derived and data-based estimations, allowing evaluation of trends proposed previously but not tested fully. As well as providing insights into the dynamics of viral shedding and symptom scores, a more profound understanding of influenza epidemiological parameters and determinants could enhance the viral kinetic studies of influenza during infection in the respiratory tracts of experimentally infected individuals.

Viral kinetics and exhaled droplet size affect indoor transmission dynamics of influenza infection.

The purpose of this paper was to investigate the effects of viral kinetics and exhaled droplet size on indoor transmission dynamics of influenza infection. The target cell-limited model with delayed virus production was adopted to strengthen the inner mechanisms of virus infection on human epithelial cell. The particle number and volume involved in the viral kinetics were linked with Wells-Riley mathematical equation to quantify the infection risk. We investigated population dynamics in a specific elementary school by using the seasonal susceptible - exposed - infected - recovery (SEIR) model. We found that exhaled pulmonary bioaerosol of sneeze (particle diameter <10 microm) have 10(2)-fold estimate higher than that of cough. Sneeze and cough caused risk probabilities range from 0.075 to 0.30 and 0.076, respectively; whereas basic reproduction numbers (R(0)) estimates range from 4 to 17 for sneeze and nearly 4 for cough, indicating sneeze-posed higher infection risk. The viral kinetics and exhaled droplet size for sneeze affect indoor transmission dynamics of influenza infection since date post-infection 1-7. This study provides direct mechanistic support that indoor influenza virus transmission can be characterized by viral kinetics in human upper respiratory tracts that are modulated by exhaled droplet size. Practical Implications This paper provides a predictive model that can integrate the influenza viral kinetics (target cell-limited model), indoor aerosol transmission potential (Wells-Riley mathematical equation), and population dynamic model [susceptible - exposed - infected - recovery (SEIR) model] in a proposed susceptible population. Viral kinetics expresses the competed results of human immunity ability with influenza virus generation. By linking the viral kinetics and different exposure parameters and environmental factors in a proposed school setting with five age groups, the influenza infection risk can be estimated. On the other hand, we implicated a new simple means of inhaling to mitigate exhaled bioaerosols through an inhaled non-toxic aerosol. The proposed predictive model may serve as a tool for further investigation of specific control measure such as the personal protection masks to alter the particle size and number concentration characteristics and minimize the exhaled bioaerosol droplet to decrease the infection risk in indoor environment settings.

Time dependent validity in the diagnosis of brain death using transcranial Doppler sonography.

OBJECTIVE: To evaluate the validity of transcranial Doppler (TCD) in confirming brain death from various pathological conditions. METHODS: An observational case-control study over a 2.5 year period, in which transcranial Doppler (TCD) examinations were done on 101 comatose patients for confirmation of brain death. Between October 2002 to May 2005, 44 clinically diagnosed brain death cases (29 male, 15 female; mean (SD) age, 46.5 (19.5) years; Glasgow Coma Scale (GCS) score, 3.0 (0.0)) and 57 controls (36 male, 21 female; age 48.1 (16.5) years; mean GCS, 4.9 (1.7)) were examined. Reverse diastolic flow, very small systolic spikes, or no signals were considered characteristic of cerebral circulatory arrest. RESULTS: The sensitivity and specificity of TCD examination of both the basilar artery and the middle cerebral arteries (MCAs) in confirming brain death were 77.2% and 100%, respectively. The sensitivity of TCD-diagnosed brain death increased with elapsed time. There was a trend for the basilar artery to have greater sensitivity (86.4% v 77.2%), higher positive predictive value (90.5% v 85.1%), and fewer false negatives (14% v 23.7%) than the MCAs for diagnosing brain death (all NS). The consistency of the basilar artery and the MCAs for diagnosing brain death was significant (kappa=0.877, p<0.001 and kappa=0.793, p<0.001, respectively). CONCLUSIONS: TCD can be a confirmatory tool for diagnosing brain death. The validity of TCD diagnosed brain death depends on the time lapse between brain death and the performance of TCD. TCD of both the basilar artery and the MCAs showed significant consistency in brain death diagnosis.

Characteristics of aerosols collected in central Taiwan during an Asian dust event in spring 2000.

Aerosol samples for PM(2.5) and PM(2.5-10) were collected at four locations in central Taiwan from 26 to 31 March 2000, a period that experienced exceedingly high PM levels from 29 to 30 March due to the passage of an Asian dust storm. The samples were analyzed for mass, metallic elements, ions, and carbon. The purpose of this paper is to investigate the influence of the dust storm on the characteristics of local ambient particulate matter. The results indicate that the concentrations of the crustal elements Ca, Mg, Al, Fe and the sea salt species Na+ and Cl- in PM(2.5-10) during the dust episode exceed the mean concentrations in the non-dust period by factors of 3.1, 2.9, 2.6, 2.2, 2.3 and 2.1 respectively. Enrichment factors of Ca, Fe, and Mg in PM(2.5-10) during the dust event are close to unity, indicating that these elements are from soil. Reconstruction of aerosol compositions revealed that soil of coarse particulates elevated approximately 50% in the dust event. It is noted that during the dust event, the ratio of Mg/Al in PM(2.5-10) ranged from 0.21 to 0.25 while that of Ca/Al ranged from 0.6 to 0.9, levels more constant than those obtained in non-dust period.

Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633.

The present study describes the preclinical pharmacology of a highly selective 5-HT1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nm at the human 5-HT1D receptor and a Ki of> 18 000 nm at the human 5-HT1B receptor. The intrinsic activity of PNU-142633 at the human 5-HT1D receptor was determined to be 70% that of 5-HT in a cytosensor cell-based assay compared with 84% for that of sumatriptan. PNU-142633 was equally effective as sumatriptan and a half-log more potent than sumatriptan in preventing plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion. Like sumatriptan, PNU-142633 reduced the increase in cat nucleus trigeminal caudalis blood flow elicited by electrical stimulation of the trigeminal ganglion compared with the vehicle control. The direct vasoconstrictor potential of PNU-142633 was evaluated in vascular beds. Sumatriptan increased vascular resistance in carotid, meningeal and coronary arteries while PNU-142633 failed to alter resistance in these vascular beds. These data are discussed in relation to the clinical findings of PNU-142633 in a phase II acute migraine study.

Allosteric modulation of the human 5-HT(7A) receptor by lipidic amphipathic compounds.

Human 5-HT7A receptors positively modulated adenylyl cyclases via Gs subtypes of G proteins in human embryonic kidney 293 cells, and bound 5-hydroxytryptamine (HT) with high and low affinity (K(I) values of 1.5 +/- 0.3 and 93 +/- 4 nM). More than 60% of 5-HT7A receptors, however, displayed the high-affinity 5-HT binding with no sensitivity to 5'-guanylylimidodiphosphate. In this study, we found that select amphipathic agents affected the high-affinity 5-HT binding to 5-HT7A. Oleic acid at low concentrations (<15 microM), but not palmitic, stearic, and arachidonic acids, increased maximal [3H]5-HT binding without affecting its K(D) value and [3H]mesulergine (antagonist) binding. Fatty acid-free bovine serum albumin (FF-BSA), a scavenger of fatty acids and lipid metabolites, substantially reduced maximal [3H]5-HT binding (no change in K(D) value and antagonist binding) but lost its action upon treatment with inactive stearic acid. FF-BSA and oleic acid produced no appreciable effects on [3H]5-HT binding to analogous 5-HT receptors 5-HT1D and 5-HT2C. Among various lysophospholipids, lysophosphatidyl choline (50 microM) decreased maximal [3H]5-HT binding, and a similar zwitterion, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS; 0.1%), increased it (no change in K(D)). Functionally, 5-HT-induced guanosine-5'-O-(3-[35S]thio)triphosphate (GTPgamma35S) binding was enhanced by oleic acid and CHAPS, but reduced by FF-BSA and lysophosphatidyl choline; the amphipathic agents and FF-BSA did not affect dopamine-induced GTPgamma35S binding at D1, a prototypic Gs-coupled receptor. At 5-HT7A, oleic acid, FF-BSA, CHAPS, and lysophosphatidyl choline also brought about corresponding changes in the half-maximal 5-HT concentration for cAMP production, without affecting the maximal and basal levels. We propose that endogenous, amphipathic lipid metabolites may modulate 5-HT7A receptors allosterically to promote high-affinity 5-HT binding and to enable receptors to couple more efficiently to Gs subtypes of G proteins.

Down-regulation of Fas-L in glioma cells by ribozyme reduces cell apoptosis, tumour-infiltrating cells, and liver damage but accelerates tumour formation in nude mice.

Fas-L (CD95L, APO-1L) expresses in a variety of tumours and has been proposed to play a role in tumour formation and metastasis. The contribution of Fas-L to tumour growth, however, is not conclusive especially in systems using cells with over-expressed Fas-L. In this study we down-regulated the expression o Fas-L in human glioma cells by a hammerhead ribozyme (Fas-L(ribozyme)) targeting against Fas-L mRNA. Fas-L(ribozyme)-carrying cells exhibited slightly enhanced growth rate and less degree of spontaneous apoptosis in vitro as compared with vector controls. In nude mice, Fas-L(ribozyme)-carrying cells grew faster with lesser apoptosis, formed bigger tumour with significantly fewer infiltrating cells in the tumour area, and triggered relatively milder tumour-associated liver damage than vector controls did. Thus, down-regulation of Fas-L not only improved viability of glioma cells but also reduces local immune responses that may consequently affect tumour formation. Taken together, our findings imply that endogenous expression of Fas-L in malignant cells is not always growth promoting.

Primary cerebral anaplastic large cell lymphoma containing abundant reactive histiocytes and eosinophils. A case report and literature review.

Primary cerebral anaplastic large cell lymphoma (ALCL) is very rare. We report on our experience with such a case and review the literature. A 46-year-old Taiwanese woman presented with headache, weakness of her right extremity, and limited eye movement. A solid mass (5 cm x 4 cm) at the left occipital lobe was almost completely removed. The neoplastic cells, some of which had reniform or embryo-like nuclei, were large and were admixed with abundant eosinophils, histiocytes, and some small lymphocytes. These neoplastic cells expressed CD30, CD43, granzyme B and T-cell intracellular antigen-1, but not ALK1, CD3, CD20, CD45, CD79a, cytokeratin, and EMA. They were positive for Epstein-Barr virus-encoded mRNA by in situ hybridization. Polymerase chain reaction study of formalin-fixed tissue showed a clonal gene arrangement of the T-cell receptor-gamma chain. ALCL of T-cell lineage with cytotoxic phenotype was diagnosed. The patient received cranial irradiation and has remained with no evidence of disease for 25 months of follow-up.

Subdural empyema in 10 infants: US characteristics and clinical correlates.

PURPOSE: To investigate the ultrasonographic (US) characteristics of subdural empyema (SDE) and its differentiation from reactive subdural effusion (RSE) in infants with meningitis. MATERIALS AND METHODS: Images in 10 infants with SDE with or without RSE complicating meningitis were retrospectively reviewed and correlated with clinical findings and compared with US and magnetic resonance (MR) images in four infants with meningitis and RSE. RESULTS: At US, 15 of 16 SDEs in the 10 infants were seen as heterogeneous to hyperechoic convexity collections. Hyperechoic strands were seen in 12 SDEs. Other findings included a thick, echogenic inner membrane (n = 9), increased echogenicity of pia-arachnoid and exudates in the subarachnoid space (n = 16), mass effect (n = 16), and loculated extraaxial collections (n = 2). MR imaging findings correlated well with US and surgical results. At computed tomography, SDE was misinterpreted as RSE in one patient, due to the absence of inner membrane contrast material enhancement. Clinical outcome was related to the degree of brain damage consequent to meningitis and the chronicity of SDE. RSEs in seven infants (three with concurrent SDE) were anechoic; an inner membrane was seen in six, and increased pia-arachnoid echogenicity was seen in four. CONCLUSION: SDE has complex US features that are helpful for differentiation from anechoic RSE in infants with meningitis.

Effects of insulin on protein phosphorylation and protein kinase C activity in human malignant gliomas.

Modulation of protein phosphorylation activities by insulin was investigated in glioma and normal glial cells. Insulin suppressed the in vitro protein phosphorylation of glioma cells in a dose-dependent manner while it stimulated that of meningiomas, neurilemmomas and glial cells. Although gliomas and glial cells contained different species of tyrosyl phosphoproteins before treatment, they expressed similar kinds of tyrosyl phosphoproteins in response to insulin. Insulin increased the activities of casein kinase II and total protein kinase C (PKC) in glioma and normal glial cells. The membrane-bound PKC activity in U373-MG cells was elevated by insulin. The PKC isozymes, including subtypes alpha, beta, delta, epsilon and gamma, were detected in gliomas, but few were found in glial cells. Insulin down regulated the cytosolic PKC-gamma and the membrane-bound PKC-epsilon proteins in gliomas. These results indicate that an altered insulin signaling pathway exists in human gliomas, which might involve differential regulation of PKC isozymes.

Risk factor of complications requiring neurosurgical intervention in infants with bacterial meningitis.

Among 50 consecutive cases of bacterial meningitis in infants aged 6 months or less, 9 (Group I) were confirmed to have complications requiring neurosurgery during the first 2 weeks of antibiotic treatment. Neurosurgery was performed in 40, 33, and 30% of cases caused by Streptococcus pneumoniae, Pseudomonas aeruginosa, and Escherichia coli, respectively. There were 5 cases of subdural empyema, 1 case of brain abscess, 1 case of subdural empyema and brain abscess, and 2 cases of ventriculitis with severe hydrocephalus. All complications requiring neurosurgery were initially detected by cranial ultrasonography. The other 41 patients who did not undergo neurosurgery were classified as Group II. Comparison of clinical presentations and laboratory findings between the two groups showed that Group 1 contained more patients with a history of inadequate treatment, and longer duration of illness before diagnosis. Except for prolonged disturbance of consciousness, there was no difference between the two groups in clinical and laboratory data on admission or in clinical course during therapy. Due to the high incidence of complications requiring neurosurgical treatment, cost-effective cranial ultrasound is recommended for screening every young infant with bacterial meningitis, especially in cases caused by S. pneumoniae.

Complications in patients with palmar hyperhidrosis treated with transthoracic endoscopic sympathectomy.

OBJECTIVE: To assess the complications in a group of patients with palmar hyperhidrosis treated with transthoracic endoscopic sympathectomy. The extraordinarily high incidence of postoperative compensatory hyperhidrosis in our series is stressed and explained. METHODS: The retrospective study included chart reviews and outpatient assessments. Seventy-two patients underwent T2 or T2-T3 endoscopic sympathectomy for primary palmar hyperhidrosis. Patients' hyperhidrosis severity, precipitating factors, postoperative complications, surgical results, and satisfaction were assessed. Severity of palmar hyperhidrosis and compensatory hyperhidrosis was classified by two grading scales. RESULTS: The success rate of sympathectomy was 93%. All patients except one suffered from compensatory sweating, which was the main cause of patients' dissatisfaction postoperatively. Seventeen percent of the patients (12 of 72 patients) experienced new symptoms of gustatory sweating (facial sweating associated with eating). Twenty-one patients experienced other complications, including pneumothorax, Horner's syndrome, nasal obstruction, and intercostal neuralgia. CONCLUSION: Transthoracic endoscopic sympathectomy is an effective and simple modality to treat palmar hyperhidrosis. However, all patients need to be warned of the common complications, particularly compensatory hyperhidrosis, before surgery.

Prognostic significance of altered cerebral blood flow velocity in acute head trauma.

From July 1992 to January 1993, 31 patients with acute closed head injuries underwent blood flow velocity (BFV) measurement in the middle cerebral artery by transcranial Doppler ultrasound. Eighteen patients had abnormal changes of BFV (group A) and 13 patients had normal BFV (group B). In group A, there were eight deaths (44%) and the Glasgow Outcome Scale score was 2.6 +/- 0.4 (mean +/- SEM). On admission, 14 group A patients had decreased BFV, including nine patients with evidence of early cerebral circulatory arrest (CCA). During hospitalization, eight group. A patients were diagnosed with global hyperemia, including two patients who had early CCA. Another six in group A had ultrasound recordings consistent with vasospasm, and three of these six also experienced early CCA. The renaming four patients in group A had persistently low BFV, progressing from early CCA. In group B there were two deaths (15%) and the mean Glasgow Outcome Scale score was 4.0 +/- 0.5. Group A had higher mortality (Fisher's exact test, p = 0.128) and a significantly higher rate of unfavorable functional outcome than group B. To evaluate the prognostic significance of these BFV changes, group A was subdivided into global hyperemia, vasopasm and early CCA subgroups. Both the vasospasm and early CCA subgroups had significantly lower Glasgow Coma Scale scores on admission and a higher rate of unfavorable functional outcomes than group B. All five survivors with vasospasm and/or early CCA showed ischemic morbidity on follow-up cranial computed tomography; though those with global hyperemia did not. There were no significant differences in the Glasgow Coma Scale score on admission, mortality or functional outcome between global hyperemia patients and group B patients. Global hyperemia may represent a recovery stage of impaired cerebral hemodynamics. This stage may occur transiently and has no major impact on morbidity or mortality. Vasospasm and early CCA may be closely related to ischemic complications, and may provide clinical information for selecting appropriate therapy in acute head trauma.