Airway mechanics, gas exchange, and blood flow in a nonlinear model of the normal human lung

A model integrating airway/lung mechanics, pulmonary blood flow, and gas exchange for a normal human subject executing the forced vital capacity (FVC) maneuver is presented. It requires as input the intrapleural pressure measured during the maneuver. Selected model-generated output variables are compared against measured data (flow at the mouth, change in lung volume, and expired O2 and CO2 concentrations at the mouth). A nonlinear parameter-estimation algorithm is employed to vary selected sensitive model parameters to obtain reasonable least squares fits to the data. This study indicates that 1) all three components of the respiratory model are necessary to characterize the FVC maneuver; 2) changes in pulmonary blood flow rate are associated with changes in alveolar and intrapleural pressures and affect gas exchange and the time course of expired gas concentrations; and 3) a collapsible midairway segment must be included to match airflow during a forced expiration. Model simulations suggest that the resistances to airflow offered by the collapsible segment and the small airways are significant throughout forced expiration; their combined effect is needed to adequately match the inspiratory and expiratory flow-volume loops. Despite the limitations of this lumped single-compartment model, a remarkable agreement with airflow and expired gas concentration measurements is obtained for normal subjects. Furthermore, the model provides insight into the important dynamic interactions between ventilation and perfusion during the FVC maneuver.     

Once-daily sparfloxacin versus high-dosage amoxicillin in the treatment of community-acquired, suspected pneumococcal pneumonia in adults. Sparfloxacin European Study Group

The objective of this randomized, double-blind, multicenter study of 329 adult patients requiring hospitalization was to compare the safety and efficacy of sparfloxacin at a dosage of 200 mg once daily (following a 400-mg loading dose on day 1) with those of amoxicillin given as a 1-g oral dose three times daily for treatment of community-acquired pneumonia suspected to be due to Streptococcus pneumoniae. Success of treatment was determined by a combination of clinical assessment and chest radiography. Pneumococcal pneumonia was the confirmed diagnosis for 177 patients (54%). Overall rates of success among evaluable patients were equivalent between drugs, both at the end of treatment (sparfloxacin, 92%; amoxicillin, 87%) and at follow-up (sparfloxacin, 89%; amoxicillin, 84%). Sparfloxacin was well-tolerated and produced fewer gastrointestinal effects than amoxicillin. In conclusion, sparfloxacin is a safe and effective alternative to high-dose amoxicillin for the treatment of suspected pneumococcal community-acquired pneumonia.     

The pharmacology of mesocortical dopamine neurons: a dual-probe microdialysis study in the ventral tegmental area and prefrontal cortex of the rat brain

The development of receptor function at corticothalamic synapses during the first 20 days of postnatal development is described. Whole cell excitatory postsynaptic currents (EPSCs) were evoked in relay neurons of the ventral posterior nucleus (VP) by stimulation of corticothalamic fibers in in vitro slices of mouse brain from postnatal day 1 (P1). During P1-P12, excitatory postsynaptic conductances showed strong voltage dependence at peak current and at 100 ms after the stimulus and were almost completely antagonized by -2-amino-5-phosphonopentoic acid (APV), indicating that N-methyl--aspartate (NMDA) receptor-mediated currents dominate corticothalamic EPSCs at this time. After P12, in 42% of cells, excitatory postsynaptic conductances showed no voltage-dependence at peak current but still showed voltage-dependence 100-ms poststimulus. This voltage-dependent conductance was antagonized by APV. The nonvoltage-dependent component was APV resistant, showed fast decay, and was antagonized by the nonNMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). In the remaining 58% of cells after P12, excitatory postsynaptic conductances showed moderate voltage dependence at peak conductance and strong voltage dependence 100 ms after the stimulus. Analysis of EPSCs before and after APV showed a significant increase in the relative contribution of the non-NMDA conductance after the second postnatal week. From P1 to P16, there was a significant decrease in the time constant of decay of the NMDA EPSC but no change in the voltage dependence of the NMDA response. After P8, slow EPSPs, 1.5-30 s in duration and mediated by metabotropic glutamate receptors (mGluRs), could be evoked by high-frequency stimulation of corticothalamic fibers in the presence of APV and CNQX. Similar slow depolarizations could be evoked by local application of the mGluR agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD) but from P0. Both conductances were blocked by the mGluR antagonist, (RS)-alpha-methyl-4-carboxyphenylglycine. Hence functional mGluR receptors are present on VP cells from birth, but their synaptic activation at corticothalamic synapses can only be detected after P8. In voltage clamp, the extrapolated reversal potential of the t-ACPD current, with potassium gluconate-based internal solution, was +12 +/- 10 (SE) mV, and the measured reversal potential with cesium gluconate-based internal solution was 1.5 +/- 9.9 mV, suggesting that the mGluR-mediated depolarization was mediated by a nonselective cation current. Replacement of NaCl in the external solution caused the reversal potential of the current to shift to -18 +/- 2 mV, indicating that Na+ is a charge carrier in the current. The current amplitude was not reduced by application of Cs+, Ba2+, and Cd2+, indicating that the t-ACPD current was distinct from the hyperpolarization-activated cation current (IH) and distinct from certain other previously characterized mGluR-activated, nonselective cation conductances.     

Clinical predictors of early embolic recurrence in presumed cardioembolic stroke

BACKGROUND: We determined clinical predictive factors of in-hospital embolic recurrence in presumed cardioembolic stroke patients by means of multivariate analysis based on clinical and neuroimaging prognostic variables assessed within 48 h of stroke onset. METHODS: Data of 347 consecutive patients with presumed cardioembolic stroke included in a prospective stroke registry were collected. Demographic characteristics, clinical events, and outcome in the recurrent and nonrecurrent embolization group were compared. The independent predictive value of each variable on the development of early embolic recurrence was analyzed in two multiple liner regression models - one based on eight demographic, anamnestic, and clinical variables and another based on 10 clinical, neuroimaging, and outcome variables. RESULTS: In-hospital recurrent embolization was diagnosed in 25 (6.9%) patients. The latency period was 12.1 days. The overall in-hospital mortality was 70.8% in the recurrent embolization group and 24.4% in the nonrecurrent embolization group (p < 0.001). Alcohol abuse, the combination of hypertension, valvular heart disease, and atrial fibrillation, nausea and vomiting, and previous cerebral infarction were predictors of recurrent embolization in the model based on clinical variables. In addition to these four variables, cardiac events were selected in the model based on clinical, neuroimaging, and outcome variables. CONCLUSIONS: A small number of clinical features that can be easily obtained on the patient's initial assessment may help clinicians to identify a subgroup of patients with cardioembolic stroke at the highest risk of developing early recurrent brain or systemic embolization.     

Subfornical organ: forebrain site of pressor and dipsogenic action of angiotensin II

Intracranial injection of angiotensin II (AII) at three brain sites elicited near simultaneous dipsogenic and pressor effects in rats. Both effects were maximal, occurred with the shortest latencies, and at the lowest doses of AII when the cannula terminated precisely within the parenchyma of the subfornical organ (SFO). Pressor effects were produced by SFO injection of a dose of AII (0.1 pg) which approximates plasma AII concentrations at the high end of the physiological range. Both the drinking and pressor effects were blocked by saralasin. Injections of AII at sites immediately adjacent to SFO produced smaller effects with longer latencies. These results ruled out the possibility that SFO injections were effective via leakage to alternative sites. The pressor effect of AII at the SFO remained in animals under chloralose anesthesia, demonstrating that it is not an artifact of drinking behavior. These results indicate that the SFO is a site of AII pressor action, and confirm previous demonstrations that the structure is a site of AII drinking action.     

Sycnthesis of quinazoline analogues of folic acid modified at postion 10

The quinazoline couterpart of folic acid (5,8-deazafolic acid) as well as its 10-methyl analogue has been shown to be an effective inhibitor of thymidylate synthetase from several different sources. This paper describes the synthesis of modifications in which the nitrogen atom at position 10 is replaced by sulfur, oxygen, or methylene affording 10-thia-5,8-deazafolic acid, 10-oxa-5,8-deazafolic acid, and 5,8,10-deazafolic acid, respectively. In preliminary testing, each of the target compounds displayed marginal activity against L1210 leukemia in mice.     

Residual effects of septic arthritis in infancy and childhood

Septic arthritis affects weight-bearing joints in three fourths of cases. When the disease occurs in infancy, joint dysfunction may not be apparent until many months later. We located 49 children who had had 50 episodes of septic arthritis from 1 1/2 to 12 years earlier (mean, 4.3 years). Thirteen patients (27%) had sequelae, and in eight (16%), there was impairment of ambulation. Residual damage was more common with hip and ankle involvement than with knee joint disease. Sequelae were equally common after Haemophilus influenzae and Staphylococcus aureus infection. Evaluation at the time of hosiptal discharge correctly identified only four of the 13 children with sequelae, and four others who were normal at follow-up had been thought to have permanent damage at discharge. Children with sequelae tended to have been sick longer before diagnosis, and drainage of pus was delayed.