Multi-electrode neurostimulation system for treatment of cognitive impairments.

Peculiarities of neurostimulation organization by a multi-electrode system are considered. The system forms the spatially distributed field of current pulses that impact the nerve centers of the neck. An example is given for technical implementation of such a system in device SYMPATHOCOR and the method of its application: the dynamic correction of activity of the sympathetic nervous system. Results of its clinic application to treating the children with the attention deficit syndrome are given. It is shown that taking into account pathophysiological peculiarities of such a syndrome, it could be considered as a general model of cognitive impairments.

Safety of paracentesis in inpatients.

INTRODUCTION: Prior research has suggested that paracentesis is free from complications such as acute renal failure (ARF) providing albumin is administered. Actual safety of paracentesis > 1,000 ml was assessed at a tertiary care hospital. METHODS: 300 inpatient paracenteses performed between 12/99 and 4/04 were identified by coding records, of which 40 procedures were excluded due to lack of pre- or post-procedure lab values. Charts were reviewed for serum creatinine (Scr) before and after procedures, ascites volume, and clinical outcomes. RESULTS: 44 deaths occurred after 260 paracenteses (16.9%). Among 33 patients with ARF, 13 (39.4%) died. Only 31/227 patients without ARF (13.7%) died (p < 0.001). Serum creatinine (Scr) > 1.6 mg/dl prior to paracentesis predicted a 22.5% rate of ARF, compared to 8% for Scr < 1.0 (p = 0.002). ARF increased as volume increased (9.9%, 12.4%, and 14.9%, for volumes of < 2,300, 2,300 - 3,200, and > 3,200 ml) but this trend did not have statistical significance (p = 0.426). ARF occurred in 11/69 (15.9%) of patients receiving albumin, compared to 22/191 (11.5%) of patients who did not (p = 0.462). CONCLUSIONS: Paracentesis in inpatients has significant rates of ARF and death. Scr > 1.6 prior to paracentesis predicts an increased rate of ARF. Development of ARF is associated with an increased rate of death. No advantage was demonstrated with administration of albumin. Pre- and post-paracentesis labwork should be routine in inpatients.

The development of a scale to assess war-time atrocities: the War Events Scale.

The War Events Scale (WES) was developed to assist clinicians with the assessment of war zone veterans' exposure to, and participation in war-time atrocities distinct from combat, and their current distress from these events. Data concerning content validity, test-retest reliability, internal consistency, as well as correlational data with the Combat Exposure Scale and the Mississippi Scale are presented. Results indicate that the WES does have adequate internal consistency and test-retest reliability, and correlates moderately with the Combat Exposure and Mississippi Scales. Initial results suggest that the WES may be helpful in collecting extremely sensitive information concerning the exposure of war zone veterans to atrocities.

Risk assessment of low-level chemical exposures from consumer products under the U.S. Consumer Product Safety Commission chronic hazard guidelines.

The U.S. Consumer Product Safety Commission (CPSC) is an independent regulatory agency that was created in 1973. The CPSC has jurisdiction over more the 15,000 types of consumer products used in and around the home or by children, except items such as food, drugs, cosmetics, medical devices, pesticides, certain radioactive materials, products that emit radiation (e.g., microwave ovens), and automobiles. The CPSC has investigated many low-level exposures from consumer products, including formaldehyde emissions from urea-formaldehyde foam insulation and pressed wood products, CO and NO2 emmissions from combustion appliances, and dioxin in paper products. Many chemical hazards are addressed under the Federal Hazardous Substances Act (FHSA), which applies to acute and chronic health effects resulting from high- or low-level exposures. In 1992 the Commission issued guidelines for assessing chronic hazards under the FHSA, including carcinogenicity, neurotoxicity, reproductive/developmental toxicity, exposure, bioavailability, risk assessment, and acceptable risk. The chronic hazard guidelines describe a series of default assumptions, which are used in the absence of evidence to the contrary. However, the guidelines are intended to be sufficiently flexible to incorporate the latest scientific information. The use of alternative procedures is permissible, on a case-by-case basis, provided that the procedures used are scientifically defensible and supported by appropriate data. The application of the chronic hazard guidelines in assessing the risks from low-level exposures is discussed.

Protein kinase C modulator effects on parathyroid hormone-induced intracellular calcium and morphologic changes in UMR 106-H5 osteoblastic cells.

The effects of parathyroid hormone (PTH) on 1,4,5-inositol triphosphate (1,4,5-IP3) and intracellular free calcium (Cai2+) in osteoblasts are variable, whereas adenylate cyclase activity is consistently stimulated. Cyclic AMP is considered a mediator in the contractile effects of PTH on osteoblasts, but the regulation and role of Cai2+ remains unclear. Recent studies indicate that protein kinase C (PKC) inhibits PTH-stimulated Cai2+ increases in osteoblastic cells. Therefore, the objectives of this study were to determine the effects of PKC modulators and PTH on UMR 106-H5 rat osteoblastic cell morphology, and the relationship between cell shape and PTH-induced Cai2+ changes. In suspended cells loaded with the calcium indicator dye fura-2, pretreatment with PKC inhibitors calphostin C (100 nM x 1 h) and H-7 (30 microM x 18 h) potentiated the effects of 1 microgram/ml bPTH (1-84) on Cai2+ (83% increase over basal) by 1.4- and 1.65-fold, respectively. In comparison, PTH (10 ng-1 micrograms/ml) was without significant effect on adherent cell Cai2+ as measured by single-cell image analysis, although another in vitro bone resorbing agent, thrombin (10 U/ml), produced an acute 3-fold increase in the ratio (R) of emission (approximately lambda 510 nm) detected and optimized at lambda 348/374 nm (i.e., Ca-bound dye/free dye) in control cells. Phase-contrast microscopy revealed PKC inhibitor-treated cells changed from a spread configuration to a stellate form with retracting processes or cell rounding and a collapse of actin stress fibers. Within 1 h of PTH addition, PKC inhibitor-treated cells continually became extended/respread up to 3 h with an associated increase in actin stress fibers that was preceded by an acute 1.6-fold Cai2+ increase. In contrast, control or PKC activator-treated cells (phorbol 12,13-dibutyrate or 12-O-tetradecanoylphorbol-13-acetate; TPA) contracted/retracted within 5 min in response to PTH. A role for Cai2+ in PTH-induced cell spreading was further indicated by a contractile response to PTH when PKC-inhibitor-treated cells were loaded with the intracellular calcium chelator dimethyl BAPTA (3 microM x 30 min). PTH-induced Cai2+ increases in adherent PKC inhibitor-treated cells were also associated with a 1.8-fold 1,4,5-IP3 increase as measured by mass assay. The data suggest PKC contributes to UMR 106-H5 cell morphology and selectively regulates signal pathways activated by PTH to promote either cell contraction (cAMP) or extension (1,4,5-IP3/Cai2+).

Profilin forms tetramers that bind to G-actin.

Profilin binds to G-actin and affects polymerization. However, regulation of profilin function is generally unknown and controversy exists regarding profilin effects on actin polymerization. Because protein-protein interactions are implicated in many cellular responses, human platelet profilin self-association and actin inter-action was examined. Silver stained SDS-PAGE of poly-l-proline/sepharose 4B column purified profilin revealed the presence of profilin (14.8 kD) and extraneous higher bands (primarily 30 kD and 58.5 kD). Re-electrophoretic analysis of gel electroelution purified profilin yielded predominantly 14.8 kD and 58.5 kD proteins. Rabbit IgG antibodies made against gel electroelution-purified profilin recognized all profilin sizes on immunoblots. Capillary electrophoresis of profilin in solution produced a single peak that resolved into three distinct peaks upon addition of reducing agent or high salt conditions. Further, G-actin did not bind to 14.8 kD profilin on immunoblot overlay assays, but surprisingly bound only to 58.5 kD profilin. The data indicate that monomeric profilin forms tetramers which are the relevant high affinity actin-binding form.

A novel phospholipase C inhibitor and phorbol esters reveal selective regulation of thrombin- and parathyroid hormone-stimulated signaling pathways in rat osteosarcoma cells.

Previous studies have demonstrated that parathyroid hormone (PTH) and human alpha-thrombin mobilize intracellular calcium from distinct pools in UMR 106-H5 rat osteosarcoma cells. The present studies were designed to explore the molecular basis of this differential signaling. Maximally effective concentrations of both PTH (240 nM) and thrombin (10 U/ml) produced a rapid intracellular free calcium (Cai++) transient (a 2- to 3-fold increase) that was inhibited by pretreatment with the phospholipase C inhibitor 1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]- 1H-pyrrole-2,5-dione (U73,122) in a dose-dependent manner (IC50 = 3 microM). Inhibition by U73,122 was not associated with a change in PTH-stimulated adenylate cyclase activity, whereas inositol phosphate accumulation, detected only in response to thrombin, was inhibited 23 to 45%. Prior exposure of cells for 5 min with the protein kinase C activators phorbol 12-myristate 13-acetate (8-80 nM) and phorbol 12,13-dibutyrate (80 nM) weakly inhibited (< or = 30%) the peak Cai++ increase in response to thrombin but completely blocked the Cai++ response to PTH. In contrast, 12-myristate 13-acetate produced a 1.55-fold increase in the maximal stimulatory effect of PTH on adenylate cyclase activity. These data suggest that activation of phospholipase C is a prerequisite for both PTH- and thrombin-stimulated increases in Cai++ and that protein kinase C differentially regulates the ability of these agents to raise Cai++. Collectively the results support the notion that the IP3/calcium mobilizing pathways utilized by PTH and thrombin are compartmentalized.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum theophylline profile with once-daily theophylline (Uniphyl) following conversion from intravenous theophylline in adult asthmatic patients.

Although guidelines are available for conversion from intravenous (IV) theophylline to twice-daily, oral, controlled-release theophylline, the optimal method for conversion to Uniphyl, a chronotherapeutically formulated, once-daily theophylline preparation, has not been previously evaluated. The present study was designed to prospectively evaluate a method for converting patients from IV theophylline to Uniphyl, to formulate simple, practical dosage recommendations for use in clinical practice. Ten patients with acute exacerbation of asthma receiving IV theophylline for > or = 48 hours and with steady state serum theophylline concentrations (STCs) between 4.5 and 15.5 mg/L (25 and 86 mumol/L) were enrolled into the study. Patients with STCs > or = 4.5 and < 12 mg/L (> or = 25 and < 66 mumol/L) and those with STCs > or = 12 and < or = 15.5 mg/L (> or = 66 and < or = 86 mumol/L) received their first Uniphyl dose immediately following termination of IV theophylline (No Time Lapse [NTL] group) and after a 4-hour delay (Time Lapse [TL] group), respectively. The differences in the area under the curve values between Uniphyl dosing and IV theophylline were 11% in the NTL group (1214.6 +/- 247.9 mumol/h.L-1 vs 1370.4 +/- 148.1 mumol/h.L-1, 95% confidence interval, 74% to 103%; P = 0.068) and 10% in the TL group (1959.4 +/- 165.1 mumol/h.L-1 vs 1784.6 +/- 119.4 mumol/h.L-1, 95% confidence interval, 103% to 117%; P = 0.013).(ABSTRACT TRUNCATED AT 250 WORDS)

E-cadherins identified in osteoblastic cells: effects of parathyroid hormone and extracellular calcium on localization.

The presence and regulation of cadherin localization in osteoblastic cells were examined. Monoclonal antibody (ECCD-1) that interferes with E-cadherin function prevented cell adhesion in UMR 106-H5 rat osteosarcoma cells and non-tumorigenic mouse calvarial MC3T3-E1 cells, whereas CCL39 fibroblast adhesion was not affected. Immunofluorescent antibodies (ECCD-2 and polyclonal L-CAMP P1) revealed cadherins are localized along the osteoblastic cell-cell boundaries. Exposure of UMR 106-H5 cells to bovine parathyroid hormone (1-84) (PTH; 10 ng/ml x 1 hr) or low calcium medium (1.0-0.025 mM) produced cellular retraction accompanied by intense immunofluorescence for cadherins throughout cells with a corresponding loss of punctate localization at remaining cell-cell adhesion points. Western immunoblot analysis indicated 108 kd and 115 kd cadherins are present, with a smaller 29.5 kd band that became predominantly associated with the cytosolic fraction of cells treated with parathyroid hormone or lowered calcium. The results demonstrate E-like cadherins are present in osteoblastic cells and implicate a regulatory role for parathyroid hormone and calcium in cadherin function and localization.

Thrombin and parathyroid hormone mobilize intracellular calcium in rat osteosarcoma cells by distinct pathways.

The mechanisms by which PTH and thrombin mobilize intracellular Ca2+ (Cai2+) were examined in UMR 106-H5 rat osteosarcoma cells. Bovine PTH-(1-34) (24 pM to 240 nM) produced a dose-dependent increase in Cai2+ (EC50, 3 nM), which returned to baseline within 75 sec. Human alpha-thrombin produced an increase in Cai2+ (ECmax, 10 U/ml) which was similar to that of PTH with respect to both magnitude and time course. Chelation of extracellular calcium with 5.0 mM EGTA did not alter the Cai2+ response to either PTH or thrombin. When added together at maximally effective concentrations, PTH and thrombin produced additive effects on Cai2+ in the presence and absence of EGTA. The additive effects of PTH and thrombin on Cai2+ were confirmed at the single cell level, using laser-based image analysis. Bradykinin (1 microM) produced a significant increase in Cai2+ in UMR 106-H5 cells which was of lesser magnitude than the peak 2- to 3-fold increase elicited by PTH or thrombin. Preexposure of cells to 10 U/ml thrombin for 2 min abolished the Cai2+ response to bradykinin, whereas preexposure to 240 nM PTH had no effect on the Cai2+ response to bradykinin. Thrombin elicited a rapid increase in the accumulation of 3H-labeled inositol phosphates (IP2 and IP3) in UMR 106-H5 cells, with increases in [3H]1,4,5-IP3 detectable as early as 15 sec after the addition of thrombin. Bradykinin increased [3H]IP production to a lesser extent than thrombin, whereas PTH neither increased [3H]IP accumulation nor potentiated the [3H]IP response to thrombin. The results suggest that thrombin and bradykinin mobilize Cai2+ from a shared IP3-responsive calcium pool, whereas PTH may use signals in addition to 1,4,5-IP3 to mobilize calcium from a distinct cellular calcium pool. Alternatively, specific calcium compartmentalization exists, and there is differential coupling of these agonists to the 1,4,5-IP3/Cai2+ pathway.

[The use of electromyostimulation for preventing and treating hypodynamic disorders in gunshot injuries to the extremities]. / Primenenie élektromiostimuliatsii dlia profilaktiki i lecheniia gipodinamicheskikh rasstroistv pri ognestrel'nykh povrezhdeniiakh konechnostei.

It was found out during the study of multichannel electromyostimulation (EMS) influence upon human organism and the adequacy of its physical load to adoptive and compensative possibilities of cardiovascular system that that method was effective for prophylaxis of disorders and rehabilitation of nervous and muscular system, and locomotor apparatus after a short period of hypodynamia. The EMS increases the working capacity of nervous and muscular apparatus, mass of muscles and their contraction strength due to improvement of nervous and muscular conductivity and blood supply of the extremity. The efficiency of EMS decreases considerably when degenerative changes are taking place.

[The optimization of combined physiotherapy in the system of rehabilitating victims with complicated fractures of the extremities]. / Optimizatsiia kompleksnoi fizioterapii v sisteme reabilitatsii postradavshikh s oslozhnennymi perelomami konechnostei.

The schemes were worked out for optimization of complex physiotherapy in rehabilitation system of patients with complicated fractures of extremities. This work was carried out on the basis of 178 dynamic clinic observations with application of biomechanical and roentgenological methods, as well as methods of mathematical modelling and prognostication. That made it possible to increase the efficiency of rehabilitation programs by 3.2--4.1 times. The article deals with the perspective trends in the development of this problem.

Thrombin stimulates inositol phosphate production and intracellular free calcium by a pertussis toxin-insensitive mechanism in osteosarcoma cells.

Human alpha-thrombin is known to elicit bone resorption in vitro and has been proposed as a mediator of increased bone turnover in inflammatory diseases. We used UMR 106-H5 rat osteoblast-like osteosarcoma cells to explore the signal transduction mechanism utilized by thrombin in bone. Thrombin produced a dose-dependent increase in the accumulation of [3H]inositol phosphates (IPs) in UMR 106-H5 cells prelabeled with [3H]myo-inositol (EC50 15 U/ml). In saponin-permeabilized cells, GTP gamma S increased [3H]IP production, whereas GDP beta S inhibited the response to both GTP gamma S and thrombin, indicating involvement of a G-protein in thrombin action. Thrombin produced a dose-dependent increase in intracellular free calcium (Cai2+) in UMR 106-H5 cells (EC50 1 U/ml; maximal increase 4-fold), as well as a small (20%) increase in [3H]thymidine incorporation. Treatment of UMR 106-H5 membranes with pertussis toxin (PT) and [32P]NAD+ resulted in labeling of a 40-kDa protein. However, pretreatment of cells with a dose of PT sufficient to produce maximal endogenous labeling of this protein failed to influence thrombin action on IP accumulation, Cai2+, or [3H]thymidine incorporation. In contrast, PT treatment of CCL39 hamster lung fibroblasts significantly blunted thrombin-stimulated [3H]IP accumulation and [3H]thymidine incorporation. These results suggest that thrombin raises Cai2+ in UMR 106-H5 cells by activating polyphosphoinositide-specific phospholipase C. Whereas in fibroblasts and platelets, thrombin receptors appear to couple to both PT-sensitive and PT-insensitive G-proteins, only a PT-insensitive G-protein appears to mediate thrombin action in UMR 106-H5 cells. Either these cells lack the relevant PT-sensitive G-protein or they possess thrombin receptors that selectively couple to a pertussis toxin-insensitive G-protein.

Conversion from intravenous procainamide to oral sustained release tablets in cardiac patients.

There is as yet no established method for converting from intravenous to oral sustained release procainamide (Procan SR; Parke-Davis Canada Inc). The pharmacokinetics of simultaneous discontinuation of intravenous procainamide and administration of oral sustained release procainamide was studied in six patients with ventricular tachyarrhythmias. Patients were converted after ensuring that steady-state concentrations were achieved with intravenous procainamide. Serum procainamide levels were obtained at the time of conversion and 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 6.0 h after conversion. The mean steady-state concentration (23.7 +/- 8.9 mumols/L) and the adjusted mean serum procainamide concentration with Procan SR (25.3 +/- 7.9 mumols/L) were not significantly different. This indicated that the serum procainamide concentration obtained with the intravenous infusion was not compromised when the patients were switched to oral therapy. Although mean percentage serum procainamide concentration fluctuation was 102.6 +/- 92.5, all patients tolerated the conversion well. Therefore, the method used in this study is an acceptable method of conversion.

G protein-dependent activation of a phosphoinositide-specific phospholipase C in UMR-106 osteosarcoma cell membranes.

Recent evidence suggests that guanyl nucleotide binding (G) proteins are involved in receptor-mediated bone resorption and in osteoblastic function, but the nature of the G protein coupled to effectors that are involved in these skeletal effects is unknown. The purposes of this study were to determine (1) whether a G protein mediates activation of phosphoinositide-specific phospholipase C in UMR-106 rat osteosarcoma cells, and (2) whether parathyroid hormone (PTH) and a PTH-like protein (PLP) associated with humoral hypercalcemia of malignancy promote GTP-dependent PIP2 hydrolysis. Addition of GTP (10(-4) M) or guanosine 5'-0-(3-thiotriphosphate, GTP gamma S, 10(-5) M) to membranes prepared from UMR-106 cells labeled with [3H]myo-inositol increased both [3H]inositol trisphosphate (IP3) and [3H]inositol bisphosphate (IP2) formation. The increases in [3H]IP2 and [3H]IP3 produced by GTP were 8.6- and 4.3-fold, respectively. GTP gamma S produced a 17.6- and 11.9-fold increase in [3H]IP2 and [3H]IP3, respectively. The stimulatory effects of GTP and GTP gamma S were dose dependent (GTP ED50 = 3.9 x 10(-6) M; GTP gamma S ED50 = 2.5 x 10(-7) M) and progressive over 10 minutes and required the presence of Mg2+.GTP (10(-4) M) and GTP gamma S (10(-5) M) decreased membrane [3H]phosphoinositides concomitantly with increased [3H]IP2 and [3H]IP3. The GDP analog guanosine 5'-O-(2-thiodiphosphate, GDP beta S) alone did not alter [3H]IP2 or [3H]IP3 production but at 10(-4) M blocks the stimulatory effects of GTP and GTP gamma S. NaF (3 x 10(-2)M) produced a 2.8- and 2.0-fold stimulation of [3H]IP2 and [3H]IP3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium-channel blockers in acute myocardial infarction.

The calcium-channel blockers are useful in treating a variety of cardiovascular disorders. Due to their antiischemic and spasmolytic properties, these agents have been studied in the prophylaxis and treatment of acute myocardial infarction. This article reviews this application with respect to reduction of mortality, infarct size, and reinfarction rate. Of the agents currently available for clinical use, nifedipine has been studied most extensively. This agent shows no beneficial effects in this setting and its use may in fact be harmful. Of the few trials that have been conducted with verapamil, none have shown decreased mortality. Verapamil may reduce infarct size although further confirmation is required. Diltiazem is the only agent that has been shown to have short- and long-term benefits in the patient with acute myocardial infarction. Proper patient selection is of utmost importance in ensuring successful therapy. In particular, those patients with non-Q-wave infarctions and/or normal left ventricular function can be expected to derive the most benefit in terms of reducing mortality and reinfarction rate associated with the acute event.