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The influence of physical factors on the mechanical impedance at the palmar surface of the finger have been investigated. The studies were conducted with 12 subjects using random vibration over the frequency range 10 to 1000 Hz. It was found that increase in contact force (from 0.25 to 8 N) caused large increases in the modulus of the point mechanical impedance over most of the frequency range, increasing the area of contact with the finger (from 12.6 mm2 to 78.5 mm2) increased impedance at frequencies below 100 Hz and above 400 Hz. The location of contact with the finger also influenced the measured mechanical impedance. The resonance frequency increased from about 30 Hz, when vibration was applied to the proximal phalanx, to 600 Hz when vibration was applied to the distal phalanx. The addition of mass to the fingernail (0.5 to 8 g) reduced the resonance frequency from 700 Hz to 180 Hz and caused increased magnitudes of impedance at resonance by about a factor of 3. Flexing the finger affected impedance at frequencies between 50 and 200 Hz. The results show that the transmission of vibration to the fingers, and therefore the effects of vibration on the fingers, are highly dependent on some aspects of the contact between the fingers and the source of excitation. These variables are not currently quantified when assessing the severity of tool vibration, yet their optimisation may help to minimise some of the adverse effects of hand transmitted vibration.

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Schizophrenic patients discharged from acute inpatient settings are often unprepared to function outside the hospital, leading to recidivism and frequent rehospitalization. Social skills training programs addressing this need have hitherto only been developed for use in outpatient or long-term inpatient settings. We describe the development of a social skills training program for application in a short-term acute inpatient unit. Nursing coordinates the program, which is designed for a 3 to 4 week hospitalization and is delivered in an open group setting. The training program emphasizes communication skills, problem solving, affect identification, needs recognition, and social relatedness. The program uses group discussions, writing tasks, physical activity, education, role-play, feed-back, and assignments. Goals include assessment of individual deficits, inculcation of awareness that life-objectives can be identified and achieved, assistance with transition to postdischarge living situation or outpatient treatment program, and development of awareness of one's roles and responsibilities. The evolution and present structure of the program are described and four representative lessons are detailed.

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Anticholinergic drugs have been assumed to have no effects on schizophrenic symptomatology. Some studies suggest, however, that anticholinergic agents may antagonize the beneficial effect of neuroleptics on positive symptoms and partially ameliorate negative symptoms. Virtually all studies have been conducted in patients receiving concomitant neuroleptic treatment, raising the possibility that neuroleptics may obscure or modify any "true" anticholinergic effect on schizophrenic symptoms. To evaluate the hypothesis that anticholinergics may increase positive and decrease negative schizophrenic symptoms, we assessed the effect of biperiden on symptoms in the medication-free state. We studied the effect of biperiden 8 mg/day for 2 days on positive and negative symptoms in 40 otherwise drug-free schizophrenic inpatients. Biperiden produced a significant increase in positive symptoms (t = 6.7, p < .001) and reduction in negative symptoms (t = -3.4, p < .01). These data indicate that cholinergic modulation significantly affects positive and negative schizophrenic symptoms and suggest the need for systematic trials of cholinergic and anticholinergic agents in the treatment of positive and negative symptoms of schizophrenia, respectively.

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Based on the implication of increased muscarinic ACh activity in the production of negative symptoms, the association of decreasing cholinergic activity with positive symptoms, and the covariance of positive and negative symptoms in the psychotic phase of schizophrenia, a model of (DA) dopaminergic/(ACh) cholinergic interactions in schizophrenia was recently formulated. It suggests that DA/ACh balance is of central importance in schizophrenic pathophysiology and that muscarinic ACh activity increases in an attempt to maintain this balance in the face of increasing DA activity that occurs in the psychotic phase of the illness. The model further suggests that the muscarinic system exerts a damping influence on the emergence of positive symptoms associated with DA hyperactivity, but that this compensatory increase in muscarinic activity is accompanied by an intensification of negative symptoms. In the present study, we tested two important postulates of this model. We tested the prediction that muscarinic activity is increased in schizophrenia by comparing the effect of biperiden, an antimuscarinic M-1 agent, on REM latency in 12 drug-free schizophrenic inpatients and matched normal controls. We found that biperiden caused a smaller increase in REM latency in schizophrenic patients, suggesting that muscarinic activity is increased in schizophrenia. We tested the prediction that an anticholinergic agent would increase positive symptoms and decrease negative symptoms by studying the effect of 8 mg of biperiden/day for 2 days on positive and negative symptoms (assessed by the BPRS) in 30 medication-free schizophrenic inpatients.(ABSTRACT TRUNCATED AT 250 WORDS)

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It is generally assumed that anticholinergic drugs have no effects on schizophrenic symptomatology. A few studies, however, indicate that anticholinergic agents aggravate psychotic symptoms and antagonize therapeutic effects of neuroleptics in schizophrenic patients; more recently, some investigators have observed that these agents appear to benefit negative symptoms. In an effort to resolve this issue, we studied the effects of 2 days of treatment with biperiden on positive and negative symptoms in 15 medication-free schizophrenic patients. Positive symptoms increased significantly, while there was a trend toward a decrease in negative symptoms. The implications of these findings for the role of the cholinergic system in schizophrenia are discussed.

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With Cl as substrate, the human red blood cell anion transport (band 3) protein can exist in four conformations: Ei, with the transport site facing the cytoplasm; Eo, with the transport site facing the external medium; and ECli and EClo, the corresponding forms loaded with Cl. Flufenamic acid (FA), an inhibitor that binds to an external site different from the transport site, binds to Eo with a dissociation constant of 0.0826 +/- 0.0049 (SE) microM. Binding of iodide or sulfate to the external-facing transport site reduces the affinity by 1.66 or 14.3-fold, respectively. Changing from Eo to Ei lowers the affinity by 3.7-fold, and binding of cytoplasmic iodide to Ei further decreases the affinity by 5.5-fold. Thus changes in orientation of the transport site and substrate binding, even at the opposite side of the membrane, cause sufficient conformational changes in band 3 to affect FA binding substantially. If the possible effects of Cl binding to the transport site on FA affinity are estimated from the iodide data, the dependence of FA inhibitory potency on Cl concentrations inside and outside the cell suggests that there are at least 6.5 times as many inward-facing as outward-facing Cl-loaded transport sites. This information can be used to calculate the distribution of capnophorin among the various conformations under different circumstances and to devise conditions for recruiting the transport molecules toward a particular conformation.

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N-(4-isothiocyano-2-nitrophenyl)-2-aminoethanesulfonate (NIP-taurine), a newly synthesized isothiocyano derivative of N-(4-azido-2-nitrophenyl)-2-aminoethanesulfonate (NAP-taurine), is a potent inhibitor of human erythrocyte chloride exchange. At 0 degrees C, the inhibition is reversible, but at 37 degrees C, NIP-taurine inhibits irreversibly, indicating that it may be a useful label for its binding site. When present at the outside of the cell, NIP-taurine binds with low affinity to a site that seems to be the Cl- transport site (on the basis of its affinity for Cl-) and with much higher affinity to a different site, MN, which has a much lower affinity for Cl-. In this respect, NIP-taurine resembles NAP-taurine, and an analysis of interactions between these two probes is consistent with the idea that they bind to the same two sites. The affinity of NIP-taurine for the high-affinity MN site is enhanced by about fourfold when the transport protein, band 3, is in the conformation with the transport site facing outward (Eo), as compared with the conformation with the transport site facing inward (Ei). External Cl-, but not cytoplasmic Cl-, competes with NIP-taurine for binding to the external, high affinity site. Thus NIP-taurine provides a label for an external site, at which Cl- and perhaps other anions bind, which is separate from both the transport site and the cytoplasmic modifier site at which high Cl- concentrations inhibit Cl- exchange.

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Experiments were performed with intact human red blood cells to determine whether the inhibitory effects of high Cl- concentrations on Cl- exchange are primarily due to interaction at the cytoplasmic or the external surface of the membrane. When internal Cl- was varied from 150 mM to 600 mM Cl- (using the nystatin technique), keeping external Cl- constant at 150 mM (with sucrose added to maintain osmotic balance), Cl- exchange was inhibited almost exactly as much as when both internal and external Cl- were increased from 150 mM to 600 mM. On the other hand, if internal Cl- was maintained constant at 600 mM, variation of external Cl- (with either sucrose, gluconate, or citrate-sucrose mixtures replacing Cl-) had no consistent effect on Cl- exchange. Even if internal Cl- was kept at 150 mM by substitution of gluconate for Cl-, an increase in external Cl- from 150 mM to 600 mM did not significantly inhibit Cl- exchange. Thus the self-inhibitory effects of Cl- seem to be caused primarily by binding to a site at the cytoplasmic side of the membrane. External Br-, on the other hand, did cause a significant inhibition of Cl- exchange. In contrast to the inhibitory effects of Cl- at neutral pH, at very high pH (around pH 11) there is an activation of Cl- exchange at very high Cl- concentrations. This effect, however, depends on binding of Cl- to an external site. Thus there seem to be at least two different low-affinity Cl- binding sites, one at the cytoplasmic side, which inhibits Cl- exchange, and one at the external side, which activates Cl- exchange at high external pH.

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Niflumic acid is a noncompetitive inhibitor of chloride exchange, which binds to a site different from the transport or modifier sites. When the internal Cl- concentration is raised, at constant extracellular Cl-, the inhibitory potency of niflumic acid increases. This effect cannot be attributed to changes in membrane potential, but rather it suggests that niflumic acid binds to the anion exchange protein band 3 only when the transport site faces outward. When the chloride gradient is reversed, with Clo greater than Cli , the inhibitory potency of niflumic acid decreases greatly, which indicates that the affinity of niflumic acid for band 3 with the transport site facing inward is almost 50 times less than when the transport site faces outward. Experiments in which Cli = Clo show no significant change in the inhibition by niflumic acid when Cl- is lowered from 150 to 10 mM. These data suggest that the intrinsic dissociation constants for Cl- at the two sides of the membrane are nearly equal. Thus, the chloride-loaded transport sites have an asymmetric orientation like that of the unloaded transport sites, with approximately 15 times more sites facing the inside than the outside. The asymmetry reflects an approximately 1.5 kcal/mol free energy difference between the inward-facing and outward-facing chloride-loaded forms of band 3. High concentrations of chloride (with Cli = Clo), which partially saturate the modifier site, have no effect on niflumic acid inhibition, which indicates that chloride binds equally well to the modifier site regardless of the orientation of the transport site.

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