Access to rehabilitation facilities in an unselected hospital population affected by acute stroke.

The aim of this study was to evaluate the selection criteria and characteristics of the patients who have access to rehabilitation facilities after having experienced an acute stroke. Between January 1993 and February 1994, 383 patients were recruited in 13 hospitals in Lombardy, and telephonically followed up four months after study entry. The data were collected by members of the Associazione Volontari Ospedalieri (Hospital Volunteers' Association). The 4-month mortality rate was 23%. The primary selection criterion for gaining access to rehabilitation facilities was the degree of disability; the secondary factor was age. Rehabilitation facilities were not available to very severely afflicted or self-sufficient patients, but were preferentially made available to young, partially-dependent patients. A rehabilitative intervention within the first month was made available to fewer than 50% of the patients for whom it was indicated. The absence of care for elderly patients and the delay in its availability for those who actually receive it underline the need for new organisational methods. The data presented here also show that voluntary associations can work as observers of the health service. A more complete study is required in order to understand the real dimensions of the problem and the clinical and social characteristics of the population involved.

[Access to rehabilitation resources for an unselected hospital population of patients with acute seizures]. / Accesso alle risorse riabilitative in una popolazione ospedaliera non selezionata di pazienti con ictus in fase acuta.

The study aimed at evaluating selection criteria and basic characteristics of acute stroke patients admitted to rehabilitation programs. From January 1993 to February 1994, 373 patients from 13 hospitals of the Lombardy region were admitted to the study. The 4 months telephone follow-up was performed by the AVO (Hospital Volunteers Association) volunteers. The 4 months fatality rate was 23%. The patients with a higher disability level were prescribed a rehabilitation program. Rehabilitation resources were not available for very severe or dependent patients being mostly the younger and partially dependent patients more often referred to the services. Only 50% of eligible patients received a rehabilitation intervention within 1 month from the index episode of stroke. The lack of caring resources and the long waiting times stress the need for a reorganization of the rehabilitation services. This study also shows that volunteers can play a role of stricter collaboration with doctors and are ready to collaborate in data collection. A larger and more detailed study is warranted in order to gain a better knowledge on the problem and on the clinical and social characteristics of the stroke victims.

Interictal abnormalities of regional cerebral blood flow in migraine with and without aura.

Some controversial issues exist whether regional cerebral blood flow (rCBF) changes are present both in migraine with and without aura during the interictal period. For this reason we have studied rCBF characteristics in migraine patients when headache-free. rCBF examinations were performed by the 133Xe inhalation method on 39 normal subjects (24 aged 45 or less and 15 older than 45), on 10 migraine patients with (A+) and on 10 without (A-) aura. The values of each patient were compared with the age-matched control population mean by a computer-assisted mapping system that allows statistical analysis in real time. To compare inter-individual variability 10 subjects, out of 39 normals, constituted an age-, sex- and CO2-matched control group (C). 8 A+ patients and 7 A- showed significant alterations of CBF in comparison with the age-matched control population. The analysis between the age-, sex- and CO2 matched groups showed significant differences of the inter-hemispheric (F = 6.669, p = 0.004) and of the frontal (F = 7.480 p = 0.0008) asymmetries. These data show that in the headache-free period a derangement of the cerebral perfusion is present in both migraine with and without aura, suggesting they are due to the same disease process. Furthermore they show the usefulness of a computer-assisted mapping system, suitable for clinical use, in discovering small alterations in cerebral perfusion.

Cerebral vascular responsiveness in chronic hypercapnia.

To assess the responsiveness of the cerebral vessels to chronic hypercapnia, we measured middle cerebral artery flow velocity by transcranial Doppler ultrasound in 20 normal subjects and in 14 COLD patients before and after stimulation by progressive hypercapnia (rebreathing test) or by intravenous administration of an acetazolamide bolus. The results showed no statistically significant difference in baseline flow velocity between the normal subjects and the COLD patients. The COLD patients showed a reduced cerebral vascular responsiveness to both stimuli. Cerebral blood flow is normal in chronic hypercapnia and the mechanism by which compensation is achieved leads to a decrease in cerebral vascular responsiveness.

Influence of erythrocyte aggregability and plasma fibrinogen concentration on CBF with aging.

The influence of the rheological properties of the blood on cerebral perfusion is still unresolved. Data on normal subjects are lacking and difficulties arise regarding the effect of blood viscosity owing to its close relationship with hematocrit. For these reasons we have studied the relationship between two rheological hematocrit-independent parameters and CBF in normal subjects of various ages. 36 normal volunteers, aged 20-74, free from risk factors, have been studied. CBF was measured by the Xenon inhalation method. Erythrocyte aggregability was expressed as Mean Erythrocyte Aggregation Index (MEA). Plasma fibrinogen concentration was evaluated by the coagulative method in 26 subjects. No correlation was found between CBF and MEA or fibrinogen in the subjects under the age of 45. A significant negative correlation was found between CBF and MEA (p = 0.015) and between CBF and fibrinogen (p = 0.011) in the subjects over 45. These data show that cerebral perfusion is influenced by the rheological properties of the microcirulation only with aging. We suggest that a "rheological autoregulation" exists and that it works properly in youth, only to be lost with physiological aging. This finding can be of significance in the pathogenesis of cerebrovascular disease processes in humans.

[Focus. An expert system for the clinical diagnosis of the location of acute neurologic events]. / Focus. Un sistema esperto per la diagnosi clinica di sede di incidenti neurologici a comparsa acuta.

Focus is an expert system developed to diagnose, by the findings on neurological examination, the anatomic location of an acute neurologic event. The inference engine uses a forward tracking algorithm and a rule based data base that includes associations of neurological signs with specific anatomic areas. Focus is linked to a data base in which all personal cases and final diagnoses confirmed by laboratory studies are stored. This makes it possible to assess the validity of the system's diagnoses and use personal cases as additional example to the revision of the rules. The program is easy to use and runs on MS-DOS microcomputer. Furthermore the diagnostic rules are accessible so Focus may furnish an interactive teaching device.

CBF side-to-side asymmetries in stenosis-occlusion of internal carotid artery. Relevance of CT findings and collateral supply.

Cerebral blood flow (CBF) was studied at rest by 133-Xenon inhalation method in 15 normal subjects, in 10 patients with cerebral infarction and normal angiograms of major cerebral arteries and in 28 patients with unilateral stenosis-occlusion of the internal carotid artery (ICA), with or without cerebral infarction. All the normals and 20 patients with ICA stenosis-occlusion were tested again after cerebral vasodilatation induced by an intravenous bolus of acetazolamide. At rest the patients with cerebral infarction, irrespective of whether ICa stenosis-occlusion was present or not, showed abnormal side-to-side CBF asymmetry. After cerebral vasodilation variations in side-to-side asymmetry were shown to depend on the inefficiency of the collaterals and not on the degree of ICA obstruction or on the presence of cerebral infarction. These data indicate that at rest side-to-side CBF distribution is influenced more by the presence of an ischemic zone than by a ICA stenosis-occlusion and that under these circumstances the hemodynamic effect of the vascular stenosis cannot be assessed. After cerebral vasodilatation a subset of patients--irrespective of the degree of ICA obstruction and of whether or not cerebral infarction is present--with true cerebrovascular insufficiency can be isolated.

Relationship between body mass and tolerance to physical stress in obese patients.

Eleven obese patients, 5 males; age: 17-42; body mass index (BMI): 40; % of ideal weight: 187%, and 10 normal subjects (5 males; age: 19-39; BMI: 22; % of ideal weight: 103%), both groups without heart and respiratory disorders, underwent a cycloergometric test with subsequent 20-watt increases every 4 min until exhaustion. During the test, ventilation/minute, expiratory gas concentration and heart rate were measured, and the anaerobic threshold (AT) was determined in each subject. The obese patients showed a significantly lower AT than normal subjects (p less than 0.01); showing values which decreased with the increase in the grade of obesity expressed in BMI or in percent of their ideal weight. Moreover, in the obese patients, the O2 consumption (VO2) had significantly increased compared to that of normal subjects at no resistance and at all work levels. The negative correlation between the AT value and the BMI in obese patients can attribute their increase in VO2 during stress to (1) the inertial overloading caused by obesity especially considering the adipose tissue of their legs, or (2) to their level of 'fitness' being lower than that of normal subjects.

Potassium tolerance and bronchial reactivity in asthmatic and nonasthmatic atopic subjects.

Abnormal autonomic nervous system responsiveness may contribute to the pathogenesis of allergic diseases. Therefore, we measured the beta-adrenergic systemic (metabolic) responsiveness by means of acute potassium load in 10 normal healthy subjects and in 19 patients with allergic asthma and/or rhinitis. Ten allergic patients showed a greater potassium increment, as in normal subjects, when potassium was infused in the presence of propranolol. There was no difference between asthmatic and rhinitic patients. We then examined the relation between the response to potassium tolerance and the nonspecific, nonpharmacological bronchial reactivity in response to inhalation of ultrasonically nebulized distilled water. Some allergic patients showed bronchial hyperreactivity, while others did not show a difference compared with the controls; there was no significant difference between asthmatics and rhinitics, and there was no relation between nonspecific bronchial reactivity and potassium load tolerance. These findings suggest that systemic beta-adrenergic hyporesponsiveness may be present only in some allergic patients. There is no demonstrable relation among atopic state, nonspecific, nonpharmacological bronchial reactivity, and systemic beta-adrenergic hyporesponsiveness.

Pressure available for expiration in chronic airway obstruction.

The pressure generated at 0.1 s after the onset of expiration measures the rate of rise of expiratory pressure potentially available for expiration. P0.1e increased with increasing the frequency of breathing and was higher in chronic obstructive pulmonary disease (COPD) patients than in controls. In normal subjects breathing under resistive load P0.1e became similar to that of patients for a given respiratory frequency. P0.1e consistently increased as the load and/or the frequency of breathing were raised. Expiratory pressure depends on elastic recoil of the respiratory system, nevertheless the action of neurally controlled respiratory muscles influence the rate of rise of expiratory pressure. The decrease of expiratory braking action by inspiratory muscles (-Pmusi) influence the rate of pressure rise in the first part of expiration, whereas the contraction of abdominal muscles (-Pmuse) increases P0.1e later from onset of expiratory occlusion. These compensatory reflexes are vagally mediated and are presumed to originate in stretch receptors. In COPD patients the braking action of inspiratory muscles was smaller and the facilitating action of abdominal muscles was higher than in controls. Both expiratory braking decay and expiratory activity increase with the rise of breathing frequency or with the increase of respiratory airflow resistance.

Antilipidemic activity of 4-oxo-functionalized ethyl 6-chlorochroman-2-carboxylate analogs and a related tricyclic lactone in three rat models.

The synthesis of ethyl cis-6-chloro-4-hydroxychroman-2-carboxylate (IV) and 6-chloro-4-hydroxy-chroman-2-carboxylic acid lactone (V) are reported. The antilipidemic properties of these compounds in 3 rat models were compared to the activity obtained for the previously synthesized related analogs ethyl 6-chlorochroman-2-carboxylate (II), ethyl 6-chlorochromanone-2-carboxylate (III) and clofibrate (I). The biologically most interesting analog, ethyl 6-chlorochroman-2-carboyxlate (II) like clofibrate (I), was an effective antitriglyceridemic and anticholesterolemic agent in Triton WR-1339 hyperlipidemic rats, sucrose-fed hyperlipidemic rats and chow-fed normolipemic rats. Ethyl 6-chlorochromanone-2-carboxylate (III) was found to be active after 7 days of administration to sucrose-fed rats. In sucrose-fed, male Sprague-Dawley rats, the comparative effects of these analogs on various hepatic drug parameters also were carried out. Consistent with previous findings, results obtained with these compounds provide evidence showing that changes in hepatic HMG-CoA reductase activity bear no relationship to serum cholesterol lowering in the sucrose-fed model.

Synthesis and pharmacological evaluation of cis-3,4,4a,9a-tetrahydro-1H-pyrano[3,4-b]benzofuran-1-ones. Tricyclic analogues related to the antilipidemic drug clofibrate.

The chemistry and pharmacology of two delta-lactones, cis-6-chloro-9a-methyl-3,4,4a,9a-tetrahydro-1H-pyrano[3,4-b]benzofuran-1-one (2) and the 9a-demethyl analogue 3, are reported. Lactones were prepared from dihydrobenzofuran precursors possessing geometrical configurations confirmed both by synthesis and 1H NMR spectroscopy. All cis-dihydrobenzofurans exhibited Jvic = 9.0-10.8 Hz, whereas their trans isomers exhibited Jvic = 5.0--6.0 Hz in agreement with predictions based on the Karplus equation. The pharmacological profiles for 2 and 3 were compared to that of clofibrate (1) in normal male Sprague-Dawley rats. Using equimolar doses (0.4 mmol/kg, po, twice daily for 7 days), 1 exhibited both anticholesterolemic and antitriglyceridemic activity, lactone 2 exhibited only antitriglyceridemic activity, and 3 was inactive as an antilipidemic agent. No correlation was observed for inhibition of hepatic HMG-CoA reductase activity and serum cholesterol lowering.

Diffference between mouth and esophageal occlusion pressure during CO2 rebreathing in chronic obstructive pulmonary disease.

During CO2 rebreathing, we measured the pressures generated at the mouth and in the esophagus during the first 0.1 sec of inspiratory effort against a closed airway in 6 normal subjects and 6 patients with chronic obstructive lung disease. Normal subjects showed similar reponses to CO2 in terms of both mouth pressure and esophageal pressure. Patients' responses at the mouth to CO2 were decreased compared to those of normal subjects, but the responses in the esophagus were not significantly different. The patients demonstrated a greater response of occlusion pressure measured in the esophagus than at the mouth. In patients with altered mechanical properties of the lung, the change in mouth occlusion pressure might be influenced by problems of equalization of pressure within the airways due to unequal time constants, by problems of regional differences in pressure gradients over the pleural surface, or both. Esophageal pressure during airway occlusion 100 msec after the onset of inspiration may be better measure of respiratory drive than mouth pressure in patients with intrinsic increase of airway resistance.

Synthesis and pharmacological evaluation of a clofibrate-related tricyclic spirolactone, 5-chloro-4',5-dihydrospiro[benzofuran-2(3H),3'(2'H)-furan]-2'-one.

The chemistry and pharmacology of the title compound, spirolactone 4, are reported. The synthesis represents a new approach to the preparation of spiro compounds. The pharmacological profiles of 4 are compared to that of clofibrate in Triton-induced hyperlipidemic, sucrose-fed, and normal Sprague-Dawley rat models. Clofibrate was effective in all animal models, but the spirolactone 4 exhibited antitriglyceridemic activity only in the Triton model. The inactivity of 4 in sucrose- and chow-fed rats could not be attributed to a resistance to hydrolysis by serum esterases. Comparative studies revealed that inhibition of hepatic HMG-CoA reductase activity may not be an index of hypocholesterolemic action in sucrose-fed rats. Additionally, only clofibrate exhibited significant changes in components of the hepatic microsomal monooxygenase system.

Maximal frequency of breathing at various tidal volumes in airways obstruction.

To determine the relative importance of control system and of mechanical and metabolic properties of the motor system on the maximal frequency of breathing (1/t) at various tidal volumes (VT), we have studied the relationship between cycle period (t) and tidal volume in 10 normal subjects, in 9 patients with chronic obstructive lung disease, and in a normal subject breathing against different resistive loads. The results, expressed according to the equation t = t0 + b VT (where t0 represents the time required for a breathing cycle at zero VT and b means the additional time required for a breathing cycle with a VT equal to vital capacity), indicate that t0 is independent from the load either in unloaded or loaded normal subjects or in obstructive patients. In fact, although b was found significantly different, t0 remained essentially constant. These findings suggest that the level of maximal voluntary ventilation may be mainly related to metabolic and mechanical properties of the motor system (muscles of breathing and load imposed on them).

Azabicyclo chemistry. 6. An investigation of one of the chemical parameters for analgetic activity. Synthesis of 2-methyl-2-azabicyclo[3.3.1]non-6-ene and -non-7-ene.

The olefins 2-methyl-2-azabicyclo[3.3.1]non-6-ene (3) and -non-7-ene (6) were prepared in order to evaluate their analgetic activity. The reduction of 2-methyl-2-azabicyclo[3.3.1]nonan-7-one (4) with NaBH4 gave, stereospecifically, the axial alcohol 5. Reaction of 5 with CH3SO2Cl-pyridine gave directly the olefins 3 and 6, both of which upon hydrogenation gave the known 2-methyl-2-azabicyclo[3.3.1]nonane (7). The structural proof of 3, 5, and 6 was ascertained by spectral methods. Of the compounds prepared, 3, 5, and 6 were essentially inactive as analgetics when tested in mice by the hot-plate method, while 4 had marginal activity.

Synthesis of ethyl 6-substituted-chroman- and -chromone-2-carboxylates. A comparative structure-activity study employing the 6-phenyl and phenoxy analogs in the triton hyperlipidemic rat model.

To explore the effect of lipophilicity on antilipidemic activity in the Triton WR-1339 induced hyperlipidemic rat model we synthesized the 6-cyclohexyl, phenyl, and phenoxy analogs of ethyl chroman-2-carboxylate. Results obtained were analyzed in light of the biological activity observed for the 6-chloro-substituted and unsubstituted chromans, the 6-chlorochroman-4-one ester, and the 6-chloro-, phenyl-, and phenoxychromone esters. The suggestion is made that chromones likely exert their antilipidemic effects by a somewhat different set of mechanisms than do the chromans and clofibrate. Whereas the 6-chlorochromanone ester is inactive, the 6-chlorochromone ester is active in both normal and hyperlipidemic Sprague-Dawley rats. The major differential effect was observed for ethyl 6-cyclohexylchroman-2-carboxylate which did not lower cholesterol levels but returned triglyceride levels to normal in hyperlipidemic rats.