An Early Onset Rehabilitation Program for Children and Adolescents after Traumatic Brain Injury (TBI): Methods and First Results

Survived traumatic brain injuries (TBI) are one of the most serious challenges to the patient's future life. Recent literature increasingly questions the long believed protective effects of functional cerebral plasticity in children. Although TBI in children and adolescents is frequent, they are less frequently admitted to rehabilitation centers as in-patients than adults. This emphasizes the role of out-patient treatment. The progressing study described here aims to achieve a contribution to a comprehensive approach in TBI-rehabilitation for youngsters. A two-stage multimethodal program, starting with stimulation in coma while the patient is on the intensive care unit, and neuropsychological therapy after regaining consciousness is to be evaluated in a controlled, prospective and randomized study. After including nearly 50 % of the planned sample (100 persons), some preliminary results can be mentioned with all applicable caution. The effectiveness of the applied therapy can be stated here with respect to the posttraumatic development of intellectual abilities in the 6- and 12 months follow ups. Moreover, in the control group development of psychopathological alterations was found to a considerable degree and also lower ratings in a quality of life questionnaire, compared to the experimental group. It is expected to prove these differences statistically, after the total sample has been included, and thus equal distributions have been achieved in all predictive variables.     

Selective inhibitors of glial GABA uptake: synthesis, absolute stereochemistry, and pharmacology of the enantiomers of 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (exo-THPO) and analogues

3-Methoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-one (20a), or the corresponding 3-ethoxy analogue (20b), and 3-chloro-4,5,6, 7-tetrahydro-1,2-benzisothiazol-4-one (51) were synthesized by regioselective chromic acid oxidation of the respective bicyclic tetrahydrobenzenes 19a,b and 50, and they were used as key intermediates for the syntheses of the target zwitterionic 3-isoxazolols 8-15 and 3-isothiazolols 16 and 17, respectively. These reaction sequences involved different reductive processes. Whereas (RS)-4-amino-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole (8, exo-THPO) was synthesized via aluminum amalgam reduction of oxime 22a or 22b, compounds 9, 11-13, and 15-17 were obtained via reductive aminations. Compound 10 was synthesized via N-ethylation of the N-Boc-protected primary amine 25. The enantiomers of 8 were obtained in high enantiomeric purities (ee >/= 99.1%) via the diastereomeric amides 32 and 33, synthesized from the primary amine 23b and (R)-alpha-methoxyphenylacetyl chloride and subsequent separation by preparative HPLC. The enantiomers of 9 were prepared analogously from the secondary amine 27. On the basis of X-ray crystallographic analyses, the configuration of oxime 22a was shown to be E and the absolute configurations of (-)-8 x HCl and (+)-9 x HBr were established to be R. The effects of the target compounds on GABA uptake mechanisms in vitro were measured using a rat brain synaptosomal preparation and primary cultures of mouse cortical neurons and glia cells (astrocytes). Whereas the classical GABA uptake inhibitor, (R)-nipecotic acid (2), nonselectively inhibits neuronal (IC(50) = 12 microM) and glial (IC(50) = 16 microM) GABA uptake and 4,5,6,7-tetrahydroisoxazolo?4,5-cpyridin-3-ol (1, THPO) shows some selectivity for glial (IC(50) = 268 microM) versus neuronal (IC(50) = 530 microM) GABA uptake, exo-THPO (8) was shown to be more potent as an inhibitor of glial (IC(50) = 200 microM) rather than neuronal (IC(50) = 900 microM) GABA uptake. This selectivity was more pronounced for 9, which showed IC(50) values of 40 and 500 microM as an inhibitor of glial and neuronal GABA uptake, respectively. These effects of 8 and 9 proved to be enantioselective, (R)-(-)-8 and (R)-(+)-9 being the active inhibitors of both uptake systems. The selectivity of 9 as a glial GABA uptake inhibitor was largely lost by replacing the N-methyl group of 9 by an ethyl group, compound 10 being an almost equipotent inhibitor of glial (IC(50) = 280 microM) and neuronal (IC(50) = 400 microM) GABA uptake. The remaining target compounds, 11-17, were very weak or inactive as inhibitors of both uptake systems. Compounds 9-13 and 15 were shown to be essentially inactive against isoniazide-induced convulsions in mice after subcutaneous administration. The isomeric pivaloyloxymethyl derivatives of 9, compounds 43 and 44, were synthesized and tested as potential prodrugs in the isoniazide animal model. Both 43 (ED(50) = 150 micromol/kg) and 44 (ED(50) = 220 micromol/kg) showed anticonvulsant effects, and this effect of 43 was shown to reside in the (R)-(+)-enantiomer, 45 (ED(50) = 44 micromol/kg). Compound 9 also showed anticonvulsant activity when administered intracerebroventricularly (ED(50) = 59 nmol).     

Neuroleptic malignant syndrome in a patient with head injury

Neuroleptic malignant syndrome is an idiosyncratic reaction associated with the use of neuroleptic drugs. We report a case of this rare syndrome in a head injury patient associated with some unusual features: rhabdomyolysis with a high level of creatine kinase, the development of acute renal failure, the early use of continuous venovenous haemofiltration in treatment and rigidity that was refractory to conventional treatment with dantrolene and bromocriptine. The diagnosis in patients with multiple injuries must be based on a high index of suspicion.     

Pharmacoeconomics and formulary decision making

Pharmacoeconomic assessment of formulary actions has become increasingly common in local, national, and international formulary decision making. Tactics for managing medication use include formulary management and drug policies. Pharmacoeconomic data can provide support for these formulary decisions. For example, pharmacoeconomic data can support the inclusion or exclusion of a drug on or from the formulary and support practice guidelines that promote the most cost-effective or appropriate utilisation of pharmaceutical products. Various strategies can be used to incorporate pharmacoeconomics into formulary decision making. These include using published pharmacoeconomic studies and economic modelling techniques, and conducting local pharmacoeconomic research. Criteria for evaluating the pharmacoeconomic literature, suggestions for employing economic models, and suggested guidelines for conducting pharmacoeconomic projects are discussed. Although most formularies are viewed as cost-containment tools, formularies should not be a list of the 'cheapest' alternatives. Today's formulary should contain agents that optimise therapeutic outcomes while controlling cost. Pharmacoeconomic assessments of formulary decisions help to ensure that the agents promoted by our formularies yield the highest outcome per dollar spent. A discussion of the process for formulary action in a US hospital, the influence of pharmacoeconomics on US formularies, and strategies for incorporating pharmacoeconomics into formulary decision making are presented in this paper.     

A comparison of laparoscopically assisted vaginal hysterectomy and abdominal hysterectomy

The goal of this study was to compare laparoscopically assisted vaginal hysterectomy (LAVH) with total abdominal hysterectomy (TAH). We performed a prospective comparison of the hospital courses of 30 women, 15 undergoing LAVH and 15 undergoing TAH, in a teaching hospital setting. Analysis of variance (ANOVA) was used, with statistical evaluation of differences by Student's t-test for normally distributed data and Kruskal-Wallis for data with dissimilar variances. Fourteen of fifteen patients scheduled for LAVH had their surgery completed without need of a laparotomy. In the LAVH group, (1) mean surgical time was 50 minutes longer, (2) blood loss, complications, and hospital costs were not statistically different, (3) hospital days averaged 1 1/2 less, and (4) postoperative pain ratings and medication requirements were significantly decreased, compared with the TAH group. In many cases, LAVH may be reasonably performed instead of an indicated TAH.     

Mechanism of toxin secretion by Vibrio cholerae investigated in strains harboring plasmids that encode heat-labile enterotoxins of Escherichia coli.

A genetically engineered Vibrio cholerae strain from which the cholera toxin genes had previously been deleted was used as a host in which to study the expression and secretion of related toxins and their subunits. Recombinant plasmids encoding heat-labile enterotoxins (LTs) from Escherichia coli of human and porcine origin were expressed in the V. cholerae host, and this resulted in the secretion of the LTs into the extracellular milieu. The secreted LTs were isolated and it was found that the A subunits of human and porcine LT were "unnicked" polypeptides, which indicates that nicking is not obligatory for toxin secretion. V. cholerae strains were also constructed that harbored plasmids encoding either the A or the B subunits of human LT (A+B-, or A-B+). Approximately 90% of the B subunits were secreted from the A-B+ strain, while all of the A subunits expressed by the A+B- strain remained cell associated. This implies that strains synthesizing both subunits assemble the A and B subunits prior to their secretion. We propose that the entry of the toxin into the secretory step of the export pathway is mediated by a secretory apparatus that recognizes structural domains within the B subunit of LT.     

Correlation between mortality trends of ischaemic cardiopathy and some nutritional factors in Spain 1968–1986

After describing the evolution of mortality from ischaemic cardiopathy (IC) in Spain from 1951 to 1986, which is tending to stabilize in some age groups, and from cerebrovascular accidents (CVA), which is clearly declining, an attempt is made to relate these developments to the prevalence of the main risk factors (hypertension, cholesterol, tobacco) associated with IC and CVA. Certain advances, though of a limited number, have been made in recent years in the control of arterial hypertension in Spain, although campaigns on a national scale as in other countries have not been carried out. Regarding alimentary factors, there is an obvious increase in the consumption of food rich in proteins and animal fats, abandoning to a great extent the traditional Mediterranean diet, with health care action being limited to the improvement of nutrition education of the public. Furthermore, the consumption of tobacco has been increasing in Spain during the study period in spite of health legislation in force in recent years.It is therefore deduced that there is no obvious relationship between mortality due to IC and CVA and the prevalence of the main risk factors associated with these diseases, especially when taking into account that preventive actions on a public health level have been very limited.Corresponding author.     

Tunicamycin Dissociates Depolarization-induced Calcium Entry From Transmitter Release. Involvement of Glycosylated Protein(s) in the Process of Neurosecretion in PC-12 Cells

The process of regulated secretion in PC-12 cells is tightly coupled to calcium entry, which is absolutely dependent on extracellular Ca2+([Ca2+]ex). Tunicamycin treatment of the cells dissociated depolarization-triggered Ca2+ influx from depolarization (high K+)-induced transmitter release into two distinct and independent phases. Deplarization-evoked Ca2+ influx was not affected by tunicamycin treatment (1 microg/ml, 72 h), whereas depolarization-evoked transmitter release was strongly inhibited (> 60%), suggesting at least a two-step process, and the participation of glycosylated protein(s) in the actual fusion/secretion step. Similarly, bradykinin-mediated transmitter release was linearly related to and absolutely dependent on Ca2+ entry, and was inhibited by tunicamycin treatment (> 80%), whereas bradykinin-evoked Ca2+ entry was not impaired, indicating that glycosylated protein(s) are essential for bradykinin-evoked release at a step subsequent to Ca2+ influx. The heavily glycosylated alpha2 subunit of the dihydropyridine-sensitive channel, which was used to monitor tunicamycin inhibition of glycosylation, was not expressed in the tunicamycin-treated cells, as shown by Western blot analysis. This observation allowed us to conclude that the alpha1 subunit of the heteromeric dihydropyridine voltage-sensitive Ca2+ channel, which is responsible for Ca2+ entry, is also fully functional when not assembled with its corresponding alpha2 subunit. The molecular properties of the alpha2 subunit, whose role in the complex structure of the channel is not yet understood, are shown for the first time for the L-type Ca2+ channel of PC-12 cells. Similar to cardiac and skeletal muscle cells, the alpha2 subunit appears to be a glycosylated polypeptide of molecular weight 170 kD and to display a characteristic mobility shift to 140 kD under reducing conditions.     

Influence of incubation time/temperature on acrosome reaction/sperm penetration assay.

The acrosomal status of human spermatozoa was studied in relation to the score of the sperm penetration assay (SPA) at low-temperature (4 degrees C) incubation for induction and synchronization of the acrosome reaction (AR) and the incubation time of spermatozoa in conventional SPA. Spermatozoa were collected from 18 patients, selected by the "swim-up" method and treated in three different ways: (1) short-term incubation group (SIG): 3 h incubation at 37 degrees C, and (2) long-term incubation group (LIG): 20 h incubation at 37 degrees C, and (3) low temperature group (LTG): 24 h incubation at 4 degrees C followed by additional incubation at 37 degrees C for 3 h. The conventional methods of incubation, i.e. SIG (3 h) and LIG (20 h) did not show any significant differences as evaluated by the sperm penetration rate and the number of decondensing sperm heads per oocyte. In contrast, in the LTG all parameters were significantly increased, especially those of penetration rate (p less than 0.0005) and decondensing sperm heads per oocyte (p less than 0.0005). The percentage of AR significantly increased (p less than 0.0005) in the LTG (14.7%) compared with SIG (6.1%) and LIG (10.6%). A significant correlation was demonstrated between AR and the parameters used for evaluation of the SPA. The penetration rate (Spearman test, r = 0.462, n = 54, p less than 0.003) was the most significant parameter correlated with AR. It would appear that only human spermatozoa having completed AR are capable of fusing with the zona-free hamster ova.(ABSTRACT TRUNCATED AT 250 WORDS)     

A new method for evaluation of the acrosome reaction in viable human spermatozoa

The acrosome reaction of human spermatozoa was induced by changes of temperature. Spermatozoa were collected from fertile donors and a patient group, and selected by the "swim-up" method. The spermatozoa were treated in two different ways: Protocol I: 24 hours at room temperature followed by additional incubation at 37 degrees C for 3 hours (control), and protocol II: 24 hours at 4 degrees C followed by additional incubation at 37 degrees C for 3 hours. The acrosome reaction of the viable spermatozoa was evaluated by a new method utilizing indirect immunofluorescence with anti-outer acrosomal membrane antibodies and exposure to a hypo-osmotic medium. In fertile donors as well as in the patient group, significant induction of the acrosome reaction (20%) was evident after exposure to low temperature (4 degrees C). The spontaneous rate of acrosome reaction in the control group was below 7%.