Analysis of reflex activity in cardiac sympathetic nerve induced by myelinated phrenic nerve afferents

Electrical stimulation of the phrenic nerve afferents evoked excitatory responses in the right inferior cardiac sympathetic nerve in chloralose-anaesthetized cats. The reflex was recorded in intact and spinal cats. The latency and threshold of the volley recorded from the phrenic nerve as well as of the cord dorsum potentials evoked by electrical stimulation of the phrenic nerve indicated that group III afferents were responsible for this reflex. The phrenicocardiac sympathetic reflex recorded in intact cats was followed by a silent period. The maximum amplitude of the reflex discharges was 800 microV, the latency was 83 ms and the central transmission time 53 ms. Duration of the silent period lasted up to 0.83 s. In spinal cats the reflex was recorded 5.5-8 h after spinalization. The maximum amplitude of the spinal reflex discharges ranged from 22 to 91 microV and the latency from 36 to 66 ms.     

Digital movement analysis,a new objective method of measuring tardive dyskinesia and drug-induced parkinsonian tremor: acceptability,reliability and validity

Digital movment analysis (DMA) is a new instrumental approach to assessing oral tardive dyskinesia (TD) by means of digital image processing of a video signal, tracking five paper dots placed around the patient's mouth. A total of 40 schizophrenic patients, 30 with and 10 without TD, were examined twice (with a 3-month interval) with this new device. The patients were further examined with two TD rating scales: the St. Hans Rating Scale for extrapyramidal syndromes (SHRS) and the Abnormal Involuntary Movement Scale (AIMS).The schizophrenic patients accepted the instrumental assessment without any anxiety or resistance. The internal relibility of the apparatus was high, with correlation coefficients of 0.80–0.99. The DMA TD values correlated with the SHRS and AIMS scores with correlation coefficients of 0.48–0.73 indicating an acceptable, although not strong, concurrent validity. Fluctuations occurred from the first to the second examination independent of medication. For these fluctuations no correlation was found between DMA values and rating scores. Finally, the DMA device was able to detect perioral tremor as a sign of parkinsonism.It has been concluded that DMA is a useful supplement to classical TD rating, although further validity evaluation is warranted.     

Dimensional alterations of the gingiva related to changes of facial/lingual tooth position in permanent anterior teeth of children

Abstract Maxillary and mandibular anterior permanent teeth in 38 children aged 7–12 years were examined 2 × with an interval of 2 years to determine whether spontaneous facial/lingual tooth position changes were related to alterations of the widths of keratinized and attached gingiva and the clinical crown height. Measurements included dental plaque, gingival inflammation, probing depth, and width of keratinized and attached gingiva. In addition, study casts from the baseline and 2-year examinations were used to measure clinical crown height and tooth position. The results showed that significant alterations in the widths of the keratinized and attached gingiva took place when the teeth changed positions in facial or lingual directions. The changes in gingival widths could to some extent be coupled to changes in clinical crown height. In teeth moving lingually, the gingival widths increased and the clinical crown height decreased. In teeth moving facially, the gingival widths decreased, and the facial gingiva sometimes receded. These gingival alterations call for examination of the facial gingiva as part of the monitoring of the development of the permanent dentition.     

The synthetic prostaglandin E1 analogue rioprostil reduces the nephrotoxic potential of cyclosporine A

Acute CyA nephrotoxicity involves alteration in the proximal tubule and leads to glomerular lesions. Administration of a vasodilatator agent such as the prostaglandin E1 analogue Rioprostil (Bayer AG, BAY 06893) might prevent preglomerular vasoconstriction and hence reduce cyclosporin nephrotoxicity. As an increased excretion of urinary enzymes as a consequence of CyA-nephrotoxicity is well known we investigated in 40 male Wistar rats the excretion of three urinary enzymes: the brush border enzyme gamma-glutamyltransferase (GGT), the leucine aminopeptidase (LAP), and the lysosomal enzyme N-acetyl-beta-glucosaminidase (NAG). Additionally we determined s-creatinine and CyA plasma level. The kidneys were studied histologically at the end of the study. Wistar rats receiving 20 or 50 mg CyA/kg/d showed a marked deterioration in renal function and an increase of all urinary enzymes determined. In the rats receiving 20 mg CyA/kg/d and Rioprostil (150 micrograms/d) renal function and the enzymes determined remained in the normal range. There was no change in the enzyme excretion and only a minor improvement of renal function in rats receiving 50 mg CyA/kg/d and Rioprostil. Histological findings showed prevention of CyA nephrotoxicity in the 20 mg/kg/d group and diminished renal damage in the 50 mg/kg/d group.     

Quantitative assessment of technetium-99m methoxyisobutylisonitrile planar perfusion heart studies: application. of multivariate analysis to patient classification

A quantified evaluation of planar cardiac perfusion scintigrams (the objective of the study), obtained using technetium-99m methoxyisobutylisonitrile (MIBI) was performed on the basis of an analysis of circumferential profile curves, representing the perfusion as seen in three typical projections. The analysis involved the curves obtained both at rest and after stress, and was based on a comparison of their shape (trend) with the normal trend (normative evaluation). The latter was obtained by means of an original method of iterative fitting of individual curves into the database. The base consisted of curves recorded in 53 patients (separately in males and females) with normal perfusion of the left ventricle (group I, the reference group). A group of 90 patients suspected of having coronary artery disease (group II) was subdivided into two subgroups on the basis of coronary arteriography: (a) those with and (b) those without critical stenosis of at least one artery. Profile curves characterising the LV perfusion were obtained at rest and after stress. Defects of perfusion were quantified by comparison of individual curves with the normal trends. By means of multivariate analysis it was demonstrated that vectors of mean values characterising the scintigraphically assessed defects of LV perfusion in the two subgroups of group II differed very significantly (P<10^–5). Applying methods of discriminant analysis, a classification of patients from group II was performed into those with probable defects of perfusion and those free of such defects. The sensitivity, specificity and accuracy of diagnosis of coronary ischaemia, based on quantified planar^99mTc-MIBI scintigraphy, reached 86%, 87% and 87%, respectively.     

Single- vs Multiple-Dose Pharmacokinetics of Clozapine in Psychiatric Patients

Clozapine plasma levels were monitored in 16 patients during a series of three consecutive treatments (single dose-multiple dose-single dose). Each patient received a single 75-mg dose (3 x 25 mg) with clozapine tablets, and serial plasma samples were collected over 48 hr after the dose. At 48 hr, a multiple-dose regimen was started, consisting of an initial dose escalation period followed by dosing at a constant regimen for at least 6 days. After the last dose, serial plasma samples were again obtained over 72 hr. Drug was then withheld for at least 7 days, a final single 75-mg dose was given, and plasma sampling was repeated. A subset of the patient population (N = 7) was used to test for a food effect during the single-dose treatments. The pharmacokinetic parameters between the initial and the final single dose periods were not significantly different. Similarly, there were no differences within patients when given the dose after fasting (fed 1 hr after dose) or with a meal. In contrast, the terminal elimination rate differed between the single-dose and the multiple-dose treatments (t1/2 m3 = 7.9 hr single dose and 14.2 hr multiple dose) (P less than 0.05) and the dose-normalized area under the plasma concentration/time curves increased 27% with multiple dosing. Since a previous study in patients (Choc et al., Pharm. Res. 4:402-405, 1987) showed dose proportionality of clozapine plasma concentrations during multiple-dose regimens, the present results cannot be described by Michaelis-Menten kinetics.     

Tissue distribution, disposition, and metabolism of cyclosporine in rats

Tissue distribution, disposition, and metabolism of 3H-cyclosporine were studied in rats after single and repeated oral doses of 10 and 30 mg/kg and after an iv dose of 3 mg/kg. The oral doses of 10 and 30 mg/kg were dissolved in polyethylene glycol 200/ethanol or in olive oil/Labrafil/ethanol. Absorption from both formulations was slow and incomplete, with peak 3H blood levels at 3-4 hr. Approximately 30% of the radioactive dose was absorbed, which is consistent with oral bioavailability data for cyclosporine. More than 70% of the radioactivity was excreted in feces and up to 15% in urine. Elimination via the bile accounted for 10 and 60% of the oral and iv doses, respectively. Since unchanged cyclosporine predominated in both blood and tissues at early time points, the half-lives of the distribution phases (t 1/2 alpha) of parent drug and of total radioactivity were similar. In blood, kidney, liver, and lymph nodes, t 1/2 alpha of cyclosporine ranged from 6-10 hr. Elimination of radioactivity from the systemic circulation was multiphasic, with a terminal half-life of 20-30 hr. 3H-Cyclosporine was extensively distributed throughout the body, with highest concentrations in liver, kidney, endocrine glands, and adipose tissue. The concentrations of both total radioactivity and parent drug were greater in tissues than in blood, which is consistent with the high lipid solubility of cyclosporine and some of its metabolites. Skin and adipose tissue were the main storage sites for unchanged cyclosporine. Elimination half-lives were slower for most tissues than for blood and increased with multiple dosing. The amount of unchanged drug was negligible in urine and bile.(ABSTRACT TRUNCATED AT 250 WORDS)     

Einsatz von Bone-morphogenetic Protein-7 (BMP-7) in der Behandlung von Pseudarthrosen der oberen und unteren Extremität

Bone morphogenetic proteins (BMPs) are bone growth factors, which regulate bone formation during fetal development and bone repair after injury in postfetal life. Since 1992 BMP-7 has been produced by recombinant technique (rhBMP-7). Numerous animal models and clinical trials have shown that rhBMP-7 can induce de novo bone formation in segmental defects of bones and in cases of nonunion. Since 2001 rhBMP-7 has been approved for treatment of tibial nonunion in Europe. The effect of rhBMP-7 is comparable to the clinical and radiological results achieved with bone autografts. The problem of donor site morbidity (which occurs in up to 20% of all cases) is eliminated by the use of BMP-7. Long-term results and experience in clinical practice are not yet available.     

EMPACT syndrome

Background: Seizure prophylaxis with phenytoin is a common measure in oncologic patients with brain metastases. In these patients, generalized severe adverse drug reactions such as erythema multiforme (EEM) may occur. However, in a subgroup of patients with brain radiation therapy, EEM‐like lesions develop particularly in the radiation field. Most recently, the acronym EMPACT ( E rythema M ultiforme associated with P henytoin A nd C ranial radiation T herapy) was proposed to specifically describe this syndrome. Patient/Method: Here, we report on EMPACT syndrome in a 46‐year‐old woman. Therapeutic measures included seizure prophylaxis with phenytoin and total brain radiation therapy of brain metastases from bronchial carcinoma. Three weeks after introduction of phenytoin, the patient presented with EEM‐like skin lesions restricted to the original radiation field and facial mucocutaneous involvement. After a few days, the rash spread to the upper part of the body. She was also in poor general condition. Results: The immediate cessation of phenytoin therapy, combined with administration of systemic corticosteroids and high dose immunoglobulins along with intensive local treatment and pain medications, resulted in complete resolution of the skin eruption. Patch testing to phenytoin was positive after 72 hours. Conclusion: EMPACT should be classified as an specific entity among the EEM‐like drug reactions as it only appears after radiotherapy and seizure prophylaxis with the anticonvulsant phenytoin. We propose including specific type IV‐sensitization to phenytoin into the definition of EMPACT.     

Sex features at menarche in relation to gonadotropin, estradiol and sex hormone-binding globulin concentrations in girls with constitutional delay of puberty. Preliminary report.

OBJECTIVE: Constitutional delay of puberty (CDP) is the absence of secondary sexual features in otherwise healthy girls past the 13th year of life. The aim of the present work was to follow the development of estrogen-dependent sexual features, determine the concentrations of gonadotropins, estradiol and sex hormone-binding globulin (SHBG) in girls with CDP at menarche and compare the findings with normal controls. METHODS: We enrolled 11 girls with CDP and 40 controls. Primary, secondary and tertiary sexual features were studied at menarche +/- 3 months. The size of the ovaries and uterus was measured using transabdominal ultrasound. Maturation of breasts and pubic hair was staged according to Tanner. Concentrations of gonadotropins (follicle-stimulating hormone (FSH), luteinizing hormone) and estradiol were measured with immunoenzymatic methods. For measurement of SHBG, a radioimmunoassay was applied. RESULTS: Menarche in CDP girls usually appeared with Stage IV or V of breast development and Stage IV of pubic hair development according to Tanner. CDP girls demonstrated a significantly smaller volume of the uterine body at menarche compared with controls (p = 0.0004). Significantly lower levels of FSH (p = 0.0363) and estradiol (p = 0.0332), as well as a tendency towards lower levels of SHBG, were revealed in CDP girls at menarche. CONCLUSION: In CDP girls, menarche is accompanied by more mature tertiary sexual features, apparently resulting from longer exposure of estrogen-dependent tissues to the action of bioactive endogenous estrogens. The smaller volume of the uterine body in CDP girls at menarche may be attributed to decreased concentrations of FSH and estradiol, as well as to the possibility of decreased insulin-like growth factor-1 and increased neuropeptide Y levels.