Characterization of the tetanus toxin model of refractory focal neocortical epilepsy in the rat

PURPOSE: To characterize in detail a model of focal neocortical epilepsy. METHODS: Chronic focal epilepsy was induced by injecting 25-50 ng of tetanus toxin or vehicle alone (controls) into the motor neocortex of rats. EEG activity was recorded from electrodes implanted at the injection site, along with facial muscle electromyographic (EMG) activity and behavioral monitoring intermittently for up to 5 months in some animals. Drug responsiveness was assessed by using the antiepileptic drugs (AEDs) diazepam (DZP) and phenytoin (PHT) delivered systemically, while 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), a competitive antagonist at AMPA receptors, was administered directly to the brain to investigate the potential benefits of focal drug delivery. RESULTS: Tetanus toxin induced mild behavioral seizures that persisted indefinitely in all animals. EEG spiking activity, occurring up to 80% of the time, correlated with clinical seizures consisting of interrupted behavioral activity, rhythmic bilateral facial twitching, and periods of abrupt motor arrest. Seizures were refractory to systemic administration of DZP and PHT. However, focal delivery of NBQX to the seizure site reversibly reduced EEG and behavioral seizure activity without detectable side effects. CONCLUSIONS: This study provides a long-term detailed characterisation of the tetanus toxin model. Spontaneous, almost continuous, well-tolerated seizures occur and persist, resembling those seen in neocortical epilepsy, including cortical myoclonus and epilepsia partialis continua. The seizures appear to be similarly resistant to conventional AEDs. The consistency, frequency, and clinical similarity of the seizures to refractory epilepsy in humans make this an ideal model for investigation of both mechanisms of seizure activity and new therapeutic approaches.     

Role of routine ultrasonography in monitoring the outcome of medical abortion in a clinical setting

BACKGROUND: Clinical methods generally used to evaluate the completeness of medical abortion are not accurate. There are no published reports evaluating the role of routine ultrasonography in monitoring the outcome of medical abortion. The purpose of this study was to investigate whether routine transvaginal ultrasonography (TVS) at the follow-up visit after medical abortion can accurately identify women who will require surgical intervention. DESIGN: Retrospective review of medical records and charts of all women undergoing medical abortion in the first trimester of pregnancy between January 1999 and December 2001. METHODS: Medical abortion was performed using oral mifepristone and a vaginal prostaglandin analog before 63 days gestation. All women had an initial TVS to confirm intrauterine pregnancy and gestational age, and another TVS at the follow-up visit 2-3 weeks later to assess the completeness of abortion. Surgical evacuation of the uterus was allowed as indicated on clinical grounds but not on the basis of ultrasound findings only. RESULTS: A total of 690 women consented to medical abortion during the study period. Eleven of these women were excluded from the study for various reasons. Of the remaining 679 cases, 95% (645/679) had a documented follow-up at the hospital. The pregnancy termination rate among these women was 99.2% (640/645) and TVS identified all five cases of continuing pregnancy at the follow-up. A total of 66 (10.2%) patients had complications. The uterine cavity was empty on TVS at the follow-up visit in 84.8% (547/645) of cases and only 3.1% (17/547) of them required surgical aspiration/curettage due to excessive or prolonged vaginal bleeding. In the remaining 15.2% (98/645) the uterine cavity was not empty, and 43.9% (43/98) of them had a curettage. The risk of requiring a surgical intervention was significantly higher [odds ratio (OR) 24.4; 95% confidence interval (95% CI) 14.9-39.7] when the uterine cavity was not demonstrated to be empty at the follow-up visit 2-3 weeks after medical abortion. However, 59.1% (55/93) of women did not require surgical intervention despite ultrasound evidence of thick endometrial echo-complex. CONCLUSION: Routine TVS 2-3 weeks after medical abortion appears to be an efficient means of accurately identifying the cases of ongoing pregnancy and diagnosing a complete abortion. Although TVS could be used as an adjunct to clinical examination to diagnose an incomplete expulsion, it does not accurately differentiate those women who require surgical intervention from those who do not.     

Improvement in mental health over time in Northern Norway

BACKGROUND: There are very few prospective studies of mental distress in the general population. Two studies of general health in Finnmark county in northern Norway, performed 9 years apart, contained questions about depression and sleeping problems, which made it possible to study change in mental distress over time in the general population. METHODS: In a self-administered questionnaire, the subjects were asked about depression and sleeping problems, both generally and related to the dark period in winter, at two points in time: in 1987/88 and 1996/97. The persons participating in the two surveys were partly the same and partly new individuals. More than 12000 persons responded in 1987/88 and more than 7000 people in 1996/97. The cohort that answered questions about sleeping problems and depression at both time-points consisted of 3318 and 3682 persons, respectively. RESULTS: The prevalence of depression and sleeping problems, both generally and related to winter,decreased significantly in the course of the 9-year time-span. The decrease was also true for the cohort that answered at both time-points, except for sleeping problems related to winter, which were unchanged. The pattern of changes was identical for both genders and all age groups. CONCLUSIONS: Mental health in the general population seems to have improved during the period studied. The findings are also relevant for the discussion of the validity of the concept Seasonal Affective Disorder, and the presumed connection to light-deprivation.     

Clinical outcome and atherothrombogenic risk profile after prolonged wash-out following long-term treatment with high doses of n-3 PUFAs in patients with an acute myocardial infarction

BACKGROUND: Sustained effects following withdrawal of n-3 PUFAs are unknown. METHODS: Clinical outcome [cardiac death, resuscitation, recurrent myocardial infarction (MI) or unstable angina pectoris] was assessed after prolonged wash-out following randomised treatment with high-dosed n-3 PUFAs or corn oil for 12-24 months in 300 acute MI patients. Atherothrombogenic risk markers, serum glucose and markers of lipid peroxidation and inflammation were evaluated in 89 out of the 100 last included patients. RESULTS: After a total median observation period of 45 (range 0-53) months no intergroup difference in prognosis was observed for any of the cardiac events. Favourable effects on serum triglycerides and HDL-cholesterol by n-3 PUFAs were lost after washout, but triglycerides decreased in the corn oil as compared to the n-3 group, P < 0.001. The decline in total cholesterol after withdrawal was similar in both groups. No intergroup difference in the change in thiobarbituric acid-malondialdehyde, a marker of lipid peroxidation, ultrasensitive C-reactive protein, homocysteine, glucose or blood platelets was noted at sustained follow-up. CONCLUSION: Clinical outcome was similar in both patient groups, and the atherothrombogenic risk improvement by n-3 PUFAs was lost after prolonged wash-out. Withdrawal did not affect homocysteine, glucose or markers of lipid peroxidation or inflammation.     

Umbilical cord plasma interleukin-6 and fetal growth restriction in preeclampsia: a prospective study in Norway

OBJECTIVE: To study the association between umbilical plasma levels of interleukin-6 (IL-6) in relation to fetal growth in subgroups of preeclampsia, and in control pregnancies. METHODS: Umbilical cord plasma was collected from 12,804 consecutive births. A total of 271 singleton cases of preeclampsia were identified, and classified as mild or severe, and as disease with early or late onset. As controls, 611 singleton pregnancies without preeclampsia were selected, and the ratio between observed and expected birth weight was used as a measure of fetal growth. In the analysis, we also included maternal smoking during pregnancy. Umbilical cord plasma IL-6 concentration was measured with an IL-6 bioassay. Comparing controls with subgroups of preeclampsia (severe and early onset), this study had a statistical power of 90% to detect a difference in cord IL-6 of 10 pg/mL. RESULTS: In severe preeclampsia, cord plasma IL-6 concentration was lower than among controls (P <.001), and there was a sharp decrease in cord plasma IL-6 with decreasing birth weight ratio (P trend <.001). By further dividing the preeclampsia group into early or late onset, the strong association between low IL-6 levels and low birth weight ratio appeared to be present mainly in early-onset disease. These results were not confounded by maternal smoking. CONCLUSION: Restricted fetal growth related to preeclampsia is associated with reduced umbilical cord plasma IL-6 concentration in cases with early-onset disease. In these cases, fetal growth restriction could be mediated by impaired trophoblast function.     

Single- and multiple-dose pharmacokinetics, kidney tolerability and plasma protein binding of tenoxicam in renally impaired patients and healthy volunteers

The 20 mg single-dose and 12 days repeated-dose pharmacokinetics of tenoxicam and the 5-OH-tenoxicam metabolite have been evaluated in healthy volunteers and two groups of patients with different degree of renal impairment, in total 20 persons. Concomitantly, the plasma protein binding of tenoxicam and the effects of treatment on renal function were evaluated. No differences were found between the investigated groups in the pharmacokinetics of total tenoxicam and the 5-OH metabolite did not interfere either with the pharmacokinetics or with the plasma protein binding of tenoxicam. A positive correlation was found between an increase in the free fraction (% F) of tenoxicam in plasma and a decrease in the plasma elimination half-life in the low creatinine clearance group (40-20 ml/min.) both after the single-dose and at steady-state. At steady-state, a non-linear correlation was demonstrated between a decrease in the urinary excretion of the 5-OH metabolite and a decrease in creatinine clearance from 130 to 20 ml/min. An increase in the plasma level of the 5-OH metabolite by three times was found in the low creatinine clearance group as compared to healthy subjects. 14C-Impurities of tenoxicam, as low as 1.2%, were shown to greatly influence the determination of the plasma protein binding (equilibrium dialysis) of the highly protein-bound tenoxicam due to a non-binding ability of the impurities to plasma proteins. No significant changes in renal parameters were found during the study. It can be concluded that the pharmacokinetics and plasma protein binding of tenoxicam and the pharmacokinetics of the 5-OH-tenoxicam metabolite are increasingly changed in subjects with a creatinine clearance below 40 ml/min. A decreased binding of tenoxicam to plasma proteins in low clearance patients is probably the reason for a faster elimination of tenoxicam in this group rather than a higher intrinsic hepatic metabolic activity. This study conducted in a low number of patients did not bring forward any new data indicating any adverse effects of tenoxicam on renal function.     

In situ expression of cytokines and cellular phenotypes in the lungs of mice with slowly progressive primary tuberculosis

The cellular phenotypes and the expression of cytokines were studied in the lungs of mice, using immunohistochemistry, during different phases of slowly progressive primary murine tuberculosis infection. During the first phase the small focal lesions in healthy mice contained predominantly interleukin-2 (IL-2)-expressing cells. A small number of tumour necrosis factor-alpha (TNF-alpha)-, monocyte chemoattractant protein-1 (MCP-1)- and IL-10-expressing cells were also present. IL-4-expressing cells were not detected. During the second phase the mice became unwell, but the bacterial counts and the size of focal lesions stabilized. IL-4-expressing cells appeared. The IL-10-, TNF-alpha- and MCP-1-expressing cells increased in number. On progression to phase three, the mice became seriously unwell and died rapidly. The inflammation spread to approximately 80% of the lung parenchyma. There was a marked increase in the number of IL-10-expressing cells. Expression of other cytokines was similar to that observed in the second phase. In the lesions, 3-6% of the macrophages (Mphi) containing mycobacterial antigens expressed high levels of IL-10 and TNF-alpha. The absolute numbers of CD3-, CD4- and CD11b-expressing cells in the lesions increased with the progression of infection. The numbers of CD8+ cells were reduced in the last phase of infection. The kinetics of T-lymphocyte subsets and the pattern of cytokine expression changed with the type and degree of tissue injury. The small number of Mphi with a heavy load of mycobacterial antigens may be the cause of this disturbance in cytokine balance, thus leading to progression of inflammation.