Adjustment of treatment increases quality of life in patients with epilepsy: a randomized controlled pragmatic trial.

BACKGROUND AND PURPOSE: Complaints about side-effects of antiepileptic drugs (AEDs) may be overlooked in clinical practice. We assessed the value and risks of an active intervention policy for reported complaints in a randomized controlled pragmatic trial. METHODS: This randomized controlled pragmatic trial included 111 adults treated for epilepsy in seven general hospitals. They were considered well-managed by their treating physician, but reported moderate to severe complaints on a questionnaire (SIDAED, assessing SIDe effects in AED treatment). The intervention was adjustment of AED treatment (53 patients), either reduction of dose or switch of AED, versus continuation of treatment unchanged (58 control patients) during 7 months. Primary outcomes were quality of life (Qolie-10) and complaints score. Secondary outcome measures were the occurrence of seizures or adverse events. RESULTS: After 7 months, the relative risk (RR) for improvement in quality of life was 1.80 (1.04-3.12) for the intervention group compared to control and the RR of decrease in complaints was 1.34 (0.88-2.05). In 58% of patients randomized to adjustment, the medication had indeed been changed. DISCUSSION: In conclusion, despite a possible risk of seizure recurrence, adjustment of drug treatment in well-managed patients with epilepsy, who report considerable complaints, improves the quality of life.

Transfer of ureteral carcinoma in a transplanted kidney presenting by early stenosis of the proximal ureter.

A 71-yr-old male kidney transplant recipient suffered from delayed graft function. Eighty days after transplantation complete obstruction of the proximal ureter was observed, complicated by recurrent urinary tract infections. Two months later, the donor kidney was removed because of infectious complications and inadequate arterial perfusion. Histological examination of the removed graft showed signs of rejection as well as a low-grade papillary urothelial cell carcinoma of donor origin in the ureter. The remaining donor ureter was removed subsequently and showed no further signs of malignancy. Follow-up of the patient until 12 months after surgery did not reveal recurrence of the tumor. This case report is the first to describe accidental transfer of urothelial cell carcinoma in the ureter by transplantation, highlighting the possibility of malignancy when early stenosis is not related to the anastomosis. It again emphasizes the need for precise and cautious screening of organ donors, especially those of higher age.

A cross-sectional study of subjective complaints in patients with epilepsy who seem to be well-controlled with anti-epileptic drugs.

OBJECTIVES: Side-effects of anti-epileptic drugs (AEDs) may be overlooked in patients with epilepsy in everyday clinical practice. The aim of this study was to assess the prevalence and severity of subjective complaints in patients who were considered to be well-controlled and to assess whether these complaints are related to medication, personality traits, or other determinants. METHODS: We included patients with epilepsy who were considered to be well-controlled in a cross-sectional study in seven hospitals in the Netherlands. Their medication had not been changed for six months and an apparent reason to change the medication was lacking at the time of enrolment. Subjective complaints were assessed with a 46-item questionnaire. Using multivariable linear regression modeling, we assessed whether patient characteristics, epilepsy characteristics, medication, quality of life (Qolie-10), and personality traits (SCL-90) explained the presence and severity of complaints. RESULTS: Of 173 included patients, 67% reported moderate to severe subjective complaints on the questionnaire. Cognitive complaints were reported most frequently. Multivariate modeling showed that 61% of the variance in reported complaints could be explained by included determinants. The prevalence and severity of complaints was associated with AED polytherapy and higher scores on psycho neuroticism. CONCLUSIONS: Patients who were considered to be well-controlled proved to report an unexpectedly high number of subjective complaints. Both medication and aspects of personality contributed to the level of complaints. Our study illustrates that subjective side-effects are easily overlooked in everyday clinical practice, possibly because in practice a generally phrased question is used to detect side-effects.

The Dutch algorithm for allocation in living donor kidney exchange.

The shortage of kidneys from brain-dead donors for transplantation has made it necessary to look for alternatives. Living kidney donation is one possibility. However, because of ABO blood group incompatibility or immunological reasons, transplantation of kidneys from a living donor is not always possible. The seven Dutch kidney transplantation centers have developed a joint protocol for crossover, or paired donor exchange, kidney transplantation. To ensure a fair chance for all participating donor-recipient pairs, the Dutch Transplantation Foundation has developed an allocation algorithm to match compatible donor-recipient pairs. A crossover match is performed every 3 months. The computer program developed by the Dutch Transplantation Foundation to match compatible donor-recipient pairs calculates the match probability (MP) of every potential recipient. The MP takes into account the peak panel-reactive antibodies (%PRA) of the recipient, the incidence within the crossover donor population of (compatible) ABO blood group, and HLA unacceptables of the recipient. The potential recipient with the lowest MP, in other words, the recipient with the smallest chance of finding a compatible donor in the pool, is ranked first. Until now, three matches have been performed in the Netherlands. A total of 53 pairs from all seven Dutch transplantation centers have participated. For 22 of the pairs a compatible donor-recipient pair was found.

Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation.

We tested the hypothesis that excessive portal venous supply of long-chain fatty acids to the liver contributes to the development of insulin resistance via activation of the hypothalamus-pituitary-adrenal axis (HPA axis) and sympathetic system. Rats received an intraportal infusion of the long-chain fatty acid oleate (150 nmol/min, 24 h), the medium-chain fatty acid caprylate, or the solvent. Corticosterone (Cort) and norepinephrine (NE) were measured as indexes for HPA axis and sympathetic activity, respectively. Insulin sensitivity was assessed by means of an intravenous glucose tolerance test (IVGTT). Oleate infusion induced increases in plasma Cort (Delta = 13.5 +/- 3.6 microg/dl; P < 0.05) and NE (Delta = 235 +/- 76 ng/l; P < 0.05), whereas caprylate and solvent had no effect. The area under the insulin response curve to the IVGTT was larger in the oleate-treated group than in the caprylate and solvent groups (area = 220 +/- 35 vs. 112 +/- 13 and 106 +/- 8, respectively, P < 0.05). The area under the glucose response curves was comparable [area = 121 +/- 13 (oleate) vs. 135 +/- 20 (caprylate) and 96 +/- 11 (solvent)]. The results are consistent with the concept that increased portal free fatty acid is involved in the induction of visceral obesity-related insulin resistance via activation of the HPA axis and sympathetic system.

The influence of beta-cyclodextrin on the solubility of chlorthalidone and its enantiomers.

The solubility of chlorthalidone in 16 solvent systems was determined in the absence and presence of different amounts of beta-cyclodextrin (beta-CD). Chlorthalidone (CT) was shown to be more soluble in hydrophilic organic solvents, with the highest solubility in ethylacetate (EtOAc) saturated with water. The solubility of CT in water, butanol, octanol, and dichloromethane (DCM) was enhanced by the addition of beta-cyclodextrin. The enantioselective partitioning of CT between water and EtOAc, DCM, butan-1-ol, butan-2-ol, and octan-1-ol was determined in the presence of beta-CD at pH 5, 7, and 9. According to the results, both the solubility and partitioning properties of CT are affected by beta-CD in aqueous solution. It was also shown that the solubility of the individual enantiomers differs in the presence of beta-CD.

Effects of lethal and sublethal concentrations of the herbicide, triclopyr butoxyethyl ester, in the diet of zebra finches.

Lethal and sublethal effects of dietary triclopyr butoxyethyl ester (TBEE) on zebra finches (Poephila guttata Gould) were determined in laboratory experiments conducted between 8 January and 1 May 1991. The 8-day median lethal dietary concentration, LC50 (95% confidence interval), of TBEE to zebra finches was 1,923 (1,627 to 2,277) mg/kg. In the sublethal effects experiment, when birds were exposed to 500 mg/kg TBEE in the diet for 29 days, food consumption and body weight were significantly depressed (P < 0.05). Similar prolonged exposures to 50 and 150 mg/kg TBEE in the diet had no significant effect on food consumption or body weight (P > 0.05). Perch-hopping activity was depressed relative to controls in the 500 mg/kg group, and elevated in the 150 mg/kg group, but neither of these differences was significantly (P > 0.05). Disappearance of TBEE residues from treated seeds over the 29 day experimental period followed an exponential decay model, with half-lives in the order of 15 to 18 days. On the basis of our observation that TBEE had no significant adverse effects at a concentration greater than the maximum expected environmental concentration, we propose that forestry applications of triclopyr at registered dosage rates pose little risk to wild songbirds.

Toxicity of a new molt-inducing insecticide (RH-5992) to aquatic macroinvertebrates.

The molt-inducing insecticide RH-5992, a potent ecdysone agonist, is being evaluated for potential use in forestry to control defoliating lepidopterans. The possible adverse effects of RH-5992 on nontarget aquatic organisms were studied in two test systems. Acute lethal effects were determined for one aquatic amphipod and 11 species of aquatic insects in laboratory flowthrough toxicity tests. Lethal and behavioral effects (drift response) on the amphipod and 8 species of stream insects were also evaluated under natural environmental conditions and more realistic exposure regimens in outdoor stream channels. There were no significant effects on drift or survival of the test species exposed to RH-5992 at the maximum test concentration of 3.5 mg/liter (100x the worst-case expected environmental concentration) in laboratory toxicity tests and stream channel treatments. Mortality of the amphipod Gammarus sp. in one toxicity test was considered an artifact, because there was no significant mortality in subsequent tests at concentrations up to 7.0 mg/liter, or in stream channels treated at 3.5 mg/liter. Yellow birch leaves were sprayed with RH-5992 at a rate of 50 g/ha and tested for residual toxic effects on two species of shredding invertebrates in the outdoor stream channels. There was no feeding inhibition or lethal effect on either test species resulting from consumption of the contaminated foliage. The candidate insecticide RH-5992 does not appear to pose undue risk of direct adverse effects to aquatic macroinvertebrates, particularly in water bodies where residues are likely to be short lived following aerial applications (e.g., lotic systems).

Cutis marmorata telangiectatica congenita.

The authors describe ten cases of cutis marmorata telangiectatica congenita (CMTC). All of these cases were sporadic. The incidence of associated anomalies was relatively low, and three patients had skin manifestations (cutaneous atrophy and nevus telangiectaticus). In two patients, the right leg was shorter and thinner. Another two showed neurologic symptoms without lasting neurologic damage. New associated anomalies, such as tendinitis stenosans and bowing of the lower legs, did not provide additional information regarding the cause of CMTC. The authors suggest that Happle's lethal gene hypothesis for Klippel-Trenaunay and Sturge-Weber syndromes also could be applied to CMTC.

Distribution of corticospinal neurons with collaterals to the lower brain stem reticular formation in monkey (Macaca fascicularis).

An earlier retrograde double-labeling study in cat showed that up to 30% of the corticospinal neurons in the medial and anterior parts of the precruciate motor area represent branching neurons which project to both the spinal cord and the reticular formation of the lower brain stem. These neurons were found to be concentrated in the rostral portion of the motor cortex, from where axial and proximal limb movements can be elicited. In the present study the findings in the macaque monkey are reported. The fluorescent retrograde tracer DY was injected unilaterally in the spinal cord at C2 and the fluorescent tracer FB was injected ipsilaterally in the medial tegmentum of the medulla oblongata. In the contralateral hemisphere large numbers of single DY-labeled corticospinal neurons and single FB-labeled corticobulbar neurons were present. A substantial number of DY-FB double-labeled corticospinal neurons were also found, which must represent branching neurons projecting to both the spinal cord and the bulbar reticular formation. These neurons were present in: 1. The anterior portion of the "cingulate corticospinal area" in the lower bank of the cingulate sulcus; 2. The supplementary motor area (SMA); 3. The rostral part of precentral corticospinal area; 4. The upper portion of the precentral face representation area; 5. The caudal bank of the inferior limb of the arcuate sulcus; 6. The posterior part of the insula. In these areas 10% to 30% of the labeled neurons were double-labeled. The functional implications of the presence of branching corticospinal neurons in these areas is discussed.

Branching cortical neurons in cat which project to the colliculi and to the pons: a retrograde fluorescent double-labeling study.

The fluorescent double-labeling technique has been used to determine whether the corticopontine and the corticotectal fibers in the cat are derived from two different sets of neurons or whether they are derived from branching neurons which distribute collaterals to the pontine grey and the colliculi. After unilateral DY.2HCl injections in the pontine grey and FB injections in the ipsilateral colliculi, large numbers of FB-DY.2HCl double-labeled neurons were present in the cortex of the ipsilateral hemisphere. However, the labeled neurons in its rostral part may have represented pyramidal tract neurons which were labeled retrogradely because their fibers descended through the DY.2HCl injection area. Therefore, also DY.2HCl injections were made in the pyramid (i.e. caudal to the pons) and the cortical pyramidal tract area, containing the retrograde DY.2HCl-labeled neurons, was delineated. In the rest of the experiments only the DY.2HCl-labeled neurons in the caudal two thirds of the hemisphere (outside the pyramidal tract area) were taken into account because only these neurons could, with confidence, be regarded as corticopontine neurons. In some anterograde HRP transport experiments the trajectories of the corticotectal and the corticopontine fibers were visualized. On the basis of the findings the DY.2HCl injections in the pontine grey were placed such that they could not involve any of the corticotectal fibers passing from the cerebral peduncle to the colliculi. Thus artifactual double-labeling of cortical neurons was avoided. However, also under these circumstances many double-labeled neurons were present in the caudal two thirds of the hemisphere. This led to the conclusion that in the cat a large proportion of the corticopontine neurons in the caudal two thirds of the hemisphere represent branching neurons which also distribute collaterals to the colliculi. The parietal (anterior part of the lateral gyrus, middle and posterior suprasylvian gyri) and the cingulate areas together contained three quarters of all labeled corticopontine neurons outside the pyramidal tract area. In the parietal areas roughly 25% of them were double-labeled and in the cingulate area 14%. However, in the visual areas 18 and 19 a much larger percentage (30-60%) was double-labeled.(ABSTRACT TRUNCATED AT 400 WORDS)

Large layer VI cells in macaque striate cortex (Meynert cells) project to both superior colliculus and prestriate visual area V5.

Layer VI of macaque striate cortex contains a number of large solitary neurones called Meynert cells. It has been shown earlier that these Meynert cells project to the posterior bank of the superior temporal sulcus (area V5), but it has also been shown that they project to the superior colliculus. In retrograde fluorescent double-labelling experiments, it was found that Meynert cells represent a class of neurones which distribute divergent axon collaterals to the posterior bank of the superior temporal sulcus and to the superior colliculus, i.e. to a distant cortical and a subcortical structure. This feature appears to be unique among projecting neurones in monkey visual cortex.

Distribution of corticospinal neurons with collaterals to lower brain stem reticular formation in cat.

The fluorescent retrograde double-labeling technique has been used to determine whether corticospinal neurons in the cat sensorimotor cortex distribute collaterals to the lower brain stem reticular formation. In this study the fluorescent tracers Nuclear Yellow and Diamidino Yellow 2HCl were used in combination with Fast Blue. One tracer was injected unilaterally in the spinal cord and the other was injected ipsilaterally in the bulbar medial reticular formation. The distribution of the retrogradely labeled neurons was studied in the contralateral hemisphere. In the sensorimotor cortex a large population of neurons was found which were labeled from the spinal cord and were double-labeled from the brain stem. These branching neurons were concentrated in the rostromedial part of the area 4 and the adjoining lateral part of area 6. In this region the percentages of corticospinal neurons which were double-labeled from the brain stem ranged from 5% laterally to 30% medially. In two cats it was demonstrated by means of the anterograde transport of HRP that the corticobulbar fibers from this region which must include the corticospinal collaterals are distributed to the reticular formation of the lower brain stem. In view of the fact that the double-labeled neurons are concentrated in the anterior part of the motor cortex, those branching neurons are in all likelihood involved in the control of neck, back and shoulder movements. This control is probably exerted by way of two routes i.e. by way of the direct corticospinal connections to spinal interneurons, and by way of the indirect cortico-reticulospinal connections established by the cortical fibers to the bulbar reticular formation. The present findings suggest that this dual control may be exerted by one and the same cell.

Collaterals of rubrospinal neurons to the cerebellum in rat. A retrograde fluorescent double labeling study.

In a previous study the collateralization of the rubrospinal tract in the spinal cord of rat, cat and monkey was studied by means of the fluorescent retrograde double labeling technique. In the present study the existence of rubrospinal collaterals to the cerebellar interpositus nucleus (NI) has been studied using the same technique. In rat 'True Blue' (TB) was injected in the cerebellar NI and 'Nuclear Yellow' (NY) was injected ipsilaterally in white and gray matter of C5-C8 spinal segments. In some cases a new fluorescent retrograde tracer was used instead of NY, i.e. 'Diamidino Yellow' (DY), which produces retrograde labeling similar to NY but which migrates only very slowly out of the retrogradely labeled neurons. In these experiments only very few single TB-labeled rubrocerebellar neurons occurred, but many (+/- 90%) of the TB-fluorescent rubrocerebellar neurons were TB-NY or TB-DY double-labeled from the spinal cord. At least 37% of the NY and DY-fluorescent rubrospinal neurons were NY-TB and DY-TB double-labeled from the cerebellum. These findings indicate that, in rat, almost all rubrocerebellar fibers represent collaterals of rubrospinal neurons, and that at least 37% of the rubrospinal neurons give rise to such cerebellar collaterals.

Diamidino yellow dihydrochloride (DY . 2HCl); a new fluorescent retrograde neuronal tracer, which migrates only very slowly out of the cell.

Earlier studies showed that Nuclear Yellow (NY), True Blue (TB) and Fast Blue (FB) are transported retrogradely through axons to their parent cell bodies. NY produces a yellow fluorescent labeling of the neuronal nucleus at 360 nm excitation wavelength, while TB and FB produce a blue fluorescence of the cytoplasm at this same wavelength. Therefore, NY may be combined with TB or FB in double-labeling experiments demonstrating the existence of axon collaterals. However, retrograde neuronal labeling with TB or FB requires a relatively long survival time, while NY requires a short survival time since NY migrates rapidly out of the retrogradely labeled neurons. This complicates double-labeling experiments since TB and FB must be injected first and NY later, a short time before the animal is sacrificed. We report a new yellow fluorescent tracer which labels mainly the nucleus and migrates much more slowly out of the retrogradely labeled neurons than NY. This new tracer can be used instead of NY in combination with TB or FB in double-labeling experiments and unlike NY can be injected at the same time as TB or FB. The new tracer is a diamidino compound (no. 28826) which is commercially available. It will be referred to as Diamidino Yellow Dihydrochloride (DY . 2HCl). According to the present study DY . 2HCl is transported over long distances in rat and cat, and produces a yellow fluorescence of the neuronal nucleus at 360 nm excitation wavelength, resembling that obtained with NY. When combined with TB or FB, DY . 2HCl is as effective as NY in double labeling of neurons by way of divergent axon collaterals.