Follow-up of solar lentigo depigmentation with a retinaldehyde-based cream by clinical evaluation and calibrated colour imaging.

BACKGROUND AND OBJECTIVE: To assess an objective method evaluating the effects of a retinaldehyde-based cream (RA-cream) on solar lentigines; 29 women randomly applied RA-cream on lentigines of one hand and a control cream on the other, once daily for 3 months. METHODS: A specific method enabling a reliable visualisation of the lesions was proposed, using high-magnification colour-calibrated camera imaging. Assessment was performed using clinical evaluation by Physician Global Assessment score and image analysis. Luminance determination on the numeric images was performed either on the basis of 5 independent expert's consensus borders or probability map analysis via an algorithm automatically detecting the pigmented area. RESULTS: Both image analysis methods showed a similar lightening of ΔL* = 2 after a 3-month treatment by RA-cream, in agreement with single-blind clinical evaluation. CONCLUSION: High-magnification colour-calibrated camera imaging combined with probability map analysis is a fast and precise method to follow lentigo depigmentation.

[The myeloproliferative neoplasms-related glomerulopathy]. / Les glomérulopathies associées aux néoplasies myéloprolifératives.

PURPOSE: Myeloproliferative neoplasms (MPN) are hematological disorders characterized by clonal expansion of one or more medullary lines. Renal complications are rare, chiefly as acute renal failure. Glomerular involvement is exceptional METHODS: We report on a retrospective multicenter case series of eight patients who presented with a glomerulopathy (GP) associated with MPN RESULTS: All GP were revealed by a major proteinuria frequently associated with nephrotic syndrome and oedema. Histology was mainly characterized by lesions of focal segmental glomerulosclerosis associated with increased mesangial cellularity. The pathophysiology is still unclear but platelet-derived growth factor (PDGF) and transforming growth factor-ß (TGF-ß), which play a central role in the MPN may be involved. A majority of patients developed chronic renal failure despite of a therapy intended to block the renin-angiotensin system CONCLUSION: Monitoring of proteinuria during the follow-up of MPN would allow earlier diagnosis of renal involvement. Further studies on a larger scale are needed to specify the pathophysiological mechanisms involved and the management of these complications.

Formulation and in vitro characterization of inhalable polyvinyl alcohol-free rifampicin-loaded PLGA microspheres prepared with sucrose palmitate as stabilizer: efficiency for ex vivo alveolar macrophage targeting.

In this work a new formulation of inhalable rifampicin-loaded PLGA microspheres (RIF-MS) is proposed for the management of tuberculosis treatment. For their formulation, the non-biodegradable polyvinyl alcohol surfactant was replaced with a biodegradable and biocompatible sucrose ester, sucrose palmitate. The effects of critical process and formulation parameters have been investigated and the obtained microspheres were characterized in terms of size, morphology, encapsulation efficiencies and RIF release profile. The optimized RIF-MS showed high drug loading (34.2%, w/w), an aerodynamic diameter compliant with deep lung delivery and an in vitro gradual and almost complete drug release over a week. The drug release data fitted well to the Higuchi models suggesting a drug release governed by Fickian diffusion. The RIF-MS uptake qualitative and quantitative studies on ex vivo rat alveolar macrophages (AM) revealed an efficient internalization of RIF-MS and their location in the perinuclear area. RIF intracellular levels were 7-fold higher in AM incubated with RIF-MS than with an equivalent amount of free RIF.

In-stream and overland dispersal across a river network influences gene flow in a freshwater insect, Calopteryx splendens.

Gene flow in riverine species is constrained by the dendritic (branching) structure of the river network. Spatial genetic structure (SGS) of freshwater insects is particularly influenced by catchment characteristics and land use in the surroundings of the river. Gene flow also depends on the life cycle of organisms. Aquatic larvae mainly drift downstream whereas flying adults can disperse actively overland and along watercourses. In-stream movements can generate isolation by distance (IBD) at a local scale and differentiation between subcatchments. However, these patterns can be disrupted by overland dispersal. We studied SGS across the Loire River in the damselfly Calopteryx splendens which is able to disperse along and between watercourses. Our sampling design allowed us to test for overland dispersal effects on genetic differentiation between watercourses. Amplified fragment length polymorphism markers revealed high genetic differentiation at the catchment scale but the genetic structure did not reflect the geographical structure of sampling sites. We observed IBD patterns when considering the distance following the watercourse but also the Euclidean distance, i.e. the shortest distance, between pairs of sites. Altogether, our results support the hypothesis of overland dispersal between watercourses. From a conservation perspective, attention should be paid to the actual pathways of gene flow across complex landscapes such as river networks.

Normal intelligence in children with prenatal exposure to carbamazepine.

OBJECTIVE: To investigate the effect of antiepileptic drugs, especially carbamazepine and valproate, on intelligence in prenatally exposed children of mothers with epilepsy. METHODS: Intelligence of 182 children of mothers with epilepsy (study group) and 141 control children was tested in a blinded setting at preschool or school age using Wechsler Preschool and Primary Scale of Intelligence-Revised or Wechsler Intelligence Scale for Children-Revised. Data on maternal antiepileptic treatment and seizures during pregnancy were gathered prospectively. The study group represented approximately 50% of the children born to mothers with epilepsy in Uusimaa province during 1989 through 1994. One hundred seven children were exposed to antiepileptic monotherapy: 86 to carbamazepine and 13 to valproate. Thirty children were exposed to polytherapy: 23 combinations included carbamazepine, and 17 included valproate. The median maternal doses and blood levels during the second half of pregnancy were 600 mg and 26 micro mol/L for carbamazepine and 950 mg and 300 micro mol/L for valproate. RESULTS: The mean verbal and nonverbal IQ scores in the children exposed in utero to carbamazepine monotherapy were 96 (95% CI, 93-100) and 103 (95% CI, 100-106). They did not differ from control subjects, whose mean verbal and nonverbal IQ scores were 95 (95% CI, 92-97) and 102 (95% CI, CI, 100-105). Significantly reduced verbal IQ scores were found in children exposed to valproate (mean, 82; 95% CI, 78-87) and to polytherapy (mean, 85; 95% CI, 80-90) compared with the other study group children and control subjects. CONCLUSIONS: Carbamazepine monotherapy with maternal serum levels within the reference range does not impair intelligence in prenatally exposed offspring. Exposures to polytherapy and to valproate during pregnancy were associated with significantly reduced verbal intelligence. The independent effects of valproate remain unconfirmed because the results were confounded by low maternal education and polytherapy.

Bias in reporting clinical trials.

AIMS: The primary aim of the present study was to identify possible occurrence of selective reporting of the results of clinical trials to the Finnish National Agency for Medicines. Selective reporting may lead to poorly informed action or inaction by regulatory authorities. METHODS: In 1987, 274 clinical drug trials were notified to the Finnish National Agency for Medicines. By December 1993, final reports had been received from 68 of these trials and statements that the trial had been suspended from 24 trials. The sponsors of the non-reported trials were requested to report the outcome. The outcomes, if any, of all reported and non-reported trials were classified as positive, inconclusive or negative. RESULTS: The total number of trials with positive, inconclusive or negative outcome were 111, 33 and 44, respectively; the outcomes of 86 trials could not be assessed. Final reports were received from 42/111 (38%) trials with positive, 6/33 (18%) with inconclusive and 9/44 (20%) with negative outcomes. CONCLUSIONS: Substantial evidence of selective reporting was detected, since trials with positive outcome resulted more often in submission of final report to regulatory authority than those with inconclusive or negative outcomes.

Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy.

PURPOSE: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and polytherapy. METHODS: Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy and for 158 children of unexposed control pregnancies. RESULTS: Overall, when comparing a subgroup of 192 children exposed to AED with 158 children of matched nonepileptic controls, there was an increased risk of major congenital malformations (MCA) in children exposed to AED during gestation [relative risk (RR) 2.3; 95% confidence interval (CI): 1.2-4.7]. A significant increase in risk was found for children exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6-15.0) or carbamazepine (CBZ) (RR 4.9; 95% CI: 1.3-18.0) in monotherapy. When comparing different AED regimens during all 1,221 pregnancies, risks of MCA were significantly increased for the combination of phenobarbital (PB) and ethosuximide (RR 9.8; 95% CI: 1.4-67.3) and the combination of phenytoin, PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1-57.6). Offspring of mothers using > 1,000 mg VPA/day were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed < or =600 mg VPA/day (RR 6.8; 95% CI: 1.4-32.7). No difference in risk of MCA was found between the offspring exposed to 601-1,000 mg/day and < or =600 mg/day. CONCLUSIONS: This reanalysis shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population-based studies are needed to evaluate the risks of many other less frequently prescribed treatment regimens, including newly marketed AEDs.

Report bias in drug research.

Selective reporting of clinical trials to regulatory authorities could result in inappropriate marketing authorization decisions. The present study was conducted to uncover such potential bias, here called 'report bias'. In 1987 the number of clinical drug trials notified to Finnish National Agency for Medicines was 274. Up to the end of 1993, a final report or a statement that the trial had been suspended had only been received in the case of 91 studies. The outcome of 183 trials was not reported. These trials were not significantly different from those reported on, in their design, in blinding, or in the use of a comparator. The distribution in phases I to IV was similar in the reported and non-reported groups. Thus incomplete reporting was not caused by differences in the investigational plan. Other factors, such as differences in results, may be responsible. It is possible that findings that do not support commercial interests are less likely to be reported. This potential bias requires to be investigated and considered.

Objectively measured perinatal exposure to meperidine and benzodiazepines in Finland.

We measured concentrations of meperidine and benzodiazepines in the umbilical serum of all live neonates born in Finland during a single week. Of the neonates, 31.1% were exposed to meperidine or benzodiazepines or both. One hundred twenty-one mothers of the 261 neonates exposed to meperidine were not recorded in the Finnish Medical Birth Registry as having received analgesic drugs. Infants born to primiparous mothers were more likely to be exposed. The exposures were associated with the type of delivery: vacuum extraction with a high proportion of neonates exposed to meperidine and elective caesarean section with a high proportion of neonates exposed to benzodiazepines. The exposures were influenced by the method of obstetric analgesia: epidural blockade was associated with more frequent exposure to meperidine. No significant circadian variation in exposures was detected. Validation of birth registry data is imperative before they are used for pharmacoepidemiologic studies.

Objectively measured tobacco exposure among pregnant women in Finland in 1986 and 1990.

OBJECTIVE: First, to study tobacco exposure among pregnant Finnish women in 1986 and 1990. Second, to study the objectively measured exposure in different socioeconomic classes and in different geographical regions. Third, to assess the value of serum thiocyanate concentrations in estimating fetal tobacco exposure. DESIGN: Tobacco exposure was measured from maternal and umbilical serum samples by measuring the concentration of nicotine metabolite, cotinine. In addition, the concentrations of thiocyanate were measured from umbilical serum samples. The occupations of the mothers were obtained from the Finnish Birth Registry, and the area of residence from laboratory records. SETTING: Finland. SUBJECTS: 1323 infants born in late February-early March in 1991, 1263 mothers of these infants during antenatal visits in Autumn 1990, and 976 pregnant mothers during antenatal visits in Autumn 1986. The mothers and infants studied represented all newborn infants and their mothers during one week in one country. MEASUREMENTS AND MAIN RESULTS: In 1986, 21.3% of Finnish mothers and in 1990 21.2% were exposed to tobacco. In 1986, exposed mothers were on average 1.4 (95% confidence interval 0.9-1.8) years younger than nonexposed mothers, and in 1990, exposed mothers were on average 1.6 years (95% confidence interval 1.1-2.3) younger than nonexposed mothers. 28.5% of mothers classified as unskilled workers were exposed, but only 9.1% of those classified as upper white-collar. There were no significant geographical differences in exposure. Although umbilical serum thiocyanate levels were always elevated in exposed infants, high serum thiocyanate concentrations were detected in infants not exposed to tobacco. CONCLUSIONS: More than 20% of pregnant Finnish mothers and their fetuses were exposed to tobacco in 1986 and 1990. Young women and women in low socioeconomic classes were the most seriously exposed. Measurement of serum thiocyanate concentrations did not yield reliable estimates of exposure.

Objectively measured tobacco exposure during pregnancy: neonatal effects and relation to maternal smoking.

OBJECTIVES: To measure quantitatively and objectively the maternal and fetal tobacco exposure during pregnancy and its neonatal effects. DESIGN: Tobacco exposure was assessed from maternal serum samples, obtained during the first half of pregnancy and from umbilical serum samples obtained at delivery, by measuring the concentration of nicotine metabolite, cotinine. Data on the respective pregnancies and neonates were collected from the Finnish Medical Birth Registry. SETTING: Finland. SUBJECTS: One thousand two hundred and thirty-seven pregnancies and newborns, representing all pregnancies resulting in a liveborn infant during one week in one country. MAIN OUTCOME MEASURES: Gestational age, birthweight and crown-heel length of newborns. RESULTS: Cotinine (> 6 micrograms/l) was detected in either maternal or umbilical serum in 300 pregnancies, and these mothers and newborns were classified as exposed. Important differences occurred between measured exposure and reported smoking behaviour. Of the exposed mothers, 38% were nonsmokers and 3.4% of the nonexposed mothers were smokers. Tobacco exposure was associated with shorter gestational age, reduced birthweight and shorter crown-heel length of the newborns. After correction for parity, gender, and gestational age, the exposed newborns were on average 188 g (95% confidence interval (CI) 123-253 g) lighter and 10 mm (95% CI 7-13 mm) shorter than the nonexposed newborns. One micrograms/ml of cotinine in maternal serum resulted in a mean decrease of 1.29 g (95% CI 0.55-2.02 g) in birthweight and in a mean decrease of 0.059 mm (95% CI 0.035-0.083 mm) in birth length. Maternal cotinine concentrations better explained the neonatal findings than the reported smoking habits. CONCLUSIONS: There is a quantitative dose and effect relation between tobacco exposure and a decrease in the gestational age at birth and size of the neonate. The smoking habit reported by mothers themselves is not an accurate measure of fetal tobacco exposure.

Reduction of antiepileptic drug dosage for monitoring epileptic seizures.

Eleven epileptic patients, candidates for surgical treatment, were examined in order to localize epileptic foci. The daily doses of antiepileptic drugs (AEDs) were reduced by fifty per cent or less, and the reduced dosages were maintained until a seizure had occurred. The reduction resulted in seizures within five days among all patients, and the number of seizures increased significantly in comparison with the five-day period before AED reduction. The seizures so provoked were typical for each patient, as confirmed by clinical observation and video-EEG telemetry. No status epilepticus or withdrawal psychosis occurred. The AED concentrations at the time of the seizures were generally within the reference values.

Decisions after first seizure.

The probability of an intracerebral neoplasm occurring in patients presenting with first seizure was calculated using the data provided by four recent studies. After recording the history of the patients and performing clinical neurological examinations, the probability of a neoplasm was increased or reduced substantially, allowing rational decision to be made for further investigation or follow-up. The impact of conventional EEG on the probabilities was weak. Decision analysis can be used to improve diagnostic practices.

Monitoring of concentrations of clobazam and norclobazam in serum and saliva of children with epilepsy.

Clobazam was added to the previous antiepileptic drug therapy of 90 children suffering from drug resistant epilepsy. Ten patients became seizure free, although four of these later developed tolerance. Thirty-three patients experienced a decrease in seizure frequency, and 24 of these, too, developed tolerance. Forty-four patients showed no change in seizure frequency, and three experienced an increase. The best results were experienced by patients with myoclonic seizures, whereas patients with complex partial seizures usually developed tolerance. The concentrations of clobazam and its active metabolite norclobazam were measured in 251 serum and 57 saliva samples. The group of seizure-free patients had the lowest clobazam and norclobazam concentrations; tolerance was associated with the highest concentrations. Beneficial side effects were associated with low, and adverse effects with high, concentrations of norclobazam. The concentrations of clobazam and norclobazam in saliva correlated with concentrations in serum. Monitoring of serum and salivary concentrations of clobazam and norclobazam is of limited value only, and no therapeutic target range can be given.

Head circumference in children of epileptic mothers: contributions of drug exposure and genetic background.

Head circumference after the first year of life was investigated in 144 children of epileptic mothers ('study group'). Fifty-two children had been exposed to phenytoin monotherapy, 19 to carbamazepine monotherapy, 27 to drug combinations including barbiturates, 29 to other drug combinations, and 17 children had not been exposed to antiepileptic drugs (AEDs) during pregnancy. The prevalence of microcephaly (2.1%) was no higher than that in the general population. Head circumference was measured at 5.5 years in 121 of the study group children, in 105 control children, and in the majority of their parents (118 mothers and 89 fathers in the study group, and 103 mothers and 65 fathers in the control group). The sex-adjusted head circumferences of the children showed a significant variation according to exposure subgroup, with the barbiturate and carbamazepine monotherapy exposed children having the lowest mean values. This result is similar to our previous findings in the same children at birth and at 18 months of age. Paternal head circumference was also below average in the same subgroups. After further adjustment for parental head circumference, the significant variation between the subgroups of children disappeared, even though the barbiturate exposed children continued to have the lowest mean value. Genetic causes may thus contribute to the relatively small head circumference in some AED exposed children of epileptic mothers. However, a mild drug effect in the barbiturate and carbamazepine exposed children cannot be excluded.

Protein binding of antiepileptic drugs during pregnancy, labor, and puerperium.

Twenty-four epileptic women were followed-up during late pregnancy, labor, and early puerperium in order to detect possible alterations in serum protein binding of antiepileptic drugs (AEDs). The total and free concentrations of carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA) in maternal serum were measured. In addition, the concentrations of albumin, alpha 1-acid glycoprotein (AGP), and free fatty acids (FFA) were also measured. Total AED concentrations during labor were influenced by changes in drug dosages; total PHT increased during the first puerperal weeks. During labor the free fraction of CBZ remained stable, whereas PHT and particularly VPA free fractions increased. This phenomenon was parallel to the increase in FFA concentration; FFA concentrations decreased again during the first days postpartum. Albumin and AGP concentrations were low during pregnancy and labor, and increased after delivery. The total umbilical CBZ and PHT concentrations were not significantly different from maternal concentrations. The total VPA concentration in umbilical serum was significantly higher than that in maternal serum. The free fraction of CBZ was higher and that of PHT and VPA lower in umbilical than in maternal serum at delivery. Umbilical cord serum had a higher albumin but a lower AGP and FFA concentration than maternal serum. The changes in PHT and particularly VPA free fraction associated with changes in FFA concentration should be considered when assessing the total concentration of these drugs in maternal and umbilical serum.

Problems in classification of epileptic seizures and syndromes.

The classification of epileptic seizures is based on clinical seizure types and on ictal and interictal electroencephalographic expressions. The classification of epileptic syndromes is based on the type of seizure and on the suspected aetiology. If the types of seizure of the patients are given, the classification of epileptic syndromes becomes unnecessary. If there is hard evidence on brain pathology, this should be given instead of aetiological speculations.

Effect of pregnancy on the electroencephalogram of epileptic women.

The electroencephalograms (EEGs) of epileptic women in late pregnancy were compared with their EEGs outside pregnancy and the puerperium. The number of epileptic interictal discharges was not modified by pregnancy. Visual scoring and frequency analysis demonstrated a slight increase in the alpha band during pregnancy. No correlations were found between the EEG findings and changes in seizure frequency.