Correlation between antifungal susceptibility testing ofCandida isolates from patients with HIV infection and clinical results after treatment with fluconazole

Summary In an open-label controlled study 23 HIV-infected patients (CDC IV A–E) with documented oropharyngeal candidosis were treated with 100 mg fluconazole orally over 5 days (53 episodes; 1–6 treatments/patient). Efficacy data were compared with a control group of 21 patients who received treatment for 10–21 days with 100 mg fluconazole for candidosis. Candida isolates were repeatedly recovered from patients before and after treatment with fluconazole and antifungal susceptibility testing (microbroth-dilution) was done. Inoculum size, medium pH, incubation time and temperature were standardized. Up to 85% of patients responded to therapy clinically and mycologically.Candida albicans was the most important yeast (86%) isolated from cultures of oral washings. In 90% ofC. albicans isolates MIC to fluconazole were low (1.56 mg/l). Primary resistance to fluconazole was not seen, but secondary resistance occurred in two cases clinically andin vitro (MIC25 mg/l). Short treatment for 5 days was as successful as for 10 to 21 days without leading to significantly more recurrences of oral candidosis in these patients. Selection ofCandida spp. other thanC. albicans (e. g.Candida krusei, Torulopsis glabrata) under repeated fluconazole treatment occurred rarely. One patient developed clinical signs of chronic recurrent candidiasis, where onlyC. krusei could be cultured repeatedly.

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Korrelation zwischen MHK-Bestimmung bei Candida-Isolaten von Patienten mit HIV-Infektion und Therapieverlauf nach Behandlung mit Fluconazol

Zusammenfassung In einer offenen kontrollierten Studie wurde bei 23 HIV-infizierten Patienten (CDC IV A–E) eine dokumentierte oropharyngeale Candidose mit 100 mg Fluconazol oral über 5 Tage behandelt (53 Episoden; 1–6 Episoden/Patient). Die Ergebnisse wurden mit einer Kontrollgruppe verglichen, in der 21 HIV-infizierte Patienten über 10–21 Tage mit 100 mg Fluconazol behandelt wurden. Von den Patienten wurden vor und nach jeder Therapie mit Fluconazol Candida-Isolate gewonnen, differenziert und einer Resistenztestung unterzogen (Mikro-Dilutionstechnik). Für die Resistenztestung wurden Inokulumgröße, pH des Mediums, Inkubationszeit und -temperatur standardisiert. Bis zu 85% der Patienten zeigten klinisch und mykologisch eine Heilung/Besserung.Candida albicans war der am häufigsten isolierte Hefepilz (86%) aus sämtlichen Proben, die mit Mundspülungen gewonnen wurden. 90% allerC. albicans-Isolate warenin vitro Fluconazol-empfindlich (MHK 1,56 mg/l). Eine Primärresistenz gegenüber Fluconazol wurde nicht beobachtet, aber in zwei Fällen trat sowohl klinisch als auchin vitro eine Fluconazol-Resistenz gegenüberC. albicans auf (MHK 25 mg/l). Eine Behandlung der Candidose mit 100 mg Fluconazol über 5 Tage führte zu einer vergleichbaren Heilungs-/Besserungsrate wie über 10–21 Tage, ohne daß die Rezidivrate wesentlich erhöht war. Eine therapiebedingte Selektion von Nicht-albicans-Arten(Candida krusei, Torulopsis glabrata) nach Fluconazol-Behandlung wurde selten beobachtet. Allerdings bestand bei einem Patienten der (klinische) Verdacht auf eine durchC. krusei unterhaltende orale Candidose, da nurC. krusei wiederholt nachgewiesen werden konnte.

     

Analysis of phosphorylation level of DNA topoisomerase-ii-alpha and topoisomerase-ii-Beta in human hela-cells

We have studied the phosphorylation of DNA topoisomerases II in HeLa cells focusing on the beta isoform of the enzyme which is very difficult to analyze because of its instability. In proliferating cells, we observed that both the a and beta isozymes are labeled after cell incubation with (32)p. The phosphorylation of beta enzyme occurs to a low extent, thus reflecting the expression of topoisomerases II during cell cycle. In cells treated with etoposide, the activity of topoisomerase II is inhibited and the level of phosphorylation decreases, suggesting a possible cooperation between this modification and drug response.     

Neuroblastoma in two siblings supports the role of 1p36 deletion in tumor development

Familial neuroblastoma occurs rarely. We studied a family with three children; one of them has a disseminated (stage 4) and another has a localized (stage 2) neuroblastoma. We observed subtelomeric locus D1Z2 (1p36) deletion in both tumors by using double-color fluorescence in situ hybridization. The MYNC gene was found in single copy in both tumors. Loss of heterozygosity (LOH) and restriction fragment length polymorphism analyses were performed by using DNA from frozen tumor cells and from microdissected tumor areas excised from paraffin-embedded sections. We detected somatic LOH at locus D1S468 (1p36) in a tumor-cell population with a trisomy 1 of the stage-2 patient. Neuroblastoma cells of the stage-4 patient were diploid and showed allelic loss at the following loci: D1S172, D1S80, D1S94, D1S243, D1S468, D1S214, D1S241, and D1S164. Haplotype study showed that the siblings inherited the same paternal 1p36-->pter chromosome region by homologous recombination and that, in the two tumors, arm 1p of different chromosomes of maternal origin was damaged. Our results suggest that the siblings inherited the predisposition to neuroblastoma associated with paternal 1p36 region and that tumors developed as a consequence of somatic loss of the maternal 1p36 allele.     

A case of gamma-hydroxybutyric acid withdrawal syndrome during alcohol addiction treatment: utility of diazepam administration

Gamma-hydroxybutyric acid (GHB) is an emerging drug for alcoholism therapy. We present a case of GHB withdrawal syndrome secondary to GHB addiction during alcoholism treatment. A complete disappearance of drug withdrawal syndrome was achieved with oral diazepam and the symptoms resolved without sequelae. GHB has been used for alcoholism therapy for only a few years now, but the trend is increasing, and other cases similar to this one are foreseeable. This risk could be higher in some countries in which GHB use is increasing not for alcoholism therapy, but for its euphoric and anabolic effects. The present experience indicates that administration of benzodiazepines would seem to be sufficient to achieve total regression of the withdrawal syndrome in a short time, at least if recognized early.     

Acyclovir treatment of relapsing-remitting multiple sclerosis

Acyclovir treatment was used in a randomized, double-blind, placebo-controlled clinical trial with parallel groups to test the hypothesis that herpes virus infections are involved in the pathogenesis of multiple sclerosis (MS). Sixty patients with the relapsing-remitting form of MS were randomized to either oral treatment with 800 mg acyclovir or placebo tablets three times daily for 2 years. The clinical effect was investigated by an extensive test battery consisting of neurological examinations, neuro-ophthalmological and neuropsychological tests, and evoked potentials. Results were based on intent-to-treat data and the primary outcome measure was the exacerbation rate. In the acyclovir group (n = 30), 62 exacerbations were recorded during the treatment period, yielding an annual exacerbation rate of 1.03. The placebo group (n = 30) had 94 exacerbations and an annual exacerbation rate of 1.57. Thus, 34% fewer exacerbations were encountered during acyclovir treatment. This difference in exacerbation rate between the treatment groups was not significant (P = 0.083). However, this trend to a lower disease activity in acyclovir-treated patients was supported in subsequent data analysis. If the patients were grouped according to exacerbation frequencies, i.e. into low (0–2), medium (3–5) and high (6–8) rate groups, the difference between acyclovir and placebo treatment was significant (P = 0.017). Moreover, in a subgroup of the population with a duration of the disease of at least 2 years providing an exacerbation rate base-line before entry, individual differences in exacerbation rates were compared between the 2-year pre-study period and the study period in acyclovir-treated (n = 19) and placebo (n = 20) patients and acyclovir-treated patients showed a significant reduction of exacerbations (P = 0.024). Otherwise, neurological parameters were essentially unaffected by acyclovir treatment and there were no convincing signs of reduced neurological deterioration in the acyclovir group. This study indicates that acyclovir treatment might inhibit the triggering of MS exacerbations and thus suggests that acyclovir-susceptible viruses might be involved in the pathogenesis of MS. This possibility warrants further investigation.     

Relevance of platelet serotonin and plasma tryptophan concentration in normal pregnant women and newborns to early child psychiatry

Dysfunctions of the serotonergic system are implicated in psychiatric disorders, and there is evidence that a familial element may be significant in childhood autism. The concentrations of platelet 5-HT and free and total plasma tryptophan were determined in healthy pregnant women at each month of pregnancy and, at delivery, in both maternal and umbilical cord blood. A significant rise in the level of platelet 5-HT occured during month 3 and 4 followed by a retum to normal from month 5 until the delivery. The level of total plasma tryptophan remained equal to that in normal healthy non pregnant women until the 6th month. By month 7, it had decreased significantly and remained low until the month 9. At delivery the level fell significantly by –41%. The concentration of free tryptophan varied widely from one month to another but there was a trend towards a progressive increase from month 1 to 9, and at delivery the level returned to basal values. The concentration of 5-HT in the umbilical cord blood was about half that of the maternal blood. Inversely the concentrations of both free and total plasma tryptophan in the umbilical cord blood were nearly twice that of the maternal blood.

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Zusammenfassung Dysfunktionen des serotoninergen Systems werden bei verschiedenen psychiatrischen Störungen angenommen, wobei es Hinweise für eine familiäre Komponente im Rahmen des kindlichen Autismus gibt. Die Konzentrationen der 5-Hydroxyindolessigsäure in Blutplättchen und des Tryptophans (freie und Gesamtplasmakonzentrationen) wurden in gesunden schwangeren Frauen sowohl im mütterlichen Blut als auch im Nabelschnurblut in jedem Schwangerschaftsmonat und bei der Geburt bestimmt. Ein signifikanter Anstieg der Konzentration der 5-Hydroxyindolessigsäure in Blutplättchen ereignete sich zwischen Mens III und IV, und von Mens V ab an bis zur Geburt normalisierte sich die Konzentration. Der Gesamtplasmaspiegel von Tryptophan glich dem in gesunden nicht-schwangeren Frauen bis zu Mens VI, in Mens VII war er signifikant abgefallen und blieb bis zur Mens IX niedrig. Zum Geburtstermin fiel der Spiegel signifikant um 41%. Die Konzentration des freien Tryptophans zeigte von Monat zu Monat deutliche Schwankungen, wobei es einen Trend in Richtung eines kontinuierlichen Anstiegs von Mens I–IX gab. Zum Termin fiel der Spiegel auf die basalen Werte ab. Die Konzentration der 5-Hydroxyindolessigsäure im Nabelschnurblut betrug ca. die Hälfte derer im maternalen Blut. Umgekehrt waren die Konzentrationen sowohl des freien als auch Gesamtplasmatryptophans im Nabelschnurblut ca. doppelt so hoch wie im maternalen Blut.

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Résumé Le système sérotonergique semble impliqué dans les psychoses infantiles précoces, et, dans la mesure où une prévalence familiale existe pour ces affections, il nous a paru intéressant de déterminer un profil normal de la sérotonine (5-HT) plaquettaire et du tryptophane au cours de la gestation. Ceci dans le but de puvoir interpréter des résultats trouvés pendant la grossesse de femmes déjà mères d'un enfant psychotique. Nous avons déterminé les concentrations en 5-HT plaquettaire et en tryptophane plasmatique total et libre chez des femmes enceintes témoins à chaque mois de grossesse et, à l'accouchement, dans le sang maternel et dans le sang du cordon. La concentration en 5-HT plaquettaire augmente significativement aux 3ème et 4ème mois puis revient à la normale à partir du 5ème mois jusqu'à l'accouchement. Le tryptophane total est normal jusqu'au 6ème mois, il diminue significativement au 7ème mois et reste bas jusqu'au 9ème mois. A l'accouchement, il s'effondre (–41%). Le tryptophane libre varie beaucoup d'un mois à l'autre, il augmente progressivement du début à la fin de la grossesse, à l'accouchement par contre, il est normal. Dans le sang du cordon, la concentration en 5-HT est environ la moitié de celle du sang maternel, le tryptophane total et le tryptophane libre environ deux fois plus élevés.

     

Pharmacokinetics of methyldopa in healthy man

Summary The pharmacokinetics of 2-¹⁴C-L--methyldopa have been investigated in five healthy volunteers following intravenous and oral administration. In the intravenous study a bi-phasic plasma concentration curve was found both for chemically determined -methyldopa and for radioactivity. The plasma level of radioactivity differed significantly from chemically determined drug, a pattern which was also found in urine. This suggests the presence of unidentified metabolite(s). The difference between plasma disappearance and urine recovery of -methyldopa and radioactivity during the first 4 h after injection suggests distribution to an extravascular compartment. Plasma half-lives of total radioactivity and of unchanged drug were calculated. In three subjects, pharmacokinetic parameters for a two-compartment open body model were calculated from urine and plasma data. Urinary recovery of radioactivity was almost complete within 48 h after intravenous administration. After oral administration, however, only about 40 per cent of the radioactive dose was recovered in the urine, and it contained approximately equal amounts of unconjugated methyldopa, acid-labile conjugated methyldopa and unidentified metabolite(s). The acid-labile conjugate was found only after oral administration, which supports the theory of a mucosal conjugation process. The lack of acid-labile conjugated drug either in the plasma or urine after intravenous injection indicates that there is no enterohepatic circulation of this drug.     

Methylated DNA collected by tampons--a new tool to detect endometrial cancer.

This proof of principle study aimed to define a new and simple strategy for detection of endometrial cancer using epigenetic markers. We investigated DNA isolated from vaginal secretion collected from tampon for aberrant methylation of five genes (CDH13, HSPA2, MLH1, RASSF1A, and SOCS2) using MethyLight in 15 patients with endometrial cancer and 109 patients without endometrial cancer. All endometrial cancer patients revealed three or more methylated genes, whereas 91% (99 of 109) of the patients without endometrial cancer had no or fewer than three genes methylated in their vaginal secretion. The methods developed in this study provide the basis for a prospective clinical trial to screen asymptomatic women who are at high risk for endometrial cancer.     

Endometrial volume change during spontaneous menstrual cycles: volumetry by transvaginal three-dimensional ultrasound

Objective: At present, only limited data are available on endometrial volume during the menstrual cycle. Most of these studies deal with animal models and use magnetic resonance imaging for volume measuring. The application of three-dimensional ultrasound in endometrial volume estimation is the subject of this study.Setting: Patients visiting the outpatient unit of the division of endocrinology and reproductive medicine of a university hospital.Patient(s): Twenty patients with a history of a normal menstrual cycle were selected.Intervention(s): Ultrasound examinations were performed during a single menstrual cycle in addition to routine laboratory tests.Main Outcome Measure(s): Uterus-endometrial volume ratio.Result(s): Data from 18 patients could be evaluated. In 81 examinations the endometrium volume could be determined. Mean endometrial volume measured by three-dimensional ultrasound was 1.23 cm'. Mean uterus volume was 48.93 cm3. The change of the uterus-endometrial volume ratio showed a good correlation with the day of menstrual cycle. Quadratic regression analysis of volume and cycle length was R² = 0.432.Conclusion(s): Three-dimensional ultrasound allows assessment of volume data of the female internal genitalia. In this study changes of the endometrial volume in menstrual cycles were measured. Additional studies are required to give information on the clinical impact of this new technique of endometrial volume estimation.