The application of population pharmacokinetic analysis to large scale clinical efficacy trials

Summary Results have been presented that demonstrate the ability to conduct population pharmacokinetic analysis as a component of clinical efficacy and safety trials. This method of analysis offers the potential to determine the pharmacokinetics of a drug in the actual patients receiving medication and to evaluate relationships between pharmacokinetics and drug action. However, active involvement in the protocol design, and data collection process are required to ensure the quality of the resultant data set.     

Postural imbalance: An early sign in HIV-1 infected patients

Summary We have recorded postural performance in 50 HIV-infected patients in different stages of the disease (Walter Reed (WR) stages I–VI) by means of a force measuring platform. The results were compared with 50 age-matched controls. A significant instability was particularly evident when standing on an unstable foot support. In patients standing with eyes closed, postural sway was significantly higher in every patient group (WR I–II:P<0.02, WR III–V:P<0.001, WR VI:P<0.001). Patients in stage WR I–II showed no relevant neurological abnormalities. In agreement with other neurophysiological data in the literature we suggest that postural imbalance could be an early sign of central nervous system penetration of HIV. No correlation with electromyographic or cerebrospinal fluid findings could be found.     

Screening for chlamydia trachomatis in military personnel by urine testing

Summary In order to determine the infection rate ofChlamydia trachomatis in young males in Austria an epidemiological study was performed on 335 male Austrian soldiers attending the military hospital for a health check-up procedure. Three hundred twenty-nine (98.2%) of the screened males were clinically asymptomatic. Chlamydial diagnosis was established by testing first catch urine (FCU). Urine sediment was tested by an enzyme immunosorbent assay (EIA) and by a direct immunofluorescent test (DIF test). Positive results in both tests were defined true positives. In 41 (12.2%) of all the 335 soldiers a genital chlamydial infection could be demonstrated by a positive result of the sediment of the FCU in both tests. 93% of the positive results in the DIF test could be confirmed by the EIA whereas only 77% of the positive EIA tests were also positive in the DIF test. Data on genital symptoms and the history of sexually transmitted diseases (STDs) as well as information about sexual relationships were available from all persons included in the study and did not differ between chlamydia positive and negative ones. The study demonstrates a high infection rate withC. trachomatis in mostly asymptomatic young males when using FCU for chlamydial diagnosis. Due to the discrepancy between the EIA and the DIF test, positive results of the sediment of FCU in the EIA test should be confirmed by the DIF test to eliminate false positive cases.

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Screening auf Chlamydia trachomatis im Urin bei Militärpersonal

Zusammenfassung Um bei vorwiegend asymptomatischen männlichen Jugendlichen die Infektionsrate mitChlamydia trachomatis zu bestimmen, wurde im Rahmen einer Routinekontrolle in einem Militärspital eine Chlamydienuntersuchung bei insgesamt 335 Soldaten durchgeführt. Neben der Diagnose vonC. trachomatis wurden Daten über klinische Beschwerden, die Zahl früherer genitaler Kontaktinfektionen sowie über das Sexualverhalten der untersuchten Personen erhoben. Die Chlamydiendiagnostik erfolgte durch die Antigenbestimmung des Harnsediments mittels Enzymimmunassay (EIA) und direkter Immunfluoreszenz (DIF). Der Nachweis vonC. trachomatis im Harnsediment war bei 41 (12,2%) Männern durch ein positives Resultat in beiden Testverfahren möglich. 93% der im DIF-Test positiven Ergebnisse stimmten mit jenen im EIA überein, während nur 77% der positiven Resultate des EIA im DIF-Test bestätigt werden konnten. 98,2% der untersuchten Männer waren klinisch asymptomatisch, chlamydien-positive Personen unterschieden sich weder im Sexualverhalten noch in der Zahl früherer Infektionen von jenen mit negativem Chlamydienergebnis. Die erhobenen Daten weisen auf eine hohe Zahl klinisch asymptomatischer Chlamydieninfektionen bei vorwiegend jungen Männern hin. Aufgrund der diskrepanten Ergebnisse positiver Resultate in beiden Testverfahren sollte ein Antigennachweis im EIA aus dem Harnsediment durch den DIF-Test bestätigt werden. Der Nachweis einer Chlamydieninfektion aus dem Harnsediment kann lediglich dann empfohlen werden, wenn die Gewinnung von Patientenmaterial aus dem Urethralsekret nicht möglich ist.

     

The relative ethylumbelliferone dealkylase activity characterizing the effect of different inducers on the hydroxylase system in the liver musomes of female mice

d,l-Camphor was detected as a new inducer of hydroxylase in the liver musomes of female mice. After a 2-day inhalation of d,l-camphor, cyt. P-450 and the ethylumbelliferone dealkylase were increased by 250 per cent and the NADPH-cyt. P-450 reductase by 350 per cent. The product [NADPH-cyt. P-450 reductase activity × cyt. P450 concentration] was shown to be a suitable reference parameter for the ethylumbelliferone dealkylase activity in the liver musomes during the treatment with four different inducers. The relative dealkylase activity Q was much decreased during inhalation of cyclohexane or d,l-camphor.

$\text{Q =}\text{mU ethylumbelliferone dealkylase}\text{mU NADPH-cty. P-450 reductase × nmoles cty. P-450/mg protein}$

Obviously these two inducers preferably enhanced cyt. P-450 species with a low dealkylase activity. The Q-values were reproducible. Q was increased by 100 per cent during induction of a MC-sensitive mouse strain with 3-methylcholanthrene, but it was only moderately decreased by induction with phenobarbital. Corresponding to this, methylcholanthrene is known to selectively induce a cyt. P-448 with high dealkylase activity whereas phenobarbital is known to change the hydroxylase specificity in the liver musomes not very much.     

Serotonin transporter gene and schizophrenia: evidence for association/linkage disequilibrium in families with affected siblings

The serotonergic (5-HT) system has been implicated in the etiopathogenesis of psychoses. Since the 5-HT transporter plays an important role in regulation of 5-HT transmission, its gene can be considered as a candidate for vulnerability to psychiatric disorders. Two polymorphic sites of the 5-HT transporter gene-5-HTTLPR, a VNTR in the 5' regulatory region, and a VNTR in the second intron-were studied in a sample of 61 families with schizophrenia for transmission disequilibrium. Each family contained at least two siblings affected with schizophrenia or schizoaffective disorder (mainly schizophrenic). One hundred and thirty-nine affected offspring with parental information for genotyping, were available for analysis. No preferential transmission of either short or long alleles of the promoter polymorphism was observed. However, a transmission distortion was detected for alleles of the intronic VNTR polymorphism (chi2TDT max =14.33; P = 0.0002; corrected P value = 0.0003) resulting in more frequent than expected transmission of the 12 repeat allele. This finding adds additional evidence to the idea that the serotonergic system may be involved in development of psychoses. Molecular Psychiatry (2000) 5, 91-95.     

Recognition of Crohn Disease on Incidental Gastric Biopsy in Childhood

The role of gastric biopsy in the diagnosis of Crohn disease (CD) in the pediatric population has not been well described. We assessed the use of gastric biopsies in the diagnosis of CD using specific histopathologic parameters: granulomata, focal gland injury with neutrophils (glandulitis or glandular abscesses), and/or focal concomitant eosinophilic infiltrates. Multiple (438) consecutive pediatric biopsies with inflammation spanning a 5-year period were identified from archival material in patients ages 2 months to 16 years. A total of 56 CD cases were confirmed using colon biopsies and clinical and radiologic data as the gold standards of diagnosis. Review of hematoxylin and eosin (H&E) slides and Diff-Quik stained slides (negative for Helicobacter pylori) isolated 53 cases which suggested CD on gastric biopsy: 20 cases with granulomata, 14 cases with focal glandulitis and glandular abscesses, and 19 cases of focal glandulitis/glandular abscesses with eosinophilic infiltrates. Seventy-seven percent (43/56) were correctly identified as patients with CD. Twenty-three percent (13/56) of CD cases were not identified primarily because of concurrent H. pylori infection identified on Diff-Quik stain with a superimposed nonspecific diffuse gastritis. The use of Diff-Quik stain to identify H. pylori cases after all other factors are considered was significant (P = 0.0145); a negative stain, combined with the identified histopathologic features indicative of CD, significantly increased the accuracy of CD diagnosis. CD was mimicked by other gastric granulomatous diseases (actinomyces, 1 case; chronic granulomatous disease of childhood, 1 case). Gastric biopsy can be used to identify or support the diagnosis of CD in children in the appropriate clinicopathologic setting.     

Classic Adamantinoma with Osteofibrous Dysplasia-like Foci and Secondary Aneurysmal Bone Cyst

Adamantinoma, a rare bone lesion of the tibia and fibula, has two distinct variants, classic adamantinoma and osteofibrous dysplasia-like adamantinoma. Composite lesions have not been described. Aneurysmal bone cyst is a benign cystic lesion which may also occur in the tibia and fibula. We report an unusual case of classic adamantinoma with osteofibrous dysplasia-like areas and foci of secondary aneurysmal bone cyst with prominent giant cells. A lesion was diagnosed in a 17-year-old girl with a 14-year history of a slowly enlarging left tibial mass and increasing deformity. Pathologically, the predominant pattern was classic adamantinoma, with minor foci of osteofibrous dysplasia-like adamantinoma and areas of secondary aneurysmal bone cyst with abundant multinucleated giant cells. We report the clinical, radiologic, and pathologic features of this case, and summarize lesions associated with secondary aneurysmal bone cyst. To our knowledge, the association of adamantinoma with secondary aneurysmal bone cyst has not been previously reported.     

Unusual Hepatic Tumor with Features of Mesenchymal Hamartoma and Congenital Solitary Nonparasitic Cyst

We report a hepatic tumor in an adolescent that does not fit into any of the described categories of liver tumors. The patient presented with hepatomegaly, abdominal pain, and normal liver function test; the tumor was cystic in imaging studies. The resected specimen, result of a partial hepatectomy, measured 21 cm and was multicystic with solid areas. Microscopically, the cysts were lined by a mucous-producing or intestinal-type epithelium, associated with smooth muscle and small mucous-producing glands. The solid component contained fibrous and adipose tissue, smooth muscle and thick-walled vessels. Aneuploidy was demonstrated by flow cytometry. We interpreted the tumor as having features of a mesenchymal hamartoma and congenital solitary nonparasitic cyst. It is conceivable that the lesions originated with small peribiliary glands with dilatation and intestinal metaplasia.     

A foreign body embedded in the mobile tongue masquerading as a neoplasm

Foreign bodies in a mobile tongue are rarely presented to the laryngologist, because such bodies are commonly lodged superficially and are easily removed by the patients themselves or by general practitioners. Thus, it is rare that a foreign body totally embedded in the mobile part of the tongue presents as an enlarged tongue mass. We have described a 64-year-old female with a 3-month history of an enlarged mass in the anterior right tongue. Physical examination showed a mass located in the anterior right tongue, with intact mucosa and normal color. A benign tongue neoplasm was considered first. However, a fish bone totally embedded in the mobile tongue with granuloma formation was encountered during the incisional biopsy operation. Complete removal of the foreign body with granuloma was achieved under local anesthesia. There was no neuromuscular or neurosensory deficit of the tongue in the follow-up period of 2 years. Although an embedded foreign body in the mobile tongue is a rare condition, it should be considered in the work-up of a patient with an enlarged tongue mass, with or without a history of swallowing a foreign body.