Effect of factors on plasma haloperidol concentration/dose ratio]

It has been known that the serum concentration of antipsychotics is varied according to individual case. There are several factors that may affect the plasma levels of antipsychotics; e.g., antipsychotic dose, body weight, interaction with other drugs, enzyme activity in the human liver, age and smoking. The enzyme cytochrome P450 2D6 (CYP2D6) is an important factor affecting the plasma levels of antipsychotics, because CYP2D6 is involved in the metabolism of these drugs. In this paper, we review the effect of several factors on plasma haloperidol concentration.     

Otoacoustic emissions as a screening test for hearing impairment in children recovering from acute bacterial meningitis

OBJECTIVES: To study the efficacy of otoacoustic emissions (OAEs) as a screening test for hearing impairment in children with acute bacterial meningitis. Hearing tests were performed before discharge from the hospital in an attempt to improve coverage and avoid delays in the diagnosis of postmeningitic hearing loss. METHODS: Children with bacterial meningitis were recruited from 21 centers. In the 48 hours before discharge from the hospital, all patients underwent a thorough audiologic assessment consisting of transient evoked OAEs, auditory brainstem responses (ABRs), otoscopy, and tympanometry. Hearing loss was defined as ABR threshold >/=30 dB. The results of OAE screening were compared with the gold standard of ABR threshold. RESULTS: Of 124 children recruited, we were able to perform both OAEs and ABRs on 110 children. Seven (6.3%) of the 110 children had ABR threshold >/=30 dB; 2 had sensorineural hearing loss and 5 had conductive hearing loss. At follow-up, hearing loss persisted in both cases of sensorineural hearing loss and no new cases were identified. All 7 children with hearing loss failed the OAE screening test. Ninety-four children with normal hearing thresholds passed the test, and 9 failed. Thus, the screening test had a sensitivity of 1.00 (95% confidence interval, 0.59 to 1.00), a specificity of 0.91 (0.85 to 0.97), a positive predictive value of 0. 44 (0.20 to 0.70), and a negative predictive value of 1.00 (0.96 to 1.00). CONCLUSIONS: OAE screening in children recovering from meningitis was found to be feasible and effective. The test was highly sensitive and reasonably specific. Inpatient OAE screening should allow early diagnosis of postmeningitic hearing loss and prompt auditory rehabilitation.     

Screening for medium chain acyl-CoA dehydrogenase deficiency using electrospray ionisation tandem mass spectrometry

OBJECTIVE: To establish criteria for the diagnosis of medium chain acyl-CoA dehydrogenase (MCAD) deficiency in the UK population using a method in which carnitine species eluted from blood spots are butylated and analysed by electrospray ionisation tandem mass spectrometry (ESI-MS/MS). DESIGN: Four groups were studied: (1) 35 children, aged 4 days to 16.2 years, with proven MCAD deficiency (mostly homozygous for the A985G mutation, none receiving carnitine supplements); (2) 2168 control children; (3) 482 neonates; and (4) 15 MCAD heterozygotes. RESULTS: All patients with MCAD deficiency had an octanoylcarnitine concentration ([C8-Cn]) > 0.38 microM and no accumulation of carnitine species > C10 or < C6. Among the patients with MCAD deficiency, the [C8-Cn] was significantly lower in children > 10 weeks old and in children with carnitine depletion (free carnitine < 20 microM). Neonatal blood spots from patients with MCAD deficiency had a [C8-Cn] > 1.5 microM, whereas in heterozygotes and other normal neonates the [C8-Cn] was < 1.0 microM. In contrast, the blood spot [C8-Cn] in eight of 27 patients with MCAD deficiency > 10 weeks old fell within the same range as five of 15 MCAD heterozygotes (0.38-1.0 microM). However, the free carnitine concentrations were reduced (< 20 microM) in the patients with MCAD deficiency but normal in the heterozygotes. CONCLUSIONS: Criteria for the diagnosis of MCAD deficiency using ESI-MS/MS must take account of age and carnitine depletion. If screening is undertaken at 7-10 days, the number of false positive and negative results should be negligible. Because there have been no instances of death or neurological damage following diagnosis of MCAD deficiency in our patient group, a strong case can be made for neonatal screening for MCAD deficiency in the UK.     

Radioresponse of Thymomas Verified with Histologic Response

Patterns of radiologic response of 10 thymomas treated by preoperative radiotherapy (RT) (18-20 Gy/2 weeks) were determined in conjunction with histologic response. Changes in tumor volume were evaluated with CT scans obtained 5 to 36 days before and 14 to 24 days after the initiation of RT and before surgery. The extent of tumor volume reduction (TR) varied widely (40-78%), while the mean daily volume decrement expressed as a percentage of the pre-RT tumor volume correlated significantly with the pre-RT tumor volume. Histologically, the tumors, all of which were resected 17 to 33 days after RT initiation, generally consisted of predominant fibrous tissues, rare necrotic foci, and few epithelial cells. The TR did not correlate with pre-RT tumor volume, observation period, histologic subtype, or quantity of remaining epithelial cells. The TR of thymomas does not predict RT impact on tumor cells but does reflect the quantity of inherent tumor stroma.     

Presenilin-1 in late-onset depressive disorder

Late-onset depressive disorder (LOD) is thought to be associated with dementia. Allele 1 in the presenilin-1 (PS-1) gene is a risk factor for Alzheimer's disease. An association study on this polymorphism was performed in depressive patients and control subjects. The patients were subdivided into those with early onset and late onset, using 50 years as the cut-off age. There was no statistically significant difference in the age of onset of depressive disorders according to the PS-1 genotype. There was also no association between early/late-onset depressive disorders and the PS-1 genotype. Our results suggest there is no association between the PS-1 allele and LOD.     

Type II brain 4.1 (4.1B/KIAA0987), a member of the protein 4.1 family, is localized to neuronal paranodes

Histochemical analyses of type II brain 4.1/4.1B/KIAA0987, a member of the protein 4.1 family, were carried out in rat brain. In situ hybridization (ISH) showed that type II brain 4.1 mRNA is expressed in a variety of neuronal cells. In particular, type II brain 4.1 mRNA was actively transcribed in the cells of the mesencephalon and the brainstem, which have large myelinated nerve fibers. Expression of type II brain 4.1 mRNA was not observed at least in glial cells distributed in nerve fiber tracts. In immunohistochemical studies using anti-type II brain 4.1-specific antibody, the major immunosignals appeared as brilliant pairs of dots along nerve fibers. Such immunosignals were detected throughout the brain, but were highly concentrated in nerve fiber tracts. These data suggested that type II brain 4.1 is predominantly localized to neuronal paranodes. Detailed analysis concentrating on the nodal region indicated that type II brain 4.1 is present at the paranodal membrane but not in the axoplasm. Weaker type II brain 4.1-specific immunosignals were observed along the internodal membrane of myelinated axons and in the cytoplasm of some neuronal cells. Finally, comparative immunohistochemical studies using antibodies against the other three protein 4.1 family members, type I brain 4.1/4.1N/KIAA0338, erythroid type 4.1 (4.1R) and 4.1G, demonstrated that each of these proteins is distributed in a unique pattern in the cerebellum. Our results are the first to show that type II brain 4.1 is the only member of the protein 4.1 family localized to neuronal paranodes.     

Caffeine induces apoptosis of human umbilical vein endothelial cells through the caspase-9 pathway.

Caffeine is known to modulate placental and fetal umbilical circulation. It is demonstrated that apoptosis of human umbilical vein endothelial cells (HUVECs) is associated with placental umbilical vascular diseases. The present study was conducted to investigate the effects of caffeine on apoptosis of HUVECs. Isolated HUVECs were cultured under serum-free conditions for 24 h, and then treated with graded concentrations of caffeine (30, 100 and 300 microM) for additional 24 h and 48 h. The number of viable HUVECs was determined by cell counting. Apoptotic HUVECs were assessed by Hoechst33342 dye staining. The expression of caspase-9, caspase-8, caspase-3 and poly(ADP-ribose) polymerase (PARP) was assessed by Western blot analysis. Caffeine induced a dose- and time-dependent decrease in the number of viable HUVECs. Caffeine at concentrations higher than 100 microM significantly increased the percentage of apoptotic HUVECs. Caffeine at concentrations higher than 100 microM significantly increased cleaved caspase-9, caspase-3 and PARP expression in HUVECs at 24-h treatment compared with untreated cultures, whereas 30 microM caffeine significantly increased only caspase-3 expression at 24 h. Caffeine did not affect cleaved caspase-8 expression at 48 h. These results suggest that high concentrations of caffeine inhibit cell growth of HUVECs and induce apoptosis through the caspase-9 pathway.