Alcohol reduces prefrontal cortical excitability in humans: a combined TMS and EEG study.

The effects of alcohol (0.8 g/kg) on the prefrontal cortex were studied in nine healthy subjects using the technique of transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG). A total of 120 magnetic pulses were delivered with a figure-of-eight coil to the left prefrontal cortex at the rate of 0.4-0.7 Hz. The EEG was recorded simultaneously with 60 scalp electrodes (41 electrodes were used for analysis); the TMS-evoked activation was estimated by the area under the global mean field amplitude (GMFA) time curve. TMS caused changes in EEG activity lasting up to 270 ms poststimulus. Alcohol decreased GMFA at 30-270 ms poststimulus (713+/-303 vs 478+/-142 microV ms; p=0.007). Alcohol-induced differences were most pronounced at anterior electrodes. These results suggest that alcohol reduces the excitability in the prefrontal cortex.     

Antibodies against copper-oxidised and malondialdehyde-modified low density lipoproteins in pre-eclamptic pregnancies

Objective To measure auto-antibodies against oxidatively modified low density lipoprotein (LDL) in pre-eclamptic pregnancies using two different techniques.
Design Clinical study comparing pre-eclamptic and normal pregnancies.
Setting Tampere University Hospital, Finland.
Population Twenty-one primigravidae with pre-eclampsia and 13 healthy, normotensive primigravidae as controls.
Methods The serum titers of antibodies against both malondialdehyde-modified and copper-oxidised LDL (MDA-LDL and copper-ox LDL) were analysed and related to parameters reflecting the severity of pre-eclampsia.
Results There was a positive correlation (   r = 0.58  ) between antibodies against MDA-LDL and copper-ox LDL in women with pre-eclampsia but not in healthy pregnant controls. The antibody levels against copper-ox LDL, but not against MDA-LDL, were higher in women with pre-eclampsia than in women with a normal pregnancy (   P < 0.01  ). While the antibody titers against copper-ox LDL did not correlate with any parameter reflecting the severity of pre-eclampsia, those against MDA-LDL showed a positive correlation with the level of diastolic blood pressure (   r = 0.54  ) and a negative correlation with platelet count (   r = 461  ) in women with pre-eclampsia.
Conclusions There are increased titers of serum autoantibodies against copper-oxidised LDL in pre-eclampsia, which may reflect enhanced lipid peroxidation involving circulating lipoproteins.     

Delivery and stability of LHRH and Nafarelin in human skin: the effect of constant/pulsed iontophoresis.

Poor absorption and stability of peptides are the major obstacles concerning the development of therapeutically relevant iontophoretic devices for the transdermal delivery of peptides. The present study examined the impact of constant and pulsed (direct/alternating) current profiles on the transport and stability of two decapeptides LHRH and Nafarelin. The stability of these peptides was studied in a physiological buffer solution, with electrical current, and when the peptide solution was exposed to the stratum corneum or to the epidermal/dermal side of human skin. Pulsed direct current profile was shown to be the most efficient in transporting both LHRH and Nafarelin across the human epidermis. Furthermore, the percentage of intact LHRH in the receiver phase was slightly higher when a pulsed current profile was used. Both the peptides were stable in a physiological buffer and under the influence of current, but LHRH was degraded especially in contact with the dermal side of the skin. Altogether five hydrolytic degradation products of LHRH were observed, and they were identified by LC-ESI/MS and LC-ESI/MS/MS. No degradation products of Nafarelin were observed. It is concluded that the pulsed direct current profile may provide at least a partial solution for the transdermal delivery of peptides in terms of improved transport efficacy and peptide stability.     

The expression of cyclooxygenase-1 and -2 in proliferative endometrium and endometrial adenocarcinoma

BACKGROUND. The activity of cyclooxygenase-2 (COX-2) is increased in inflammation and in several cancer types. We investigated the expression of COX-2, cyclooxygenase-1 (COX-1), nitric oxide synthase-2 (NOS-2) and nitric oxide synthase-3 (NOS-3) in normal proliferative and secretory human endometrium, and in endometrial adenocarcinoma. METHODS. Human endometrium was collected at hysterectomy. Seven samples were in proliferative and 11 samples in secretory stage. Twelve specimens from endometrial carcinoma were collected, as well. Immunohistochemistry was used to investigate the expression of COX-1, COX-2, NOS-2 and NOS-3. RESULTS. COX-2 immunostaining was detected in most specimens of normal proliferative glandular epithelium (86%) and of endometrial carcinomas (92%). COX-2 staining was often detected in cancer cells on the border areas of the tumour and on the areas of invasive growth. Staining for COX-2 was seen in proliferative glands usually only in the basal layer of the endometrium. NOS-2 was usually absent or negligible in proliferative endometrial glands and also in the cancer cells of endometrial adenocarcinomas. No staining for either COX-2 or NOS-2 was seen in specimens of secretory glandular epithelium. The expression of the constitutive COX-1 and NOS-3 was negligible or weak in the glandular epithelium of proliferative and secretory endometrium and in endometrial cancer cells. CONCLUSIONS. The expression of the inducible COX-2 but not of COX-1 is stimulated in the glandular epithelium of proliferative endometrium and in the cancer cells of human endometrial adenocarcinoma, in particular in those in the borders of carcinoma and spreading into lymphatic vessels.     

Monitoring of gliomas in vivo by diffusion MRI and 1H MRS during gene therapy‐induced apoptosis: interrelationships between water diffusion and mobile lipids

The measurement of water diffusion by diffusion‐weighted MRI (DWI) in vivo offers a non‐invasive method for assessing tissue responses to anti‐cancer therapies. The pathway of cell death after anti‐cancer treatment is often apoptosis, which leads to accumulation of mobile lipids detectable by ¹H MRS in vivo. However, it is not known how these discrete MR markers of cell death relate to each other. In a rodent tumour model [i.e. ganciclovir‐treated herpes simplex thymidine kinase (HSV‐tk) gene‐transfected BT4C gliomas], we studied the interrelationships between water diffusion (Trace{D}) and mobile lipids during apoptosis. Water diffusion and water‐referenced concentrations of mobile lipids showed clearly increasing and interconnected trends during treatment. Of the accumulating ¹H MRS‐visible lipids, the fatty acid ? CH ?CH ? groups and cholesterol compounds showed the strongest associations with water diffusion (r² = 0.30; P < 0.05 and r² = 0.48; P < 0.01, respectively). These results indicate that the tumour histopathology and apoptotic processes during tumour shrinkage can be interrelated in vivo by DWI of tissue water and ¹H MRS of mobile lipids, respectively. However, there is considerable individual variation in the associations, particularly at the end of the treatment period, and in the relative compositions of the accumulating NMR‐visible lipids. The findings suggest that the assessment of individual treatment response in vivo may benefit from combining DWI and ¹H MRS. Absolute and relative changes in mobile lipids may indicate initiation of tumour shrinkage even when changes in tissue water diffusion are still small. Conversely, greatly increased water diffusion probably indicates that substantial cell decomposition has taken place in the tumour tissue when the ¹H MRS resonances of mobile lipids alone can no longer give a reliable estimate of tissue conditions. Copyright © 2008 John Wiley & Sons, Ltd.     

Diagnostic tools in respiratory tract infections: use and comparison with Finnish guidelines

The objectives of this prospective epidemiological study were to describe the diagnosis and treatment of respiratory tract infections by Finnish general practitioners and to compare current practice with national evidence-based guidelines. All patients (n = 4386) seeking primary care for a respiratory tract infection for the first time in 30 health centres during 1 week in November 1998 participated in the study. The main outcome measures were the amounts and types of diagnostic tests used and antimicrobials prescribed. Tympanometry was used in 1% of patients with acute otitis media. Ultrasonography, sinus radiography or both were used in 80% of cases of sinusitis and antigen detection or culture for Streptococci in 57% of throat infections. In acute bronchitis, a chest radiograph was taken in 5% of cases and the CRP level determined in 8%. The corresponding figures for pneumonia were 49% and 39%. In pneumonia and throat infection, diagnostic testing was statistically significantly associated with the use of antimicrobials, but not in otitis, sinusitis or acute bronchitis. Diagnostic tests were underused in respiratory tract infections compared to evidence-based recommendations.     

Quantitative ADME Proteomics – CYP and UGT Enzymes in the Beagle Dog Liver and Intestine

Pharmaceutical Research - Beagle dogs are used to study oral pharmacokinetics and guide development of drug formulations for human use. Since mechanistic insight into species differences is needed...