Penetration and distribution of three lipophilic probes in vitro in human skin focusing on the hair follicle.

Fluorescent model substances of increasing lipophilicity (Oregon Green) 488, Bodipy, FL C5 and Bodipy 564/570 C5) were selected to enable the visualization in the skin using confocal laser scanning microscopy. After measuring the penetration for 18 h, the nonfixed human scalp skin was imaged from the bottom parallel to the stratum corneum and in a cross-section view perpendicular to the skin surface. The images were evaluated by calculating relative accumulation values for different penetrants. The studies indicate that the penetrated amount is highest for Bodipy FL C5 (medium lipophilicity) and lowest for Bodipy 564/570 C5 (high lipophilicity) whereas Bodipy 564/570 C5 (high lipophilicity) reveals the highest relative accumulation in parts of the hair follicle compared to Oregon Green 488 (low lipophilicity). The addition of 30% (v/v) ethanol to the donor phase of substance with a low lipophilicity increases the follicular delivery. From our results we conclude that delivery to the hair follicle can be improved by increasing the drugs lipophilicity and optimizing the composition of the donor phase. However, no conclusion can be drawn about the actual route of transport to the hair follicle.     

Effect of ionenes on structure and catalytic activity of cobaltphthalocyanine, 1. Visible light spectroscopic investigations

The structural behaviour of cobalt(II)phthalocyanine-tetrasodium sulfonate (CoPc(NaSO₃)₄) ( 1 ), a catalyst used in thiol oxidation, was investigated in the presence of ionenes (poly-quaternary ammonium salts), ( 2 ) using visible light spectroscopy. It was observed that ionenes, which have been shown to promote the catalytic activity, strongly enhance the aggregation of the cobalt complex. No cobalt site isolation occurred up to N⁺/Co = 10⁵. Furthermore, a stoichiometric CoPc(NaSO₃)₄/ionene complex appeared to be formed with an N⁺/Co-ratio of 4:1. This ratio was found to hold for ionenes with M?_n varying from 6 100 to 22 000 and charge densities from 0,8 to 1,5. As the charge density was increased, the observed CoPc(NaSO₃)₄ spectrum was more affected. Experiments with oxygen in alkaline solution revealed that the complex was resistant toward oxygen adduct formation in the presence of ionenes. This phenomenon is discussed in relation to the catalytic activity of the system.     

How does a Belgian health care provider deal with a request for emergency contraception?

OBJECTIVE: To evaluate how Belgian health care providers deal with a request for emergency contraception. METHOD: In 2002-2003 we conducted 12 focus groups with pharmacists, general practitioners and school physicians. A skilled moderator accompanied by an observer conducted the focus groups using a semi-structured screenplay. RESULTS: All these health care providers agree with the free access to emergency contraception (EC), but experience considerable frustration with regard to the practical aspects and the legal framework. General practitioners (GPs) claim to spend a lot of time on requests for EC and they are concerned about the quality of the counselling provided in pharmacies. Pharmacists are creative when giving counselling in the pharmacy, but there is, nevertheless, a problem with a lack of privacy. School physicians are frustrated that there is no legal possibility to respond to a request for EC when they feel they are ideally placed to advise adolescents. CONCLUSION: The over-the-counter sale of EC offers women better access, but many barriers still interfere with optimal care. Pharmacists experience a lack of skills to communicate with adolescents and a lack of privacy to give counselling. GPs have good intentions, but are confronted with a lack of willingness on the part of the patients and also financial barriers. School physicians want more possibilities to help adolescents.     

Conversion from Cyclosporine to Tacrolimus Improves Quality-of-Life Indices, Renal Graft Function and Cardiovascular Risk Profile

Long-term use of cyclosporine after renal transplantation results in nephrotoxicity and an increased cardiovascular risk profile. Tacrolimus may be more favorable in this respect. In this randomized controlled study in 124 renal transplant patients, the effects of conversion from cyclosporine to tacrolimus on renal function, cardiovascular risk factors, and perceived side-effects were investigated after a follow-up of 2 years. After conversion from cyclosporine to tacrolimus renal function remained stable, whereas continuation of cyclosporine was accompanied by a rise in serum creatinine from 142 +/- 48 micromol/L to 157 +/- 62 micromol/L (p < 0.05 comparing both groups). Conversion to tacrolimus resulted in a sustained reduction in systolic and diastolic blood pressure, and a sustained improvement in the serum lipid profile, leading to a reduction in the Framingham risk score from 5.7 +/- 4.3 to 4.8 +/- 5.3 (p < 0.05). Finally, conversion to tacrolimus resulted in decreased scores for occurrence of and distress due to side-effects. In conclusion, conversion from cyclosporine to tacrolimus in stable renal transplant patients is beneficial with respect to renal function, cardiovascular risk profile, and side-effects. Therefore, for most renal transplant patients tacrolimus will be the drug of choice when long-term treatment with a calcineurin inhibitor is indicated.     

Failure of oral implants: aetiology, symptoms and influencing factors

The use of oral implants opened a wide range of prosthetic treatment possibilities in edentulous patients. Although the reported success rates of oral implants are high, failures do occur. This paper reviews the current knowledge about the aetiology, the signs and symptoms and the possible influencing factors of implant failure. Possible causes of implant failure are thought to be infection of the periimplant tissues, occlusal overload, or a combination of both. Nevertheless, pinpointing one of these as the aetiological factor in a particular case is difficult and should be handled reluctantly. Although the cause might seem obvious, influencing factors could play a role as well. Gaining insight into these processes might stimulate the adoption of preventive action and therefore increase the predictability of the treatment outcome with oral implants. Received: 4 April 1997 / Accepted: 27 November 1997     

FISH mapping and molecular organization of the major repetitive sequences of tomato

This paper presents a bird’s-eye view of the major repeats and chromatin types of tomato. Using fluorescence in-situ hybridization (FISH) with Cot-1, Cot-10 and Cot-100 DNA as probes we mapped repetitive sequences of different complexity on pachytene complements. Cot-100 was found to cover all heterochromatin regions, and could be used to identify repeat-rich clones in BAC filter hybridization. Next we established the chromosomal locations of the tandem and dispersed repeats with respect to euchromatin, nucleolar organizer regions (NORs), heterochromatin, and centromeres. The tomato genomic repeats TGRII and TGRIII appeared to be major components of the pericentromeres, whereas the newly discovered TGRIV repeat was found mainly in the structural centromeres. The highly methylated NOR of chromosome 2 is rich in [GACA]₄, a microsatellite that also forms part of the pericentromeres, together with [GA]₈, [GATA]₄ and Ty1-copia. Based on the morphology of pachytene chromosomes and the distribution of repeats studied so far, we now propose six different chromatin classes for tomato: (1) euchromatin, (2) chromomeres, (3) distal heterochromatin and interstitial heterochromatic knobs, (4) pericentromere heterochromatin, (5) functional centromere heterochromatin and (6) nucleolar organizer region.     

Efficacy and onset of action of fluticasone propionate aqueous nasal spray on nasal symptoms, eosinophil count, and mediator release after nasal allergen challenge in patients with seasonal allergic rhinitis

We studied the effect and onset of action of fluticasone propionate aqueous nasal spray (FPANS) on mediator release and eosinophil accumulation in nasal secretions and on nasal symptoms of patients with seasonal allergic rhinitis after nasal allergen challenge (NAC). At the end of the pollen season, 28 patients were randomized in a double-blind and crossover design to receive 7 days' treatment with FPANS (200 μg, once daily) and matching placebo. NACs were performed before and at 6 h and 1. 2. 3. and 7 days during treatment with FPANS or placebo. Nasal secretions were collected for a quantitative determination of mediators and eosinophil count before and 5 min after each challenge. Nasal symptoms were assessed by scales grading the severity of symptoms at the same time. Results showed that for mediator concentrations there was a significant decrease of leukotriene C4 (P<0.001) at 7 days after the first administration of FPANS as compared to placebo. Two days after FPANS. both eosinophil counts and eosinophil cationic protein (ECP) concentrations were lower than those of placebo (eosinophils; f=0.032; ECP; F=0.038). The onset became even more important at day 7 (eosinophils; P=0.001; ECP; P=0.009) during the FPANS treatment period. For the subjective nasal symptoms, a significant reduction of symptom scores for nasal obstruction occurred also at day 3 (F=0.017) and for sneezing at day 7 (f=0.003). There was not yet any significant improvement of the objective nasal airway resistance after the different NACs during the study period. In conclusion, this study demonstrated that topical fluticasone propionate is effective in the treatment of mucosal inflammation induced by NAC. For optimal control of nasal symptoms induced by repeated maximal allergen challenges, a treatment period of more than 1 week is required.     

Localizing a putative mutation as the major contributor to the development of sporadic Hirschsprung disease to the RET genomic sequence between the promoter region and exon 2

Hirschsprung disease (HSCR), a congenital disorder characterized by intestinal obstruction due to absence of enteric ganglia along variable lengths of the intestinal tract, occurs both in familial and sporadic cases. RET mutations have been found in approximately 50% of the families, but explains only a minority of sporadic cases. This study aims at investigating a possible role of RET in sporadic HSCR patients. Haplotypes of 13 DNA markers, within and flanking RET, have been determined for 117 sporadic HSCR patients and their parents. Strong association was observed for six markers in the 5' region of RET. The largest distortions in allele transmission were found at the same markers. One single haplotype composed of these six markers was present in 55.6% of patients versus 16.2% of controls. Odds ratios (ORs) revealed a highly increased risk of homozygotes for this haplotype to develop HSCR (OR>20). These results allowed us to conclude that RET plays a crucial role in HSCR even when no RET mutations are found. An unknown functional disease variant(s) with a dosage-dependent effect in HSCR is likely located between the promoter region and exon 2 of RET.     

Epithelium-Free Area in The Thymic Cortex of Rats

The histology of epithelium-free areas in the subcapsular region of the thymus was studied in Wistar rats. Lymphocytes in these areas were CD4/CD8 double-positive, TCR α/β positive in low intensity, and in CD5 labeling either negative or positive in low intensity. There was a high proliferative activity as assessed by bromodeoxyuridine incorporation in vivo and detected by immunohistochemistry. Various macrophage types were observed. They were either large and round to slightly dendritic, or small and dendritic. Most large cells were positive for MHC Class II, and labeled by the antimacrophage antibodies ED1 and ED2. A few cells were strongly positive for Sudan black, Oil red O, nonspecific esterase, and acid phosphatase; they resembled the large rounded macrophages in the corticomedullary zone, although their MHC Class II and ED2 staining was more intense. A few cells showed features of tingible body macrophages, as they contained cellular debris.Serial sections showed that epithelium-free areas run from the subcapsular area to deep in the cortex, and often border the medulla. This opens the opportunity for immature lymphocytes to move into the medulla and corticomedullary zone without contacting and potential selection with cortical stromal elements other than macrophages in the epithelium-free areas. In this case, the epithelium-free areas may offer a separate intrathymic pathway for T lymphocytes.     

Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3

Genetic linkage studies have indicated that chromosome 14q24.3harbours a major locus for early-onset (onset age <65 years)Alzheimer's disease (AD3). Positional cloning efforts have identifieda novel gene S182 or presenilin 1 as the AD3 gene. We have mappedS182 in the AD3 candidate region between D14S277 and D14S284defined by genetic linkage studies in the two chromosome 14linked, early-onset AD families AD/A and AD/B. We have shownthat S182 is expressed in lymphoblasts and have determined thecomplete cDNA in both brain and lymphoblasts by RT-PCR sequencing.S182 is alternatively spliced in both brain and lymphoblastswithin a putative phosphorylation site located 5' in the codingregion. We identified two novel mutations, Ile143Thr and Gly384Alalocated in, respectively, the second transmembrane domain andin the sixth hydrophilic loop of the putative transmembranestructure of S182. As families AD/A and AD/B have a very similarAD phenotype our observation of two mutations in functionallydifferent domains suggest that onset age and severity of ADmay not be very helpful predictors of the location of putativeS182 mutations.