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.     

Does antenatal identification of small-for-gestational age fetuses significantly improve their outcome?

OBJECTIVES: Most obstetric clinics have a program for the identification of small-for-gestational age (SGA) fetuses because of the increased risk of fetal complications that they present. We have a structured model for the identification and follow-up of SGA pregnancies. We aimed to determine whether the recognition of SGA antepartum improves fetal outcome. METHODS: All pregnancies at Malm? University Hospital from 1990 to 1998 (n = 26 968) were reviewed. SGA fetuses identified prior to delivery (n = 681) were compared with those not identified (n = 573). Also, all pregnancies with SGA fetuses were compared with those appropriate-for-gestational age (AGA) (n = 24 585). The risk of serious fetal complications (hypoxic encephalopathy grade 2 or 3, intracranial hemorrhage, Apgar score <4 at 5 min, neonatal convulsions, umbilical pH <7.0, cerebral palsy, mental retardation, stillbirth, intrapartum or infant death) was assessed with cross-tabulation and logistic regression analysis, adjusted for gestational age and degree of SGA. RESULTS: When compared with SGA fetuses identified before delivery (54%), SGA fetuses not identified before delivery were characterized by a four-fold increased risk of adverse fetal outcome (odds ratio, 4.1; 95% CI, 2.5-6.8). Similarly, compared with AGA fetuses, SGA fetuses were associated with a four-fold increased risk of serious fetal complications. CONCLUSIONS: A structured antenatal surveillance program for fetuses identified as SGA results in a lower risk of adverse fetal outcome, compared with cases of SGA fetuses not identified antepartum.     

The expression of hypoxia-inducible factor 1alpha is a favorable independent prognostic factor in renal cell carcinoma.

PURPOSE: Renal cell carcinoma (RCC) is the most common malignancy of the kidney composed of specific tumor types. The sporadic conventional RCCs are, in contrast to the other RCC types, characterized by a high rate of von Hippel-Lindau (VHL) mutations and hypermethylation. The majority of these tumors lack functional VHL protein (pVHL) that leads to increased hypoxia-inducible factor 1alpha (HIF-1alpha) expression. The pVHL is the physiologic regulator of the activity of HIF-1alpha by targeting it to the proteasome for degradation under normoxia. Both pVHL and HIF-1alpha target other genes that are important for cancer survival and proliferation. Expression of HIF-1alpha has been linked to poor prognosis in different malignancies, although few studies have been done on the relation between HIF-1alpha and clinical variables in RCC. EXPERIMENTAL DESIGN: HIF-1alpha protein expression was analyzed in tumor tissue from 92 patients with RCC. HIF-1alpha was quantified by Western blot relative to a positive control. RESULTS: The HIF-1alpha protein was expressed as two bands which strongly correlated (r = 0.906, P < 0.001); therefore, they were added and the sum evaluated against clinicopathologic variables. There was no association between HIF-1alpha and gender, stage, grade, tumor size, or vein invasion. Conventional RCCs had significantly higher HIF-1alpha expression compared with papillary and chromophobe RCCs and kidney cortex. In conventional RCC, HIF-1alpha was an independent prognostic factor. CONCLUSION: HIF-1alpha levels varied significantly between the different RCC types. In conventional RCC, HIF-1alpha was an independent prognostic factor. These data indicate that HIF-1alpha is involved in tumorogenesis and progression of RCC. Evaluation of other HIF target gene products and correlation to angiogenesis seems warranted.     

Hearing-related,health-related quality of life in patients who have undergone otosclerosis surgery: A long-term follow-up study

Objectives: The aims of the study were to assess health-related quality of life and hearing-related disability in subjects with otosclerosis 30 years after surgery. Design: An observational study was performed. Medical records were reviewed, a clinical examination as well as audiometric assessments were performed. Generic health-related quality of life was assessed by the SF-36v2 and hearing disability by a shortened version of SSQ (speech spatial and qualities of hearing scale). Study sample: Sixty-five individuals, who had undergone stapedectomy in 1977-79 at a tertiary referral center. Results: Generic health-related quality of life according to SF-36 subscale scores was comparable to that of an age- and sex-matched reference population. The SF-36 mental component summary score (MCS) was, however, significantly better than that of the reference population. The mental and physical summary component scores correlated significantly to hearing disability measured by the SSQ but not to hearing impairment. Hearing disability was displayed in all SSQ sub-scores, especially in more complex listening situations and in the localization of sounds. Conclusions: This study shows that individuals with otosclerosis, 30 years after surgery, have a good generic health-related quality of life, despite moderate to severe hearing loss and significant hearing disabilities.     

Endoscopic biopsies in Ussing chambers evaluated for studies of macromolecular permeability in the human colon

OBJECTIVE: Studies of mucosal permeability to protein antigens in humans are limited to in vitro techniques. The use of surgical specimens for such studies has major shortcomings. Endoscopic biopsies in Ussing chambers have been introduced as a means of studying secretion and transepithelial permeability, but have not been evaluated for studies of protein antigen uptake in human intestine. MATERIAL AND METHODS: Standard forceps biopsies from the sigmoid colon of 24 healthy volunteers were mounted in Ussing chambers with an exposed tissue area of 1.76 mm2. 51Cr-EDTA (paracellular probe) and horseradish peroxidase (HRP; 45 kDa protein antigen) were used as permeability markers. Mucosal permeability, electrophysiology, histology and energy contents of the biopsies were studied over time. To evaluate the ability of the technique to detect permeability changes, the mucosa was modulated with capric acid, a medium-chain fatty acid, known to affect tight junctions. RESULTS: In the Ussing chamber the mucosal biopsies were viable for 160 min with stable levels of ATP and lactate, and only minor changes in morphology. Steady-state permeability with low variability was seen for both markers during the 30-90 min period. Exposure to capric acid induced a rapid decrease in short-circuit current (Isc) and a slower reversible decrease in transepithelial resistance (TER), as well as an increased permeability to 51Cr-EDTA and HRP. CONCLUSIONS: Endoscopic biopsies of human colon are viable in Ussing chambers and are reliable tools for studies of mucosal permeability to protein antigens. The technique offers a broad potential for studies of mucosal function in the pathophysiology of human gastrointestinal diseases.     

In vitro fertilisation in domestic mammals—a brief overview

Many factors influence the final oocyte maturation, fertilisation, and early embryo development, and there are both similarities and differences between species. When comparing the advancement of assisted reproductive technologies (ARTs), the development in the bovine species is not far behind the medical front, with around one million in vitro-produced bovine embryos each year. This rate of progress is not seen in the other domestic species. This review aims to give an overview of the development and specific difficulties of in vitro embryo production in various domestic animal species, with the main focus on cows, pigs, and cats. In production animals, the aim of ARTs is commonly to increase the genetic progress, not to treat reproductive failure. The ARTs are also used for preservation of genetic diversity for the future. However, specifically for oocyte maturation, fertilisation, and early embryonic development, domestic mammals such as the cow and pig can be used as models for humans. This is particularly attractive from an animal welfare point of view since bovine and porcine oocytes are available in large numbers from discarded slaughterhouse material, thereby decreasing the need for research animals. Both for researchers on the animal and human medical fronts, we aim for the development of in vitro production systems that will produce embryos and offspring that are no different from those conceived and developed in vivo. Species-comparative research and development can provide us with crucial knowledge to achieve this aim and hopefully help us avoid unnecessary problems in the future.