Serum basal hormone concentrations and muscle mass in aging women: effects of strength training and diet

This study examined the effects of strength training and diet on serum basal hormone concentrations and muscle mass in aging women. Fifty-one women age 49 to 74 y were divided into two groups: strength training and nutritional counseling (n = 25), and strength training (n = 26). Both groups performed strength training twice a week for 21 wk. Nutritional counseling was given to attain sufficient energy and protein intake and recommended intake of fat and fiber. We found that the cross-sectional area of the quadriceps femoris increased by 9.5 +/- 4.1% in the nutritional counseling group versus 6.8 +/- 3.5% in the strength training only group after training (P < 0.052). Nutritional counseling evoked dietary changes such as increases in the proportion of energy from protein and the ratio of polyunsaturated and saturated fatty acids. Strength training increased testosterone and testosterone/sex hormone-binding globulin ratio after the first half of training, but these returned to baseline values at the end of the entire training period. Changes in serum basal hormone concentrations did not differ between the groups. Our results support the conclusion that nutritional counseling can contribute to the increase in the muscle cross-sectional area during prolonged strength training in aging women.     

Safety profile of plasmid/liposomes and virus vectors in clinical gene therapy

Despite of more than 500 gene therapy trials worldwide very little systematic safety information is available from gene therapy. Safety information was collected from 146 consecutive patients who participated in three randomized, controlled phase II gene therapy trials in cardiovascular diseases and malignant glioma using adenoviruses, plasmid/liposomes and retrovirus packaging cells. Total follow-up time of the patients was 78794 days which equals 1.5 years per patient. The main outcome measures were serious adverse events, other adverse events and changes in general laboratory parameters. Except fever and increases in CRP values plasmid/liposomes were safe and well tolerated. The incidence of serious adverse events in adenovirus-treated patients was 0.9 and 4.0/10000 patient days in cardiovascular and malignant glioma trials as compared to 0.5 and 2.1 in randomized control patients, respectively. Transient fever, leukopenia and increases in CRP and liver enzymes were detected in virus-treated patients. No deaths from side effects or no new cancers were associated with gene therapy. It is concluded that gene therapy, like any other therapy, is associated with side effects which depend on the administered vector, dose, and route of delivery and properties of the transgene. However, given the limitations of this study and length of the follow-up, the safety profile of gene therapy seems to be acceptable for the treatment of severe human diseases.     

RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability

The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P= 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G>A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxy-terminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer.     

Chronic bilateral subdural haematoma in adults

Summary Twenty-nine patients with chronic bilateral subdural haematomas were surgically treated during 1966 to 1977. Twenty-four of them (83%) had a history of head injury, which caused unconsciousness in eight cases. The mean interval from trauma to operation was eleven weeks. The mean age of the patients was 60 years. The prevalence of the most commonly encountered symptoms and signs was: headache 72%, mental symptoms 48%, papilloedema 41%, vertigo 31%, nausea 28%, reduced consciousness 28%, walking difficulties 24%, hemiparesis 24%, and paraparesis 14%. The aggregate thickness of haematomas was 34 mm, 36 mm, and 40 mm in age groups of 20–39, 40–59, and over 60 years, respectively. All patients were operated on, four of them only unilaterally. Three patients in the whole series died. Two of them had been operated upon only on one side in the first session, the haematoma of the other side being evacuated 81/2 hours and four days later, respectively. Unilateral operation is likely to cause sever e distortion of the midline structures and the brain stem and thus aggravates the cerebral situation. Therefore the necessity of simultaneous evacuation of the haematomas on both sides is stressed. The reason for the death of the third patient was delay in diagnosis.All three patients who died belonged to the group of eight patients with a reduced level of consciousness before surgery.Twenty-three of the survivors were fully independent in their daily lives, and three needed some help after operative treatment.     

Ultrastructure of the corneal nerves after fixation with potassium permanganate

The innervation of the rat cornea was investigated electron microscopically after KMnO₄ fixation. Myelinated nerve fibres were observed only in the limbal margin of the cornea, whereas the axons located in the stroma of the avascular cornea were surrounded by the Schwann cell cytoplasm. Axon profiles with small (300-500 A) granular vesicles and another type with agranular vesicles were seen among the non-vesiculated fibres in all parts of the cornea. After superior cervical ganglionectomy it was not possible to find any axons with small granular vesicles. On the other hand, some degenerating axon profiles were observed in the stromal nerve trunks after ganglionectomy. In the epithelium-naked axons with an occasional mitochondrion and a few agranular vesicles penetrated between the epithelial cells. Moreover, axons filled with several mito-chondria were rarely observed in the epithelium, but these were difficult to differentiate from the surrounding epithelial cells. The role of the different nerve types observed in the cornea is discussed. The results suggest that the rat cornea has a dual vegetative innervation.     

Long-term results of surgery for lumbar spinal stenosis: a randomised controlled trial

We randomised a total of 94 patients with long-standing moderate lumbar spinal stenosis (LSS) into a surgical group and a non-operative group, with 50 and 44 patients, respectively. The operative treatment comprised undercutting laminectomy of stenotic segments, augmented with transpedicular-instrumented fusion in suspected lumbar instability. The primary outcome was the Oswestry disability index (ODI), and the other main outcomes included assessments of leg and back pain and self-reported walking ability, all based on questionnaire data from 85 patients at the 6-year follow-up. At the 6-year follow-up, the mean difference in ODI in favour of surgery was 9.5 (95% confidence interval 0.9–18.1, P-value for global difference 0.006), whereas the intensity of leg or back pain did not differ between the two treatment groups any longer. Walking ability did not differ between the treatment groups at any time. Decompressive surgery of LSS provided modest but consistent improvement in functional ability, surpassing that obtained after non-operative measures.     

Use of cancer‐specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors

Detection of recurrent somatic rearrangements routinely allows monitoring of residual disease burden in leukemias, but is not used for most solid tumors. However, next‐generation sequencing now allows rapid identification of patient‐specific rearrangements in solid tumors. We mapped genomic rearrangements in three cancers and showed that PCR assays for rearrangements could detect a single copy of the tumor genome in plasma without false positives. Disease status, drug responsiveness, and incipient relapse could be serially assessed. In future, this strategy could be readily established in diagnostic laboratories, with major impact on monitoring of disease status and personalizing treatment of solid tumors. © 2010 Wiley‐Liss, Inc.     

Effluxing ABC transporters in human corneal epithelium

ATP-binding cassette (ABC) transporters are able to efflux their substrate drugs from the cells. We compared expression of efflux proteins in normal human corneal epithelial tissue, primary human corneal epithelial cells (HCEpiC), and corneal epithelial cell culture model (HCE model) based on human immortal cell line. Expression of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1–6 (MRP1–6) and breast cancer resistance protein (BCRP) was studied using quantitative RT-PCR, Western blot, and immunohistochemistry. Only MRP1, MRP5, and BCRP were expressed in the freshly excised human corneal epithelial tissue. Expression of MRP1 and MRP5 was localized predominantly in the basal cells of the central cornea and limbus. Functional efflux activity was shown in the cell models, but they showed over-expression of most efflux transporters compared to that of normal corneal epithelium. In conclusion, MRP1, MRP5, and BCRP are expressed in the corneal epithelium, but MDR1, MRP2, MRP3, MRP4, and MRP6 are not significantly expressed. HCE cell model and commercially available primary cells deviate from this expression profile. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1087–1098, 2010