Human leukocyte antigen-B8-DR3 is a more important risk factor for severe Puumala hantavirus infection than the tumor necrosis factor-alpha(-308) G/A polymorphism

The tumor necrosis factor (TNF)-alpha(-308) G/A polymorphism (TNF-2) is in linkage disequilibrium with the human leukocyte antigen (HLA)-B8-DR3 haplotype. Both factors have been associated with severe Puumala hantavirus-induced nephropathia epidemica (NE). To examine which part of this extended haplotype might show the strongest association with the outcome of NE, the HLA-B, HLA-DRB1, and TNF-alpha(-308) alleles in 116 hospital-treated patients with NE were analyzed. The findings pointing to clinically severe NE were strongly associated with HLA-B8-DR3 haplotype. There was a trend toward severe disease in persons positive for TNF-2. This was probably due to strong linkage disequilibrium with HLA-B8-DR3, since there were no differences in the clinical severity of NE when TNF-2-positive/B8-DR3-negative persons were compared with TNF-2-negative/B8-DR3-negative persons. It is concluded that the HLA-B8-DR3 haplotype is an important contributor to the course of NE. The data indicate that the TNF-2 allele is not an independent risk factor for severe NE but a passive component in the extended haplotype.     

The polymorphic androgen receptor gene CAG repeat,pituitary-testicular function and andropausal symptoms in ageing men

The activity of androgen receptor (AR) is modulated by a polymorphic CAG trinucleotide repeat in the AR gene. In the present study, we investigated hormonal changes among ageing men, and whether the number of AR CAG triplets is related to the appearance of these changes, as well as symptoms and diseases associated with ageing. A total of 213 41-70-year-old men donated blood for hormone analyses (LH, testosterone, oestradiol and SHBG) and answered questions concerning diseases and symptoms associated with ageing and/or androgen deficiency. Of these men, 172 donated blood for the measurement of the CAG repeat length of AR. The CAG repeat region of the AR gene was amplified by polymerase chain reaction (PCR) and the products were sized on polyacrylamide gels. The repeat number was analysed as a dichotomized variable divided according to cut-off limits of the lowest (< or =20 repeats) and the highest quartile (> or =23 repeats), and as a continuous variable. The proportion of men with serum LH in the uppermost quartile (>6.0 IU/L) with normal serum testosterone (>9.8 nmol/L, above the lowest 10%) increased significantly with age (p = 0.01). There were fewer men with this hormonal condition among those with CAG repeat number in the uppermost quartile (> or =23 repeats) (p = 0.03). These men also reported less decreased potency (p < 0.05). The repeat number was positively correlated with depression, as expressed by the wish to be dead (r = 0.45; p < 0.0001), depressed mood (r = 0.23; p = 0.003), anxiety (r = 0.15; p < 0.05), deterioration of general well-being (r = 0.22; p = 0.004), as well as decreased beard growth (r = 0.49; p < 0.0001). A hormonal condition where serum testosterone is normal but LH increased is a frequent finding in male ageing. Only certain types of age-related changes in ageing men were associated with the length of the AR gene CAG repeat, suggesting that this parameter may play a role in setting different thresholds for the array of androgen actions in the male.     

Nitric oxide and cyclic GMP enhance aqueous humor outflow facility in rabbits

PURPOSE: Nitric oxide (NO) may control intraocular pressure (IOP)-regulating mechanisms physiologically and in ocular diseases such as glaucoma. The aim of the present study was to clarify whether an increase in aqueous humor outflow facility could explain the IOP-lowering effect of the NO/cyclic GMP pathway we recently described. METHODS: Test compounds were administered to anesthetized rabbits (New Zealand White, n = 6) intracamerally (5 microl) in the following doses: nitrosocaptopril 12.3 microg, captopril 10.9 microg, sodium nitroprusside (SNP) 13.1 microg and 8-Br-cGMP 22.3 microg. Outflow facility (C) was determined by the two-level constant pressure infusion method. Outflow facility, C( 1) and C(2), was measured at lower and higher pressure levels, respectively. RESULTS: Outflow facility was increased after treatment with SNP (increase in C in the experimental eye as compared to the control eye C( 1) 80% and C(2) 74%), nitrosocaptopril (C(1) 69% and C(2) 64%) and 8-Br-cGMP (C(1) 35% and C(2) 33%). Captopril had no effect on outflow facility (C(1) -12% and C(2) 2%). Blood pressure was not affected by the drugs. CONCLUSIONS: We conclude that enhancement of outflow facility by nitrosocaptopril, SNP and 8-Br-cGMP, their second messenger derivative, at least partly explains the IOP-lowering effect of NO releasing compounds.     

Aqueous humour flow after a single oral dose of isosorbide-5-mononitrate in healthy volunteers

PURPOSE: To investigate whether a nitric oxide donor given as a single oral dose is able to modify aqueous humour flow in healthy volunteers. METHODS: Ten healthy volunteers participated in a randomized, double-masked and placebo-controlled cross-over study. Aqueous humour flow was assessed by fluorophotometry after intake of isosorbide-5-mononitrate (ISMN), 10 mg. Topical timolol maleate, which is known to reduce aqueous humour flow, was used as a positive control. Intraocular pressure (IOP) was measured by applanation tonometry and blood pressure was registered. RESULTS: The basal rate of aqueous humour flow did not change significantly after a single oral dose of ISMN. The aqueous humour flow in the timolol-treated eye was reduced as compared to the contralateral control eye (p = 0.002). Mean IOP 6 hours after placebo and ISMN intake did not differ significantly. Timolol lowered IOP by 4 mmHg (p < 0.001). ISMN did not lower systolic blood pressure, but diastolic blood pressure was reduced by 4 mmHg (p = 0.048). CONCLUSION: A single oral dose of 10 mg ISMN had no significant effect on aqueous humour flow in healthy volunteers.     

Quantifying tumour hypoxia with fluorine-18 fluoroerythronitroimidazole ([<Superscript>18</Superscript>F]FETNIM) and PET using the tumour to plasma ratio

Fluorine-18 fluoroerythronitroimidazole ([(18)F]FETNIM) is a nitroimidazole compound that is potentially useful as a hypoxia marker in positron emission tomography (PET) studies of oncological patients. Our aim was to develop a simple protocol to quantitate uptake of [(18)F]FETNIM in hypoxic tumours. Dynamic imaging data from ten patients with head and neck cancer undergoing [(18)F]FETNIM PET was used in simulations and model fits to assess hypoxia marker uptake under different levels of blood flow. The distribution volume determined from dynamic PET study was compared with simple tumour to plasma and tumour to muscle ratios at 90-120 min. In skeletal muscle having a low but variable blood flow [2-6 ml/(100 gxmin)], differences in hypoxia-specific uptake of [(18)F]FETNIM remain small and may be hard to detect with PET. At higher blood flow [>20 ml/(100 gxmin)], the retention of [(18)F]FETNIM reflects the oxygenation status well and results in satisfactory contrast between hypoxic and well-oxygenated tissue. A good estimate of tissue hypoxia is accomplished by measuring the tissue to plasma [(18)F]FETNIM activity ratio using only a few late time points. The increased hypoxia-specific retention of [(18)F]FETNIM in tissues with high blood flow, such as malignant tumours, may facilitate application of [(18)F]FETNIM as a hypoxia marker in oncological patients. In the assessment of the tumour to non-target uptake ratio, plasma is the preferred reference tissue rather than muscle, which may show a more heterogeneous tracer uptake not easily controlled for.     

Inhibition of autocrine secretion of myostatin enhances terminal differentiation in human rhabdomyosarcoma cells

Rhabdomyosarcomas (RMSs) are one of the most common solid tumor of childhood. Rhabdomyosarcoma (RMS) cells fail to both complete the skeletal muscle differentiation program and irreversibly exit the cell cycle as a consequence of an active repression exerted on the muscle-promoting factor MyoD. Myostatin is a negative regulator of normal muscle growth, we have thus studied its possible role in RMS cells. Here, we present evidence that overexpression of myostatin is a common feature of RMS since both subtypes of RMS (embryonal RD and alveolar Rh30 cells) express high levels of myostatin when compared to nontumoral skeletal muscle cells. Interestingly, we found that inactivation of myostatin through overexpression of antisense myostatin or of follistatin (a myostatin antagonist) constructs enhanced differentiation of RD cells. In addition, RD and Rh30 cells treated with blocking antimyostatin antibodies progress into the myogenic terminal differentiation program. Finally, our results suggest that high levels of myostatin could impair MyoD function in RMS cells. These results show that an autocrine myostatin loop contributes to maintain RMS cells in an undifferentiating stage and suggest that new therapeutic approaches could be exploited for the treatment of RMS based on inactivation of myostatin protein.     

The two part picture in detection of visuospatial neglect

Thirty-four patients with right hemispheric cerebrovascular accident and 31 control subjects were examined with a new picture scanning task, the Two Part Picture, as well as with two picture scanning tasks and conventional tests from the Behavioural Inattention Test (BIT). The sensitivity of these tasks in detecting visuospatial neglect was evaluated, and compared to conventional neglect tests. The three pictures varied markedly in their ability to identify neglect. The Two Part Picture was clearly the most sensitive picture scanning task, also showing high agreement with the conventional tests of the BIT. The Two Part Picture is recommended as a useful detector for screening of visuospatial neglect.