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Objective To assess the optimum light energy needed to induce only superficial bladder wall damage during photodynamic therapy (PDT) as a treatment for bladder cancer. Materials and methods The urinary bladder (with normal epithelium) of 64 female rats was treated with PDT using a continuous‐wave argon‐ion laser as an energy source and aminolaevulinic acid (ALA)‐induced protoporphyrin IX photosensitizer. Four hours after the intravenous administration of ALA (300 mg/kg) the bladders were intravesically exposed to light fluences of 20–80 J/cm2. The control rats received no ALA and were exposed to 20 J/cm2 light. After 1, 3, 7 and 21 days the animals were killed and the morphological changes in bladder wall analysed both macroscopically and using light and scanning electron microscopy. Results At the dose of ALA given, a fluence of 20–40 J/cm2 caused mainly superficial damage, whereas 80 J/cm2 produced full‐thickness injuries to the bladder wall. The maximum effect of PDT occurred after 1 and 3 days of irradiation. After 3 weeks of PDT the histology showed few full‐thickness injuries and only in those treated with 80 J/cm2 light. Conclusion These results indicate that PDT can be used to safely induce a selective superficial removal of bladder mucosa with no fibrotic effects on detrusor musculature, when optimum photosensitizing drug and fluences are used. These findings support the use of PDT in the therapy of superficial bladder cancer. [ABSTRACT FROM AUTHOR]

In this study we report an improved method for in vivo gene transfer to liver. Repeated injections of Moloney murine leukemia virus-derived retroviruses containing LDL receptor cDNA were given to the portal vein in combination with a 10% partial liver resection and stimulation of hepatocyte proliferation by plasmid/liposome-mediated thymidine kinase gene transfer and ganciclovir treatment. The method was used for the treatment of LDL receptor deficiency in Watanabe heritable hyperlipidemic rabbits. We demonstrate an increase in hepatocyte proliferation index by thymidine kinase and ganciclovir treatment from 0.9 to 1.35% and a maximum of 35% decrease in total plasma cholesterol level 2–3 months after the gene transfer. A 20% decline was still present after a 52-week follow-up period. A 50% decrease was also observed in plasma triglycerides. Liver function tests indicated a transient increase in plasma alkaline phosphatase level up to 12 weeks after the gene transfer. In situ PCR and RT-PCR analyses indicated that the transgene was present in periportal areas and was transcribed to mRNA 1 week after the gene transfer. Because of the relatively simple and controllable technique we suggest that repeated retrovirus injections via a portal vein catheter together with the limited partial liver resection and plasmid/liposome-mediated thymidine kinase gene transfer–ganciclovir treatment may be used to improve the results of retrovirus-mediated liver gene therapy. [ABSTRACT FROM AUTHOR]

Results on fracture risk among physically active persons are contradictory. The aim of this study was to investigate the long-term association between the self-reported physical activity (PA), the risk of fractures, and bone loss among peri- and postmenopausal women. The association between PA and fracture risk was examined during 15 years of follow-up in the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study among 8560 women with a mean age of 52.2 years (range 47 to 56 years) at baseline. The amount and type of PA, as well as the types and mechanisms of fractures, were registered with self-administered questionnaires at 5-year intervals (ie, 1989, 1994, 1999, and 2004). A total of 2641 follow-up fractures were verified in 2073 women (24.2%). The study cohort was divided into quartiles by average hours of reported PA during the whole follow-up. Areal bone mineral density (aBMD) at the proximal femur (n = 2050) and lumbar spine (L(2)-L(4); n = 1417) was followed at 5-year intervals from a random stratified subsample with dual X-ray absorptiometry (DXA). Risk of fracture was estimated by using the Cox proportional hazards model with a mean follow-up time of 15.2 years. Weekly average time spent on leisure-time PA was 0.4, 1.7, 3.3, and 7.0 hours from the least to the most active quartiles, respectively. The risk of wrist fracture was higher in the active quartiles (II to IV) than in the most inactive quartile (I), with hazard ratios (HRs) of 1.3 [95% confidence interval (CI) 1.05-1.57, p = .014] for the second (II), 1.2 (95% CI 1.01-1.51, p = .045) for the third (III), and 1.4 (95% CI 1.14-1.69, p = .001) for the fourth (IV) quartile, respectively. Overall, most of the fractures were reported as a result of a fall (69.0%), with a 2.1 times higher rate of wrist fractures during the winter (November to April) than during summer season. There were no significant associations of PA with any other fracture types. Bone loss at the femoral neck, trochanter, and Ward's triangle was significantly associated with long-term PA (ANCOVA p < .05), whereas no associations of bone loss and PA in lumbar spine were seen. PA is associated with a moderate rise in wrist fracture risk, which might be explained in part by a higher number of outdoor activities. Regular PA of at least 1½ hours per week does not seem to increase the risk of other fractures and might significantly decrease proximal femur bone loss among peri- and postmenopausal women., (© 2010 American Society for Bone and Mineral Research.)

Objective: To determine the effects of HRT with or without clodronate on bone mineral density (BMD) change and bone turnover markers., Design: Prospective, partly randomized trial., Setting: Kuopio University Hospital, Finland., Population: 167 osteoporotic women (61+/-2.7 years; T-score

Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women., (2010 American Society for Bone and Mineral Research.)

The differences in cholesterol metabolism after the 2 most common forms of obesity surgery, Roux-en-Y gastric bypass (RYGB) and gastric banding (GB), have not been well characterized. In this study, effects of RYGB and GB on cholesterol absorption and synthesis were investigated. To this aim, 1-year follow-up of cholesterol metabolism in 2 nonrandomized cohorts undergoing either RYGB (n = 29; age, 45.2 +/- 7.7 years; body mass index [BMI], 46.0 +/- 6.1 kg/m(2)) or GB (n = 26; age, 45.9 +/- 8.6 years; BMI, 50.1 +/- 7.7 kg/m(2)) was performed in a university hospital center specializing in the treatment of morbid obesity. Serum markers of cholesterol synthesis (cholestenol, desmosterol, and lathosterol) and cholesterol absorption (campesterol, sitosterol, avenasterol, and cholestanol) were measured preoperatively and at follow-up and expressed as ratios to cholesterol. As expected based on observed weight loss (25% after RYGB and 17% after GB, P < .001 between groups), both operations decreased serum levels of cholesterol synthesis markers by 12% to 28% (all Ps < .001). A decrease in cholesterol absorption markers was only observed after RYGB (-26% for sitosterol) and not after GB (+16%, P = 2 x 10(-6) for difference between the groups). The difference in sitosterol ratio between the groups remained significant after adjustment for age, BMI, fasting insulin levels, and nutritional status (P = 2 x 10(-4)), indicating a specific effect related to RYGB. We conclude that decrease in cholesterol absorption is a novel beneficial effect of RYGB. Together with an improved control of blood glucose, this may contribute to a better cardiovascular risk profile after RYGB., (Copyright 2010 Elsevier Inc. All rights reserved.)

Aim was to investigate fracture risk (FR) according to bone loss (BL) rate. A random sample of 1652 women aged 53.5 years was measured with dual X-ray absorptiometry in femoral neck in 1989 and 1994 and divided into tertiles of annual BL rate: high >0.84%, moderate 0.13%-0.84%, and low <0.13%. Low trauma energy fractures during following 10 years were recorded. There were no differences in FR between BL tertiles in Cox regression model. Factors predicting lower FR in Cox model were in high tertile: high T-score (HR 0.71; 95% CI 0.54-0.93, P = .012), no sister's fracture (HR 0.35; 0.19-0.64, P = .001), no mother's fracture (HR 0.52; 0.31-0.88, P = .015), in moderate tertile: high T-score (HR 0.69;0.53-0.91, P = .008) and good grip strength (HR 0.98; 0.97-0.99, P = .022). In low tertile there were no predictors for FR. BL predicted FR in women with mother's fracture in univariate and multivariate model (OR 2.6; 1.15-5.7, P = .021) but with sister's fracture this was observed only in multivariate model (OR 2.66; 1.09-6.7, P = .039). Accordingly, the risk factors for postmenopausal fractures, especially mother's fracture, may interact with BL.

Objectives: The purpose of this population-based prospective cohort study was to examine the effect of hormone therapy (HT) on incidence of diabetes mellitus (DM)., Design and Methods: Eight thousand four hundred and eighty-three DM-free post-menopausal women aged 52-62 from the population-based Kuopio osteoporosis risk factor and prevention study were followed for 5 years from 1994-1999. Information about the use of HT and health events was obtained from three repeated questionnaires in 1989, 1994, and 1999. DM morbidity before and during the follow-up was obtained from the Registry of Specially Refunded Drugs of the Finnish Social Insurance Institution. Kaplan-Meyer survival curves and Cox's proportional-hazards models were used to estimate the risk of incident DM in relation to the use of HT., Results: During the follow-up, 40.8% DM-free post-menopausal women had never used HT, 27.3% women were HT past users and 31.9% women had used HT presently during the follow-up. During the follow-up, 162 incident DM cases were recorded. Compared with never users of HT, the adjusted hazard ratio of DM was 0.81 (95% confidence interval (CI) 0.57-1.16) for only past users, 0.53 (95% CI 0.24-1.15) in part-time (during the follow-up <2.5 years) users and 0.31 (95% CI 0.16-0.60) in continuous (during the follow-up 2.5-5.0 years) users of HT., Conclusions: HT use decreases the incidence of DM in post-menopausal women.

Introduction: There is a need for cost-effective clinical methods to select women for bone densitometry. The aim of the present study was to determine whether relatively simple and clinically applicable physical tests could be useful in prediction of bone density in postmenopausal women., Methods: A total of 606 women (age range 66-71 years) taking part in the population based OSTPRE Fracture Prevention Study were investigated. Spinal and femoral bone mineral density (BMD) was measured by Dual X-ray Absorptiometry (DXA). Physical tests included the standing-on-one-foot (SOOF), grip strength (GS), leg extension strength, ability to squat down, standing 10 s eyes closed, chair rising, regular walk for 10 m and tandem walk for 6 m. All linear regression models were adjusted for age, body mass index, years on hormone therapy, years since menopause, current smoking and use of oral glucocorticoids., Results: The SOOF was associated with lumbar spine BMD (r2=0.16, p=0.004) and the femoral regions (r2 values from 0.17 to 0.23 and p-values all<0.001). The GS was associated with lumbar spine BMD (r2=0.16, p=0.011) and the femoral regions (r2 values from 0.16 to 0.21 and p-values from <0.001 to 0.004). The ability to squat down on the floor was associated with the femoral regions (r2 values from 0.15 to 0.21 and p-values from 0.028 to 0.040). In addition, functional capacity was decreased in women with femoral neck osteoporosis (WHO classification) compared to women with normal or osteopenic BMD: SOOF -39% (p=0.001), GS -18% (p<0.001), leg extension strength -19% (p=0.007) and ability to squat down on the floor -40% (p=0.004). For osteoporosis prediction (ROC analysis) a threshold of a 22 kg in GS would yield a true-positive rate (sensitivity) of about 58% and a true-negative rate (specificity) of 86% (AUC 0.76)., Conclusions: We suggest that grip strength could be used in medical decision making to identify those women who would benefit from BMD measurements albeit alone it may not provide accurate enough tool for osteoporosis screening.

Objectives: We investigated the incidence of new non-vertebral fractures during HRT or low-dose vitamin (Vit) D3 supplementation in a 5-year prospective trial., Methods: A total of 464 early postmenopausal women, (a subgroup of the Kuopio Osteoporosis Study, n = 13100) were randomized to four groups: (1) HRT, a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate; (2) Vit D (300 IU/day and 100 IU/day during the fifth year); (3) HRT + Vit D; and (4) placebo. Lumbar (L2-4) and femoral neck bone mineral densities (BMD) were determined by dual X-ray absorptiometry (DXA) at baseline, after 2.5 and 5 years of treatment. All new symptomatic non-vertebral, radiographically defined fractures were recorded., Results: Altogether, 368 women (79%) completed the 5 year treatment. In all, 32 women had 39 non-vertebral fractures during a mean of 4.3 year follow-up (HRT 4, Vit D 10, HRT + Vit D 8 and placebo 17). The reduction in the incidence of new non-verterbral fractures was significant in women with HRT alone (P = 0.032) when adjusted by baseline BMD and previous fractures; observed also with the intention-to-treat principle (P = 0.048). When the HRT groups were pooled, HRT showed a significantly lower incidence of new non-vertebral fractures (P = 0.042) than women receiving placebo and also after adjusting as above (P = 0.016); both in valid-case and in the intention-to-treat analysis. In the Vit D group, the fracture incidence was non-significantly decreased (P = 0.229) in comparison with the placebo group. The estimated risk of new non-vertebral fractures among women treated with HRT alone was 0.29 (95% CI, 0.10-0.90) and with Vit D 0.47 (95% CI, 0.20-1.14) and with HRT + Vit D 0.44 (95% CI, 0.17-1.15), in comparison with the placebo group (adjusted by femoral BMD and previous fractures)., Conclusions: This study is the first prospective trial confirming the beneficial effect of HRT on prevention of peripheral fractures in non-osteoporotic postmenopausal women. The effect of low-dose Vit D remains to be proved.

Unlabelled: This study of postmenopausal women (n=2,928) with an eight-year follow-up revealed that impairment in functional status associated with the increased fracture risk. The standing-on-one-foot and grip strength tests and a question about self-assessed ability to move can be used to identify women with a high risk of suffering a fracture., Introduction: Poor functional status has pointed to associate with injurious falls and consequent fractures. Our aim was to define association between functional capacity and fractures., Methods: This study was based on the Osteoporosis Risk Factor and Prevention Study (OSTPRE). A total of 2,928 postmenopausal women took part in the functional capacity and muscle strength tests. The duration of fracture follow-up varied from 6.43 to 9.86 (mean 8.37) years and the first fracture was the end-point event for the statistical analyses. All analyses were done with Cox-regression., Results: A total of 261 end-point fractures occurred. In multivariate analysis the inability to stand-on-one-foot for 10 seconds increased the risk of hip fracture (hazard ratio with 95% CI) 9.11-fold (1.98-42.00). Decreased grip strength associated with 1.05-fold (1.01-1.09) increased risk of hip fractures. Low leg extension strength associated with 1.02-fold (1.00-1.03) higher risk for all fractures. The self-assessed ability to walk less than 100 meters at baseline increased the risk of ankle 2.36-fold (1.10-5.08), hip 11.57-fold (2.73-49.15) and clinical vertebral fractures 3.85-fold (1.45-10.22)., Conclusion: According to these results the standing-on-one-foot less than 10 seconds, grip strength and a question about ability to walk less than 100 meters may help to predict postmenopausal fractures.

The aim of the present study was to investigate the ability of grip strength measurements to predict fracture risk in perimenopausal women according to bone mineral density (BMD). A random sample of 971 perimenopausal women from the Kuopio Osteoporosis Risk Factor and Prevention study cohort was measured with dual-energy X-ray absorptiometry (DXA) at the femoral neck and grip strength with a pneumatic squeeze dynamometer in 5-year intervals from baseline (1989-1991). Fractures during the 15-year follow-up were recorded based on self-reports and validated from medical records. In the total sample and in osteopenic or osteoporotic women (T score < -1, n = 284) grip strength was not significantly associated with fracture-free survival rate (P = nonsignificant in Cox regression). In women with normal baseline BMD (N-BMD, T score > -1, n = 687) the lowest grip strength quartile had a significantly lower fracture-free survival rate in the Cox proportional hazard model (P = 0.005, hazard ratio [HR] = 2.0). In the multivariate Cox regression model, T score and grip strength were the only significant predictors of 15-year fracture-free survival in the N-BMD group and a risk index (RI) was formed according to HRs of these two variables. High RI (0-5 points) was associated with significantly lower 15-year fracture-free survival rate (P = 0.001, HR = 0.137) in the N-BMD group. In contrast, 5-year T score was no better a predictor of fractures in the baseline N-BMD group (P = 0.04, HR = 0.36). In conclusion, grip strength predicts 15-year fracture-free survival in perimenopausal women with N-BMD, while 5-year DXA does not seem to be any better a predictor of fracture risk. DXA measurements could be coupled with simple and cost-effective grip strength measurements. Controlling BMD in women with N-BMD could be abandoned.

Purpose: To evaluate the drainage and antireflux characteristics of a new self-expandable self-reinforced poly-L,D-lactide partial ureteral stent (SR-PLA 96) in an experimental model., Materials and Methods: Twelve dogs were used as experimental animals. A low-midline laparotomy and cystotomy were performed on all animals. In group A (six animals), 50-mm long SR-PLA 96 ureteral stents with a double-helical spiral design were inserted into both ureters, leaving the lower ends 2 cm above the ureterovesical junction. In group B (six animals), both ureters were stented with traditional pigtail stents (C-Flex) Double-J; Cook Urological), which were removed 8 weeks after surgery. Renal function and ureteral patency were evaluated by dynamic kidney imaging and urography examinations at 6 and 12 weeks postoperatively. The degrees of vesicoureteral reflux at two levels of the ureters and at the level of the renal pelvis were evaluated by nuclear voiding cystograms at 6 weeks., Results: The partial SR-PLA 96 stent design showed more favorable antireflux properties that the Double-J stent design. The degree of vesicoureteral reflux, reflected in an increase of nuclear enhancement at 6 weeks, was lower in the distal (7.9% +/- 14.7% v 63.2% +/- 17.3%; P < 0.05) and middle (6.1% +/- 8.1% v. 45.5% +/- 19.5%; P = 0.15) levels of the ureters as well as at the level of the renal pelvis (-3.4% +/- 3.6% v 6.2% +/- 3.9%; P = 0.65) than in the Double-J-stented ureters. No significant differences in renal function or ureteral patency were observed at 12 weeks after the Double-J stents had been removed and the SR-PLA 96 stents had fragmented., Conclusion: A self-expandable, self-reinforced SR-PLA 96 partial ureteral stent showed more favorable antireflux properties than a Double-J stent.

To investigate tissue metabolism during suboptimal blood perfusion, we used in situ microdialysis in an experimental model of myocutaneous flaps. We assessed concentrations of glucose, lactate, and pyruvate in flaps subjected to partial pedicle obstruction and to hemorrhagic shock. When the arterial flow was restricted, the glucose concentration decreased in the flap muscle, and the lactate concentration increased in all flap components. The restriction ofvenous outflow resulted in lactate overproduction and a decrease of glucose in skin and muscle. The lactate-to-pyruvate ratio remained normal during arterial obstruction but increased during venous obstruction. During hypovolemic shock, the lactate production increased and the glucose concentration decreased or remained normal. The metabolic changes occurring during partial pedicle obstruction and hypovolemic shock are moderate and different from those seen in total pedicle obstruction. Microdialysis is a feasible method for assessing local tissue metabolism and can be used to monitor flap ischemia.

According to our previous studies, heat shock preconditioning of gastric mucosa requires modulation of protein synthesis and eicosanoid pathways to induce protection against superficial injury. This may be caused by heat shock-induced oxidative stress. We studied the effect of heat shock preconditioning with normothermic recovery on redox status in superficially injured (1.25 mmol NaCl for 5 min) Ussing chamber perfused guinea pig gastric mucosa allowed to recover for 3 hr after injury. Protein oxidation, lipid peroxidation, level of superoxide dismutase, level of heat shock protein 72 (HSP72), and level of oxygen radical absorbance capacity were measured. Superficial injury increased lipid peroxidation. Heat shock preconditioning decreased oxygen radical absorbance capacity and increased protein carbonyl and HSP72 levels, but inhibited electrophysiologic recovery. Exposure to indomethacin and arachidonic acid (AA) partially abolished this pro-oxidative and inhibitory effect on recovery, but maintained HSP72 levels and decreased protein carbonyls, lipid peroxidation, and oxygen radical absorbance capacity. In conclusion, superficial injury increased lipid peroxidation. Heat shock preconditioning alone induced oxidative stress via indomethacin- and AA-sensitive mechanisms. The development of optimal cytoprotective strategy may therefore require control of oxidative stress and modulation of the eicosanoid pathways.

Background: There has been a lack of methods to provide quantitative information of local tissue edema after burn injury. Noninvasive dielectric measurements provide this information. The measured value, the dielectric constant, is directly related to the amount of water in tissue. Using probes of different sizes, the measurements give information from different tissue depths. The aim of this study was to characterize edema formation at different tissue depths and to examine whether the dielectric measurements could be used to distinguish partial- and full-thickness burns in pigs., Methods: An experimental animal study with pigs (n = 6) was performed in which dielectric measurements were taken of superficial, partial-thickness, and full-thickness burns for 72 hours., Results: There was an increase in tissue water content in the superficial dermis in the partial-thickness burns at 48 hours. In whole dermis, the superficial burns resulted in increased tissue water content at 8 hours, and the partial-thickness burns resulted in increased tissue water content at 8, 24, and 72 hours. In deep burns, the water content was significantly decreased in the superficial dermis at 24 hours. All burns resulted in a considerable increase in fat water content. The dielectric probes could be used to differentiate partial- and full-thickness burns as early as 8 hours after burn. Receiver operating curve analysis of the measurements indicated 70 to 90 percent sensitivity and 80 to 100 percent specificity after 8 hours., Conclusions: The dielectric measurements provide a sensitive and noninvasive method for examining tissue edema and differentiate partial- and full-thickness burns in experimental burns. Thus, they are of clinical interest for early burn depth determination.

Studies regarding high bone mineral density (HBMD) are few. In the population-based Kuopio Osteoporosis Risk Factor and Prevention Study, BMDs of women were measured from 1990-1991 and 1995-1997. The mean age of the 1,873 women studied was 53.5 years at baseline (range 48.0-59.6). In all, 248 women were excluded because of BMD measurement errors or artifacts: 41 from the HBMD group (20.6%) and 207 (12.4%) from the control group. The final study group consisted of 1,551 women, 168 in the HBMD group (baseline lumbar BMD >1.23 g/cm2; femoral BMD >1.01 g/cm2, and 5-year follow-up lumbar BMD >1.21 g/cm2; femoral BMD >0.98 g/cm2, respectively) and 1,383 in the control group. The predictors for HBMD in the multivariate regression analysis were as follows: hormone therapy (HT) during the follow-up from 0.5 to 2 years and for over 2 years (OR 2.06, CI: 1.11-3.81 and OR 2.16, CI 1.43-3.26) and being overweight (BMI from 25 kg/m2 to 30 kg/m2, and BMI >30 kg/m2) at baseline (OR 2.84, CI: 1.82-4.42; OR 5.94, CI: 3.47-10.16, respectively). High physical activity while 11-18 years of age was associated with HBMD (OR 1.69, CI: 1.17-2.45). Parity predicted HBMD so that after one to two births the OR was 2.66 (CI: 1.03-6.88) and 3.03 (CI: 1.16-7.90) after three or more births. Menopause was negatively associated with HBMD (OR 0.57, CI 0.38-0.85). There were more premenopausal women in the HBMD group (53.9 vs. 34.6%, P <0.001). The HBMD group showed fewer fractures. In conclusion, being overweight, parity, HT use, premenopause and high physical activity in adolescence seemed to be predictors for persistently high BMD in early postmenopausal women. We suggest that the fracture risk is low in these women, and thus they are neither primary candidates for BMD screening nor for osteoporosis medication.

Only a few studies have examined the risk of individual chronic health disorders on perimenopausal (i.e., around menopause) fractures in a single study. We evaluated the effect of chronic illnesses on fracture rate in a prospective cohort study of 3,078 women. These women were a stratified sample from the population base of 14,220 women aged 47-56 years and residing in the province of Kuopio in eastern Finland in 1989. Data on physician-diagnosed chronic diseases were collected by a baseline questionnaire in 1989. For certain diseases, questionnaire information of self-reported chronic disorders were compared with drug reimbursement data provided by the Social Insurance Institution of Finland. Axial bone mineral density (BMD) measurements from the femoral neck and lumbar spine were performed in 1989-91. Two hundred sixty-five (265) women experienced at least one fracture during the follow-up period of 3.6 years (SD+/-0.78). The first fracture during the follow-up period was taken to be the end-point event. The risk of follow-up fracture for an individual health disorder was estimated with the Cox's proportional hazards model. Several chronic health disorders increased the fracture risk in perimenopausal women. However, hypertension was a statistically significant (p=0.018) risk factor for fracture (adjusted hazard ratio [HR], 1.4; 95% confidence interval [CI], 1.1-1.9), especially in overweight and obese (body mass index > or =28) women (HR, 2.0; 95% CI, 1.4-3.0). In addition, coronary heart disease (adjusted HR, 1.76; 95% CI, 1.13-2.76), hyperthyroidism (adjusted HR, 1.7; 95% CI, 1.0-2.9), epilepsy (adjusted HR, 2.0; 95% CI, 1.1-3.6), alcoholism (adjusted HR, 3.5; 95% CI, 1.3-9.5) and chronic hepatic disease (adjusted HR, 5.2; 95% CI, 1.7-16.4) predicted fracture. BMD was either normal or even elevated in disease groups. However, women with a fracture during the follow-up usually had decreased bone density, although the difference was statistically significant only in women with hypertension and hyperthyroidism. We conclude that hypertension, coronary heart disease, alcoholism, epilepsy and hyperthyroidism can markedly increase the risk of fracture in perimenopausal women and should be taken into account when assessing the risk of future fracture in an individual patient. Furthermore, in contrast to previous data, obesity alone does not increase the risk of perimenopausal fracture, but in association with hypertension the risk seems to be markedly elevated.

Background: Adjustable gastric banding is currently the most common bariatric operation. This study is a retrospective analysis of the Finnish experience with this procedure over the last 10 years., Methods: Between March 1993 and June 1999, 123 patients underwent either open (36) or laparoscopic (87) surgery for morbid obesity by the application of an adjustable gastric band. Data on preoperative clinical characteristics and postoperative outcome and weight-loss patterns up to 9 years (mean 55 months) are presented and also evaluated by the Bariatric Analysis and Reporting Outcome System (BAROS). Sex ratio was 31% males / 69% females, mean age 44 years and mean +/- SD preoperative BMI 49 +/- 8 kg/m(2) (range 33.6-85.1)., Results: During the evaluation period (March 1993 December 2002), 54% of patients experienced postoperative complications requiring hospital treatment >or= 7 days, and 52% underwent a reoperation. 33% of bands were removed. The most important late complications were esophagitis (30%), obstruction due to slippage / pouch dilatation (21%), incisional hernia (9%) and band erosion (9%). Mean excess weight loss at 1 and 2 year follow-up was 36% and 38%, which later stabilized to 30%. During the evaluation period, there were 10 deaths, 2 of which were 30-day deaths, and the remainder were not associated with the band. According to BAROS, the outcome was regarded as "very good" in 3%, "good" in 7%, "fair" in 40% and "failure" in 50%., Conclusion: Our long-term data found that weight reduction is acceptable,but the incidence of late complications and reoperations was high.

Lung cancer is a group of diseases that are difficult to cure and new treatment modalities, like gene therapy are actively tested to find alternatives for currently used strategies. Herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) method is one of the most frequently utilized forms of gene therapy and it has been tested on lung cancer, but no systematic study with comparison of different lung cancer types has been published. In this study, we examined in vitro and in vivo how good targets non-small cell lung cancer (NSCLC) cell lines representing adenocarcinoma, squamous cell lung cancer and large cell lung cancer are for adenovirus-mediated HSV-TK/GCV gene therapy. By using an adenovirus vector carrying a fusion gene of HSV-TK and green fluorescent protein (GFP), we found that: a) adenoviruses were efficient gene transfer vehicles for all types of NSCLCs; b) all adenocarcinoma and large cell lung cancer cells were good targets for HSV-TK/GCV therapy, whereas one of the squamous cell carcinoma cell lines was not responsive to the treatment; c) bystander effect played a major role in the success of this gene therapy form; d) subcutaneous tumors representing all three NSCLC types were efficiently treated with adenovirus-mediated HSV-TK/GCV gene therapy. In summary, this form of gene therapy appeared to be efficient treatment for human NSCLC and these results warrant further studies with primary lung cancer cells and orthotopic lung tumor models.

The objects of this study were first to compare how well the recently constructed structure-inhibition activity relationship models of mouse CYP2A5 and human CYP2A6 predict the interaction of naphthalene in liver microsomes and secondly to study if these CYP enzymes actually oxidize naphthalene. The CoMFA model of CYP2A5 predicted the IC(50) value of naphthalene to be 42 microM (18-115 microM 95% CL) whereas in the in vitro experiment the result was 74 microM (65-83 microM) with the corresponding values for CYP2A6 being 41 microM (18-112 microM) and 25 microM (21-30 microM), respectively. Naphthalene appeared to be a competitive inhibitor both for mouse and human liver microsomal coumarin 7-hydroxylase, which is the specific probe activity for CYP2A5 and CYP2A6. The K(i)-value for the mouse enzyme was between 12-26 microM and for the human enzyme 1.2-5.6 microM. A 1-h in vitro incubation of naphthalene with human and pyrazole treated mouse liver microsomes produced more 1-naphthol than 2-naphthol. Antibody against the purified CYP2A5 inhibited 50-60% of the formation of 1-naphthol and 30-40% of the formation of 2-naphthol. These results indicate that in silico CoMFA models predict relatively well the interaction of naphthalene with CYP2A5 and CYP2A6 and that these CYPs actually oxidize naphthalene in vitro. CoMFA CYP2A5 and CYP2A6 models are thus useful as a technique for elucidating the interaction and potency of untested chemicals with these CYPs.

Aim: In restitution after superficial injury of the gastric mucosa, the epithelial continuity is restored by cellular migration. We have shown that heat shock preconditioning inhibits restitution after superficial injury. This study investigates the effect of heat shock preconditioning on tissue proliferation and apoptosis., Experimental Design: Paired guinea pig gastric mucosae were mounted and perfused in Ussing chambers (37 degrees C). After heat shock preconditioning (42 degrees C) (30 min) and normothermic recovery (37 degrees C) (150 min) or normothermic perfusion, a superficial injury was induced by luminal exposure to 1.25 mol/L NaCl (5 min) followed by a 3 h restitution. During perfusion, the mucosa was exposed to 30 micromol/L arachidonic acid (AA) to enhance heat shock response, to 50 micromol/L quercetin (Q) to inhibit the metabolism of arachidonic acid via lipoxygenases, to 50 micromol/L indomethacin (In) to inhibit the metabolism of arachidonic acid via cyclo-oxygenases, or to 150 micromol/L cycloheximide (CHX) to inhibit de novo protein synthesis. After the experiment the mucosa was prepared for immunohistochemical analysis of the expression of Mib-1 proliferation antigen and pro-apoptotic protein Bax., Results: Heat shock decreased Mib-1/Bax ratio and this effect was maintained after superficial injury and exposure to Q, to AA+CHX or to In+CHX. Exposure to CHX, to AA, to In+Q, to In+AA, In+AA+Q or to In+AA+CHX, however, blocked the effect of heat shock preconditioning. The decreasing effect of heat shock preconditioning on Mib-1/Bax ratio could be reversed by exposure to AA+Q or to In., Conclusion: The heat-preconditioning-induced effects on the mucosa are reversible and sensitive to exogenous pharmacological modulation. Heat shock preconditioning inhibits proliferation of superficially injured isolated gastric mucosa by a mechanism involving eicosanoid pathways and de novo protein synthesis.

The aim was to study the effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma2 gene on the expression of PPARgamma target genes in adipose tissue. Adipose tissue samples were collected from 30 massively obese subjects (10 men and 20 women) from omental, sc abdominal, and femoral depots. The mRNA expression of PPARgamma1, PPARgamma2, lipoprotein lipase, p85alpha phosphatidylinositol 3-kinase, and uncoupling protein 2 were quantified by reverse transcription-competitive PCR. The genotypes of Pro12Ala polymorphism were determined by single-strand conformation polymorphism analysis. The frequency of the Ala12 allele was 13.3% (8 Pro12Ala and 22 Pro12Pro). There were no differences in body weight, fat mass, and fasting serum leptin between the genotypes. The mRNA expression of p85alpha phosphatidylinositol 3-kinase was significantly lower in the omental fat of the Pro12Ala carriers than the Pro12Pro carriers (P < 0.01). It also appeared that PPARgamma2 expression was higher in men with Ala12 allele (P < 0.01). Interestingly, particularly in women, the expression of both PPARgamma splice variants was lower in omental than sc fat independently of the genotype (P < 0.05-0.01). The common Pro12Ala polymorphism of the PPARgamma2 gene has minor influence on mRNA expression of PPARgamma target genes in adipose tissue of obese subjects. Expression of both PPARgamma splice variants is dependent on fat depot: omental fat shows lower mRNA levels, compared with sc fat depots.

In this study, the bioelectrical impedance analysis (BIA), skinfold thickness measurement (STM) and dual-energy X-ray absorptiometry (DXA), as a reference method, were compared with each other in the assessment of body composition in elderly (62-72-year-old) Finnish women (n=93). BIA had better agreement with DXA in the assessment of fat free mass (FFM, R2=0.70, Sres=2.1) and fat mass (FM, R2=0.93, Sres=2.3) than the STM (FFM, R2=0.62, Sres=2.4; FM, R2=0.89,Sres=2.8). There was quite a large variation in the estimates when different BIA prediction equations were used. The equation developed in this study, FFM (kg)=-128.06 + 1.85 x BMI-0.63 x weight + 1.07 x height - 0.03 x resistance +10.0 x waist-hip ratio, yielded a small and unbiased error (0.5 +/- 1.6 kg), with a small residual standard deviation (R2=0.83, Sres=1.6). However, error associated with the estimate of FM was positively related to the degree of FM. BIA(Heitmann) equation yielded unbiased estimates of both FFM and FM (FFM, R2=0.77, Sres=1.8; FM, R2=0.95, Sres=1.9). Both the STM and BIA (manufacturer's equation) resulted in error which was statistically significant and positively correlated with FFM and FM. These results indicate that BIA prediction equations, chosen with care, can improve the performance of equations based upon anthropometric measurements alone in the assessment of body composition in elderly women.

We evaluated the hepatic arterial buffer response (HABR) to portal vein (PV) occlusion during 2 h of reduced superior mesenteric arterial blood flow (median 2 mL min(-1) kg(-1), range of 1-3 mL min(-1) kg(-1)) and 1 h of reperfusion in seven pigs and in seven controls. In animals with reduced mesenteric blood flow, celiac trunk blood flow (Qtr) increased during mesenteric hypoperfusion from 4 +/- 1 mL min(-1) kg(-1) (mean +/- SD) to 16 +/- 3 mL min(-1) kg(-1) (P = 0.028), and hepatic arterial blood flow (Qha) increased from 2 +/- 1 to 10 +/- 4 mL min(-1) kg(-1) (P= 0.018). The extra-hepatic fraction of Qtr (Qtr-Qha) also increased (P = 0.028). In controls, Qtr and Qha also increased, but to lower levels. At baseline, acute PV occlusion increased Qha by 5.0 +/- 2.8 mL min(-1) kg(-1) (P < 0.001), whereas Qtr-Qha decreased by 1.6 +/- 1.6 mL min(-1) kg(-1) (P = 0.007). After 120 min of reduced mesenteric blood flow, the HABR was exhausted (change in Qha to PV occlusion of 0.7 +/- 1.6 mL min(-1) kg(-1) [P= 0.27]). The efficacy of the HABR was also reduced in controls animals. Despite increased cardiac output, all flows from the celiac trunk decreased during reperfusion (P = 0.028) and the HABR partially recovered. We conclude that reduced mesenteric perfusion impairs the HABR, which recovers only partially after reperfusion. The distribution of the increased celiac trunk flow secondary to PV occlusion ranges from increased HABR and decreased non-hepatic blood flow (a steal) to decreased hepatic arterial blood flow and increased non-hepatic blood flow (an inverse steal).

Vascular endothelial growth factor (VEGF) gene therapy may be useful for the treatment of lower-limb ischemia. The objectives of this study were to evaluate safety and angiographic and hemodynamic responses of local catheter-mediated VEGF gene therapy in ischemic lower-limb arteries after percutaneous transluminal angioplasty (PTA). For this study, we recruited patients with chronic lower-limb ischemia and atherosclerotic infrainguinal occlusion or stenosis suitable for PTA. In the study, 18 patients received 2x10(10) plaque-forming units (pfu) VEGF-adenovirus (VEGF-Ad), 17 patients received VEGF-plasmid/liposome (VEGF-P/L; 2000 microg of VEGF plasmid, 2000 microl of DOTMA:DOPE), and 19 control patients received Ringer's lactate at the angioplasty site. Digital subtraction angiography (DSA) was used to evaluate vascularity before, immediately after, and 3 months after the PTA. Clinical follow-up data, basic laboratory tests, and ankle-brachial index (ABI) were evaluated. Primary endpoint was DSA analysis of vascularity, and secondary endpoints were restenosis rate, Rutherford class, and ABI after 3 months follow-up. No major gene transfer-related side effects or differences in laboratory tests were detected between the study groups. However, anti-adenovirus antibodies increased in 61% of the patients treated with VEGF-Ad. For the primary endpoint, follow-up DSA revealed increased vascularity in the VEGF-treated groups distally to the gene transfer site (VEGF-Ad P=0.03, VEGFP/L P=0.02) and in the VEGF-Ad group in the region of the clinically most severe ischemia (P=0.01). As for the secondary endpoints, mean Rutherford class and ABI showed statistically significant improvements in the VEGF-Ad and VEGF-P/L groups, but similar improvements were also seen in the control patients. We conclude that catheter-mediated VEGF gene therapy is safe and well tolerated. Angiography demonstrated that VEGF gene transfer increased vascularity after PTA in both VEGF-Ad- and VEGF-P/L-treated groups.

Background: Recent studies have suggested the therapeutic potential of vascular endothelial growth factor (VEGF) gene therapy in ischemic skeletal muscle. However, only limited information is available about the effects of VEGF gene therapy in different regions of ischemic limbs, effects of control adenoviruses, and biodistribution of the transgenes after intramuscular (i.m.) administration. Here we studied angiogenesis and side effects of adenovirus-mediated VEGF and beta-galactosidase (LacZ) gene transfers in ischemic rabbit hindlimbs., Methods and Results: Ten days after induction of ischemia, rabbits were treated with i.m. injections of saline, LacZ adenovirus (AdLacZ; 2x10(10) pfu) or adenovirus encoding mouse VEGF(164) (AdVEGF; 2x10(10) pfu). In rabbits treated with AdVEGF an increase in serum VEGF(164) levels was detected by ELISA three and seven days after the gene transfer. 30 days after the gene transfer a positive effect on capillary density was observed in the thigh region both in rabbits treated with AdVEGF and AdLacZ compared with animals that received saline. On the other hand, AdVEGF and AdLacZ gene transfers had no effect on the capillary density in the calf region on day 30. A positive correlation between the capillary density and the number of collateral arteries was observed in the thigh. Hindlimb and testis edema and excess non-physiological growth of capillaries were detected as adverse effects of the AdVEGF gene therapy. Biodistribution analysis showed that the transgene was present not only in the target muscle, but also in ectopic tissues seven days after i.m. gene transfer., Conclusions: The results suggest that a high dose of adenoviral vector encoding either AdVEGF or AdLacZ induces angiogenesis in the rabbit hindlimb ischemia model; i.m. injection of adenovirus leads to the transfection of ectopic organs; and AdVEGF gene transfer induces edema in ischemic skeletal muscle., (Copyright 2002 John Wiley & Sons, Ltd.)

Purpose: Photodynamic therapy is an alternative intravesical therapy modality for superficial bladder cancer. Aminolevulinic acid (ALA) induces the production of the endogenous photosensitizer protoporphyrin IX (PpIX). We compared intravenous versus intravesical administration of ALA and established the proper timing and dose of ALA for photodynamic therapy. To characterize the distribution of ALA in rat bladder tumor and normal bladder layers a cooled charge coupled device camera was used., Materials and Methods: A total of 40 female Fisher F344 rats were used as test animals, including 36 inoculated with AY-27 tumor cells intravesically. PpIX accumulation was investigated by fluorescence microscopy comparing 100 and 300 mg./kg. intravenous administration with a 100 mg./ml. intravesical dose of ALA. Three areas of urothelium, submucosa and muscularis of the bladder wall were chosen for analysis. The software used allowed semiquantitative analysis by calculating the mean fluorescence count plus or minus standard error of mean within any chosen area on the fluorescence image., Results: In this study the highest fluorescence difference in PpIX accumulation in tumor and the normal epithelium to the muscularis layer was achieved at 2 hours with intravenous administration (7:1 to 50:1). The highest absolute fluorescence levels were observed at 2 hours with the 100 mg./kg. intravenous dose and at 4 hours with the higher 300 mg./kg. dose. The difference in fluorescence intensity in tumor tissue to normal urothelium was 2:1 to 3:1 at 2 hours. At 4 hours it was less than 2:1. After intravesical administration no difference in PpIX accumulation in tumor and normal urothelium was observed. However, there was a 7:1 ratio in regard to the muscularis layer at 4 hours., Conclusions: According to the results of this study a difference in PpIX accumulation in urothelial carcinoma or normal urothelium and the muscular layer of the bladder can be achieved by each route of ALA administration. Although intravesical installation provided tumor and normal urothelium labeling comparable to the intravenous route, it lost the selectivity of PpIX accumulation in tumor and normal urothelium. The effect of this finding on clinical therapy results remains to be resolved in the future.

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible endothelial cell mitogen and survival factor. Its receptor VEGFR-2 (KDR/Flk-1) mediates these effects. We studied the expression of VEGF and VEGFR-2 in ischemic human and rabbit skeletal muscle by immunohistochemistry and in situ hybridization. Human samples were obtained from eight lower limb amputations because of acute or chronic critical ischemia. In chronically ischemic human skeletal muscle VEGF and VEGFR-2 expression was restricted to atrophic and regenerating skeletal myocytes, whereas in acutely ischemic limbs VEGF and VEGFR-2 were expressed diffusely in the affected muscle. Hypoxia-inducible factor-1alpha was associated with VEGF and VEGFR-2 expression both in acute and chronic ischemia but not in regeneration. Hindlimb ischemia was induced in 20 New Zealand White rabbits by excising the femoral artery. Magnetic resonance imaging and histological sections revealed extensive ischemic damage in the thigh and leg muscles of ischemic rabbit hindlimbs with VEGF expression similar to acute human lower limb ischemia. After 1 and 3 weeks of ischemia VEGF expression was restricted to regenerating myotubes and by 6 weeks regeneration and expression of VEGF was diminished. VEGFR-2 expression was co-localized with VEGF expression in regenerating myotubes. Macrophages and an increased number of capillaries were associated with areas of ischemic muscle expressing VEGF and VEGFR-2. In conclusion, two patterns of VEGF and VEGFR-2 expression in human and rabbit ischemic skeletal muscle are demonstrated. In acute skeletal muscle ischemia VEGF and VEGFR-2 are expressed diffusely in the affected muscle. In chronic skeletal muscle ischemia and in skeletal muscle recovering from ischemia VEGF and VEGFR-2 expression are restricted to atrophic and regenerating muscle cells suggesting the operation of an autocrine pathway that may promote survival and regeneration of myocytes.

The extracellular polysaccharide hyaluronan (HA) controls cell migration, differentiation, and proliferation, and is supposed to contribute to the spreading of several human cancers. Little is known about the role of HA in the development and progression of differentiated thyroid carcinoma (DTC). The expression and prognostic value of HA were therefore evaluated in 204 consecutive patients with DTC. A biotinylated affinity probe specific for HA was applied to paraffin-embedded tumour samples to assay the expression of HA in carcinoma cells and in intra/peritumoural stroma. In a majority of the samples, a high percentage (>or=90%) of normal thyroid follicle epithelial cells were HA-positive. This high percentage was also found in 80 (47%) papillary carcinomas, but only in seven (21%) follicular carcinomas (p=0.004). Age (>60 years) of the patients was significantly associated with a low percentage of HA-positive cancer cells (p=0.013). Cancer cell-associated HA correlated significantly with the percentage of cells expressing total CD44 and its isoforms containing exons v3 and v6 (r=0.223-0.289, p<0.001 for all). The tumour stroma was always positive for HA. Stromal staining intensity did not differ markedly between papillary and follicular carcinomas. A strong stromal HA staining intensity was related to distant metastases (p=0.044), high pTNM stage (p=0.024), old age (>60 years) (p=0.043), and cancer-related mortality (p=0.001). In a log-rank univariate survival analysis, strong stromal HA staining intensity was related to DTC mortality (p=0.0007). Cancer cell-associated HA expression did not significantly correlate with patient survival. In Cox's multivariate survival analysis, age (>60 years, p=0.0164), gender (p=0.0251), and pTNM stage (p=0.0121) were significant independent prognostic factors for DTC-related death. These results suggest that strong stromal HA staining intensity is related to progression and unfavourable outcome in DTC patients, while the clinical factors remain more powerful in predicting DTC-related death., (Copyright 2001 John Wiley & Sons, Ltd.)

We measured bone mineral density (BMD) using dual X-ray absorptiometry (DXA) at several sites in both fractured and nonfractured limbs in eight patients with femoral shaft fracture and six with tibial shaft fracture at the time of the intramedullary (IM) nail removal. Seven patients were followed up for an average of 13 months. The BMD at the proximal part of the femur and tibia was from 3% to 11% lower in the fractured side as compared to the nonfractured side. The greatest bone loss (13%-21%) was found in the operated distal tibia of the patients with tibial shaft fractures. At the fracture site of the femur, BMD was 10.5% ( P < 0.05) higher, possibly owing to fracture callus formation, whereas tibial shaft BMD was not increased. However, a calculated apparent volumetric BMDvol at the fracture site was 15%-16% decreased. Although BMDs of the fractured side almost reached the baseline level of the nonfractured side (96.9%-102.1%) by the final follow-up (>12 months), the absolute deficit was still 3%-9%. Surprisingly, significant BMD increases (5%-6%) were also detected in all proximal femoral measurement sites of the contralateral limb, which indirectly suggests that the uninjured limb may also suffer from bone loss after lower-extremity trauma. We conclude that clinically important bone loss exists in the proximal femur and proximal and distal tibia of the fractured limb at the time of IM nail removal. Although areal BMD was higher at the femoral fracture site, the lower apparent volumetric BMDvol suggests decreased mineralization and reduced strength of the fracture site. Although the present results do not suggest special recommendations for restricted weight bearing after the removal of IM nails, the relationship between decreased bone density and increased risk of fractures should be borne in mind.

Objective: Investigation of the expression of sterol regulatory element binding protein-1c (SREBP-1c) in different adipose tissue depots in morbidly obese subjects before and after 1 year of weight loss induced by gastric banding operation., Research Methods and Procedures: SREBP-1c expression was studied in 20 massively obese subjects (6 men and 14 women; age: 41 +/- 9 years; weight: 148 +/- 34 kg; percentage of body fat: 42 +/- 4; mean +/- SD) using reverse transcription competitive polymerase chain reaction. Adipose tissue biopsies were taken from omental, subcutaneous abdominal, and femoral depots before weight loss, and from subcutaneous depots after weight loss. Subcutaneous samples were taken also from 6 normal weight subjects., Results: The level of SREBP-1c mRNA was significantly lower in omental (1.8 +/- 0.2 amol/microg of total RNA) than in subcutaneous abdominal (3.7 +/- 0.4 amol/microg of total RNA) or femoral (3.9 +/- 0.4 amol/microg of total RNA; p < 0.001, mean +/- SEM) depots. The values in subcutaneous depots were about twice as high in normal weight (7.4 +/- 2.5 for abdominal and 6.5 +/- 1.5 for femoral, p < 0.01) as in obese subjects. After weight loss, the mRNA levels of SREBP-1c increased in obese subjects, both in subcutaneous abdominal (5.3 +/- 0.7, p < 0.01) and in femoral (4.8 +/- 0.8, p < 0.05) tissue., Discussion: SREBP-1c mRNA expression was lower in omental adipose tissue than in subcutaneous depots in obese subjects before weight loss. Furthermore, the expression of SREBP-1c in obese subjects was clearly lower than in normal weight subjects, but mRNA levels increased along with weight reduction. Weight reduction was associated with increased mRNA levels of SREBP-1c in obese subjects. The reduced expression of SREBP-1c in obesity could be ascribed to lowered action or concentration of insulin, changeable along with weight reduction. However, changes in SREBP-1c expression after weight reduction could also be ascribed to the changes in calorie intake or nutritional habits after gastric banding operation.

Aims: To investigate whether the three different AP-2 isoforms are expressed differently in colorectal adenomas and carcinomas., Methods: The study comprised 43 randomly selected patients diagnosed and treated at Kuopio University Hospital in 1996 for colorectal adenocarcinoma (n = 30) and colorectal adenoma (n = 13). The expression of AP-2alpha, AP-2beta, and AP-2gamma was analysed by immunohistochemistry (IHC) and the mRNA status of AP-2alpha was determined by in situ hybridisation (ISH) and confirmed by reverse transcription polymerase chain reaction (RT-PCR). AP-2 expression patterns were correlated with clinicopathological variables., Results: In adenomas and carcinomas, AP-2beta cytoplasmic positivity was higher than that of AP-2alpha or AP-2gamma. AP-2alpha expression was reduced in advanced Dukes's stage carcinomas. In high grade carcinomas, both AP-2alpha and AP-2gamma expression was reduced. ISH demonstrated increased AP-2alpha values in high grade carcinomas. Seven of 30 carcinoma specimens displayed a moderate or strong mRNA signal, despite being negative for AP-2alpha protein. RT-PCR from AP-2alpha mRNA and protein positive tumours confirmed that the positive signal in ISH originated from the exon 2 of TFAP2A., Conclusions: AP-2alpha was reduced in advanced Dukes's stage adenocarcinomas. Together with reduced AP-2gamma expression in high grade carcinomas, this might contribute to tumour progression. The discrepancy between mRNA and protein expression suggests that post-transcriptional regulatory mechanisms might modify the availability of functional AP-2alpha protein in colorectal carcinoma.

Photodynamic therapy (PDT) produces localized necrosis with light after prior administration of a photosensitizing drug. The problems with laser light dosimetry and complications relating to bladder function appear to be important limiting factors of PDT in urology. Photodynamic therapy on urinary bladder with normal epithelium of rats was performed using an argon ion laser as an energy source, with aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) photosensitizer. Four hours after ALA intravenous administration, the bladders were intravesically radiated with light doses 20, 40, or 80 J/cm2. Animals in the control group did not receive ALA and were radiated with 20 J/cm2 light dose. Three weeks prior to PDT, the bladder capacity and pressure changes during filling cystometry were assessed. Cystometrics were repeated 1, 3, 7, or 21 days after laser therapy. The light dose 20 J/cm2 and 40 J/cm2 together with the used ALA dose caused no reduction in bladder capacity, whereas 80 J/cm2 light dose produced up to 50% reduction in the capacity at 3 weeks postoperatively. In control group without ALA, the animals did not regain more than 34% of the capacity of their control values at 3 weeks. The light dose of 20 J/cm2 and 40 J/cm2 with ALA induced functional changes that subsided after day 1. Our results indicate that with proper dosing of photosensitizing drug and light energy, the functional impairment of urinary bladder may be reduced as transient. These findings support the use of PDT as safe therapy of superficial bladder cancer.

Objective: To assess the impact of surgical treatment on health-related quality of life (QoL) and its various dimensions in four common gastrointestinal diseases, to compare it with that of the general population, and to assess the relationship between the patient's and the surgeon's satisfaction., Design: Prospective, observational study., Setting: Tertiary care centre, Finland., Patients: 131 patients, of whom 77 had cholecystectomy, 20 fundoplication, 20 incisional herniorrhaphy, 12 large bowel resection, and 2 construction of a stoma only because of unresectable colorectal cancer., Interventions: Routine operative treatment of four gastrointestinal diseases., Main Outcome Measures: QoL measured by a generic 15-dimensional instrument., Results: The health-related QoL improved postoperatively in the entire group. Discomfort, symptoms, and vitality were all reduced at 2 months, whereas bowel movements, eating, and usual activities had been restored at 12 months. The health related QoL was comparable with that of the general population at 12 months except for breathing and sleeping. The pattern of recovery varied among diagnostic subgroups, being most improved in patients operated on for biliary disease, those aged 60 years or younger, women and otherwise previously healthy patients. There was a close agreement between the patient's and the surgeon's opinion of outcome., Conclusions: Gastrointestinal surgery improves quality of life. Separating a generic health-related QoL measure into dimensions allows a more appropriate estimation of quality of life than a single index score. Because some dimensions were made worse soon after operation and some were restored slowly, a minimum 12-month follow-up may be needed to assess the effect of gastrointestinal surgery on health- related QoL.

Insertion of a metallic implant into the femur changes bone loading conditions and results in remodeling of femoral bone. To quantify changes in bone mass after uncemented total hip arthroplasty (THA), we monitored femoral bone with dual-energy X-ray absorptiometry (DXA). The periprosthetic bone mineral density (BMD) was measured with Lunar DPX densitometry in seven Gruen zones and the total periprosthetic area at scheduled time intervals in 22 patients during a 3-year follow-up. BMD decreased significantly almost in all Gruen zones during the first 3 months, ranging from 3.4% to 14.4% (p < 0.05 top < 0.001). At the end of the first year, the most remarkable decrease in BMD was found in the calcar (zone 7; -22.9%). During the second postoperative year, a slight restoration of periprosthetic bone mass was recorded. During the third year, no significant changes in BMD were found. The preoperative BMD was the only factor that was significantly related to the periprosthetic bone loss. Clearly, the early periprosthetic bone loss noticed during the 3 months after THA is caused by mainly limited weight bearing to the operated hip and stress shielding. We suggest that the restoration of bone mass is a sign of successful osteointegration between bone and metallic implant. DXA is a suitable tool to follow the bone response to prosthetization and will increase our knowledge on the behavior of bone after THA.

Gastric surgery is mostly needed for treatment of gastric malignancy. To investigate the effect of total gastrectomy on bone mineral density (BMD) and bone mineral metabolism we evaluated 18 patients after total gastrectomy. Mean interval since operation was 71 +/- 20 months. BMD results were compared with age- and gender-matched controls (n = 46) and also expressed as T and Z scores. Bone mineral density measured by dual-energy X-ray absorptiometry (DXA) was found to be significantly lower in patients after total gastrectomy compared with healthy controls in the lumbar spine (p = 0.017 for women, p = 0.002 for men), femoral neck (p = 0.004 for women, p = 0.001 for men), Ward's triangle (p = 0.031 for women, p = 0.003 for men), and greater trochanter (p = 0.001 for women, p = 0.001 for men). Z scores for lumbar spine, femoral neck, Ward's triangle, and greater trochanter were -0.83, -1.54, -1.02, and -1.19, respectively. Biochemical measurements correlated poorly with BMD and were found to be of lesser value in diagnosing reduced bone mass as well as in differential diagnosis of etiology of osteopenia. The results of our study show the deleterious effect of total gastrectomy on bone mineral status and suggest an increased fracture risk in these patients.

Background and Aims: We examined the effect of alendronate on bone following orchidectomy-induced osteoporosis., Material and Methods: Eighty male rats were used. Group I (C) served as the untreated control. In group II (ALN), alendronate was administered subcutaneously (18 microg/kg). In group III (ORC), rats were castrated only. In group IV (ORC+ALN), administration of alendronate (18 microg/kg) was started immediately after castration, and in group V (ORC + ALN-21) medication was started 21 days after castration. Alendronate was given twice a week for eight weeks in the treatment groups. Bone mineral density (BMD) of the proximal femur, ultimate bending forces of femoral diaphyses, ash weights of femurs (AWcc) and the calcium content (Ca) of femoral ash were determined. Histomorphometric analysis was performed on trabecular bone of proximal tibiae., Results: BMD of the proximal femur was significantly decreased by orchidectomy compared with C and ALN. However, no statistical difference was observed between alendronate-treated groups (ORC + ALN and ORC + ALN-21) and the ORC group. Histologically, alendronate reduced the trabecular bone turnover. Ultimate bending force increased significantly in the ORC+ALN-21 group compared with group C, and had a good correlation with the cortical width of tibia (r = 0.53, p < 0.001). Ash weight per bone volume (AWcc) was lowest in the ORC group, whilst alendronate maintained AWcc after orchidectomy., Conclusion: Alendronate increased the ultimate bending force of the femoral diaphysis after orchidectomy. On the other hand, ALN treatment was not able to maintain the BMD of the proximal femur at the pre-orchidectomy level. Our results suggest that the remodelling and modelling of bone may influence the response to ALN treatment.

Background and Aims: Bone metabolism in celiac patients is not well understood and there are no previous histomorphometric studies on bone of patients with celiac disease. The aim of the study was to investigate bone metabolism in celiac patients using bone histomorphometry, measurement of bone mineral density (BMD) and biochemical parameters., Material and Methods: The patient groups included 19 men and 23 women with previously diagnosed celiac disease in remission (group I), 7 women not in remission (group II) and 19 women and 9 men with newly diagnosed celiac disease (group III). Static and dynamic parameters of bone structure, formation and resorption were measured using undecalcified sections. The following parameters were obtained: bone volume (BV/TV; %), osteoid volume (OV/BV; %), osteoid surface (OS/BS; %), resoprtion surface (ES/BS; %), osteoid thickness(Oth; microm), mineral apposition rate (MAR; microm/day), and mineralization lag time (MinLag; day). BMD was measured at the spine (L2-4) and left femoral neck, trochanter and Ward's triangle. Serum calcium (S-Ca; mmol/L), alkaline phosphatase (AP; U/L), intact parathyroid hormone (S-PTH; ng/L), 25-hydroxyvitamin D (S-25(OH)D; nmol/L), cross-linked carboxyterminal telopeptide of human type I collagen (S-ICTP; microg/L) and C-terminal extension peptide of type I procollagen (S-PICP; microg/L) were analysed., Results: In the histomorphometric analysis there were no significant differences in static or dynamic parameters between the groups. Very low bone mass (< 10%) was found in one patient in every group. OV/BV was increased (> 3.5%) in all groups (31% in group I, 13% in group II and 29% in group III). OS/BS was increased (> 36.5%) in groups I and III (17% and 29% respectively). In group II OS/BS was normal in all patients. Mineralization defect was found in four patients in group I and in two patients in group III with otherwise normal histomorphometric results. ES/BS was increased in three patients in group I and III and in one patient in group II. One female patient in group III had increased osteoid parameters, resorption surface, S-PTH and low concentration of vitamin D reflecting hyperparathyroid changes in bone. S-PTH was increased (66-87 ng/L) in four patients in group III and one of these patients had hyperparathyroid histological changes in bone., Conclusions: Static and dynamic histomorphometry of iliac crest bone biopsy are useful tools to evaluate bone metabolism in celiac disease especially if hyperparathyroidism or mineralization defect are suspected. Hyperparathyroidism may be a problem in the patients before introducing gluten-free diet. Mineralization defect and osteomalacic changes are common later on irrespective of whether the patients are in remission or not.

The aim of the study was to investigate the effects of regular aerobic exercise training on bone mineral density (BMD) in middle-aged men. A population based sample of 140 men (53-62 years) was randomly assigned into the exercise and reference groups. BMD and apparent volumetric BMD (BMDvol) of the proximal femur and lumbar spine (dual-energy X-ray absorptiometry, DXA) and anthropomorphic measurements were performed at the randomization and 2 and up to 4 years later. The participation rate was 97% and 94% at the second and third BMD measurements, respectively. As another indication of excellent adherence and compliance, the cardiorespiratory fitness (aerobic threshold) increased by 13% in the exercise group. The 2% decrease in the reference group is regarded as an age-related change in cardiorespiratory fitness. Regardless of the group, there was no association between the increase in aerobic threshold and change in BMD. In the entire group, age-related bone loss was seen in the femoral neck BMD and BMDvol (p < 0.01). BMD and BMDvol values increased with age in L2-L4 (p < 0.004). An increased rate of bone loss at the femoral neck was observed in men with a low energy-adjusted calcium intake (p = 0.003). Men who increased their alcohol intake during the intervention showed a decrease in the rate of bone loss at the femoral neck (p = 0.040). A decrease in body height associated with decreased total femoral BMD (r = 0.19, p = 0.04) and the change in body height was a predictor of bone loss in the femoral neck (beta = 0.201). Long-term regular aerobic physical activity in middle-aged men had no effect on the age-related loss of femoral BMD. On the other hand, possible structural alterations, which are also essential for the mechanical strength of bone, can not be detected by the DXA measurements used in this study. The increase seen in lumbar BMD reflects age-related changes in the spine, thus making it an unreliable site for BMD follow-up in men.

Background and Aims: Osteopenia is a common consequence of immobilization. We investigated the effects of pamidronate on immobilized bone in male rats., Material and Methods: Eighty male Wistar rats (5 months old) were divided in five groups (control (C); pamidronate at 0.5 mg/kg per dose (Pam0.5); immobilization (N); pamidronate at 0.05 mg/kg per dose + immobilization (N + Pam0.05); and pamidronate at 0.5 mg/kg per dose + immobilization (N + Pam0.5). The rats were immobilized on their right side by sciatic neurectomy. Pamidronate was given subcutaneously three times a week for three weeks. Trabecular bone mineral density (TBMD) of the upper femur, ultimate failure load of the femoral diaphysis, ash weight of femur, calcium content of femoral ash, and ash weight corrected with bone volume (AWcc [g/cm3]) were determined. Histomorphometry of proximal tibiae was performed by a semiautomatic method., Results: TBMD was higher on both sides in Pam0.5 and N + Pam0.5 groups than in C or N groups. Ultimate failure load was not altered significantly with treatment. AWcc of the immobilized femur was lower (p < 0.001) than in the contralateral limb in N, N + Pam0.05 and N + Pam0.5 groups. Both resorption and formation parameters were suppressed by pamidronate., Conclusion: Pamidronate treatment seemed to increase trabecular bone density, although it was not effective in maintaining the AWcc of the operated extremity. Pamidronate did not seem to affect the ultimate failure load of cortical bone.