Gadolinium retention in the tunica media of arterial walls-a complementary study using elemental bioimaging and immunogold staining.

Gadolinium (Gd) deposition has been found in both animal and human tissues after injections of Gd-based contrast agents (GBCAs). Without the knowledge of which tissues are most affected, it is difficult to determine whether Gd accumulation could lead to any pathological changes. The current study aims at investigating histological sections of three patients who were exposed to GBCAs during their lifetime, and identify areas of Gd accumulation. Tissue sections of three autopsy cases were investigated by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to assess the distribution of Gd, and the deposition within tissue sections was quantified. Additional application of laser ablation-inductively coupled plasma-optical emission spectroscopy (LA-ICP-OES) enabled a sensitive detection of calcium (Ca) in the vessel walls, which is usually impeded in LA-ICP-MS due to the isobaric interference with argon. Complementary LA-ICP-MS and LA-ICP-OES analysis revealed that Gd was co-localized with zinc and Ca, in the area where smooth muscle actin was present. Notably, high levels of Gd were found in the tunica media of arterial walls, which requires further research into potential Gd-related toxicity in this specific location.

Critical evaluation of human health risks due to hydraulic fracturing in natural gas and petroleum production.

The use of hydraulic fracturing (HF) to extract oil and natural gas has increased, along with intensive discussions on the associated risks to human health. Three technical processes should be differentiated when evaluating human health risks, namely (1) drilling of the borehole, (2) hydraulic stimulation, and (3) gas or oil production. During the drilling phase, emissions such as NOx, NMVOCs (non-methane volatile organic compounds) as precursors for tropospheric ozone formation, and SOx have been shown to be higher compared to the subsequent phases. In relation to hydraulic stimulation, the toxicity of frac fluids is of relevance. More than 1100 compounds have been identified as components. A trend is to use fewer, less hazardous and more biodegradable substances; however, the use of hydrocarbons, such as kerosene and diesel, is still allowed in the USA. Methane in drinking water is of low toxicological relevance but may indicate inadequate integrity of the gas well. There is a great concern regarding the contamination of ground- and surface water during the production phase. Water that flows to the surface from oil and gas wells, so-called 'produced water', represents a mixture of flow-back, the injected frac fluid returning to the surface, and the reservoir water present in natural oil and gas deposits. Among numerous hazardous compounds, produced water may contain bromide, arsenic, strontium, mercury, barium, radioactive isotopes and organic compounds, particularly benzene, toluene, ethylbenzene and xylenes (BTEX). The sewage outflow, even from specialized treatment plants, may still contain critical concentrations of barium, strontium and arsenic. Evidence suggests that the quality of groundwater and surface water may be compromised by disposal of produced water. Particularly critical is the use of produced water for watering of agricultural areas, where persistent compounds may accumulate. Air contamination can occur as a result of several HF-associated activities. In addition to BTEX, 20 HF-associated air contaminants are group 1A or 1B carcinogens according to the IARC. In the U.S., oil and gas production (including conventional production) represents the second largest source of anthropogenic methane emissions. High-quality epidemiological studies are required, especially in light of recent observations of an association between childhood leukemia and multiple myeloma in the neighborhood of oil and gas production sites. In conclusion, (1) strong evidence supports the conclusion that frac fluids can lead to local environmental contamination; (2) while changes in the chemical composition of soil, water and air are likely to occur, the increased levels are still often below threshold values for safety; (3) point source pollution due to poor maintenance of wells and pipelines can be monitored and remedied; (4) risk assessment should be based on both hazard and exposure evaluation; (5) while the concentrations of frac fluid chemicals are low, some are known carcinogens; therefore, thorough, well-designed studies are needed to assess the risk to human health with high certainty; (6) HF can represent a health risk via long-lasting contamination of soil and water, when strict safety measures are not rigorously applied.

Effects of surgical and dietary weight loss therapy for obesity on gut microbiota composition and nutrient absorption.

Evidence suggests a correlation between the gut microbiota composition and weight loss caused by caloric restriction. Laparoscopic sleeve gastrectomy (LSG), a surgical intervention for obesity, is classified as predominantly restrictive procedure. In this study we investigated functional weight loss mechanisms with regard to gut microbial changes and energy harvest induced by LSG and a very low calorie diet in ten obese subjects (n = 5 per group) demonstrating identical weight loss during a follow-up period of six months. For gut microbiome analysis next generation sequencing was performed and faeces were analyzed for targeted metabolomics. The energy-reabsorbing potential of the gut microbiota decreased following LSG, indicated by the Bacteroidetes/Firmicutes ratio, but increased during diet. Changes in butyrate-producing bacterial species were responsible for the Firmicutes changes in both groups. No alteration of faecal butyrate was observed, but the microbial capacity for butyrate fermentation decreased following LSG and increased following dietetic intervention. LSG resulted in enhanced faecal excretion of nonesterified fatty acids and bile acids. LSG, but not dietetic restriction, improved the obesity-associated gut microbiota composition towards a lean microbiome phenotype. Moreover, LSG increased malabsorption due to loss in energy-rich faecal substrates and impairment of bile acid circulation. This trial is registered with ClinicalTrials.gov NCT01344525.

Effect of Urocortin on strength and microarchitecture of osteopenic rat femur.

As yet there is no evidence of the potential antiosteoporotic effect of Urocortin-1 (UCN), a corticotropin releasing factor related peptide, in vivo. In this study, and for the first time, we investigated the effect of UCN in a rat osteopenia model. Sixty female Sprague-Dawley rats were divided into 5 groups: (1) sham-operated, (2) untreated ovariectomized (OVX) rats, (3) and (4) OVX animals treated for 5 weeks with daily subcutaneous low-dose UCN (3 µg/kg of BW) or high-dose UCN (30 µg/kg of BW) 8 weeks after ovariectomy, and (5) OVX rats treated with daily estrogen (0.2 mg/kg of BW p.o) 8 weeks after ovariectomy for 5 weeks (E). After sacrifice, the femurs were reserved for biomechanical, histomorphometric and ash testing. In the biomechanical test, the high-dose UCN rats showed significantly improved mechanical stiffness (341.6 N/mm) compared with the untreated OVX animals (275.9 N/mm). In the histomorphometric evaluation, the high-dose UCN rats demonstrated an improved trabecular microarchitecture especially and significantly at the distal femur (distal femur Tb.Ar = 41.4% and N.Nd/mm(2) = 26.8, proximal femur Tb.Ar = 71.8% and N.Nd/mm(2) = 28.7) compared with untreated OVX rats (distal femur Tb.Ar = 23.3% and N.Nd/mm(2) = 11.7, proximal femur Tb.Ar = 60.2% and N.Nd/mm(2) = 25.2). Our results show that short-term treatment with UCN seems to have a positive effect on the metaphyseal bone structure and strength of the femur in ovariectomized rats.

Iodine status in Danish pregnant and breastfeeding women including studies of some challenges in urinary iodine status evaluation.

Denmark was previously iodine deficient with regional differences. Moderate iodine deficiency appeared in West Denmark and mild iodine deficiency in East Denmark and also Danish pregnant and breastfeeding women suffered from iodine deficiency. The Danish mandatory iodine fortification of salt was introduced in the year 2000 and has increased iodine intake in the Danish population. However, median urinary iodine concentration in the general population and in pregnant and breastfeeding women is still below the level recommended, corresponding to mild iodine deficiency. Certain characteristics may challenge the evaluation of urinary iodine status in pregnancy and during breastfeeding. This review also addresses methodological challenges related to spot urine sampling conditions and the use of iodine supplement and discusses the use of non-pregnant population groups as a proxy for iodine intake in pregnant women.

Concentrated green tea extract induces severe acute hepatitis in a 63-year-old woman--a case report with pharmaceutical analysis.

UNLABELLED: ETNOPHARMACOLOGICAL RELEVANCE: The popularity of concentrated green tea extracts as dietary supplements for a wide range of applications is increasing due to their health-promoting effects attributed to the high amounts of catechins they contain. The most important of the green tea catechins is (-)-epigallocatechin-3-O-gallate (EGCG). While their beneficiary effects have been studied extensively, a small number of adverse events have been reported in the medical literature. Here we present a typical reversible course of severe hepatitis after green tea consumption. MATERIALS AND METHODS: The case study describes in a 63-year old woman during treatment with green tea-capsules upon recommendation of a cancer support group. RESULTS: The histological finding was consistent with drug induced hepatitis, and other possible causes of hepatitis were excluded. According to the CIOMS/RUCAM score the causality was assessed as "probable". After discontinuation of medication, followed by extracorporal albumin dialysis, rapid and sustained recovery occurred. Pharmaceutically analysis (HPLC) of the green tea capsules did not give evidence for contaminants but revealed the two typical compounds of green tea, namely (-)-epigallocatechin-3-O-gallate (EGCG, 93.2%) and epicatechin (EC, 6.8%) at a very high dose level. CONCLUSION: The present case highlights the fact that such concentrated herbal extracts from green tea may not be free of adverse effects under certain circumstances. There is still a lack of a uniform European Union-wide surveillance system for adverse drug reactions of herbal products. Therefore this case underlines the importance of public awareness in the potential risks in use of herbal products.

Pre- and postoperative nutritional deficiencies in obese patients undergoing laparoscopic sleeve gastrectomy.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has been identified as an innovative surgical approach for the treatment of obesity and is increasingly applied worldwide. However, data on outcome of LSG regarding nutrient deficiencies, protein status, and body composition are scarce. METHODS: Obese subjects (54; f:m = 4:1) scheduled for LSG were included in this study. Micronutrient analysis, protein status assessment, and bioimpedance measures were performed before and 1, 3, 6, and 12 months after LSG. RESULTS: In 51% of the subjects, at least one micronutrient deficiency was found prior to surgery. Baseline concentrations were below normal for 25-OH vitamin D (27%), iron (29%), vitamin B6 (11%), vitamin B12 (9%), folate (6%), and potassium (7%). Frequencies of deficiencies for vitamin B12, folate, iron, and vitamin B6 tended to increase following LSG within the first year after intervention. Also, parameters of protein status (albumin, transferrin, cholinesterase, and total protein) decreased. After surgery, bioimpedance measures indicated a reduction of total body fat, but also of body cell mass. CONCLUSIONS: Preoperative micronutrient deficiencies were common in morbid obese individuals scheduled for LSG. LSG had a modest effect on micronutrient status by further reducing iron, vitamin B12, vitamin B6, and folate within the first year after intervention. Our data suggest that especially obese patients with preoperative deficits require control and supplementation of micronutrients and protein in the postoperative period.

Association between lymph node silicosis and lung silicosis in 4,384 German uranium miners with lung cancer.

This study investigates the association between lymph node-only and lung silicosis in uranium miners with lung cancer and exposure to quartz dust. Tissue slides of 4,384 German uranium miners with lung cancer were retrieved from an autopsy archive and reviewed by 3 pathologists regarding silicosis in the lungs and lymph nodes. Cumulative exposure to quartz dust was assessed with a quantitative job-exposure matrix. The occurrence of silicosis by site was investigated with regression models for exposure to quartz dust. Miners with lung silicosis had highest cumulative quartz exposure, followed by lymph node-only silicosis and no silicosis. At a cumulative quartz exposure of 40 mg/m(3) × years, the probability of lung silicosis was above 90% and the likelihood of lymph node-only silicosis and no silicosis do not differ anymore. The results support that lymph node silicosis can precede lung silicosis, at least in a proportion of subjects developing silicosis, and that lung silicosis strongly depends on the cumulative quartz dose.

TRAIL-induced apoptosis is preferentially mediated via TRAIL receptor 1 in pancreatic carcinoma cells and profoundly enhanced by XIAP inhibitors.

PURPOSE: We previously reported that small molecule X-linked inhibitor of apoptosis (XIAP) inhibitors synergize with soluble TRAIL to trigger apoptosis in pancreatic carcinoma cells. Because cancers may preferentially signal via 1 of the 2 agonistic TRAIL receptors, we investigated these receptors as a therapeutic target in pancreatic cancer in the present study. EXPERIMENTAL DESIGN: We examined TRAIL receptor expression and cytotoxicity of specific monoclonal antibodies to TRAIL-R1 (HGS-ETR1, mapatumumab) or TRAIL-R2 (HGS-ETR2, lexatumumab) and of TRAIL receptor selective mutants alone and in combination with small molecule XIAP inhibitors in pancreatic cancer cell lines, in primary specimens, and in a xenotransplant model in vivo. RESULTS: The majority of primary pancreatic carcinoma samples and all cell lines express one or both agonistic TRAIL receptors. Nine of 13 cell lines are more sensitive to mapatumumab-induced apoptosis, whereas lexatumumab requires cross-linking for maximal activity. Similarly, TRAIL-R1 selective mutants display higher cytotoxicity than TRAIL-R2 selective mutants. Small molecule XIAP inhibitors preferentially act in concert with mapatumumab to trigger caspase activation, caspase-dependent apoptosis, and suppress clonogenic survival. Also, primary cultured pancreatic carcinoma cells are more susceptible to mapatumumab than lexatumumab, which is significantly enhanced by a XIAP inhibitor. Importantly, combined treatment with mapatumumab and a XIAP inhibitor cooperates to suppress tumor growth in vivo. CONCLUSIONS: Mapatumumab exerts antitumor activity, especially in combination with XIAP inhibitors against most pancreatic carcinoma cell lines, whereas lexatumumab requires cross-linking for optimal cytotoxicity. These findings have important implications for the design of TRAIL-based protocols for pancreatic cancer.

Absence of positive effect of black cohosh (Cimicifuga racemosa) on fracture healing in osteopenic rodent model.

The healing of predominantly metaphyseal fractures in postmenopausal osteoporosis is delayed and comparatively poor. Due to the potential side effects of HRT, natural alternatives are appealing. The aim of this study was to determine whether Cimicifuga racemosa extract BNO 1055 improves metaphyseal fracture healing in severe osteopenic bone in rats. Thirty-three 12-week-old female rats developed severe osteopenia during 10 weeks after ovariectomy. After metaphyseal tibial-osteotomy and standardized T-plate-osteosynthesis, the healing periods in ovariectomized rats (C), 17-α-estradiol (E) and Cimicifuga racemosa (CR) supplemented diets were assessed for 35 days. Changes in callus morphology were evaluated qualitatively by biomechanical testing and quantitatively in microradiographies and fluorochrome-labeled histological sections. The CR-supplementation slightly improved callus quality and trabecular bone formation. It significantly enhanced the endosteal callus density compared to C group (Cl.Dn.e C: 59.08 ± 21.89, E: 45.95 ± 18.39, CR: 60.85 ± 18.66*), though most of the other morphological parameters examined showed no improvement. The time course of fracture healing did not change due to CR. Estrogen-supplementation enhanced the biomechanical properties of the fracture site. Trabecular bone was improved indicating the physiological endosteal healing process. The CR-supplementation did not exhibit positive effects in severe (senile) osteopenic fracture healing as seen in early (postmenopausal) osteoporosis in rats. Callus formation was slightly improved under CR. Estrogen improved fracture healing in severe osteopenic bone, while the extent of callus formation played a minor role.

A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T cell responsiveness.

OBJECTIVE: Leptin, a protein product of adipocytes, plays a critical role in the regulation of body weight, immune function, pubertal development, and fertility. So far, only three homozygous mutations in the leptin gene in a total of 13 individuals have been found leading to a phenotype of extreme obesity with marked hyperphagia and impaired immune function. DESIGN: Serum leptin was measured by ELISA. The leptin gene (OB) was sequenced in patient DNA. The effect of the identified novel mutation was assessed using HEK293 cells. RESULTS: We describe a 14-yr-old child of nonobese Austrian parents without known consanguinity. She had a body mass index of 31.5 kg/m(2) (+2.46 SD score) and undetectable leptin serum levels. Sequencing of the leptin gene revealed a hitherto unknown homozygous transition (TTA to TCA) in exon 3 of the LEP gene resulting in a L72S replacement in the leptin protein. RT-PCR, Western blot, and immunohistochemical analysis indicated that the mutant leptin was expressed in the patient's adipose tissue but retained within the cell. Using a heterologous cell system, we confirmed this finding and demonstrated that the side chain of Leu72 is crucial for intracellular leptin trafficking. Our patient showed signs of a hypogonadotropic hypogonadism. However, in contrast to the literature, she showed only mild obesity and a normal T cell responsiveness. CONCLUSIONS: These findings shed a new light on the clinical consequences of leptin deficiency. Congenital leptin deficiency should be considered possible in pediatric patients with mild obesity even if parents are lean and unrelated.

Effects of black cohosh (Cimicifuga racemosa) and estrogen on metaphyseal fracture healing in the early stage of osteoporosis in ovariectomized rats.

Osteoporosis and its accompanying, predominantly metaphyseal, fractures are a major health problem. Black cohosh (Cimicifuga racemosa) and estrogen positively influence osteoporotic bone. Both substances may improve fracture healing in early osteoporosis as well. In 48 twelve-week-old ovariectomized or, respectively, sham-operated (SHAM) rats, a standardized metaphyseal tibia osteotomy with bridging T-plate fixation was performed. During the healing process of 35 days, rats received soy-free (SHAM, osteopenic C), estrogen- (E) or Cimicifuga racemosa- (CR) supplemented diets. After sacrifice, the callus formation was analyzed with regard to biomechanical quality, morphology, quantity, time course of new bone built and gene expression. CR induced a high rate of metaphyseal callus formation. The biomechanical properties and the amount of new callus formation indicated that fracture healing was still in progress. Therefore, gene expression of osteoblasts was comparatively high. Body weight and the trabecular structure were influenced little by CR. Estrogen improved the biomechanical properties of the callus. Resistance to microfracturing was significantly enhanced in the E group and even superior to SHAM. Remodeling of the callus formation had already begun. The trabecular network and the typical endosteal fracture healing were especially improved. Osteoporotic metaphyseal fracture healing was improved by estrogen more than by Cimicifuga racemosa. The process of fracture healing occurred nearly physiologically. The generation of callus formation was supported by Cimicifuga racemosa as well, but the five-week duration of application was too short for Cimicifuga racemosa to show its complete potential. Already-initiated Cimicifuga racemosa therapy for menopausal symptoms could be continued during fracture healing without hesitation.

Changes in the histomorphometric and biomechanical properties of the proximal femur of ovariectomized rat after treatment with the phytoestrogens genistein and equol.

The isoflavonoids found in soy have attracted great interest as dietary phytoestrogens that might be effective for postmenopausal hormone replacement therapy. Special attention has been devoted to the hormonal effects of various isoflavonoids, like genistein (GEN) and daidzein's (DAID) potent metabolite, equol (EQ). Here we aimed to investigate the short-term effects of genistein and equol on the proximal femur of ovariectomized (OVX) rats. Forty-eight, 3-month-old female Sprague-Dawley rats were ovarectomized; after eight weeks the bilateral osteotomy and osteosynthesis (OS) of their tibiae was performed and the rats were randomly divided into the following four groups: OVX control group (C), treated with estradiol-17beta (E2) -benzoate (E; daily intake 0.086 mg/d per animal), genistein (GEN; daily intake 12.7 mg/d per animal) and equol (EQ; daily intake 4.65 mg/d per animal). At 5 weeks postoperatively (OS), the breaking test was performed on the trochanteric region of femur. Additionally, histomorphometric assessment, and trabecular and cortical bone microstructure analyses were performed. The relative gain of body weight (BW) in the EQ (24 %) group was significantly (p < 0.05) lower than in the C (33 %) and GEN (30 %) groups. After treatment for 5 weeks, the maximal load (F(max)) and yield load (yL) were higher (p < 0.05 for the weight-adapted results) in the E (188.4 N resp. 113.1 N) and EQ (177.3 N resp. 112 N) groups as compared to C (162.8 N resp. 109.1 N) and GEN (165.7 N resp. 108.8 N). In the histomorphometric tests the E- (trabecular area (Tb.Ar) = 74.93 %, trabecular nodes/mm(2) (N.Nd/mm(2)) = 48.65) and EQ-treated (Tb.Ar = 63.13 %, N.Nd/mm(2) = 43.72) animals showed significant improvement with regard to Tb.Ar and trabecular connectivity (N.Nd./mm(2)) in comparison to C (Tb.Ar = 46.84, N.Nd/mm(2) = 31.86) and GEN (Tb.Ar = 48.22 %, N.Nd/mm(2) = 34.15). There were no differences in relative cortical width (Ct.Wi) among the four groups. The treatment with EQ resulted in improved biomechanical and histomorphometric properties as compared to the treatment with GEN. Thus, of the studied substances, EQ seems to be a possible alternative to hormone replacement therapy, but further studies are needed.

Impaired gastric acidification negatively affects calcium homeostasis and bone mass.

Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. Here we show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells, have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia. These results suggest that alterations in calcium homeostasis can be driven by defects in gastric acidification, especially given that calcium gluconate supplementation fully rescues the phenotype of the Cckbr-mutant mice. Finally, mice deficient in Tcirg1, encoding a subunit of the vacuolar proton pump specifically expressed in both osteoclasts and parietal cells, show hypocalcemia and osteopetrorickets. Although neither Src- nor Cckbr-deficient mice have this latter phenotype, the combined deficiency of both genes results in osteopetrorickets. Thus, we find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification.

The use of flat panel volumetric computed tomography (fpVCT) in osteoporosis research.

RATIONALE AND OBJECTIVES: Improvements in imaging technology have led to the increased use of computed tomography (CT). For example, micro-CT and quantitative CT (QCT) are now often used in osteoporosis research, in which micro-CT is able to analyze small bones or bone samples with high spatial resolution. In contrast, QCT is able to investigate large samples with low spatial resolution. The aim of this study was to test the usefulness of flat-panel volumetric CT (fpVCT) in a rat model of osteopenia. MATERIAL AND METHODS: Twenty-two 3-month-old rats underwent ovariectomy and were either left untreated or supplemented with estradiol for 15 weeks. After sacrificing, the rats' second lumbar vertebral body bone mineral density (BMD) was analyzed using fpVCT and ashing. The results were compared to those of a microstructural analysis of the first lumbar vertebrae and a biomechanical evaluation of the fourth lumbar vertebrae. RESULTS: BMD measurements using both fpVCT (0.39 vs 0.35 mg/cm(3)) and ashing (0.52 vs 0.48 mg/cm(3)) demonstrated a significant improvement after estradiol supplementation. The correlation coefficient of the two methods was 0.858. After estradiol supplementation, the bone microstructural and bone biomechanical parameters were improved, compared to no treatment. The correlations of both the microstructural and the biomechanical evaluations were closer for BMD measured using fpVCT (r = 0.482-0.769) than on the basis of ashing (r = 0.345-0.573). FpVCT was not able to display the trabecular microstructure of the rat lumbar vertebrae. CONCLUSION: The use of fpVCT demonstrated a close relationship between morphologic and biomechanical evaluations in a rat model of osteopenia. Because of its different proportions, fpVCT might be able to bridge the gap between micro-CT and QCT in analyzing larger animals.

Effect of daidzein, 4-methylbenzylidene camphor or estrogen on gastrocnemius muscle of osteoporotic rats undergoing tibia healing period.

The effect of daidzein (D), 4-methylbenzylidene camphor (4-MBC) or estradiol-17beta-benzoate (E(2)) on muscle of osteoporotic rats during fracture healing was studied. After performing a metaphyseal tibia osteotomy in 96 osteoporotic 5-month-old female Sprague-Dawley rats, they received daily 50 mg D, 200 mg 4-MBC or 0.4 mg E(2) per kg body weight, or soy free (SF) diet up to 36 and 72 days. Mitochondrial activity, fiber area, and capillary density were analyzed in M. gastrocnemius. Osseous callus bridging of fracture was observed in half of the rats after 36 days. By day 72, fracture was healed in most of the animals. State 3 mitochondrial respiration significantly enhanced in E(2), 4-MBC and D groups versus SF after 36 days (30, 32 and 32 vs 23 pmol O(2)/s per mg). It declined after 72 days, however, in E(2) group it was still at a higher level versus SF (25, 23 and 21 vs 20 pmol O(2)/s per mg). Size of fast oxidative glycolytic (FOG) and fast glycolytic (FG) fibers, capillary density did not differ significantly between the groups, however, at day 36 an increase in D and 4-MBC groups was detectable. FOG diameter was 64, 66, 68, and 58 microm and FG diameter was 88, 98, 95, and 89 microm in SF, D, 4-MBC, and E(2) groups. The ratio of capillaries to muscle fiber was 1.1, 1.4, 1.3, and 1.1 in SF, D, 4-MBC and E(2) groups by day 36. D and 4-MBC react similar to estrogen thereby improving oxidative cell metabolism in severe osteoporotic rats. The level of mitochondrial activity was higher, though no significant morphological differences could be shown.

Equol but not genistein improves early metaphyseal fracture healing in osteoporotic rats.

Healing of predominantly metaphyseal fractures in postmenopausal osteoporosis is delayed and comparatively poor. Hormone replacement therapy could improve fracture healing, but, because of its potential side effects, natural alternatives are more appealing. The aim of this study was to determine if the soy metabolite equol and the native isoflavone genistein, in comparison to 17beta-estradiol, improve metaphyseal fracture healing in ovariectomy-induced osteoporotic bone of the rat. Forty-eight 12-week-old female rats developed severe osteoporosis ten weeks after ovariectomy. After metaphyseal tibial osteotomy and standardized stable internal fixation, changes in callus morphology were evaluated biomechanically, qualitatively and quantitatively in fluorochrome-labeled histological sections and microradiographs in ovariectomized rats (C) and under standardized 17beta-estradiol (E), equol (EQ) and genistein (G) supplemented rats over a period of five weeks. Estrogen and equol were able to improve the elasticity of callus formation significantly in postmenopausal osteoporotic bone (stiffness of C: 121.40 +/- 47.08 N/mm, E: 147.90 +/- 39.38 N/mm, EQ: 167.8 +/- 59.90 N/mm). The effects of estrogen were more anabolic than those of equol and were visible in changes to the trabecular bone (N.Nd of E: 6.47 +/- 7.68, EQ: 4.25 +/- 3.96). However, in terms of the whole body, equol seemed to induce less of an adverse reaction than estrogen (body weight of C: 342.20 +/- 19.91 g, E: 280.25 +/- 12.05 g, EQ: 308.75 +/- 24.28 g). Genistein as an osteoclast inhibitor influenced callus stiffness (G: 144.50 +/- 61.52 N/mm) and negatively impacted trabecular structure (N.Nd of G: 0.59 +/- 1.01) in severely osteoporotic bones. Estrogen and equol were able to improve fracture healing in ovariectomy-induced osteoporotic bones, and the extent of callus formation played only a minor role. Genistein rather negatively influenced fracture healing. The metaphyseal osteotomy model in ovariectomized rats allows an accurate study of the therapeutic effects of antiosteoporotic substances on the fracture healing process.

Major histopathological patterns of lung cancer related to arsenic exposure in German uranium miners.

OBJECTIVE: The mechanisms of action of arsenic in the development of lung cancer are still not yet elucidated. Considering the relationship between arsenic and squamous cell carcinomas of the skin, we hypothesized that arsenic exposure may be more closely associated with squamous cell carcinoma of the lung. METHODS: A comprehensive histopathological database and a detailed job-exposure matrix developed for former German uranium miners with exposure to arsenic, radon, and quartz were analyzed to quantitatively assess the effect of arsenic regarding cell type of lung cancer. The distributions of major lung cancer cell types in 1,786 German uranium miners were associated with levels of arsenic exposure under control for the other lung carcinogens. To evaluate the arsenic effects in association with a frequent occupational lung disease in miners stratification by silicosis was performed. RESULTS: There was an arsenic-related increase of the proportion of squamous cell carcinoma of the lung but restricted to miners without silicosis. The increase was found at all levels of co-exposure to radon and quartz dust. In miners with silicosis, the proportion of adenocarcinoma increased with rising arsenic exposure. Arsenic exposure was associated with non-small cell lung cancer. Silicosis turned out as major determinant of the cell type related with arsenic. CONCLUSION: These results indicate a cell type characteristic effect of arsenic in the development of lung cancer.

Comparison of the phytohormones genistein, resveratrol and 8-prenylnaringenin as agents for preventing osteoporosis.

As the average age of society increases, identifying and preventing osteoporosis becomes more important. According to the results of the Women's Health Initiative study, substitution of estradiol is not recommended in hormone replacement therapy (HRT), although phytoestrogens might be a safe alternative. In this study, the osteoprotective effects of genistein (Gen), resveratrol (Res) and 8-prenylnaringenin (8PN) were evaluated by analysing bone biomechanical strength and bone mineral density. After ovariectomy, 88 female rats received soy-free food (C), and according to their grouping, were fed estradiol (E), GEN, RES or 8PN for 12 weeks. The phytohormones were given in two dosages. To analyse the osteoprotective effects of the tested substances, bone biomechanical properties and bone mineral density (BMD) were evaluated on the upper tibial metaphysis. Bone biomechanical properties were significantly improved after treatment with E (F (max): 90.6 N) and 8PN (85.0 N) compared to GEN (76.0 N), RES (72.6 N) and C (76.6 N). Bone biomechanical properties with 8PN (yL: 55.7 N) supplementation reached a level similar to that seen after E (49.3 N) supplementation. Treatment with GEN (38.5 N) was not as effective as E and 8PN, but demonstrated improved biomechanical properties compared to C (40.1 N) and RES (36.3 N). E (Cn.Dn. 217 mg/cm (3)) and 8PN (165 mg/cm3) showed superior results in the analysis of bone mineral density compared to C (112 mg/cm (3)). GEN (164 mg/cm (3)) also demonstrated superior results, though not as good as E and 8PN. RES (124 mg/cm (3)) revealed no effect on bone density. Treatment with 8PN resulted in very good biomechanical properties and showed an increased BMD. GEN had a smaller effect on bone biomechanical strength, while RES did not have an effect on bone biomechanical strength or BMD. Therefore, 8PN might be a safe alternative for HRT, but further studies are needed.

[The meaning of wholeness in medical philosophy]. / Was bedeutet Ganzheit in der Philosophie der Medizin?

Organisms are "wholes" insofar as togetherness with others is essential for their development and identity. The female egg is the first and original environment into which a human individual develops. The three main spheres of holistic togetherness in which man further becomes himself in joining the world are (1) psychic togetherness of the organs, (2) social togetherness with fellow human beings and (3) natural togetherness or connaturality, in the whole of nature. Health and disease can originate on any of these levels. On the first one psychosomatic experiences tend to be confirmed by recent results of psychoneuroimmunology. On the second level health or pathogenicity of private or professional social environments tend to be much better known in social medicine (public health) than in medical practice. Corresponding research on the third level is much less advanced. Medical care can be secondary to cultivating social and natural togetherness.