The Oncogenic PI3K-Induced Transcriptomic Landscape Reveals Key Functions in Splicing and Gene Expression Regulation.

The phosphoinositide 3-kinase (PI3K) pathway regulates proliferation, survival, and metabolism and is frequently activated across human cancers. A comprehensive elucidation of how this signaling pathway controls transcriptional and cotranscriptional processes could provide new insights into the key functions of PI3K signaling in cancer. Here, we undertook a transcriptomic approach to investigate genome-wide gene expression and transcription factor activity changes, as well as splicing and isoform usage dynamics, downstream of PI3K. These analyses uncovered widespread alternatively spliced isoforms linked to proliferation, metabolism, and splicing in PIK3CA-mutant cells, which were reversed by inhibition of PI3Kα. Analysis of paired tumor biopsies from patients with PIK3CA-mutated breast cancer undergoing treatment with PI3Kα inhibitors identified widespread splicing alterations that affect specific isoforms in common with the preclinical models, and these alterations, namely PTK2/FRNK and AFMID isoforms, were validated as functional drivers of cancer cell growth or migration. Mechanistically, isoform-specific splicing factors mediated PI3K-dependent RNA splicing. Treatment with splicing inhibitors rendered breast cancer cells more sensitive to the PI3Kα inhibitor alpelisib, resulting in greater growth inhibition than alpelisib alone. This study provides the first comprehensive analysis of widespread splicing alterations driven by oncogenic PI3K in breast cancer. The atlas of PI3K-mediated splicing programs establishes a key role for the PI3K pathway in regulating splicing, opening new avenues for exploiting PI3K signaling as a therapeutic vulnerability in breast cancer. SIGNIFICANCE: Transcriptomic analysis reveals a key role for the PI3K pathway in regulating RNA splicing, uncovering new mechanisms by which PI3K regulates proliferation and metabolism in breast cancer. See related commentary by Claridge and Hopkins, p. 2216.

Influência do sistema de criação em piso sobre cama e gaiola sobre as características ósseas e a qualidade físico-química e microbiológica de ovos de galinhas / Influence of the floor and cage creation system on the bony characteristics and the physical-chemical and microbiological quality of hen eggs

O experimento foi realizado no setor de avicultura/UFRRJ, utilizando 348 galinhas semipesadas (linhagem Dekalb Brown), com 52 semanas de idade, criadas sob dois sistemas de produção: cage-free e em gaiolas. Os dados obtidos pela análise físico-química e microbiológica dos ovos e a resistência óssea à quebra foram submetidos à análise de variância. No caso de ocorrerem efeitos dos diferentes sistemas de produção, foi aplicado o teste de Tukey a 5% de probabilidade para comparação das médias. A qualidade físico-química foi igualmente favorecida pelos dois sistemas de produção, indicando que as circunstâncias experimentais propiciaram condições adequadas para a formação de ovos de boa qualidade. O sistema de gaiola não desfavoreceu as características ósseas das galinhas, apontando que, em densidades adequadas, a gaiola pode não exercer um fator prejudicial para a qualidade óssea. O sistema de produção cage-free piorou a contaminação da casca, comprovando que ovos postos em ninhos são mais contaminados em comparação aos produzidos em gaiolas.(AU)

The experiment was carried out in the poultry sector / UFRRJ, using 348 semi-heavy hens (Dekalb Brown line), 52 weeks old, raised under two cage-free production systems and cages. The data obtained by the physical-chemical and microbiological analysis of the eggs and the bone resistance to the break were submitted to analysis of variance, in case of effects of the different production systems, the Tukey's test was applied at 5% of probability for comparison of the means. The physical-chemical quality was also favored by the two production systems, indicating that the experimental circumstances provided adequate conditions for the formation of good quality eggs. The cage system did not disfavor the bony characteristics of the hens, indicating that at suitable densities, the cage may not exert a detrimental factor to bone quality. The cage-free production system worsened shell contamination by proving that nesting eggs are more contaminated compared to those produced in cages.(AU)

[Influence of Selected Reproductive Factors and Smoking on Age at Menopause]. / Einfluss ausgewählter Reproduktionsfaktoren sowie des Rauchens auf das Alter bei Eintreten der Menopause.

Introduction: Early menopause may be associated with serious health risks resulting from, for example, decreased oestrogen levels. This may occur despite hormone replacement therapy. Aim: The aim of this study was the determination of the effect of selected reproductive factors and smoking on age at the onset of menopause in women from Szczecin and surrounding areas. Material and Methods: 305 women after natural menopause were asked to complete a questionnaire, and blood samples were collected from them to test for the levels of follicle stimulating hormone (FSH) and oestradiol (E2). Results: Smoking women experienced menopause on average more than a year earlier than non-smokers, but this difference was not statistically significant. There was no statistically significant effect of age at menarche or first birth on age at the last menstrual period. Conclusions: Age at menarche and first birth were not related to age at menopause. In smoking women, menopause occurred earlier but the difference was not statistically significant.

Long-term dietary sodium restriction increases adiponectin expression and ameliorates the proinflammatory adipokine profile in obesity.

BACKGROUND/AIM: Obesity is associated with changes in adiponectin and pro-inflammatory adipokines. Sodium intake can affect adipokine secretion suggesting a role in cardiovascular dysfunction. We tested if long-term dietary sodium restriction modifies the expression of adiponectin and ameliorates the pro-inflammatory profile of obese, diabetic mice. METHODS/RESULTS: Db/db mice were randomized to high sodium (HS 1.6% Na+, n = 6) or low sodium (LS 0.03% Na+, n = 8) diet for 16 weeks and compared with lean, db/+ mice on HS diet (n = 8). Insulin levels were 50% lower in the db/db mice on LS diet when compared with HS db/db (p < 0.05). LS diet increased cardiac adiponectin mRNA levels in db/db mice by 5-fold when compared with db/db mice on HS diet and by 2-fold when compared with HS lean mice (both p < 0.01). LS diet increased adiponectin in adipose tissue compared with db/db mice on HS diet, achieving levels similar to those of lean mice. MCP-1, IL-6 and TNF-α expression were reduced more than 50% in adipose tissue of db/db mice on LS diet when compared with HS db/db mice (all p < 0.05), to levels observed in the HS lean mice. Further, LS db/db mice had significantly reduced circulating MCP-1 and IL-6 levels when compared with HS db/db mice (both p < 0.01). CONCLUSION: In obese-diabetic mice, long-term LS diet increases adiponectin in heart and adipose tissue and reduces pro-inflammatory factors in adipose tissue and plasma. These additive mechanisms may contribute to the potential cardioprotective benefits of LS diet in obesity-related metabolic disorders.

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study.

BACKGROUND: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. METHODS: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5)). RESULTS: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). CONCLUSION: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.

Possible counter effect in newborns of 1936A>G (I646V) polymorphism in the AKAP10 gene encoding A-kinase-anchoring protein 10.

OBJECTIVE: Cyclic adenosine monophosphate/protein kinase A (PKA) is important in embryonic development. The human AKAP10 gene is polymorphic: 1936A>G results in changes to a PKA-binding domain and increased targeting to mitochondria. Previous studies found G1936 as 'deleterious' in adults, and this study investigates whether this holds true in preterm birth. STUDY DESIGN: Study group consisted of 80 preterm newborns (PTNs) born before the 38th gestation week. Control group consisted of 123 full-term healthy newborns born after the 37th gestation week with uncomplicated pregnancies. Genomic DNA was extracted from umbilical blood and AKAP10 genotypes were identified by PCR/restriction enzyme. RESULT: Significant differences in frequencies of 1936A>G genotypes/alleles between both groups were found. PTNs had increased frequency (55%) of AA homozygotes (odds ratio, AA versus AG+GG: 2.63 (95% confidence interval: 1.33 to 5.20), P=0.006) after adjustments: mothers with previous PTNs, smoking, first pregnancy, first delivery and Cesarean section. CONCLUSION: Results suggest G1936 is preventative factor against preterm birth, in contrast with previously asserted negative effects in adults.

A single dose of intravenous zoledronate prevents glucocorticoid therapy-associated bone loss in acute flare of Crohn's disease, a randomized controlled trial.

OBJECTIVES: To assess the effectiveness and safety of zoledronate (ZOL) in preventing glucocorticoid therapy-associated bone loss in patients with acute flare of Crohn's disease (CD) in a randomized, double-blind, placebo-controlled trial. METHODS: Forty CD patients starting a glucocorticoid therapy (60 mg prednisolone per day) for acute flare (CD activity index (CDAI) >220) were randomized to compare the effect of ZOL (4 mg intravenous, n=20) or placebo (n=20) on change in lumbar bone mineral density (BMD). All patients received calcium citrate (800 mg) and colecalciferol (1,000 IU) daily. Dual energy X-ray absorptiometry (DXA) of the lumbar spine (L1-L4) was performed at baseline and day 90. Follow-up examinations at day 1/7/14/30 and 90 included laboratory tests and adverse event/serious adverse events reports. RESULTS: Thirty-six patients were available for per-protocol analysis. With placebo (n=18), a decrease in BMD was seen (T-score: -0.98 ± 0.8, day 0 and -1.25 ± 0.77, day 90, P=0.06), with ZOL (n=18) BMD increased (-1.15 ± 1.02, day 0 and -0.74 ± 1.09, day 90, P=0.03). The change in BMD under placebo (-0.26 ± 0.21) vs. ZOL (+0.41 ± 0.19) was highly significant (P=0.006). In all, 14 out of 18 patients with ZOL had an increase in BMD (+0.64 ± 0.48), 12 of 18 with placebo a decrease (-0.50 ± 0.39). Changes of clinical findings and laboratory results of inflammation (leukocytes, platelets, and C-reactive protein) were the same in- and between-groups throughout the study. With ZOL, serum bone degradation marker ß-Cross-Laps decreased. Study medication was safe and well tolerated. CONCLUSIONS: ZOL is effective in preventing glucocorticoid therapy-induced bone loss in patients with acute flare of CD and should be considered whenever a glucocorticoid therapy is started in CD patients.

Difficult diagnosis of a large cystic retroperitoneal tumor mimicking a hepatic origin.

Schwannomas are rare tumors, usually benign, originating from the nerve sheath, and found only infrequently in the retroperitoneal space. We report on a 67-year-old woman who was initially misdiagnosed and treated for a liver hydatid cyst. After incomplete resection and recurrence of the tumor, we were able to diagnose a large retroperitoneal schwannoma that completely displaced the liver to the left abdomen. The patient underwent surgical resection of the schwannoma; pathological evaluation revealed a cystic tumor measuring 18.5 × 18 × 12.5 cm, with tumor cells staining strongly positive for S-100. Retroperitoneal schwannomas may mimic cystic hepatic tumors and should, therefore, be considered as a differential diagnosis in such cases. We describe the diagnostic modalities and difficulties in the approach of a cystic liver tumor.

[A prospective comparison of video colonoscopy and CT colonography in asymptomatic patients screened for colorectal cancer]. / CT-Kolonographie versus Videokoloskopie zum Nachweis kolorektaler Läsionen in der Vorsorgepopulation.

BACKGROUND AND OBJECTIVE: It was the aim of this study to compare the sensitivity and specificity of low-dose CT colonography (CTC) with that of optical colonoscopy (OC) in asymptomatic patients undergoing these tests in a screening program for colonic cancer. PATIENTS AND METHODS: 58 patients (mean age 62.6 years) were included. They underwent low dose CTC and, immediately afterwards, colonoscopy. The colonoscopists were unaware of the CTC findings. A "second look" was performed if a lesion seen in CTC had been missed in the first colonoscopy. RESULTS: A total of 150 lesions were detected and histologically confirmed. 136 were found to be polypoid lesions, classified as either hyperplastic polyps (n = 66) or polyps with intraepithelial neoplasia (n = 70). In the per-patient analysis only 22.4 % of patients had no polypoid lesion, 27.6 % had at least one hyperplastic and 50.0 % had at least one adenomatous lesion. Sensitivity for adenomas of all size categories was calculated 55.7 % for CTC and 92.9 % for OC. This marked difference (both for the detection of individual lesions and the per-patient analyses) does not reach significance in the two-sided McNemar test. CONCLUSIONS: There was a high prevalence of lesions with intraepithelial neoplasia in this screening group. OC had a higher sensitivity than CTC in the detection of lesions smaller than 10 mm.

[Personalized therapy of gastrointestinal cancers--possibilities and limitations]. / Der Weg in die personalisierte Therapie von gastrointestinalen Tumorerkrankungen--Möglichkeiten und Limitationen.

The aim of palliative chemotherapy is to increase survival whilst maintaining optimal quality of life for the individual patient. While the best use of traditional chemotherapeutical agents continues to be explored, the introduction of targeted therapies has significantly broadened the therapeutic options. Yet it is interesting to note that the results of current trials did not always confirm the underlying molecular concepts. Recent data have suggested that altered pathways underlie the development of cancer, not just altered genes. Thus an effective therapeutic agent will have to target pathophysiologically relevant signalling networks, rather than individual proteins. This review presents current concepts and problems of cancer treatment, highlighting results from recent clinical trials of colorectal and pancreatic cancer patients and to discuss the current understanding of the underlying mechanisms.

The zinc-finger protein KCMF1 is overexpressed during pancreatic cancer development and downregulation of KCMF1 inhibits pancreatic cancer development in mice.

Potassium channel modulatory factor 1 (KCMF1) was found upregulated in a differential screen in the metaplastic epithelium in the pancreas of transforming growth factor (TGF)-alpha transgenic mice. Expression analysis indicated broad overexpression in human cancer tissues. Therefore, we investigated the hypothesis that KCMF1 promotes metaplastic changes and tumor development. KCMF1 represents an evolutionarily highly conserved protein with a 95% identity between human and zebrafish. KCMF1 is expressed during embryonic development and in the majority of adult tissues investigated. Upregulation of nuclear KCMF1 expression is evident in preneoplastic lesions and in several epithelial malignancies, such as pancreatic cancer in mice and humans. In cell culture and in the chicken chorioallantoic membrane model, KCMF1 enhances proliferation, migration and invasion of HEK-293 and Panc1 cells. In crossbreeding experiments, KCMF1-knockdown gene trap mice showed a reduced number and size of premalignant lesions and absence of pancreatic cancer formation in TGF-alpha transgenic mice. This effect is related to the decreased expression of G1 to S cell-cycle regulators such as cyclin D and cyclin-dependent kinase (CDK) 4. Our data support the hypothesis that KCMF1 mediates pro-oncogenic functions in vitro and in vivo and downregulation of KCMF1 results in the inhibition of pancreatic cancer formation in mice. These effects are mediated through downregulation of cell-cycle control genes such as cyclin D and CDK4.

Substrate stiffness and the receptor-type tyrosine-protein phosphatase alpha regulate spreading of colon cancer cells through cytoskeletal contractility.

Microenvironmental clues are critical to cell behavior. One of the key elements of migration is the generation and response to forces. Up to now, there is no definitive concept on how the generation and responses to cellular forces influence cancer-cell behavior. Here, we show that expression of receptor-type tyrosine-protein phosphatase alpha (RPTPalpha) in human SW480 colon cancer cells sets a threshold for the response to matrix forces by changing cellular contractility. This can be explained as an RPTPalpha-mediated increase in contractility with a consecutive increase in number and size of adhesion sites and stress fibers. These effects are mediated through myosin light chain kinase and largely independent of Rho/Rho-kinase (ROCK) signaling. In addition, we report that RPTPalpha influences spreading on low-rigidity surfaces, binding of collagen-coated beads and expression of RPTPalpha is required for invasion into the chorioallantoic membrane. These data suggest that force-responsive proteins such as RPTPalpha can influence cancer-cell behavior and identify potential targets for cancer therapy.

Increased Duodeno-Gastro-Esophageal Reflux (DGER) in symptomatic GERD patients with a history of cholecystectomy.

BACKGROUND: Duodenal-Gastro-Esophageal Reflux (DGER) represents an independent risk factor for the development of complicated Gastro-esophageal-reflux-disease (GERD) and Barrett's esophagus. Clinical and epidemiological data suggest a potential association between cholecystectomy (CCE) and augmented bile reflux. METHODS: 132 patients (67 women, 65 men, median age 55) with typical symptoms of GERD were enrolled in the study and divided in cholecystectomized (CCE-group: n = 107) and non- cholecystectomized (nCCE-group: n = 25) patients. Standardized clinical work-up of patients included combined esophageal 24 h pH-measurement and Bilitec 2000 esophageal manometry and upper endoscopy. RESULTS: In the statistical analysis no differences between the cholecystectomized group (CCE-group, n = 25) and the patients without cholecystectomy (nCCE-group, n = 107) could be observed in quantity or quality of reflux symptoms. Furthermore, neither acid reflux nor severity of inflammation and frequency of Barrett's esophagus significantly differed between the nCCE and CCE-group. However, the percentage of patients with pathological DGER were significantly higher in the CCE-group as compared to the nCCE-group (76 vs. 55 %, p < 0.01). Moreover, the CCE-group revealed significant higher levels of pathological DGER compared to the nCCE-group (15.5 % +/- 14.1 vs. 8.6 % +/- 15.4; p < 0.05). CONCLUSION: To conclude, our data provide first evidence of elevated DGER after CCE in patients with typical clinical symptoms of GERD using the Bilitec device. Both the frequency and the extent of DGER was significantly increased in the CCE-group. Prospective studies are urgently needed to elucidate the impact of CCE on DGER in patients with clinical symptoms of a reflux disease.

CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models.

BACKGROUND: CD147 (basigin, EMMPRIN) is a multifunctional, highly conserved glycoprotein enriched in pancreatic ductal adenocarcinomas (PDACs) which is associated with poor prognosis in many malignancies. The role of CD147 in pancreatic cancer, however, remains elusive. METHODS AND RESULTS: Silencing of CD147 by RNA interference (RNAi) reduced the proliferation rate of MiaPaCa2 and Panc1 cells. CD147 is required for the function and expression of the monocarboxylate transporters MCT1 and MCT4 that are expressed in human PDAC cells as demonstrated by real-time reverse transcription-PCR (RT-PCR) as well as immunohistology. MCT1 and MCT4 are the natural transporters of lactate, and MiaPaCa2 cells exhibited a high rate of lactate production, which is characteristic for the Warburg effect, an early hallmark of cancer that confers a significant growth advantage. Further induction of lactate production by sodium azide in MiaPaCa2 cells increased MCT1 as well as MCT4 expression. CD147 silencing inhibited the expression and function of MCT1 and MCT4 and resulted in an increased intracellular lactate concentration. Addition of exogenous lactate inhibited cancer cell growth in a dose-dependent fashion. In vivo, knock-down of CD147 in MiaPaCa2 cells by inducible short hairpin RNA (shRNA)-mediated CD147 silencing reduced invasiveness through the chorioallantoic membrane of chick embryos (CAM assay) and inhibited tumourigenicity in a xenograft model in nude mice. CONCLUSION: The function of CD147 as an ancillary protein that is required to sustain the expression and function of MCT1 and MCT4 is involved in the association of CD147 expression with the malignant potential of pancreatic cancer cells exhibiting the Warburg effect.

Impact of pantoprazole on duodeno-gastro-esophageal reflux (DGER).

BACKGROUND: Duodeno-gastro-esophageal reflux (DGER) is considered as an independent risk factor for complicated reflux disease (GERD). Patients with Barrett's esophagus have significantly higher levels of DGER than patients with uncomplicated GERD. However, the clinical response to conventional high-dose PPI therapy in patients with uncomplicated GERD and DGER is largely unknown. METHODS: 30 patients with uncomplicated GERD and combined pathological reflux (acid and bile) were enrolled in the study. Clinical work-up included evaluation of clinical symptoms, esophageal manometry and upper endoscopy. After 6 - 8 weeks of treatment with Pantoprazole 80 mg/d pH measurement and Bilitec 2000 were repeated, and the pattern of symptoms was re-evaluated. RESULTS: Under treatment with Pantoprazole 80 mg/d acid reflux was normalised in 28 patients (93 %). Similarly the mean percentage of DGER (time with an absorption greater than 0.14) was significantly reduced from 19.6 % (+/- 13.7) to 5.7 % (+/- 7.7, p < 0.05). In 15 patients (50 %) an elevated DGER persisted under treatment with Pantoprazole (DGER-NR group) whereas in 15 cases (50 %) a normalisation could be achieved (DGER-R group). The DGER-NR group had significantly higher levels of bile reflux before (and under) treatment compared to the DGER-R group: 22.9 % (9.98 %) vs. 15.6 % (0.72 %), respectively. Overall, the median quality of life index (QLI) improved from 4.78 (+/- 0.86) before to 8.04 +/- 1.84) under therapy. The clinical response under treatment was marikedly reduced in the DGER-NR group compared to the DGER-R group: QLI 7.3 vs. 8.9. Particularly heartburn and nocturnal coughing persisted. CONCLUSIONS: Our data confirm that high-dose pantoprazole therapy effectively exerts acid suppression in GERD patients with combined pathological reflux. However, DGER could only normalised in 50 % of patients. High levels of DGER at diagnosis enhance the risk of persistent DGER under PPI therapy and are associated with a reduced clinical outcome.

Bones and Crohn's: estradiol deficiency in men with Crohn's disease is not associated with reduced bone mineral density.

BACKGROUND: Reduced bone mineral density (BMD) and osteoporosis are frequent in Crohn's disease (CD), but the underlying mechanisms are still not fully understood. Deficiency of sex steroids, especially estradiol (E2), is an established risk factor in postmenopausal osteoporosis. AIM: To assess if hormonal deficiencies in male CD patients are frequent we investigated both, sex steroids, bone density and bone metabolism markers. METHODS: 111 male CD patients underwent osteodensitometry (DXA) of the spine (L1-L4). Disease related data were recorded. Disease activity was estimated using Crohn's disease activity index (CDAI). Testosterone (T), dihydrotestosterone (DHT), estradiol (E2), sex hormone binding globulin (SHBG), Osteocalcin and carboxyterminal cross-linked telopeptids (ICTP) were measured in 111 patients and 99 age-matched controls. RESULTS: Patients had lower T, E2 and SHBG serum levels (p < 0.001) compared to age-matched controls. E2 deficiency was seen in 30 (27.0%) and T deficiency in 3 (2.7%) patients but only in 5 (5.1%) and 1 (1%) controls. Patients with E2 deficiency had significantly decreased T and DHT serum levels. Use of corticosteroids for 3 of 12 months was associated with lower E2 levels (p < 0.05). Patients with life-time steroids >10 g had lower BMD. 32 (28.8%) patients showed osteoporosis, 55 (49.5%) osteopenia and 24 (21.6%) had normal BMD. Patients with normal or decreased BMD showed no significant difference in their hormonal status. No correlation between markers of bone turnover and sex steroids could be found. ICTP was increased in CD patients (p < 0.001), and patients with osteoporosis had higher ICTP levels than those with normal BMD. CONCLUSION: We found an altered hormonal status--i.e. E2 and, to a lesser extent T deficiency--in male CD patients but failed to show an association to bone density or markers of bone turnover. The role of E2 in the negative skeletal balance in males with CD, analogous to E2 deficiency in postmenopausal females, deserves further attention.

Expression of E-SOD, GPX5 mRNAs and immunoexpression of Cu/ZnSOD in epididymal epithelial cells of finasteride-treated rats.

We studied the immunoexpression of Cu/Zn superoxide dismutase (Cu/ZnSOD) and mRNAs expression of extracellular superoxide dismutase (E-SOD), and epididymal specific glutathione peroxidase 5 (GPX5), in epithelial cells of caput and cauda epididymis of rats treated with finasteride, a steroid-based inhibitor of 5alpha-reductase. The 5alpha-reductase is known to exist in two isoforms. Both 5alpha-red1 and 5alpha-red2 catalyse the irreversible conversion of T into DHT. Formation of DHT in the epididymis is mostly due to the action of 5alpha-red2 and finasteride is more potent inhibitor of this isoform. Rats were treated with finasteride for 56 days covering the duration of one spermatogenesis (four cycles of the seminiferous epithelium). Although E-SOD mRNA is normally expressed in cells of cauda but not of caput epididymis, treatment with finasteride produced the E-SOD transcript in cells of caput epididymis too. The GPX5 transcript was detected in cells of caput epididymis of control and experimental rats, but the level of expression measured densitometrically was significantly lower in finasteride-treated rats. The immunoexpression of Cu/ZnSOD was also changed in epididymis of finasteride-treated rats. Finasteride appears to change the pattern of expression of antioxidant enzymes and may alter the protective function of the epididymis in relation to spermatozoa.

[Prevalence of a pathological DGER (duodeno-gastric-oesophageal reflux) in patients with clinical symptoms of reflux disease]. / Prävalenz eines pathologischen Duodeno-Gastro-Osophagealen Refluxes (DGER) bei Patienten mit klinischen Beschwerden einer Refluxerkrankung.

BACKGROUND: According to recent studies DGER (duodeno-gastric-oesophageal reflux) is considered as an independent risk factor for the development of reflux esophagitis and the Barrett metaplasia. The Bilitec 2000 allows a qualitative and quantitative measurement of DGER in patients with symptoms of reflux disease. The aim of the present study was to investigate the prevalence of DGER in patients with reflux symptoms. METHODS: 146 patients with symptoms of gastro-oesophageal reflux disease were enrolled in this study. Patients underwent upper gastrointestinal endoscopy, oesophageal manometry and simultaneous 24 h oesophageal pH and bilirubin monitoring. The presence of pathological DGER and its relations to the symptom pattern, distal oesophageal acid exposure and endoscopic findings were analysed. RESULTS: In 74 out of 146 patients (51 %, 39 men, 34 women) a DGER could be detected. Twenty-eight (32 %) of these patients suffered from an isolated DGER, while 46 (32 %) had a combined acid and DGER reflux. An isolated acid reflux was found in additional 28 (19 %) patients. The degrees of both acid and DGER were significantly higher in those patients with oesophageal lesions. CONCLUSIONS: 1. There is a high prevalence of DGER in patients with the clinical symptoms of a reflux disease. 2. The combined measurement of acid reflux and DGER helps to better define the cause of reflux symptoms. 3. In analogy to the acid reflux DGER increases with the gravity of oesophageal lesions.