Return to fertility after extended chemical castration with a GnRH antagonist

BACKGROUND: Antagonistic analogues of GnRH for the treatment of prostate cancer may be used clinically in persons for whom return to fertility after such treatment is important or desirable. The purpose of this study was, therefore, to evaluate the effects of a long term treatment with orntide, a GnRH antagonist, on testosterone levels and fertility in male rats. METHODS: Two groups of male rats received either 120-day orntide microspheres (8.8 mg orntide/kg/120 days) or vehicle alone (control group). Serum orntide and testosterone levels in both groups were monitored at certain intervals for 9 months from the initiation of treatment. After recovery of normal serum testosterone levels in the treated animals, each rat was housed with two proven breeder, but drug-naive, females. RESULTS: All mates of treated rats achieved pregnancy as rapidly as the mates of control rats although two of the control rats did not sire a litter with either female and one sired only one litter. The mean size of the litters of treated (12.3 offspring per litter) and control (10.6 offspring per litter) were similar. All offspring were grossly normal morphologically and behaviorally during the time to weaning. CONCLUSIONS: These results suggest that lack of fertility due to testosterone suppression is reversible after cessation of treatment with this GnRH antagonist

Expression of V1A and GRP receptors leads to cellular transformation and increased sensitivity to substance-P analogue-induced growth inhibition.

Small-cell lung cancer (SCLC) is a particularly aggressive cancer, which metastasises early. Despite initial sensitivity to radio- and chemo-therapy, it invariably relapses, so that the 2-year survival remains less than 5%. Neuropeptides particularly arginine vasopressin (AVP) and gastrin-releasing peptide (GRP) act as autocrine and paracrine growth factors and the expression of these and their receptors are a hallmark of the disease. Substance-P analogues including [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance-P (SP-D) and [Arg6,D-Trp7,9,NmePhe8]-substance-P (6-11) (SP-G) inhibit the growth of SCLC cells by modulating neuropeptide signalling. We show that GRP and V1A receptors expression leads to the development of a transformed phenotype. Addition of neuropeptide provides some protection from etoposide-induced cytotoxicity. Receptor expression also leads to an increased sensitivity to substance-P analogue-induced growth inhibition. We show that SP-D and SP-G act as biased agonists at GRP and V1A receptors causing blockade of Gq-mediated Ca2+ release while directing signalling to activate ERK via a pertussis toxin-sensitive pathway. This is the first description of biased agonism at V1A receptors. This unique pharmacology governs the antiproliferative properties of these agents and highlights their potential therapeutic potential for the treatment of SCLC and particularly in tumours, which have developed resistance to chemotherapy

Role of PACAP and VIP Signalling in Regulation of Chondrogenesis and Osteogenesis

Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are multifunctional proteins that can regulate diverse physiological processes. These are also regarded as neurotrophic and anti-inflammatory substances in the CNS, and PACAP is reported to prevent harmful effects of oxidative stress. In the last decade more and more data accumulated on the similar function of PACAP in various tissues, but its cartilage- and bone-related presence and functions have not been widely investigated yet. In this summary we plan to verify the presence and function of PACAP and VIP signalling tool kit during cartilage differentiation and bone formation. We give evidence about the protective function of PACAP in cartilage regeneration with oxidative or mechanically stress and also with the modulation of PACAP signalling in vitro in osteogenic cells. Our observations imply the therapeutic perspective that PACAP might be applicable as a natural agent exerting protecting effect during joint inflammation and/or may promote cartilage regeneration during degenerative diseases of articular cartilage

Occurrence and Functions of PACAP in the Placenta

Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous neuropeptide with a widespread distribution both in the nervous system and peripheral organs. The peptide is also present in the female gonadal system, indicating its role in reproductive functions. While a lot of data are known on PACAP-induced effects in oogenesis and in the regulation of gonadotropin secretion at pituitary level, its placental effects are somewhat neglected in spite of the documented implantation deficit in mice lacking endogenous PACAP. The aim of the present review is to give a brief summary on the occurrence and actions of PACAP and its receptors in the placenta. Radioimmunoassay (RIA) measurements revealed increased serum PACAP levels during the third trimester and several changes in placental PACAP content in obstetrical pathological conditions, further supporting the function of PACAP during pregnancy. Both the peptide and its receptors have been shown in different parts of the placenta and the umbilical cord. PACAP influences blood vessel and smooth muscle contractility of the uteroplacental unit and is involved in regulation of local hormone secretion. The effects of PACAP on trophoblast cells have been mainly studied in vitro. Effects of PACAP on cell survival, angiogenesis and invasion/proliferation have been described in different trophoblast cell lines. PACAP increases proliferation and decreases invasion in proliferative extravillous trophoblast cells, but not in primary trophoblast cells, where PACAP decreased the secretion of various angiogenic markers. PACAP pretreatment enhances survival of non-tumorous primary trophoblast cells exposed to oxidative stress, but it does not influence the cell death-inducing effects of methotrexate in proliferative extravillous cytotrophoblast cells. Interestingly, PACAP has pro-apoptotic effect in choriocarcinoma cells suggesting that the effect of PACAP depends on the type of trophoblast cells. These data strongly support that PACAP plays a role in normal and pathological pregnancies and our review provides an overview of currently available experimental data worth to be further investigated to elucidate the exact role of this peptide in the placenta

Development of the burden of citizens on housing expenditure in Czech Republic

Cílem práce je analýza vývoje zatížení občanů ČR výdaji na bydlení, zejména v sektoru vlastnického bydlení. Teoretická část obsahuje teoretická východiska ekonomiky bydlení, literární rešerši témat jako je bydlení, bytový fond, sociální bydlení, či koncepce bytové politiky. K provázanosti s praktickou částí přispívá teoretická kapitola o vývoji bytové výstavby v ČR. Praktická část pomocí analýzy a srovnání ukazuje, že za růstem cen vlastnického bydlení nestály ceny stavebních materiálů, ale faktory jako vstup ČR do EU, silné populační vlny, cenová bublina kolem roku 2007, zájem zahraničních investorů, či stěhování lidí z venkova do měst. Ceny rostou, protože na výkyvy poptávky není možné rychle a pružně reagovat navýšením nabídky, neboť výstavba bytových projektů je v ČR dlouholetý proces. Občané ČR byli zatíženi výdaji na vlastnické bydlení nejvíce v období kolem roku 2008. Nejméně naopak v letech 2011–2016. Poté zatížení opět roste vzhledem k nedostatečné intenzitě bytové výstavby. Vlastnického bydlení si lze dnes „pořídit“ za průměrnou hrubou měsíční mzdu o něco méně než v roce 2005, zatímco potravin o 23 % více, položek z oblasti dopravy o 60 % více a obuvi a oděvů dokonce o 70 % více.The aim of the thesis is to analyze the development of the burden of Czech citizens on housing expenditure, especially in the house ownership sector. The theoretical part contains the theoretical starting points of housing economy, literary research of topics such as housing, housing fund, social housing, or the concept of housing policy. The theoretical chapter on the development of housing construction in the Czech Republic contributes to the practical part. The practical part, through analysis and comparison, shows that the rise in prices of apartments was not caused by the rise in prices of building materials, but by factors such as the Czech Republic's entry into the EU, strong population waves, the price bubble around 2007, the interest of foreign investors, or the migration of people from rural areas to cities. Prices rise as demand fluctuations can not be quickly and flexibly responded by increasing supply, as the construction of housing projects is a long-term process in the Czech Republic. Citizens of the Czech Republic were burdened most with the home ownership in the period around 2008. On the contrary, least in 2011-2016. Then the load grows again due to the insufficient intensity of housing construction. If we consider the growth of the average gross monthly wage since 2005, it can be said that we can buy little less of housing today, while 23 % more food, 60% more transport items and shoes and clothes even 70 % more

Pelvic pain in endometriosis: Painkillers or sport to alleviate symptoms?

To assess potential individual factors influencing quality of life and pain scores of patients suffering from histologically confirmed endometriosis. Study using a questionnaire among patients of reproductive age undergoing laparoscopy with a presumed diagnosis of endometriosis. Details of fertility, previous treatments and quality of life, sexual activity, as well as linear pain scores for several symptoms, were recorded. Details of intraoperative findings were also collected and only those data were used where endometriosis was intraoperatively and histologically proven. A questionnaire before surgery gathered information from women on the following groups of variables: age, marital status, education, reproductive and medical history including previous pregnancies and parity, knowledge of accompanying pelvic disorders, regular sport activity, as well as general quality of life estimates including self-image. Pelvic pain was scored using a visual analogue scale. Data were statistically evaluated. Eighty-one patients complaining about persistent pelvic pain were later intraoperatively and histologically proven to have endometriosis. Thirty-one of them (38.2%) reported regular sport as part of their daily life schedule while 50 of them (61.8%) performed no physical activity at all. Fourteen patients among regular exercisers and 33 patients among those without physical activity reported the effectiveness of painkillers for pelvic pain, corresponding to 45.1% and 66% of these subgroups, respectively (difference statistically significant, p<0.05). Based on our results, we can conclude, that taking painkillers might be less effective among endometriosis patients performing regular daily sport activities, and, thus it might impose them to an unnecessary burden of possible side-effects

Environmental Enrichment Decreases Asphyxia-Induced Neurobehavioral Developmental Delay in Neonatal Rats

Perinatal asphyxia during delivery produces long-term disability and represents a major problem in neonatal and pediatric care. Numerous neuroprotective approaches have been described to decrease the effects of perinatal asphyxia. Enriched environment is a popular strategy to counteract nervous system injuries. The aim of the present study was to investigate whether enriched environment is able to decrease the asphyxia-induced neurobehavioral developmental delay in neonatal rats. Asphyxia was induced in ready-to-deliver mothers by removing the pups by caesarian section after 15 min of asphyxia. Somatic and neurobehavioral development was tested daily and motor coordination weekly. Our results show that rats undergoing perinatal asphyxia had a marked developmental delay and worse performance in motor coordination tests. However, pups kept in enriched environment showed a decrease in the developmental delay observed in control asphyctic pups. Rats growing up in enriched environment did not show decrease in weight gain after the first week and the delay in reflex appearance was not as marked as in control rats. In addition, the development of motor coordination was not as strikingly delayed as in the control group. Short-term neurofunctional outcome are known to correlate with long-term deficits. Our results thus show that enriched environment could be a powerful strategy to decrease the deleterious developmental effects of perinatal asphyxia

Inhibition of the UCI‐107 human ovarian carcinoma cell line by a targeted cytotoxic analog of somatostatin, AN‐238

BACKGROUND Cytotoxic analogs of somatostatin (SST), such as AN‐238, which consists of 2‐pyrrolinodoxorubicin (AN‐201) linked to the SST carrier RC‐121, can be targeted to tumors that express SST receptors. Because SST receptors are present in ovarian carcinoma cells, the authors evaluated the effect of AN‐238 on the UCI‐107 ovarian carcinoma cell line. METHODS An analysis of microsatellite alleles in cocultured SST receptor positive and receptor negative cells was used for the demonstration of in vitro targeting. The toxicity and antitumor effects of AN‐238 in nude mice bearing UCI‐107 human ovarian tumors were investigated with or without pharmacologic inhibition of serum carboxylesterases (CE). The expression of SST receptor subtypes was determined by reverse transcriptase‐polymerase chain reaction analysis, and the binding affinity of AN‐238 to SST receptors was determined by radioligand assays. RESULTS The proliferation of SST receptor positive UCI‐107 cells in vitro was inhibited preferentially by AN‐238. AN‐238 showed high‐affinity binding to UCI‐107 tumor membranes at a 50% inhibition concentration of 3.39 nM ± 0.74 nM. In vivo, the volume and weights of UCI‐107 tumors treated with AN‐238 were decreased by more than 60% (P < 0.05) compared with controls. Cytotoxic radical AN‐201 or the unconjugated mixture of AN‐201 with carrier RC‐121 had no significant effects on tumors and were toxic. In mice with inhibited serum CE activity, AN‐201 at 400 nmol/kg was lethal, whereas AN‐238 at a total dose of 800 nmol/kg caused only 22% mortality and reduced tumor weight by 69% and volume by 70% (P < 0.05 vs. control). CONCLUSIONS Targeted chemotherapy with the SST conjugate AN‐238 inhibits SST receptor positive experimental ovarian tumors. AN‐238 may provide a new treatment modality for patients with advanced ovarian carcinoma. Cancer 2001;92:1168–76. © 2001 American Cancer Society. The effectiveness and toxicity of the targeted, cytotoxic analog of somatostatin, AN‐238, was evaluated in a UCI‐107 model of human ovarian carcinoma cells. The study demonstrates that AN‐238 inhibits the growth of ovarian carcinoma cells that express somatostatin receptors, whereas its cytotoxic radical, 2‐pyrrolinodoxorubicin (AN‐201), is ineffective and toxic

Source of Sustained Voltage Difference between the Xylem of a Potted Ficus benjamina Tree and Its Soil

It has long been known that there is a sustained electrical potential (voltage) difference between the xylem of many plants and their surrounding soil, but the mechanism behind this voltage has remained controversial. After eliminating any extraneous capacitive or inductive couplings and ground-mediated electric current flows, we have measured sustained differences of 50–200 mV between the xylem region of a Faraday-caged, intact, potted Ficus benjamina tree and its soil, as well as between its cut branches and soils and ionic solutions standardized to various pH values. Using identical platinum electrodes, no correlation between the voltage and time of day, illumination, sap flow, electrode elevation, or ionic composition of soil was found, suggesting no direct connection to simple dissimilar-metal redox reactions or transpirational activity. Instead, a clear relationship between the voltage polarity and magnitude and the pH difference between xylem and soil was observed. We attribute these sustained voltages to a biological concentration cell likely set up by the homeostatic mechanisms of the tree. Potential applications of this finding are briefly explored