Presynaptic effects of moxonidine in isolated buffer perfused rat hearts: role of imidazoline-1 receptors and alpha2-adrenoceptors

Numerous studies support the concept that centrally acting antihypertensive drugs, such as imidazolines, mediate sympathoinhibition not only via activation of central nervous alpha2-adrenoceptors (alpha2-AR) but also via imidazoline-1 receptors (I1-R). An additional presynaptic involvement in sympathetic neurotransmission of imidazolines, via I1-R independent of alpha2-AR, is still controversial and remains to be clarified in the heart. Concentration response curves on endogenous norepinephrine (NE) overflow evoked by stimulation of epicardial postganglionic sympathetic nerves in isolated buffer-perfused rat hearts were performed for brimonidine, moxonidine, rauwolscine, 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane (AGN192403), and efaroxan. To unmask an I1-R-mediated effect of moxonidine, hearts were pre-exposed in additional experiments with brimonidine or rauwolscine with or without AGN192403 or efaroxan, respectively. Moxonidine reduced stimulated NE overflow (log EC50: -6.15 +/- 0.14). AGN192403, a selective ligand at I1-R, had no influence on the dose-response curve of moxonidine (log EC50: -6.01 +/- 0.25). After pre-exposure to brimonidine [ stimulation 1 (S1) + stimulation 2 (S2); 10(-5) M], the inhibitory action of moxonidine was potentiated compared with control (32.0 +/- 2.8 versus 73.13 +/- 3.0%) and completely abolished with AGN192403 or efaroxan. This effect was also totally inhibited by pre-exposure with indomethacin (10(-7) M) and tricyclodecan-9-yl-xanthogenate (D-609), an inhibitor of phosphatidylcholine-selective phospholipase C (PC-PLC; 10(-7) M). Conversely, moxonidine was without modulating efficacy under alpha2-AR-blockade by rauwolscine. In summary, we demonstrate that moxonidine reduces NE release independently of I1-R, demonstrating the prominent effect of alpha2-AR in cardiac tissue under basal conditions. We also demonstrate that I1-R are involved in NE release under conditions of alpha2-AR-stimulation involving both a pathway of prostaglandins and PC-PLC.     

The monoclonal antibody GZS-1 detects a maturation-associated antigen of human spermatozoa that is also present on the surface of human mononuclear blood cells

A monoclonal antibody (GZS-1) has been generated by fusion of mouse myeloma cells with spleen cells from BALB/c mice immunised with human sperm cells. The antibody was determined to be an IgG₁. The corresponding antigen is present on the whole surface of ejaculated human spermatozoa. It is not detectable on spermatozoa of other mammalian species (rabbit, cat, dog, sheep, boar, bull, horse). In human male genital organs, immunostaining with GZS-1 is observed on sperm cells in the epididymis and the ductus deferens together with the lining epithelium of those organs. No reactivity of sperm cells or germ cell precursors in the testis has been detected. Functional tests using the antibody show a strong inhibitory effect on human sperm in the hamster egg penetration assay. Furthermore, the GZS-1 antigen is detectable on the surface of human lymphocytes and monocytes by immunogold electron microscopy and FACS analysis. By Western blotting of human sperm and seminal plasma performed under reducing conditions immunostaining was detected at 21–25, 31, 51–54, and 62 kDa. The reaction with human lymphocytes shows one major band at 62 kDa and additional bands at 31 and 54 kDa. The results suggest that the monoclonal antibody GZS-1 may recognise an antigen which is secreted from the epithelial cells of the epididymis and binds to ejaculated spermatozoa as a sperm coating antigen. This component may be involved in the capacitation of the sperm and the acrosome reaction. Molecules that are expressed both on sperm and on immunocompetent cells may be relevant for the regulation of immunological processes or for the development of the related immunological tolerance of sperm in the female reproductive tract.     

Three-dimensional controlled interstitial hyperthermia combined with radiotherapy for locally advanced prostate carcinoma--a feasibility study

PURPOSE: To perform a feasibility study of three-dimensional spatially controlled interstitial hyperthermia for locally advanced prostate cancer. METHODS AND MATERIALS: Twelve patients with prostate cancer (T3NxM0) were treated with conventional external beam radiotherapy and one interstitial hyperthermia treatment. Hyperthermia was delivered with the 27-MHz multielectrode current source (MECS) interstitial hyperthermia technique on an outpatient basis. Guided by transrectal ultrasonography, 12 catheters (range 7-16) were placed in the prostate through a template. Two electrodes per probe were inserted. Thermometry (average 100 sensors) was performed from within the probes for online temperature control. Additional thermometry was done in the prostate, rectum, urethra, and bladder. Reconstruction was done by sonography. Prostate perfusion was estimated from the thermal decay at the end of treatment. The full three-dimensional temperature distribution was calculated. RESULTS: No toxicities greater than Grade 2 were recorded. A learning curve for implantation, position verification, reconstruction, and temperature simulation was experienced. Perfusion was 47 mL/100 g/min (range 30-65). The average measured temperature was T(90) (90% of the prostate reached a temperature of at least:) 39.9 degrees C and T(50) 44.1 degrees C. The average calculated temperatures were lower: T(90), 39.4 degrees C and T(50), 41.8 degrees C, because the entire prostate was taken into account. The tumor temperatures were T(90), 40.7 degrees C and T(50), 43.0 degrees C. The bladder and rectal temperatures were below the safety limits. CONCLUSION: Multielectrode-current-source interstitial hyperthermia is technically feasible and well tolerated. It was not possible to achieve the goal temperature of 42-43 degrees C because of high perfusion and implantation limitations.     

The meaning of acute confusional state from the perspective of elderly patients

OBJECTIVES: The aim of this study was to illuminate lived experience of having been in an acute confusional state (ACS) as narrated by elderly patients in orthopaedic care. METHOD: Qualitative study with phenomenological hermeneutic method for analysing the data based on narrative interviews. Fifty patients (67-96 years of age) who developed ACS during hospitalisation and in all cases the ACS ceased during their stay on the ward were interviewed once lucid again regarding the course of the event, their experiences, memories and interpretation of what had happened during the ACS. RESULTS: The meaning of the patients' lived experiences of being and having been confused was interpreted as 'Being trapped in incomprehensible experiences and a turmoil of past and present and here and there', comprising the themes trying to get a grip on the experience of the confusion, encountering past, present and the realm of the imagination as reality during the period of confusion and confronting the idea of having been confused. Contradictory to earlier research the patients remembered and could tell in great detail about their ACS. While confused, the confusional state means that impressions of all kinds invade the mind of the person and are experienced as reality, making him/her a victim of these impressions rather than the one who controls what comes into his/her mind. While in the middle of these experiences the person simultaneously senses that the impressions are unreal, thus indicating that he/she is in some sort of borderland between understanding and not understanding. The things that come into the mind of the person can either be frightening or neutral or enjoyable scenarios that seem to be mainly familiar but can also be unknown. These scenarios seem to be a mixture of past and present, of events and people while they seem to float from location to location. CONCLUSIONS: The findings indicates that what takes place during the ACS is not nonsense but probably a mix of the patient's life history, their present situation and above all a form of communication concerning their emotional state and inner experiences in this new situation. The findings also indicated that one possible approach to the patients is to confirm and support the patients in narrating their experiences both during the confusion and also after the ACS had ceased.     

Influence of subchronic administration of oestrone-3-O-sulphamate on oestrone sulphatase activity in liver, spleen and white blood cells of ovariectomized rats

Inhibition of oestrone sulphatase followed by oestrogen removal from tumour cells may be a new form of endocrine therapy of breast cancer in women. We investigated the inhibitory effect of the subchronic administration of oestrone-3-O-sulphamate (EMATE), a steroid sulphatase inhibitor, to ovariectomized rats, to evaluate this method for testing new nonsteroidal inhibitors. EMATE in DMSO was administered both orally and subcutaneously (s.c.) for 7 days at doses of 0.5 and 2.5 mg/kg. In addition the rats were injected s.c. with 0.5 mg oestrone sulphate/kg 26 and 2 h before decapitation under ether anaesthesia. Oestrone sulphatase activity (ESA) was measured radiometrically using [3H]oestrone sulphate as substrate for desulphuration in white blood cells, liver homogenate, microsomes and spleen homogenate. ESA in liver microsomes was found to be nearly 40 times higher than in white blood cells while in spleen ESA was nearly half of that found in liver homogenates and white blood cells. ESA can be inhibited by EMATE down to 50-1.5% of control activity depending on the dose and administration route. The inhibition was in the order, liver homogenate < spleen < liver microsomes < white blood cells, and was more pronounced after s.c. administration of the inhibitor than after oral administration. Ovariectomy was found to be not necessary for oestrone sulphatase-inhibiting studies. Two sequential s.c. injections of oestrone sulphate enhanced the enzyme activities significantly in liver and white blood cells, but not in spleen. In conclusion, white blood cells and liver microsomes of intact female rats can be used for ESA-inhibiting studies. Sulphate-conjugated oestrone can induce oestrone sulphatase in vivo in liver and white blood cells thereby enhancing oestrogen supply in the peripheral organs.     

Pindolol augmentation in patients with treatment-resistant panic disorder: A double-blind, placebo-controlled trial

The objective of this study was to determine the efficacy of pindolol as an augmentor of fluoxetine in treatment-resistant panic disorder (PD). Twenty-five outpatients having PD with or without agoraphobia were included. These patients had not responded to two different trials with antidepressants and an 8-week trial of fluoxetine 20 mg/day. Treatment-resistant PD was defined as a less than 20% reduction in score on the Panic Self-Questionnaire (number of attacks per week) (PSQ) and the Clinical Anxiety Scale With Panic Attacks (CAS+PA). These patients continued to receive fluoxetine 20 mg/day and were randomly assigned to additionally receive either pindolol (2.5 mg three times daily) or placebo for the following 4 weeks. Evaluations were performed weekly using the Hamilton Rating Scale for Anxiety, the Hamilton Rating Scale for Depression (HAM-D), the CAS+PA, the NIMH Anxiety Scale, the PSQ, and the Clinical Global Impression Scale. The data were analyzed using a repeated-measures analysis of variance (ANOVA) and a t-test for independent samples. Patients treated with the combination of pindolol and fluoxetine (N = 13) demonstrated a significant improvement over the patients treated with fluoxetine and placebo on all rating scales, with the exception of HAM-D. The statistical differences were shown using the repeated-measures ANOVA (baseline, week 2, week 4) and also with t-tests from the second week of the trial. These preliminary results demonstrate that pindolol has an augmenting effect on fluoxetine in patients with treatment-resistant PD.