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An integrated model for the regulation of glucose and insulin concentrations following intravenous glucose provocations in healthy volunteers and type 2 diabetic patients was developed. Data from 72 individuals were included. Total glucose, labeled glucose, and insulin concentrations were determined. Simultaneous analysis of all data by nonlinear mixed effect modeling was performed in NONMEM. Integrated models for glucose, labeled glucose, and insulin were developed. Control mechanisms for regulation of glucose production, insulin secretion, and glucose uptake were incorporated. Physiologically relevant differences between healthy volunteers and patients were identified in the regulation of glucose production, elimination rate of glucose, and secretion of insulin. The model was able to describe the insulin and glucose profiles well and also showed a good ability to simulate data. The features of the present model are likely to be of interest for analysis of data collected in antidiabetic drug development and for optimization of study design.

Background: Allergic asthma is associated with an increased number of eosinophils in the airway wall. Eosinophils secrete cationic proteins, particularly major basic protein (MBP)., Aim: To investigate the effect of synthetic cationic polypeptides such as poly-L-arginine, which can mimic the effect of MBP, on airway epithelial cells., Methods: Cultured airway epithelial cells were exposed to poly-L-arginine, and effects were determined by light and electron microscopy., Results: Poly-L-arginine induced apoptosis and necrosis. Transmission electron microscopy showed mitochondrial damage and changes in the nucleus. The tight junctions were damaged, as evidenced by penetration of lanthanum. Scanning electron microscopy showed a damaged cell membrane with many pores. Microanalysis showed a significant decrease in the cellular content of magnesium, phosphorus, sodium, potassium and chlorine, and an increase in calcium. Plakoglobin immunoreactivity in the cell membrane was decreased, indicating a decrease in the number of desmosomes, Conclusions: The results point to poly-L-arginine induced membrane damage, resulting in increased permeability, loss of cell-cell contacts and generalized cell damage.

Although hypertension is recognised as one of the major health hazards in the developed world, compliance with antihypertensive regimens is still undesirably low. This brings important costs, both to patients in increased morbidity and mortality, and to society in hospitalisations and lost productivity. This review surveys possible reasons for non-compliance with treatments generally and antihypertensive medications specifically. It also looks at how insights into reasons for non-compliance can help us design more effective treatments, and discusses current and emerging medications in the context of compliance. As one of the reasons for low compliance is thought to be the impact of a drug on the patient's lifestyle, recently developed agents such as angiotensin II-receptor blockers may be expected to have less effect on patients' daily lives than earlier treatments, which brings hope for increased compliance with these regimens.

Background: Etoposide-induced apoptosis in prostate carcinoma cells is associated with changes in the elemental content of the cells. The authors previously reported that calcitonin and bombesin inhibited etoposide-induced apoptosis in these cells. In the current study, the authors investigated whether these neuropeptides block the etoposide-induced changes in elemental content., Methods: Cells from the PC-3 and Du 145 prostate carcinoma cell lines were grown either on solid substrates or on thin plastic films on titanium electron microscopy grids, and they were exposed to etoposide for 48 hours in the absence or presence of calcitonin and bombesin. After the exposure, the cells were frozen and freeze dried, and their elemental content was analyzed by energy-dispersive X-ray microanalysis in both in the scanning electron microscope and the scanning transmission electron microscope., Results: Etoposide treatment consistently induced an increase in the cellular Na concentration and a decrease in the cellular K concentration, resulting in a marked increase of the Na/K ratio and also an increase in the phosphorus:sulphur (P/S) ratio. Both bombesin and calcitonin inhibited the etoposide-induced changes in the cellular Na/K ratio, and calcitonin, but not bombesin, inhibited the changes in the P/S ratio. No significant elemental changes were found with bombesin or calcitonin alone., Conclusions: The neuropeptides bombesin and calcitonin, which inhibited etoposide-induced apoptosis, also inhibited the etoposide-induced elemental changes in prostate carcinoma cells. This important fact strengthens the link between apoptosis and changes in the intracellular elemental content. This correlation provides an objective basis for the study of neuropeptide target points and may be helpful for alternative therapeutic protocols using neuropeptide inhibitors in the treatment of patients with advanced prostatic carcinoma.

Background: This report comprises women from one center, who all participated in a larger European multi-center study, which included 2758 healthy women, of whom 1821 were randomly allocated to the levonorgestrel-releasing intrauterine system (Lng-IUS) and 937 to a copper-IUD (Nova-T). At the end of the 5 year study period, 109 of the 300 women, who originally were allocated to the Lng-IUS at this center, were still using the Lng-IUS. The women were offered the opportunity to continue the Lng-IUS and 100 women chose to do so. After a total period of almost 7 years of continuous use, a second Lng-IUS was offered and 82 of the women chose to start a second segment of Lng-IUS use. After another 5 years, 69 of the women were fitted with their third Lng-IUS., Methods: These 82 women were examined yearly throughout the study period and bleeding pattern, hemoglobin, weight, blood-pressure, general well-being and intercurrent disease were analyzed to assess long-term effects., Results: No pregnancy occurred during the follow-up. One case of partial expulsion occurred and one case of pelvic inflammatory disease. Seventy-seven percent of the women did not report any health problems at all during the entire follow-up period of 13 years. At the end of the second period with the Lng-IUS, 60% reported amenorrhea, 12% infrequent, scanty bleeds and 28% regular, scanty bleeds. As a consequence, the hemoglobin values increased, with a mean increase, after 12-13 years, being 1.35 g/dl. Blood pressure increased slightly and body weight increased with a mean increase of 0.49 kg/year. Seven women became postmenopausal during the follow-up and started estrogen replacement therapy with the Lng-IUS in situ., Conclusions: This follow-up study suggests that the Lng-IUS remains a safe and effective method of contraception, allowing women prolonged relief of menstrual problems, and for women in their late reproductive years, offering a convenient and bleeding-free transition into the menopause.

Psychosocial functioning was assessed in 26 subjects treated with autologous bone marrow transplantation (ABMT) for leukaemia or lymphoma before the age of 18 years. The median time from ABMT was 7 years (range 2-10 years), and the median age of the subjects at the evaluation was 16 years (range 7-24 years). Patients, parents and teachers were used as informants. Parents of subjects in the ABMT group reported more behaviour problems than in a normative sample of school children, in particular of the internalising problem type, a finding also supported by the teachers' report on the children's behaviour at school. The magnitude of the behaviour problems correlated positively to CNS treatment intensity. The parents rated their children's school competence as lower than did parents of a normative sample. All school children (n = 18) were in regular education, although five pupils were receiving individual tutorial help. Overall, the patients reported a positive view on their own functioning, in contrast to the higher levels of psychosocial problems reported by their parents and teachers. The results thus show, that the psychosocial functioning seen in children treated because of cancer is dependent on the type of informant used.

Background: Locally advanced breast carcinoma is associated with a poor prognosis. With single treatment modalities, i.e., surgery and/or radiation therapy, results have been consistently dismal. However, several earlier reports have indicated improvement in survival with a combined modality approach, i.e., the utilization of systemic therapy., Methods: Between 1991 and 1994, 128 patients with locally advanced noninflammatory or inflammatory breast carcinoma (LABC) were treated with a combined modality strategy consisting of 4-6 courses of preoperative 5-fluorouracil (600 mg/m2), epirubicin (60 mg/m2), and cyclophosphamide (600 mg/m2) (FEC) every 3 weeks, followed by modified radical mastectomy or sector resection with axillary dissection in combination with postoperative radiotherapy and concomitant cyclophosphamide (850 mg/m2). Postoperatively, 3-5 adjuvant courses of FEC therapy were given. Nine percent of the patients received preoperative radiotherapy because the FEC therapy was not sufficiently effective. One-third of the patients were given tamoxifen (20 or 40 mg daily) at the end of the multimodal therapy., Results: Clinical responses were observed in 60% of the patients; 5% had complete responses (CR) and 55% had partial responses (PR). Stable disease (SD) was observed in 40%. No patient had progressive disease (PD) preoperatively. With a median follow-up of 37 months, the median disease free survival (DFS) and median overall survival (OS) were 29 and 54 months, respectively. The actuarial 5-year DFS and OS were 36% and 49%, respectively. The locoregional recurrence rate was 20%, and 53% of the patients experienced systemic relapse. Univariate analysis revealed a significant prognostic difference according to clinical stage of LABC in favor of less advanced stages. Clinical and biologic parameters linked to a significantly worse prognosis were the presence of inflammatory breast carcinoma and peau d'orange. There was a significant trend of worse prognosis for patients receiving below 60% and 75% of the intended dose intensity with reference to DFS and OS, respectively., Conclusions: Standard dose preoperative and postoperative FEC therapy combined with surgery and radiotherapy in the era of mammography screening seem to yield results comparable to those achieved with other conventional strategies in the treatment of unscreened populations.

In this study, patterns of analgesic use among persons with headache in the general Swedish population were analyzed in association with health factors, health care utilization, sociodemographic factors, and life-style. Data from the Swedish Survey of Living Conditions for the 2-year period 1988 through 1989 were used. In this survey, a probability sample of the Swedish population aged 16 years and older was interviewed. Persons with headache were identified by the question, "Have you (during the last 2 weeks) had recurrent headache or migraine?" Analgesic use was defined by the question, "Have you (during the last 2 weeks) used prescription or nonprescription analgesics?" Persons who answered both these questions were included in the present study, yielding a study population of 11,975 persons. Sixteen percent of all women and 8.2 percent of all men reported headache. Seventy-four percent of all women with headache reported analgesic use as compared to 64% of all men with headache. Analgesic use increased with increasing age among women but not men. While few of the studied factors were associated with analgesic use among persons with headache, the associations found differed by gender. Poor social network and musculoskeletal pain were associated with analgesic use among men with headache; age, being underweight, and visits to a physiotherapist were associated with analgesic use among women with headache. Those studying medication use among persons with headache might consider including these factors in future studies to help better understand the mechanisms behind the decision to use or avoid analgesics.

Headache is a common health problem that causes individual suffering as well as public expense. Because epidemiological studies have shown that headache is most prevalent among persons younger than 55 years, the influence of working conditions is of interest. In this study, we examined the importance of working conditions as a risk factor for frequent headache among the general Swedish population. Data from the Swedish Survey of Living Conditions for the 2-year period, 1988 and 1989, were used. In this survey, a probability sample of the Swedish population aged 16 years and older was interviewed. Frequent headache was defined as a positive answer to the question, "Have you (during the last 2 weeks) had recurrent headache or migraine?" Work stress was studied for two indices: physical work stress and mental work stress. The physical work stress index contained measurements of seven working conditions, and the mental work stress index contained measurements of three working conditions. The proportion of persons who reported frequent headache was greater among women than men, and frequent headache was most common in the age group 25 to 44 years. The logistic regression analyses showed that both physical and mental work stress were strongly associated with frequent headache among both men and women even after controlling for potential confounders. The associations between work stress and frequent headache may be dose-dependent. Heavy mental work stress was most strongly associated with frequent headache among men (odds ratio 3.03 [1.92 to 4.78]) while heavy physical work stress was most strongly associated with frequent headache among women (odds ratio 3.48 [1.13 to 10.65]). Improved working conditions could be one way of preventing headache, thereby decreasing individual suffering and employer as well as public expense.

Objectives: The primary objective was to investigate the effective permeability and the hepatic extraction of fluvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, during a jejunal perfusion in humans. The secondary objective was to investigate the relationship between human jejunal effective permeability values and physicochemical properties for four different drugs., Methods: Nine healthy male volunteers were included in the study, which consisted of two sequential study parts. In the first part, the jejunal effective permeability of fluvastatin, antipyrine, metoprolol, and atenolol was assessed with use of the regional jejunal perfusion approach (150 minutes, 2.0 ml/min). After a washout period of at least 5 days, the same subjects received an intravenous infusion of fluvastatin (20 minutes, 2.0 mg). Plasma samples were taken in both parts of the study and were analyzed for the content of fluvastatin., Results: The mean hepatic extraction of fluvastatin was 67% after the jejunal perfusion and 73% after the intravenous infusion. The half-life of fluvastatin was approximately 60 minutes after both administration routes. The jejunal effective permeability and the fraction absorbed both correlated (r2 = 0.968, p < 0.05; and r2 = 0.994, p < 0.05) with the partition coefficient (log D, pH 6.5) but not with the molecular size or the hydrogen bond number., Conclusion: Fluvastatin is extracted by the liver to a large extent (about 70%) and has a short half-life after both oral and intravenous administration. In this study, the human jejunal effective permeability and the fraction absorbed for these four drugs were better predicted by log D (pH 6.5) than both the molecular size and the hydrogen bond number.

Hyaluronan is a major component of synovial tissue and fluid as well as other soft connective tissues. It is a high-Mr polysaccharide which forms entangled networks already at dilute concentrations (< 1 mg/mL) and endows its solutions with unique rheological properties. Physiological functions of hyaluronan (lubrication, water homeostasis, macromolecular filtering, exclusion, etc.) have been ascribed to the properties of these networks. Recently a number of specific interactions between hyaluronan and a group of proteins named hyaladherins have also pointed towards a role of hyaluronan in recognition and the regulation of cellular activities. Many more or less well documented hypotheses have been proposed for the function of hyaluronan in joints, for example, that it should lubricate, protect cartilage surfaces, scavenge free radicals and debris, keep the joint cavities open, form flow barriers in the synovium and prevent capillary growth.

Continuous beds derivatized with three triazine dyes (Cibacron Blue 3G-A, Pricon Red HE-3B and Pricon Red H-3B) were used for chromatographic purification of dehydrogenases from yeast enzyme concentrate. All three columns, which were prepared by a very simple and cost-effective method, provided strong binding of glucose-6-phosphate dehydrogenase and lactate dehydrogenase. The Cibacron Blue 3G-A column showed high affinity for alcohol dehydrogenase. Under the same conditions, the Pricon Red HE-3B column showed a lower affinity and the Pricon Red H-3B column showed none. The adsorbed dehydrogenases were eluted specifically from the columns in high yields (71-113% by desorption with the coenzymes NADP, NADH and NAD respectively). Non-specific binding of human serum albumin and transferrin to these columns was also investigated. Enzyme assays and analyses by capillary electrophoresis showed that the continuous beds derivatized with triazine dyes gave a high degree of purification.

Objective: To study the predictive value of the history of genital pain, psychiatric complaints and menstrual symptoms on a woman's sexual life before and after subtotal hysterectomy., Material and Method: One hundred and four premenopausal women were interviewed one month before and one year after surgery. A latent variable for pre- and postoperative sexuality was constructed from the intercorrelation between the measured parameters of frequency of desire for sex, coital frequency, cyclicity of desire and existence of multiple orgasm, and other variables for genital pain, psychiatric morbidity and menstrual symptoms were compared to the latent factors for sexuality., Results: No difference was seen in postoperative sexuality in women with and without a history of psychiatric complaints. The regular use of analgetics, a need to stay home from work because of menstruation, and the occurrence of dyspareunia were positively correlated to the latent factors for sexuality before and after the operation. A history of the need to use psychopharmaceuticals, such as sedatives or antidepressants, had a negative influence on preoperative, but not on postoperative sexuality. Dysmenorrhea had a positive influence on postoperative, but not on preoperative, sexuality., Conclusion: Among variables studied, dysmenorrhea was the best predictor for postoperative sexuality. That is: women with dysmenorrhea do not only invariably experience relief from the pain, but also have a chance to improve their sexual lives after removal of their malfunctioning uterus. Presence of psychiatric problems had, in general, little influence on sexuality.

An epoxy-activated continuous bed can be prepared for immobilization of proteins in a simple, rapid, and cost-effective way. The concentration of epoxy groups on the continuous bed was as high as 600 mumol/mL compressed bed (compression of the bed decreases the peak broadening). Human transferrin, human serum albumin and particularly urease were employed as model proteins. The immobilization of urease was virtually completed within 1 h in 1 M potassium phosphate, pH 7.4. The binding capacity was 97 mg of urease/mL compressed bed. This bed is of clinical interest, since it is inexpensive to prepare and permits reproducible enzymatic determination of urea in serum and urine (the chromatographic step is finished within 1-2 min).

Background: To increase the knowledge about the palliative effects of chemotherapy in patients with symptomatic advanced colorectal cancer, physician- and patient-rated "quality of life" was studied in a randomized multicenter trial comparing a regimen of methotrexate/5-fluorouracil (5-FU) followed by leucovorin rescue (MFL) with a regimen of 5-FU/leucovorin (FLV)., Methods: Between January 1989 and December 1990, 70 patients completed a quality of life questionnaire at randomization and after every fourth treatment course. At one of the hospitals, the evaluation was done as an interview (interview group, n = 24), whereas a questionnaire was used at the other hospitals (questionnaire group, n = 46)., Results: Objective responses (complete response plus partial response) were obtained in 15 (21%) patients, subjective responses in 29 (41%) patients, and an overall improved quality of life in 25 (36%) patients. In addition, 16 (23%) patients had unchanged quality of life during at least 4 months. There was a correlation between objective responses, subjective responses, and improvements in quality of life, although discrepancies were noticed, particularly in patients with only slight symptoms. Response rates were higher in the interview group than in the questionnaire group (P < 0.01). This difference could be related to a more favorable outcome when 5-FU was given as a bolus injection, rather than as a short-term infusion (more than 5 minutes)., Conclusions: Improvements or prolonged stabilization of disease in quality of life can be achieved in at least half of the patients with tumor-related symptoms. However, factors related to the administration of chemotherapy may influence this proportion.

First catch urine (FCU) from 751 asymptomatic adolescent female high school students, with sexual debut, were screened for the presence of Chlamydia trachomatis (Group A). The prevalence of C. trachomatis infection in Group A was 2.1% (16/751). In Group B, 619 asymptomatic adolescent females attending a youth and a family planning clinic were screened for C. trachomatis by testing FCU and cervical specimens. An enzyme immunoassay (IDEIA-III) was used to detect C. trachomatis verified by fluorescein isothiocyanate-conjugated (FITC) monoclonal antibodies. Only samples positive in both tests were regarded as true positive. The cervical samples from the women in Group B were positive in 7.8% (48/619), while the FCU were positive in 6.0% (37/619). Detection of C. trachomatis by EIA in FCU samples was found useful for screening females for genital chlamydial infection. The prevalence of C. trachomatis in an unselected asymptomatic population was found to be lower than in age-matched individuals seeking medical advice in the same coherent area.

A number of novel gene detection techniques all revolve around the ligation of synthetic nucleic acid probes. In such ligase-assisted gene detection reactions, specific DNA or RNA sequences are investigated by using them as guides for the covalent joining of pairs of probe molecules. The probes are designed to hybridize immediately next to each other on the target nucleic acid strand. Demonstration of ligated probes results in highly specific detection of and efficient distinction between similar sequence variants under standard reaction conditions. Accordingly, the principle has been applied in automated genetic screening procedures. Ligation reactions are also integral to a number of amplification procedures and they will be of value in an expanding range of genetic analyses.

1. The effects of 300 mg kg-1 of the nitric oxide (NO) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on the regional blood flow, on the flow response to 1 mg kg-1 of thyrotropin-releasing hormone (TRH) and on cerebral blood flow autoregulation were studied in urethane anesthetized rabbits subjected to unilateral sectioning of the cervical sympathetic claim. The blood flow measurements were performed by the tracer microspheres method. 2. The cerebral arteriovenous difference in oxygen saturation (CAVOD) was measured before and after the administration of L-NAME and TRH in order to ascertain whether the effects on cerebral blood flow that were observed were secondary to changes in cerebral metabolism. 3. L-NAME caused a significant decrease in blood flow in several cerebral regions; CBFtot decreased to 72 +/- 4% of control (P < 0.001). An increase in blood pressure and a concurrent decrease in heart rate and cardiac output were noted. 4. In the eye, L-NAME caused a reduction in uveal blood flow which was more pronounced on the sympathetically intact side; in the retina the blood flow decreased to 50% of control on both sides. 5. The administration of TRH in animals pretreated with L-NAME caused a significant increase in blood pressure and cerebral blood flow. 6. In L-NAME-treated animals the CBF was not affected when the mean arterial blood pressure was increased by ligation of the abdominal aorta. 7. The CAVOD increased from 56.0 +/- 5.2 to 73.6 +/- 3.5%, 20 min after the administration of L-NAME. In animals given 1 mg kg-1 TRH after L-NAME the CAVOD decreased to 54.6 +/- 4.6%, 5 min after the injection of TRH.8. The results of the present study indicate that endogenous NO is involved in the regulation of regional blood flow and blood pressure in the anaesthetized rabbit. The reduction in cerebral blood flow that was caused by L-NAME was not due to a reduction in cerebral metabolism. An interaction between the NO synthesis/release/effect and the sympathetic nervous system was found in the uvea. There was no evidence for a major involvement of NO in the cardiovascular responses to TRH and autoregulation of cerebral blood flow was not abolished by L-NAME.

The effects of dietary supplementation with n-3 fatty acids on lipid and glucose metabolism and on fibrinolysis were evaluated in 14 non-insulin-dependent diabetic patients who were given 10 g of MaxEPA (3 g n-3 fatty acids) or placebo (olive oil) per day in a randomized double-blind cross-over study during two consecutive 8-week periods. The serum triglyceride (TG) concentrations decreased by 27% (P < 0.01) after addition of MaxEPA with a reduction of VLDL TG by 36% (P < 0.05) while LDL cholesterol increased by 6% (P = 0.05). The fasting blood sugar and HbA1c concentrations increased significantly after addition of MaxEPA but the changes were not significantly different from those during the placebo period. The highest glucose concentrations at fasting and after an i.v. glucose injection were seen after MaxEPA while the serum insulin concentrations were unchanged. The peripheral insulin sensitivity, as measured by a euglycaemic, hyperinsulinaemic clamp technique, did not change during the study. The mean plasminogen inhibitor-1 (PAI-1) activity of the patients was elevated compared with healthy controls. In spite of the reduction of the triglyceride concentrations and unchanged insulin levels, there was a significant increase of the activity of PAI-1 (+21%, P < 0.01) after MaxEPA suggesting a possible impairment of the fibrinolytic capacity. In many situations there seems to be a reduction of PAI-1 when the triglycerides are lowered. In the diabetic patients given n-3 fatty acids this was not the case.

The appropriate role for additional radiotherapy in patients with resectable rectal cancer is not yet settled. Irradiation has been considered by surgeons and radiotherapists as superfluous since no effect on survival has been shown. However, numerous trials have demonstrated that peri-operative radiotherapy decreases an often high local recurrence rate while others believe it has a definite place in routine management. Several surgeons have, on the contrary, claimed that a skilled surgeon compared to a less skilled surgeon, will get the same acceptably low local recurrence rates. Since we will probably never have a randomized trial comparing "good" and "bad" surgeons, this argument cannot be settled. A further obstacle arises in the difficulty of persuading surgeons to organize their routine work so that it is performed in an optimal way by those specializing in this field. The question also arises whether radiotherapy should be delivered pre-operatively, postoperatively or as a "sandwich" technique, i.e., both pre-operatively and postoperatively. According to radio-biological considerations and results from reported trials, the best effect on local tumor control has been achieved using pre-operative radiotherapy.

Human papillomavirus (HPV) detection was done using the polymerase chain reaction technique on tumor tissue from 44 patients with transitional cell carcinoma of the urinary bladder. Only one of the 44 was associated with HPV infection. The HPV-positive patient was not known to have immunodeficiency or genital warts, and the tumor was not morphologically different from the other tumors. Control experiments excluded the possibility that this finding was caused by contamination of the sample. This study confirms that HPV infection is a rare condition in bladder carcinoma.

Pharmacokinetics of haloperidol in the rat following intravenous bolus doses of 0.5, 1.0, and 2.5 mg kg-1, respectively, were investigated. It was found that haloperidol was a high extraction ratio drug with a total blood clearance averaging 83 ml min-1 kg-1. The volumes of distribution were large with a mean of 5.5 1 kg-1 (Vc), 11.11 kg-1 (V beta), and 9.61 kg-1 (Vss), respectively. The terminal half-life was 1.5 h. The disposition kinetics of haloperidol was found to be linear over the dose range studied. After constant intravenous infusions of haloperidol by different infusion rates during 12 h, steady-state levels were reached in the blood. The measured steady-state blood concentrations were consistent with those predicted by a biexponential infusion model based on the parameters obtained from the intravenous bolus study. The total blood clearance at steady-state was concentration-independent within the investigated range of 5 to 20 ng ml-1.

This report provides insight into parathyroid gland physiology and the pathophysiology of hyperparathyroidism (HPT). Increases in the extracellular calcium concentration constitute the primary physiological signal for inhibition of parathyroid hormone (PTH) release. Transduction of the external signal into a cellular response involves activation of a cation receptor mechanism on the plasma membrane with rapid rise in the cytoplasmic calcium concentration of the cells. This recently discovered parathyroid calcium receptor has been characterized as a glycoprotein of unusually high molecular weight, which may play a key role in calcium homeostasis since it is also expressed in the kidney and placenta. Binding of external calcium to the receptor is associated with mobilization of intracellular calcium as well as calcium influx into the cells and phosphoinositol hydrolysis. These events rapidly interfere with the release process through essentially unknown mechanisms and probably also at sustained stimulation inhibit PTH gene transcription. The relative calcium insensitivity of the PTH release in HPT is associated with a deranged regulation of cytoplasmic calcium within pathological parathyroid cells. The molecular basis for this disturbance comprises down regulation of the cation receptor, whereby external calcium is translated into abnormally low levels of cytoplasmic calcium and insufficient inhibition of PTH release. Studies on expression of the functionally important cation sensing glycoprotein and its associated cellular signal systems may provide novel means for interference with the pathophysiological derangements of HPT.

A recently proposed method for bioavailability estimation, called the semi-simultaneous method, was evaluated in vivo in rats using methysergide as a test substance. In this method the test and the reference dose are administered with a short time interval and a model including the bioavailability parameters is fitted to the concentration-time profile. In the present study, in order to control the true bioavailability, intravenous infusion was used to mimic extravascular administration and various input profiles were produced. Mono-, bi- and triexponential disposition functions with the true and also various erroneous input models were fitted to the individual data sets. The models were also fitted to truncated data sets to mimic a situation where a long duration of sampling is precluded. A combined fitting-deconvolution procedure was also applied. The simi-simultaneous method gave precise and accurate estimates of the bioavailability in most groups and a robustness in the estimate concerning the model fitted was noted. The true input model could be identified for all data sets using common goodness-of-fit criteria. In the groups where a 'flip-flop' situation was created (slower input than elimination) a poorer precision and accuracy and a higher sensitivity concerning the model fitted was observed. The model fitting and the fitting-deconvolution procedure generally gave very similar results.

Chemical derivatization by phenylglyoxal (PGX) was applied to the identification of arginine in the neuropeptides dynorphin A (1-6) and substance P. The obtained products were separated on a short reversed phase C18 column and analysed on-line with the photodiode array UV technique. The selective attachment of a chromogenic molecule into the arginine residue resulted in significant change in the absorbance spectra around 250 nm, depending on the number of PGX molecules attracted. Further analysis employed fast atom bombardment mass spectrometry (FAB MS) and C-terminal sequencing for detailed verification of the derivatives formed during modification with PGX. The results clearly demonstrated that the photodiode array technique, when combined with chemical modification of certain amino acids, provides new possibilities for the analysis of peptide structures.

The fission yeast, Schizosaccharomyces pombe, expresses one of two alternative mating types. They are specified by one of two determinants (M or P) present at the mat1 locus. In addition, silent copies of M and P are present on the same chromosome. In the present work we demonstrate that the difference between the active and the silent stage of the P determinant is controlled by four repressive elements that are located at the silent locus. There are two elements to the left and two to the right of the mating type cassette. Both elements to the left and either one of the two elements to the right are required for an effective blockage of transcription. When they are combined, the four elements define a highly efficient silencer functionally similar to the HMRE and HMLE and HMLI silencers in Saccharomyces cerevisiae. In addition, the DNA surrounding the silent P locus confers symmetric partitioning in mitosis to Schizosaccharomyces pombe ars plasmids.

1. Slices of rat cuneate nucleus were used to study whether or not gonadal steroids influence the gamma-aminobutyric acid (GABA) system in vivo. Females in different stages of the oestrous cycle as well as steroid-treated (oestrogen, progesterone or both) ovariectomized animals were used. 2. Functional changes in the GABAA receptors were assayed using the effects of potentiators (benzodiazepine, barbiturate) and antagonists (picrotoxin) on the muscimol control dose-response curves. 3. The potentiating effect of the benzodiazepine, flurazepam was unchanged during the oestrous cycle, and the hormone treatments did not alter this effect. 4. During oestrus, an increase was seen in the potentiating effect of the barbiturate (pentobarbitone). This suggests a synergistic effect between barbiturates and gonadal steroids. Progesterone treatment also increased the effect of pentobarbitone. 5. The antagonistic action of picrotoxin was unaffected during the oestrous cycle. However, progesterone (or progesterone and oestrogen) treatment reduced the potency of picrotoxin. 6. This study supports the idea that endogenous steroids (presumably progesterone) affect the GABAA receptors during the oestrous cycle by a mechanism associated with the barbiturate site of the GABAA receptor complex.

It has been suggested that a high level of hyaluronan (hyaluronic acid, HYA) in pleural fluid is an indicator of malignant mesothelioma. In 78 consecutive patients with pleural effusion of various causes the HYA concentration was measured in pleural fluid samples and in serum. Nine patients had malignant pleural mesothelioma, and in three of them the HYA level in pleural fluid was 100 mg/l or more. In 42 patients with effusions due to metastatic malignancy, the mean HYA in the pleural fluid was 75 mg/l, and in five the HYA level was above 100 mg/l. Cardiac insufficiency caused the effusion in 11 patients, of whom two had a level above 100 mg/l in pleural fluid. Four patients had a serologically confirmed viral infection and had HYA levels in pleural fluid of 8, 157, 335, and 554 mg/l, respectively. One patient had postinfectious effusion with an HYA level in pleural exudate of 748 mg/l, the highest in this investigation. Two patients had benign asbestos pleural effusions, and both had high pleural HYA levels (256 and 490 mg/l, respectively). The serum HYA values were much lower than in the pleural fluid, namely from 15 to 480 micrograms/l; the levels were independent of the levels in the pleural fluid. Thus, a high level of HYA in pleural fluid is not specific for mesothelioma but can occur in other malignant or benign diseases, and a low level does not exclude mesothelioma.

The pharmacokinetics of pafenolol, a highly selective beta 1-adrenoceptor antagonist, have been studied in starved and unstarved rats. Separate groups received intravenous doses (0.3 and 3.0 mumol kg-1) and oral doses (1 and 25 mumol kg-1). The systemic clearance of pafenolol was constant in the dose range investigated where the absolute oral bioavailability increased from 15 to 27 per cent in the starved and from 9.1 to 21 per cent in the unstarved rats, when the oral dose was raised from 1 to 25 mumol kg-1. The blood concentration profile after an oral solution of pafenolol exhibited two peaks in the majority of the rats. The major part of the absorption was associated with the second peak which appeared about 4 h after dosing in both starved and unstarved rats. Food lowered the degree of bioavailability and shifted the tmax1 to about 1 hour compared to half an hour in starved rats. The low bioavailability was primarily due to incomplete uptake from the gastrointestinal tract. Our study shows that pafenolol is absorbed in a similar way to that in man. The mechanisms behind the dose-dependent bioavailability and the two peaks in the absorption profile after an oral solution will be further explained in the rat.

The effects of glucose on the cytoplasmic Ca2+ concentration (Ca2+i) regulating insulin release were investigated using pancreatic beta-cells representative for the normal and diabetic situations. Increase of the glucose concentration resulted in a slight lowering of Ca2+i followed by a rise, often manifested as high amplitude oscillations. The Ca2+i-lowering component in the glucose action associated with suppression of insulin release became particularly prominent when the beta-cells were already depolarized by tolbutamide. Glucose-induced inhibition of insulin release was observed also in experiments with rats made diabetic with streptozotocin or alloxan. Other studies indicated lowering of plasma insulin after intravenous glucose administration in patients with insulin- and noninsulin-dependent diabetes mellitus. Brief exposure of beta-cells to 2.2 mmol l-1 streptozotocin resulted in impairment of the response to glucose, manifested as disappearance of the cyclic variation of Ca2+i. The results indicate that glucose-induced depolarisation is a vulnerable process, the disturbance of which may contribute to insulin secretory defects in diabetes mellitus.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalyses the rate-limiting step in cholesterol synthesis. Glutathione (GSH) has been postulated to be an important activator of HMG-CoA reductase in vivo. HMG-CoA reductase activity was assayed in cultured fibroblasts from healthy children. Solubilized enzyme preparations were prepared by ultracentrifugation after freezing and thawing of fibroblasts. Such treatment increased the relative enzyme activity markedly. Enzymological assay conditions were established. Addition of GSH stimulated the reaction, whereas there was inhibition after addition of glutathione disulphide (GSSG). The inhibitory effect of GSSG could be reversed by the addition of excess GSH. Fibroblast preparations, deficient in GSH, were obtained from children with glutathione synthetase deficiency or from normal subjects after the growth of fibroblasts in the presence of buthionine sulphoximine. Solubilized enzyme preparations from GSH-deficient fibroblasts had HMG-CoA reductase activities lower than or comparable with those of control preparations. The results indicate only some reduction in the capacity for cholesterol synthesis in subjects with glutathione deficiency. The existence of additional activation mechanisms in vivo, alternative to GSH, for thiol-dependent modulation of HMG-CoA reductase activity seems likely.

Racemic 5-hydroxy-2-(dipropylamino)tetralin (5-OH DPAT), a potent and selective dopamine (DA) D2-receptor agonist, was resolved into the enantiomers by a new method. The enantiomers of 5-OH DPAT were determined by chiral ion-pair chromatography using N-benzyloxycarbonylglycyl-L-proline as the counter ion. The enantiomeric purity of (R)-5-OH DPAT was found to be greater than 99.7%. The ability of the enantiomers to change the rat brain DOPA levels was evaluated in vivo. The results indicate that (R)-5-OH DPAT is a weakly potent DA D2-receptor antagonist.

We studied the oxidation capacity in liver biopsies of a series of extensive metabolizers (n = 10) and poor metabolizers (n = 2) as identified by in vivo phenotyping with dextromethorphan. Codeine and dextromethorphan were used as probe drugs in vitro. The data were compared with the contents of cytochrome P-450IID1 as quantitated by Western immunoblotting by use of a specific monoclonal antibody (MAb 114/2). The O-demethylation of codeine was highly correlated with the O-demethylation of dextromethorphan (r = 0.90). The N-demethylation of codeine was catalyzed at a considerably higher rate than the O-demethylation. The N-demethylation to O-demethylation ratio of codeine was 46 in the poor metabolizer and, on average, 6.2 (range, 2.6 to 11) in the extensive metabolizers, respectively. The band intensity in Western blots correlated with the rate of O-demethylation of codeine (r = 0.95) and of dextromethorphan (r = 0.88) in the extensive metabolizers. The comeasurement of the O-demethylation and N-demethylation of codeine may provide a tool with which to phenotype individuals in vitro with respect to the polymorphism of the cytochrome P-450IID1.

The risk of traumatic injury and low Apgar score was studied in 473 infants with a birth weight of 4500 g or more at term (LFD) and 473 infants with normal weight (NFD, birth weight +/- 1 SD of mean for the respective gestational age). The LFD group comprised 3.2% of all infants delivered during a 5-year period. Traumatic injuries were observed in 8.0% of the LFD versus 0.6% of the NFD group. The injuries in the LFD group were 28 fractured clavicles, four fractured humerus and 12 brachial plexus injuries. Six of the LFD infants had multiple injuries. The injuries in the NFD group were three fractured clavicles. All infants with traumatic injuries were delivered vaginally. Contributory obstetrical factors for traumatic injury were forceps, post-term pregnancy and vacuum extraction. High birth weight was correlated to a low Apgar score at one minute, as also was post-term pregnancy.

Benzodiazepines exert their effects by facilitating neurotransmission in GABAergic synapses, probably by increasing the affinity of the GABA receptor to GABA. Stimulation of GABA receptors (at least of the A type) opens chloride ion channels which inhibits the ability of the cell (e.g. monoaminergic or cholinergic) to conduct nerve impulses. The endogenous ligand for the benzodiazepine receptor is probably a peptide, which is able to induce "anxiety" in rats. Thus, if the benzodiazepines are receptor agonists, the endogenous ligand would be an antagonist. The clinical effects resulting from the above mechanism of action (anticonvulsant, muscle relaxant, anxiolytic, sedative-hypnotic and amnesic) are discussed with special attention to preoperative sedation in dental practice.

The purpose here is to demonstrate that perinatal statistics serve as a powerful tool for peer review, thereby improving the standard of maternity care. These data were used as an instrument for peer review, first by comparing perinatal mortality between one country and another. More detailed statistics, rapidly fed back to the delivery units, acted as a strong inducement to practitioners at all levels who wanted to do at least as well as their neighbors. Examples are given from Sweden, Scotland and Germany.

1 Exposure to ATP (2-200 microM) resulted in a prominent peak of 45Ca efflux, when beta-cell-rich pancreatic islets from ob/ob-mice were perifused with a Ca2+-deficient medium. ADP and the stable alpha/beta-methylene analogues of ATP and ADP also had stimulatory effects. 2 The nucleotide initiation of 45Ca efflux mimicked that obtained with carbachol both in requiring previous exposure to glucose and in being more pronounced after replacing extracellular Na+ by K+. 3 It was possible to induce repeated peaks of stimulated 45Ca efflux, when the exposure to ATP was interrupted with intervals of perifusion with glucose-containing media. 4 The observations are consistent with the existence of P2-purinoceptors in islets, suggesting that these receptors mediate a similar mobilization of calcium as noted when activating polyphosphoinositide breakdown with carbachol. In view of the high contents of ATP and ADP in the beta-cell secretory granules, activation of P2-purinoceptors should be considered as a possible mechanism for amplification of the initial insulin secretory response.

1. The effect of acute and chronic (16 days) administration of nicotine on cortical acetylcholine (ACh) release, gross behaviour and brain nicotinic binding sites was investigated in rats and guinea-pigs. 2. The drug, injected either subcutaneously (0.45-0.90 mg kg-1) or intracerebroventricularly (1, 3 and 5 micrograms) increased the cortical ACh release, in a dose-dependent manner, through mecamylamine-sensitive receptors for 1-2 h in both species. 3. Chronic treatment significantly increased basal ACh release in the rat and slightly lowered it in the guinea-pig, but the response to a challenging dose of nicotine was proportionally maintained in both species. 4. The number of nicotinic receptors was four times higher in the rat than in the guinea-pig and was not dependent on the radioligand used ([3H]-nicotine or [3H]-ACh, in the presence of atropine) to determine this. The nicotinic binding sites showed an apparent increase in chronically treated rats but no change in guinea-pigs. 5. Tolerance to the inhibitory effect of the drug, assessed with the T maze test, was found in the rat. No apparent change in gross behaviour was detected in the guinea-pig. 6. It is concluded that chronic nicotine treatment causes evident tolerance to its inhibitory effect on behaviour in the rat, but no adaptation to its excitatory properties on the cholinergic brain structures in rats and guinea-pigs.

Different strategies for HPLC separation, including molecular sieving, ion-exchange, and hydrophobic interaction as well as reversed phase chromatography, were used to study molecular components in human cerebrospinal fluid (CSF). The separations were followed by photodiode-array UV detection, which is a recently developed technique allowing a direct and rapid discrimination between peptides and proteins differing in their content of aromatic amino acids. By the various HPLC techniques in conjunction with diode-array detection it was possible to identify and characterize several protein and peptide components present in CSF. The procedure also allowed quantitative analysis of CSF proteins using minute amounts of the fluid.

1. The effects of thyrotropin releasing hormone (TRH) on regional cerebral blood flow were studied in rabbits anaesthetized with pentobarbitone or ketamine. The blood flow was determined with the labelled microsphere method before and after the i.v. administration of either 50 micrograms kg-1 or 2 mg kg-1 TRH. 2. In order to measure the cerebral O2 consumption the arteriovenous difference in oxygen saturation in the brain (CAVOD) was measured before and after the administration of 2 mg kg-1 TRH. 3. In animals under pentobarbitone anaesthesia 50 micrograms kg-1 TRH elicited an increase in mean arterial blood pressure (MAP) of about 1 kPa and 2 mg kg-1 TRH elevated the MAP by about 2 kPa. With ketamine as the anaesthetic the corresponding values were 0.5 kPa and 7 kPa, respectively. TRH induced significant vasoconstriction in several peripheral tissues. 4. The total cerebral blood flow (CBFtot) increased from 54 +/- 4 to 78 +/- 5 g min-1 100 g-1 after the administration of 50 micrograms kg-1 TRH in pentobarbitone-anaesthetized animals. An even greater effect was elicited by 2 mg kg-1 TRH, from 48 +/- 6 to 113 +/- 19 g min-1 100 g-1. In ketamine-anaesthetized rabbits, 50 micrograms kg-1 TRH tended to enhance the CBFtot and 2 mg kg-1 increased it from 71 +/- 6 to 141 +/- 19 g min-1 100 g-1. 5. In animals anaesthetized with pentobarbitone, the CAVOD decreased from 47.3 +/- 1.7% to 35.1 +/- 2.2% at 3 min after TRH delivery, and then gradually increased to the control level. In animals under ketamine anaesthesia the CAVOD decreased from 63.3 + 2.0% to 45.2 + 7.4% after the administration of 2 mg kg'- TRH. 6. It is concluded that TRH elicits cerebral vasodilatation in excess of that required by the change in cerebral metabolism which may have taken place. The pattern of responses was similar to that produced in rabbits under urethane anaesthesia.