Fosfomycin/metronidazole compared with doxycycline/metronidazole for the prophylaxis of infection after elective colorectal surgery. A randomised double-blind multicentre trial in 517 patients.

To find out if fosfomycin together with metronidazole was any better than doxycycline with metronidazole for the prophylaxis of infection before elective colorectal operations. Multicentre, double blind, random control trial. Nine Swedish hospitals. SUBJECTS-559 patients admitted for elective colorectal operations. Fosfomycin 8 g and metronidazole 1 g before operation and fosfomycin 8 g eight hours afterwards, or doxycycline 400 mg and metronidazole 1 g before operation, and placebo eight hours afterwards. Incidence of all types of infection, mortality, and side effects. There were no significant differences between the groups for any of the outcome measures studied, the overall abdominal infection rates (wound, deep, and septicaemia) being 4.6% and 7.4%, and the remote infection rates (pneumonia, urinary tract, and central venous line) 15.1% and 12.8%, respectively. Of the predictors studied, only duration of operation was significantly related to risk of infection. The combination of fosfomycin and metronidazole was as safe and effective as that of doxycycline and metronidazole in preventing infections after elective colorectal operations.


Ischemic colitis complicating imipramine overdose and alcohol ingestion. Case report.

Patients on antidepressant medication are instructed to avoid alcohol because of possible additive effects on cognitive function. An unusual case of colonic gangrene following overdose of imipramine and alcohol is presented. The patient recovered.


Misleading cause of acute arterial insufficiency: ergotamine intoxication. Case report.

In a woman arteriographically indicated spasm of the iliac, femoral and popliteal arteries did not respond to intra-arterial tolazoline. At operation groin pulsations were normal. Bilateral lumbar sympathectomy was performed. Subsequently it emerged that she had been using ergotamine. Surgery could have been avoided if nitroprusside had been given.


Mammary arteritis mimicking cancer. Case report.

Giant cell arteritis and polyarteritis nodosa are systemic diseases which rarely involve the breasts. Two cases are reported in which breast masses, clinically suspected to be malignant, were found to be isolated vasculitis--bilateral giant cell mammary arteritis in a 67-year-old woman and isolated mammary polyarteritis nodosa in a 45-year-old woman. Vasculitis should be considered in the differential diagnosis of breast masses.


Connective tissue repair in zinc deficiency. An ultrastructural morphometric study in perforated mesentery in rats.

To quantify measures of healing in zinc-deficient and healthy rats. Randomized study. 30 male Sprague-Dawley rats. Zinc deficiency was induced in half the rats. All rats underwent laparotomy and standard perforations were made in the small intestinal mesentery with a scalpel. At 1, 3, 5, 7 and 10 days after operation 6 rats were killed by overdose of anaesthetic agents and the specimens of the mesentery were fixed. Measurement of cellular volume density, surface density of the rough endoplasmic reticulum, and surface density of the plasma membrane. Perforations started to close on day 4, and most were closed by day 10. Cellular volume density reached its peak between days 3 and 5, as did surface density of rough endoplasmic reticulum. There were no significant differences between the two groups for either measurement. The surface density of the rough endoplasmic reticulum, however, was significantly higher in controls than in zinc deficient animals on days 3-10 (p less than 0.001). The surface density of the plasma membrane was significantly higher in zinc-deficient animals on days 1-3 (p less than 0.04), and in control animals on days 5-10 (p less than 0.01). Protein synthesis and formation of scar tissue were slightly lower in the zinc-deficient animals, and the higher plasma membrane surface density implies that contraction may be an important part of healing in the small intestinal mesentery in rats.


Gene expression of insulin-like growth factor-I and IGF-I receptor during wound healing in rats.

To measure the time course of changes in the concentrations of insulin-like growth factor-I (IGF-I), IGF-I messenger RNA (mRNA), and IGF-I receptor mRNA during wound healing. Open experimental study. 40 male Sprague-Dawley rats, each weighing 300 g. Stainless steel wire mesh cylinders implanted in the subcutaneous tissue of the back. Five rats killed at each time point (1.5, 2, 3, 4, 5, 7, 11, and 18 weeks). Wet weight and concentrations of IGF-I mRNA, and IGF-I receptor mRNA of granulation tissue, and concentration of IGF-I in wound fluid. The wet weight of granulation tissue increased significantly between week 1.5 and weeks 4-5, and then decreased. IGF-I mRNA concentration (amol/microgram DNA) increased significantly (threefold) between week 1.5 and weeks 3-5, and decreased between weeks 5 and 7. The concentration of IGF-I receptor RNA remained constant throughout the study, and the concentration of IGF-I in wound fluid remained constant until week 8 and then increased to a higher level at weeks 11-18. There is a transient rise in the gene expression of IGF-I but not of IGF-I receptor mRNA during wound healing.


Diagnostic accuracy of ultrasonography and C reactive protein concentration in acute cholecystitis: a prospective clinical study.

To assess the value of ultrasonography together with C reactive protein concentration in predicting which patients with acute cholecystitis require immediate operation. Prospective study. Oulu University Hospital, Finland. 129 consecutive patients admitted with suspected acute cholecystitis 1988-89. Correlation of ultrasonographic findings and C reactive protein concentrations with histological findings. Ultrasonography correctly classified 86 of 108 patients with acute cholecystitis (79%). When the findings were combined with those of increased concentrations of C reactive protein the accuracy rose to 105 of 108 (97%). Large increases in C reactive protein concentrations were associated with both infected bile and gangrene of the gall bladder. The combination of ultrasonography and measurement of C reactive protein concentration is recommended in the routine investigation of all patients with suspected acute cholecystitis. Serum C reactive protein concentrations should be monitored regularly to select those patients who require emergency operation.


Development of stress ulcers assessed by gastric electrical potential difference, pH of gastric juice, and endoscopy in patients in the intensive care unit.

To assess measurement of gastric electrical potential difference, pH of gastric mucosa, and endoscopic findings in patients in intensive care units who are at risk of developing stress ulcers. Open comparison with age- and sex-matched control subjects. Herlev Hospital, Denmark. Sixteen consecutive patients with no history of gastrointestinal haemorrhage, coagulopathy, or ulcer disease who had been admitted to the intensive care unit, and 16 age- and sex-matched outpatients with normal endoscopic findings. Upper gastrointestinal endoscopy, during which any lesions that were found were scored according to severity, the gastric potential difference, and the pH of gastric juice were measured. Correlation between the incidence of stress ulceration found at endoscopy, gastric potential difference, and gastric pH. Gastric potential difference was significantly reduced and gastric pH significantly increased in the patients in the intensive care unit (p less than 0.05 in both cases), all of whom had stress ulcers in more than one gastric segment. Nine of the patients had gastric pH readings of greater than 4. Gastric electrical potential difference may be useful measurement for the assessment of stress ulceration in patients in intensive care units.


Morbidity and short term results in a randomised trial of open compared with closed treatment of chronic pilonidal sinus.

To evaluate the morbidity and short term results after open compared with closed treatment of chronic pilonidal sinus. Randomised control trial. 120 of 164 patients with chronic pilonidal sinus treated between April 1987 and April 1989. 60 patients were treated by excision and primary suture, and 60 by excision and open packing. Incidence of early complications (bleeding that needed treatment, wound breakdown, infection, haematoma, or wound pain), number of postoperative visits required, and length of sick leave taken. Those patients who underwent excision and suture had slightly but not significantly fewer early complications (16/60, 27%, compared with 23/60, 38%). Most of the early complications were the result of infection (8, 13% compared with 18, 30%, respectively). They also required fewer followup visits and less sick leave, and their wounds healed more quickly. At one year the numbers of late complications were 19 (32%) and 14 (23%), respectively. Excision and primary closure of chronic pilonidal sinus causes less morbidity and is more cost effective than excision and open packing. We plan a three year follow-up to see if these results are maintained.


Comparison between sterile saline and tap water for the cleaning of acute traumatic soft tissue wounds.

To find out if there were any differences in infection rates if acute traumatic soft tissue wounds were cleaned with tap water instead of sterile saline. Randomised study. Emergency department at one city hospital. 705 consecutive patient with soft tissue wounds less than six hours old that did not penetrate a viscus, cavity, or joint and could be treated by primary suture. Randomly allocated to have the wound cleaned with either sterile saline or tap water in addition to debridement. Rate of wound infection, the presence of which was indicated by pus in the wound and prolonged healing. The infection rate in wounds cleaned with sterile saline was 10.3% compared with 5.4% in wounds cleaned with tap water (p less than 0.05). Infected wounds were significantly larger than uninfected ones (p less than 0.05) and more likely to be located on a lower extremity (p less than 0.05). There were no microbiological differences between the two groups, and no bacterial species grown from tap water was subsequently grown from an infected wound. Sterile saline should be replaced by tap water for the cleaning of acute traumatic superficial soft tissue wounds.


Blood transfusion and recurrence of colorectal cancer.

Because perioperative blood transfusions have been shown to have an impaired effect on survival in patients with colorectal cancer, we examined retrospectively the records of 882 patients who had undergone curative operations: 170 patients had distant metastases at the time of operation. Of the 499 patients with colonic cancer 332 (67%) had received perioperative blood transfusions. The corresponding figure for the 213 patients with rectal cancer was 190 (89%). Colonic tumors recurred in 45% of the patients who received blood transfusions and in 39% of those who did not. Corresponding figures for tumors in the rectum were 54% and 55%. When dividing the patients with colonic cancer into different subgroups according to Dukes' grade we found differences in survival rates. The poorer survival for transfused patients was, however, only significant for those with Dukes' A tumors (p less than 0.05). This difference disappeared when the influence of age was eliminated. The estimated risk ratio of recurrence and death was 1.23 with the 95% confidence interval (0.99, 1.53) when taking Dukes' grade, current age and localization into account. Blood transfusion should be avoided if possible until adequate prospective studies have been carried out.


Bleeding from an epiphrenic oesophageal diverticulum.

A 49-year-old woman with a 2-month history of mild dysphagia and three episodes of haematemesis was found at endoscopy and barium swallow to have an epiphrenic oesophageal diverticulum containing an ulcerating crypt, but no ectopic gastric epithelium. Diverticulectomy and lower oesophageal myotomy gave a good result.


Validation of subjective measures of fatigue after elective operations.

To find out if it was possible to evaluate postoperative fatigue by questionnaire. Open study. University hospital. 23 patients about to undergo elective general surgical operations. A questionnaire was filled in before, and 2-46 days after, operation. Six measures of fatigue were derived from the questionnaire and validated objectively with changes in body weight, exercise tolerance (n = 10), or grip strength (n = 21). The six measures all showed a significant increase after operation. The changes in fatigue correlated well, but there were differences in sensitivity to changes in perceived weakness compared with perceived tiredness. Each measure correlated significantly with either body weight, exercise tolerance or grip strength. Questionnaires can provide reliable results in the assessment of postoperative fatigue.


Bone mineral density in patients with familial hypocalciuric hypercalcaemia (FHH).

To find out whether chronic hypercalcaemia and excessive secretion of parathyroid hormone (PTH) is associated with skeletal demineralisation in familial hypocalciuric hypercalcaemia (FHH). Open study. Huddinge University Hospital, Sweden. Nine affected and three unaffected members of two kindreds with FHH, and 12 age- and sex-matched controls. Measurement of bone mineral density (g/cm2) in the proximal femur and lumbar spine by dual photon absorptiometry, and of bone mineral content in the distal radius and midradius (g/cm) by single photon absorptiometry. Measurement of serum concentrations of PTH, total and ionised calcium, phosphate, and magnesium, and alkaline phosphatase activity, and 24 hour urinary calcium excretion were also made. Bone mineral density was significantly higher in Wards's triangle of the femur (p < 0.05) in the members of families with FHH than in control subjects. In the other parts of the femur and in the lumbar vertebrae it was slightly but not significantly higher, as was the bone mineral content of the distal radius and midradius. Family members with FHH all had increased total and ionised serum calcium concentrations, except for the index case in one of the families who developed hypoparathyroidism postoperatively. Twenty-four urinary calcium excretion was less than 5 mmol (the upper limit of the reference range for FHH) in all the affected patients. Chronic hypercalcaemia in affected members of families with FHH is not the result of an increase rate of bone mineralisation, because they have normal bone mass. They seem to be relatively insensitive to the deleterious effects of PTH on bone mineral state, because raised concentrations of PTH were not associated with reduced bone mass.


Long term results after Nissen fundoplication and Belsey Mark IV operation in patients with reflux oesophagitis and stricture.

This retrospective study was undertaken to compare long term results of Nissen fundoplication and the Belsey Mark IV repair in patients with reflux oesophagitis and stricture between 1972 and 1987. 105 patients were operated on for reflux oesophagitis, and 43 of the patients had stricture. There was one postoperative death (after a Belsey Mark IV repair). The cumulative recurrence rate after the Nissen operation was 9%, all recurrences of oesophagitis occurring within the first two years. The cumulative recurrence after the Belsey repair was 37%. Only 15 of 32 patients treated with Nissen fundoplication for stricture needed dilatation after operation, and then only during the first two years. "Gas-bloat" occurred in 18% of the patients treated with Nissen fundoplication. We conclude that the Nissen fundoplication is a good operation for patients with severe reflux oesophagitis and for those with peptic strictures of the oesophagus. The Belsey Mark IV repair, however, cannot be recommended for patients with strictures.


Open management with mesh and zipper of patients with intra-abdominal abscesses or diffuse peritonitis.

To evaluate the open management of intra-abdominal abscesses and persistent peritonitis by the "mesh and zipper" technique, and to assess the predictive value of the APACHE II score. Prospective open study. 21 consecutive patients with life-threatening peritonitis. Insertion of mesh and zipper and lavage once or twice daily with several litres of warmed saline. Mortality. Eleven of the 21 patients died (52%). The APACHE II score accurately predicted outcome, in that no patient who scored less than 20 points died, and no patient who scored more than 26 points lived. The mesh and zipper technique with daily intraperitoneal lavage is effective in the treatment of life-threatening peritonitis and the APACHE II score is an accurate predictor of survival.


Erythromycin accelerates delayed gastric emptying of solids in patients after truncal vagotomy and pyloroplasty.

To find out if erythromycin (a motilin agonist) accelerated gastric emptying after vagotomy and in normal subjects. Double blind controlled study. Two referral centres. 15 patients who had previously undergone vagotomy and who did (n = 8) or did not (n = 7) have symptoms of gastric stasis and 10 normal controls. A standard meal containing 185 x 10(5) Bq -99mTc was eaten after either erythromycin 200 mg or 40 ml placebo (normal saline) had been given intravenously. Subjects were then scanned by gamma camera. Measurement of: the length of time from completion of the meal to the onset of gastric emptying; the length of time from completion of the meal until half of the meal had left the stomach; the length of the time from the onset of gastric emptying until half of the meal had left the stomach; and the percentage of the meal that was left in the stomach at 60 and 120 min after the end of the meal. Gastric emptying was significantly delayed in those patients with symptoms compared with normal subjects and patients without symptoms. Erythromycin accelerated the first two phases of gastric emptying in all patients and normal subjects, but did not affect the length of time from the onset of gastric emptying until half the meal had left the stomach. Erythromycin could be a useful gastrokinetic agent in patients with symptoms of gastric stasis after vagotomy.


R2 compared with R1 resection for gastric cancer: morbidity and mortality in a prospective, randomised trial.

To compare the postoperative course of patients in the Dutch nationwide randomised trial of R1 (conventional) compared with R2 resection (including extended lymph node dissection) in the treatment of gastric cancer. Prospective randomised controlled trial. National multicentre trial with 72 participating hospitals in The Netherlands. 192 patients who were operated on between August 1989 and May 1990. 96 patients were randomised for a R1, and 96 for a R2 resection. Morbidity and mortality among 131 patients (64 R1 and 67 R2) for whom the resection was performed with curative intent. The groups were comparable for age, sex, type of resection, site of tumour and depth of invasion. Complications developed in 23 R1 (36%) and in 29 R2 patients (43%). Seven patients died in the postoperative period. Median hospital stay was significantly longer after R2 (18 days, range 7-122) than after R1 resection (15 days, range 2-63) (p < 0.05). Morbidity and mortality among the patients whose R2 resection was done by the Japanese instructor (n = 34) did not differ significantly from those among patients operated on by the Dutch supervisors (n = 33), but those operated on by the Japanese instructor stayed in hospital significantly longer (20 compared with 16 days, p < 0.05). If R2 resections are carried out by properly trained surgeons under supervision, they can be done safely. The reported high morbidity after R2 resection in Western countries seems to result from a lack of proper instruction and quality control.


Rectal leiomyosarcoma: acute presentation after local injury.

Rectal leiomyosarcoma is rare, often large and found in the distal third of the rectum. Most symptoms differ from those of an adenocarcinoma. Staging is difficult and should include tumour size, necrosis, cellularity, number of mitoses and anaplasia. Abdominoperineal excision (APE) remains the only effective treatment. A 66 year old asymptomatic female presented with painless rectal bleeding after a fall. Digital examination and proctoscopy revealed a mass on the posterior rectal wall. Pelvic ultrasonography, arteriography and CT-Scan showed a huge retro-rectal lesion. Following APE, histopathology confirmed a leiomyosarcoma. No adjuvant therapy was given; there is no recurrence 4 years later.


Adverse effects of perioperative blood transfusion in patients with colorectal cancer.

To assess the effects of perioperative blood transfusion on cancer related survival and infective complications after radical operations for colorectal cancer. Retrospective study. District hospital in Sweden. 217 patients who fulfilled the criteria for inclusion, out of 392 consecutive patients operated on for colorectal cancer between 1975 and 1979. Morbidity and cancer related mortality depending on whether blood was transfused and, if so, how much. Dukes' stage (p < 0.001), rectal tumours (p < 0.05) and the number of units transfused (p < 0.05) were significantly associated with cancer related mortality. Patients with rectal cancer transfused with 1-2 units had significantly better survival than those transfused with more than 4 units (p < 0.05), but this was not the case for colonic tumours. There was no significant association between blood transfusion and the incidence of infective complications. Though there seems to be an association between the number of units of blood transfused and cancer related survival in patients with rectal cancer, this does not necessarily imply causation. We recommend that until this is clarified by large, prospective investigations, autologous blood should be used whenever possible, and unnecessary blood transfusion should be avoided.


Eosinophilic gastroenteritis: report of two cases and comment on the literature.

Two cases of eosinophilic gastroenteritis (EGE) are reported. One recovered spontaneously, the other relapsed after bowel resection. Comments outline the immunological processes. They relate EGE to the hypereosinophilic syndrome (HES) and other collagenous diseases. Bowel resection is discouraged in favor of more conservative treatment.


Clinical predictors of relapse following neuroleptic withdrawal.

The validity of previously hypothesized predictors of elapse following neuroleptic discontinuation was examined. One hundred sixty-two outpatients, with either Research Diagnostic Criteria schizophrenia or schizoaffective disorder, were discontinued from neuroleptic medication for a 28-day period or until judged to be relapsed. Pre-discontinuation neuroleptic dosage level, the severity of psychotic symptoms, and the presence of dyskinetic movements prior to neuroleptic discontinuation were the predictor variables. Of the 162 patients, 62.7% did not relapse during the study period. There were no differences in the survival rates between the patients withdrawn from oral versus depot neuroleptics. Neuroleptic dosage, but not severity of psychotic symptoms or dyskinetic movements, predicted relapse. These results support the hypothesis that pre-withdrawal neuroleptic dosage level predicts relapse, but fail to validate either severity of psychotic symptoms or presence of dyskinetic movements as predictors of relapse.


MDMA (Ecstasy) precipitation of panic disorder.

The authors describe three patients whose panic disorder began during recreational use of MDMA (Ecstasy) and was subsequently complicated by agoraphobic avoidance that continued autonomously after cessation of the drug. Their panic disorder responded well to serotoninergic antidepressant drugs. Theoretical and practical implications are discussed.


Impaired detoxification of reactive oxygen and consequent oxidative stress in experimentally cryptorchid rat testis.

The effect of experimental cryptorchidism on the level of oxidative stress and antioxidant functions in rat testis was studied. Adult male Sprague-Dawley rats were rendered unilaterally cryptorchid (by suturing one testis to the abdominal wall) and killed 1, 3, or 7 days after the operation. As an indicator of oxidative stress, lipid peroxidation was measured by the diene conjugation method in testis homogenates. The activities of the antioxidant enzymes were determined either in the 10,000 x g supernatant fraction (glutathione [GSH] peroxidase, GSH transferase, hexose monophosphate shunt) or in crude testis homogenates (superoxide dismutase, catalase). An expected reduction (48%) in weight of the abdominal testes was evident by postoperative Day 7. The catalytic activities per testis of superoxide dismutase (Cu/Zn form) and catalase were found to decrease in cryptorchidism. The effect was seen on the first postoperative day and was most profound on Day 7 after surgery. The principal antioxidant enzyme, superoxide dismutase, was most sensitive to cryptorchidism, the activity in the abdominal testes being 74% or 85% (per gram of tissue or per whole testis, respectively; p less than 0.01). After impairment of the reactive oxygen detoxifying capacity, lipid peroxidation was increased in the abdominal testis by 46% (p less than 0.01) on postoperative Day 7. Slight concomitant increases were detected in the activities of GSH-peroxidase (p less than 0.01), GSH-transferase (p less than 0.001), and the hexose monophosphate shunt (p less than 0.001). This effect was seen only when calculated per gram of tissue, not per whole testis.(ABSTRACT TRUNCATED AT 250 WORDS)


[Applications of positron emission tomography (PET) to the measurement of regional cerebral pharmacokinetics].

Positron emission tomography (PET) has not only a variety of applications to functional diagnostics using methods of nuclear medicine and for the investigation of pathophysiological processes, it also offers new possibilities for pharmacology. As PET is able to quantitatively record "from outside" the regional concentration of a positron emitter in a living primate, the distribution and kinetics of a labelled drug at the site of action can be determined non-invasively. This is always the case if the research substance can be labelled practically carrier-free with a short-lived positron emitter such as 11C (T1/2 = 20 min) or if applicable 18F (T1/2 = 110 min). The quantities applied in this case are so small that pharmacodynamic effects do not occur. Therefore, this method is particularly suitable for measuring in vivo the regional cerebral pharmacokinetics of centrally acting drugs in humans.


[Diffuse pulmonary hemorrhage due to capillaritis in a patient with typical periarteritis nodosa and necrotizing glomerulonephritis. Relationship with overlapping vasculitic syndrome and Wegener's granulomatosis].

Clinical and pathological postmortem study of a patient with NPA which died due to a fulminant pulmonary hemorrhage. In the postmortem study, diffuse pulmonary capillaries was observed as the cause of the disease, as well as lesions of necrotizing glomerulonephritis with granulomas, within the framework of a typical NPA. Correlation with the NPA-type overlapping polyangiitic syndrome and microscopic polyarteritis are discussed, as well as the correlation between the latter and Wegener's granulomatosis.


Anxiolytic-like actions of anpirtoline in a mouse light-dark aversion paradigm.

The anxiolytic-like potential of anpirtoline was assessed in a mouse light/dark aversion test. Anpirtoline (1.0 ng kg(-1)-1.0 micrograms kg-1 i.p.) reduced the aversive responding of mice. This was detected as an increase in the latency to locate the non-aversive compartment and by decreases in the percentage of the time spent in the dark compartment, and the numbers of rears and line crossings in the dark compartment. In radioligand binding studies anpirtoline displayed submicromolar affinity for 5-HT1A, 5-HT1B and 5-HT3 receptor recognition sites (Ki = 151, 28 and 30 nM, respectively) and more modest affinity for 5-HT2 receptor recognition sites (Ki = 1.48 microM). It is concluded that anpirtoline has a unique spectrum of affinity for 5-HT receptor subtypes, its interaction with which may account for its anxiolytic-like activity.


Forcing expression of a soybean root glutamine synthetase gene in tobacco leaves induces a native gene encoding cytosolic enzyme.

Glutamine synthetase (GS; EC 6.3.1.2) is present in different subcellular compartments in plants. It is located in the cytoplasm in root and root nodules while generally present in the chloroplasts in leaves. The expression of GS gene(s) is enhanced in root nodules and in soybean roots treated with ammonia. We have isolated four genes encoding subunits of cytosolic GS from soybean (Glycine max L. cv. Prize). Promoter analysis of one of these genes (GS15) showed that it is expressed in a root-specific manner in transgenic tobacco and Lotus corniculatus, but is induced by ammonia only in the legume background. Making the GS15 gene expression constitutive by fusion with the CaMV-35S promoter led to the expression of GS in the leaves of transgenic tobacco plants. The soybean GS was functional and was located in the cytoplasm in tobacco leaves where this enzyme is not normally present. Forcing this change in the location of GS caused concomitant induction of the mRNA for a native cytosolic GS in the leaves of transgenic tobacco. Shifting the subcellular location of GS in transgenic plants apparently altered the nitrogen metabolism and forced the induction in leaves of a native GS gene encoding a cytosolic enzyme. The latter is normally expressed only in the root tissue of tobacco. This phenomenon may suggest a hitherto uncharacterized metabolic control on the expression of certain genes in plants.


Neurotransmission in human resistance arteries: contribution of alpha 1- and alpha 2-adrenoceptors but not P 2-purinoceptors.

The contribution of postjunctional alpha 1- and alpha 2-adrenoceptors and P2-purinoceptors to the neuroeffector response was examined in isolated segments of human subcutaneous resistance arteries. Electrical field stimulation (EFS, 20 V, 0.2 ms, 1-25 Hz) elicited a maximum contractile response which was 38.2 +/- 1.6% of that elicited by exogenously applied (5 microM) noradrenaline (n = 56). Tetrodotoxin (1 microM), used to inhibit neurotransmission, reduced the electrically evoked response to 24.7 +/- 4.4% (n = 10) of the control response. The alpha 1-adrenoceptor antagonist prazosin (1 microM) reduced the maximum EFS contractile response to 64.8 +/- 5.5% of the control response (n = 17). Application of the alpha 2-adrenoceptor antagonist yohimbine (0.1 microM) reduced the maximum EFS response to 68.2 +/- 8.2% of the control response (n = 9). In the presence of prazosin plus yohimbine at the above-mentioned concentrations the maximum response to EFS was reduced to 47.6 +/- 6.7% (n = 11). Responses following alpha-blockade were not statistically different from those in the presence of tetrodotoxin, but the mean responses indicate that a non-adrenergic component to the EFS response cannot be discounted. Desensitisation of P 2-purinoceptors with alpha, beta-methylene ATP had no effect on responses to EFS; therefore under the conditions studied these receptors do not appear to be involved in neurotransmission. These results confirm the presence of postjunctional alpha 1- and alpha 2-adrenoceptors in human resistance arteries and for the first time demonstrate that the postjunctional alpha 2-adrenoceptor is important in modulating vascular responses elicited by intramural sympathetic nerve fibres.


Antigen presentation by B lymphocytes to CD4+ T lymphocytes in vivo: importance for B lymphocyte and T lymphocyte activation.

B lymphocytes, like macrophages and dendritic cells, can present antigen to CD4+ T cells. Antigen presentation by B cells is essential for the generation of an in vivo T cell dependent antibody response, and repeated antigen presentation by B cells to T cells is necessary to induce B cell clonal expansion. Presentation of antigen by resting B cells to unprimed T cells tolerizes T cells, while anti-IgD antibody activates B cells and allows B cell antigen presentation that productively activates T cells. However, activation is not all that is required for B cells to productively present antigen to T cells.


[Biokinetics of a new prodrug gidazepam and its metabolite].

Pharmacodynamics and pharmacokinetics of a novel tranquilizing agent--gidazepam (I), a prodrug, and its physiologically active metabolite--7-bromo-5-phenyl-1,2-di-hydro-3H-1,4- benzodiazepine-2-one (II) in mice organism were studied. The form of relationship was determined between the dynamics of the anticonvulsant effect of labelled (2-14C-) I and II and the kinetics of the content of 14C-compounds in the experimental animals brain. It was noted that the biophase of the effect and the effector fragment of the scheme of biokinetics for I and II are identical. The effector prognosis of pharmacokinetics of I was realized. The comparison of the main characteristics of biokinetics for the prodrug (I) and drug (II) allowed us to reveal the nature of the quantitative differences of these pharmacological effects.


[Characterization of cloned alpha-satellite sequence from the extrachromosomal DNA of HeLa cell culture].

We have obtained the alphoid DNA clones, pK1 and pK2, from the extrachromosomal DNA of Hela cells treated by cycloheximide (30 micrograms/ml). Nucleotide sequences of the clones were aligned. The sides of the pK1 and pK2 are 390 and 184 bp, respectively. The marked RELP for the clones was not observed. The results of in situ hybridization have shown an approximately equal distribution of Ag-grains over major part of human chromosomes, with a slight preference for chromosomes 1, 5 and 19 (the 1-st group of alpha-satellite DNA). Therefore, the obtained alphoid sequences seem to be rather conservative and non-chromosome-specific. We suppose that increase of the alphoid DNA content in the fraction of the extrachromosomal DNA under the cycloheximide treatment is a result of the sporadic statistical processes rather then consequence of the specific excision.


[Tyrosine hydroxylase activity and expression of its gene in mice with contrasting capacity to dominate in social stress].

Changes of tyrosine hydroxylase (TH) activity and level of mRNA of TH gene in PT and CBA/Lac mouse strains, which are contrast by ability to dominate in heterogenous populations, were investigated. It was established, that the activity of TH both in dominate PT and subordinate CBA/Lac mice in hypothalamus, hippocampus and brain stem elevated in one hour after forming of micropopulations. But the appearance of this increase was different: activation of TH in hypothalamus and brain stem of PT mice was stronger then one in CBA/Lac mice. Moreover, the beginning of the reaction in brain stem of PT mice was earlier then that of CBA/Lac mice. MRNA level of TH gene in hypothalamus and brain stem in one hour was elevated only in PT mice for 50% and 200%, respectively. No changing in expression TH gene was found in hippocampus. In conclusion, it was suggested that the activation of catecholamine biosynthesis under social stress in hypothalamus and brain stem of male mice was due to the TH activation and increase of its gene expression.


[Effects of amiridin and tacrine, drugs effective in Alzheimer's disease, on synaptosomal uptake of neuromediators].

The study of the drugs effective in the treatment of cognitive deficits and memory loss associated with senile dementia of the Alzheimer's type--tacrine and amiridin, acetylcholinesterase inhibitor physostigmine and nootrop piracetam on uptake of 3H-serotonin (3H-5-HT), 3H-adrenaline (3H-AD), 3H-noradrenaline (3H-HA), 2H-dopamine (3H-DA), 3H-gamma-aminobutyric acid (3H-GABA), 3H-glutamic acid (3H-GLU), 3H-aspartic acid (3H-ASP) and 3H-glycine (3H-GLI) showed that tacrine and amiridin (5 x 10(-5) M) statistically significantly (P less than 0.05) inhibited the uptake of 3H-DA and 3H-5-HT. Physostigmine at concentration 5 x 10(-4) M statistically significantly (P less than 0.05) inhibited uptake of 3H-5-HT only. Piracetam at concentration range 1-5 x 10(-3) M had no effect on uptake of all investigated neurotransmitters. The above finding suggest that the uptake of neurotransmitter in nerve terminals is not the main target of amiridin and tacrine.


[Secretory activity of lactotrophs and its regulation by hypothalamic hormones in primary cultures of pituitary cells of rats of different ages].

Basal prolactin (PRL) secretion and the responses of lactotrophs to thyroliberin, dopamine and somatostatin were studied in the experiments employing primary monolayer cultures of pituitary cells obtained from developing rats of different ages. High responsiveness of PRL-secreting cells to the action of hypothalamic hormones was observed in the group of neonatal rats, although basal PRL release was about two orders lower in pituitary cultures of neonatal rats as compared to the cultures of immature, pubertal and adult animals. The investigation performed could reveal quantitative, but not qualitative differences in the reactions of lactotrophs of various age groups. It is concluded that postnatal development in the rat is coupled with significant changes of basal PRL release and to a lesser extent, with changes of lactotroph responsiveness to hypothalamic hormones.


[Regulation of hormone secretion in primary cell cultures of human somatotropinomas].

The effects of somatostatin and thyroliberin (thyrotropin-releasing hormone; TRH) on growth hormone (GH) and prolactin (PRL) secretion were studied in short-term (0.5-3h) or long-term (21-24h) incubations using monolayer cell cultures of somatotropin obtained from surgical material of patients with acromegaly. High sensitivity of both GH and PRL release to inhibitory action of somatostatin (10(-11) M) was established. We could not reveal the unambiguous influence of TRH on somatotropic function in the in vivo and in vitro conditions, as compared to the action of this tripeptide on PRL secretion. The results obtained permit us to propose that cell cultures of pituitary adenomata represent adequate and convenient models for studying the pathogenesis of tumor processes in the pituitary gland and for the development of new procedures of pharmacotherapy.


Clonal involvement of granulocytes and monocytes, but not of T and B lymphocytes and natural killer cells in patients with myelodysplasia: analysis by X-linked restriction fragment length polymorphisms and polymerase chain reaction of the phosphoglycerate kinase gene.

To determine the clonal nature of hematopoiesis and to assess lineage involvement in patients with myelodysplastic syndromes (MDS), we used restriction fragment length polymorphisms of the X-linked genes phosphoglycerate kinase (PGK1) and hypoxanthine phosphoribosyltransferase (HPRT) and the X-linked probe M27 beta. Eleven female MDS patients heterozygous for at least one of these probes were studied: 3 with refractory anemia (RA), 2 with RA with ringed sideroblasts (RARS), 2 with chronic myelomonocytic leukemia (CMML), and 4 with RA with excess of blasts in transformation (RAEB-t). All exhibited clonal hematopoiesis as determined by Southern analysis of DNA prepared from peripheral blood (PB) and/or bone marrow (BM) cells. In three of the six patients heterozygous for the PGK1 gene, purified cell suspensions of polymorphonuclear cells (PMN), monocytes, lymphocytes, and/or T cells prepared from PB were tested. In addition, five of these patients were analyzed by a polymerase chain reaction (PCR)-based procedure as described recently. This method was slightly adapted to facilitate the analysis of cell lysates of fluorescence-activated cell sorted (FACS) monocytes, T and B lymphocytes, and natural killer (NK) cells. The outcome of Southern and PCR analysis was concordant, showing that PMN and monocytes were clonally derived, whereas circulating T and B lymphocytes and NK cells exhibited random X-chromosome inactivation compatible with a polyclonal pattern. To address the question of whether T cells are derived from unaffected progenitor cells or that their origin had antedated the onset of MDS, naive and memory T cells were analyzed separately. Both subsets showed a polyclonal pattern. However, in one patient analysis of constitutive DNA suggested a skewed methylation, and the presence of clonal lymphocytes against a background of polyclonal lymphoid cells cannot be ruled out in this patient. PCR analysis of PB and BM cells showed a nonrandom, unilateral pattern of X-inactivation, compatible with a mixture of clonally (myeloid) and polyclonally (lymphoid) derived cells. In conclusion, in some patients, MDS represents a disorder with clonal hematopoiesis restricted to cells of myeloid origin, whereas a random X-inactivation pattern is found in lymphoid cells.


Deletions involving two distinct regions of 6q in B-cell non-Hodgkin lymphoma.

The recurrent loss of genetic material from a specific chromosomal region in a given tumor type suggests the presence of a tumor-suppressor gene, the loss or inactivation of which may be relevant for tumorigenesis. In this study, we provide molecular evidence for the recurrent association between deletions on the long arm of chromosome 6 and B-cell non-Hodgkin lymphoma (B-NHL). Normal and tumor DNAs from 71 cases of B-NHL were studied for loss of constitutional heterozygosity (LOH) at 19 loci on chromosome 6 using a panel of restriction fragment length polymorphism (RFLP) probes. LOH, indicating deletion of all or part of 6q, was detected in 16 of 71 cases (22.5%), ranging from low-grade to high-grade B-NHL. The isolated loss of 6p or the loss of other chromosomes (8, 17, 22) tested as controls for specificity was not observed in any case. Comparison of the extent of the deletions among different cases allowed the identification of two distinct regions of minimal deletion (RMD) at 6q25 to 6q27 (RMD-1) and at 6q21 to 6q23 (RMD-2), respectively, suggesting the existence of two tumor-suppressor genes. These data support a role for 6q deletions in B-NHL pathogenesis and provide a basis for identifying the corresponding tumor-suppressor genes.


Phenotypic analysis of mouse hematopoietic stem cells shows a Thy-1-negative subset.

Mouse hematopoietic stem cells can be identified and enriched from populations of normal bone marrow cells by immunofluorescent labeling of cell surface molecules followed by flow cytometric separation. We show here that the majority of hematopoietic stem cell activity, as defined by long-term competitive repopulation of irradiated animals and by a secondary transplant assay for spleen colony-forming units (CFU-S), could be localized in Ly-6b haplotype mice to a fraction of bone marrow cells that expresses the Ly-6A/E (Sca-1) molecule. Further, an analysis of hematopoietic stem cell activity in bone marrow of mouse strains expressing the Thy-1.1 allele indicated that the vast majority of activity was included in the Thy-1low population. In contrast, hematopoietic stem cell activity found in the bone marrow of Thy-1.2 genotype mouse strains was recovered in both the Thy-1neg and the Thy-1low populations. However, similar to Thy-1.1 strains, most activity was localized to the Ly-6A/E+ population of cells. The difference in Thy-1 phenotype of hematopoietic stem cell activity apparent between Thy-1.1- and Thy-1.2-expressing mouse strains was not caused by differences in the staining intensity of monoclonal antibodies (MoAbs) specific for the Thy-1 alleles. Furthermore, an antiframework MoAb that stains both alleles of Thy-1 separated hematopoietic stem cell activity from mice expressing the two alleles in the same manner as did allele-specific MoAb. The results of this study show that Thy-1 expression is not an invariant characteristic of mouse hematopoietic stem cells, and that mice expressing the Thy-1.1 allele are unique in that hematopoietic stem cell activity is found exclusively in the Thy-1low population.


Glutathione depletion in chronic lymphocytic leukemia B lymphocytes.

Glutathione (GSH) content may be the major determinant of a cell's sensitivity to cytotoxic alkylating agents. In the present study, the GSH concentration was determined in lymphocytes isolated from the blood of normal subjects and patients with chronic lymphocytic leukemia (CLL). Comparable levels were found in both types of cells. Incubation for 20 hours led to a decrease in GSH to 51% of baseline values in CLL B cells. Under the same conditions, normal B- or T-lymphocyte GSH content remained constant. GSH depletion was shown to be a characteristic of the B-CLL B lymphocyte. It was not found in the T cells of patients with B-CLL or in cells from patients with T-CLL. Chlorambucil (CLB) contributes to the decrease in GSH in B-CLL lymphocytes; after incubation with the drug, lower levels of GSH were found than in the normal B or T lymphocytes, B-CLL T cells, or T-CLL (CD4 or CD8) cells. GSH depletion of CLL B lymphocytes may be related to the greater therapeutic efficacy of CLB in B-CLL than in T-CLL.


Progressive disease after high-dose therapy and autologous transplantation for lymphoid malignancy: clinical course and patient follow-up.

Of 364 patients with lymphoid malignancy who underwent high-dose therapy with autologous bone marrow transplantation (ABMT) or peripheral stem cell transplantation (PSCT), 169 patients have had progressive disease after the procedure. The median survival from the time of relapse for patients with Hodgkin's disease (HD) who progressed after the transplant was 10.5 months. This compares with a median survival of 3 months for relapsed non-Hodgkin's lymphoma (NHL) patients (P = .0036). After failing transplantation, 56 patients were treated with further chemotherapy, 35 with involved field irradiation therapy, and 18 patients were treated with combination chemotherapy and irradiation. Seven patients received biologic therapy and seven patients underwent a second bone marrow transplant. The remainder of the patients were believed to be too ill for further therapy or chose not to receive further treatment for their recurrent lymphoid malignancy. Sixty of the 169 patients with progressive disease after the transplant are still alive; however, only 18 patients are alive off therapy without evidence of active disease after their relapse. Ten of the 18 patients are still less than 12 months past their posttransplant salvage therapy and are at high-risk for relapse. Five patients are progression free at 15 to 36 months after their posttransplant relapse. Only three patients (two NHL and one HD) treated with other modalities after autologous transplant failure are alive without evidence of disease and have been observed at least 4 years postrelapse. Although a few patients will have a durable response to subsequent therapy, the majority of patients who have progressive disease after an autologous transplant for lymphoid malignancy will succumb to recurrent disease within a short period of time.


Overview of new treatments for breast cancer.

Progress in the treatment of breast cancer developed along multiple directions of research during the last decade. The concept of dose-intensity was addressed through retrospective analyses and prospective randomized trials. It was confirmed that dose-intensity correlates with higher response rates, but the effect of dose-intensive treatments on survival still needs to be established. Several new cytotoxic drugs have appeared during the last several years. Taxol, navelbine, and anthrapyrazole CI-941 have been found to have major efficacy against breast cancer, with response rates exceeding 50%. Amonafide, lonidamine, and elliptinium analogs were also shown to be effective, although to a lesser degree. Antiestrogen analogs, new aromatase inhibitors, and LHRH analogs are recent developments that are changing the face of hormonal therapy. Monoclonal antibodies are being developed and evaluated for tumor imaging applications and as vehicles for specific antitumor agents (cytotoxics, radioisotopes, and toxins). Expanding knowledge about the basic biology of breast cancer has led to the identification of growth factors and their receptors, which may be exploited for therapeutic purposes in the not too distant future.


Comparison of PCNA/cyclin immunohistochemistry with flow cytometric S-phase fraction in breast cancer.

Kinetic index determined by enumeration of neoplastic cells positive for proliferative cell nuclear antigen (PCNA) in 70 breast carcinomas (avidin-biotin immunoperoxidase technique) was compared to synthesis-phase fraction (S-phase, or SPF) values obtained by flow cytometry (FCM) using a multiparametric, 2 color method (dual-label propidium iodide/cytokeratin-FITC). The percent PCNA positive tumor cells (12.5% mean, range 1-28%) was significantly greater in aneuploid tumors (14.2% mean, N = 35) compared to diploid range tumors (10.7% mean, N = 35) (p less than 0.05), and was correlated with SPF derived from ungated DNA histograms (12.5% mean +/- 5.5%, r = 0.45, p less than 0.001). Marginally stronger statistical correlations were observed between the PCNA index and SPF values calculated from cytokeratin-gated (15.8% mean, r = 0.53, p less than 0.001) DNA histograms or from SPF values obtained following linear baseline debris subtraction (mean = 8.1%, r = 0.48, p less than 0.001). Significant associations were identified between PCNA index and prognostically important clinicopathologic parameters including nuclear grade (p = 0.014), presence of necrosis (p = 0.005), and angiolymphatic invasion (p = 0.003). We conclude: 1) PCNA index is comparable to FCM SPF and correlates with factors of known prognostic importance in carcinoma of the breast; 2) baseline debris and contaminating events derived from non-epithelial cells both represent significant artifacts in proliferative fraction estimates derived from FCM DNA histograms; and 3) multiparametric analysis may represent one means of improving the specificity and clinical value of FCM SPF determinations.


Gastric acid inhibitory profile of ebrotidine, a novel H2-receptor antagonist in humans.

This study was designed to assess the gastric secretory effects of ebrotidine, a novel H2 receptor antagonist, in humans. Three groups (A, B and C) of male subjects with normal gastric mucosa were used. Group A (6 subjects) was used to determine the dose-dependency of gastric inhibitory effect of ebrotidine on basal and pentagastrin-induced maximal acid output. Group B (8 subjects) was employed to examine the duration of the inhibitory effect of ebrotidine on basal and pentagastrin-induced acid secretion. In group C (6 subjects), the 24h pH-metry was assessed using intraluminal pH-electrode placed in the gastric corpus and connected to a portable recording unit. Single oral dose of ebrotidine (200, 400 or 800 mg) caused a dose-dependent reduction in basal and pentagastrin-induced acid secretion that at a dose of 800 mg amounted to about 89% and 93%, respectively. This inhibition was still observed after 6h and averaged 72% and 50%, respectively. After 12 and 24h upon the drug intake, both basal and pentagastrin-induced acid secretion returned to the control values. Single oral dose of ebrotidine (800 mg) caused a significant reduction in circadian acidity and resulted in a marked and significant reduction of intragastric acidity for about 6h upon the administration. This inhibition was accompanied by a transient increase in basal and postprandial gastrin levels. We conclude that ebrotidine is highly effective inhibitor of basal, pentagastrin-induced and circadian gastric acid secretion in humans.


Computer-assisted video measurement of inhibition of ciliary beat frequency of human nasal epithelium in vitro by xylometazoline.

The effect of xylometazoline, an alpha-adrenergic agonist, on ciliary beat frequency (CBF) was tested on samples of human nasal epithelium in vitro. Ciliated tissue was obtained from the inferior nasal turbinates of five normal individuals. CBF was measured from video recordings of ciliary activity using a computer-assisted photometric technique. The mean CBF of cells from the five subjects, followed for 40 min without xylometazoline, was 12.0 +/- 1.1 Hz. All concentrations of xylometazoline significantly decreased ciliary beat frequency. After a 10-min exposure, the mean CBF dropped to 3.8 +/- 0.4 with 0.1% xylometazoline, 4.9 +/- 1.0 with 0.05%, and 8.1 +/- 0.9 with 0.025%. Washing with control culture medium at least partially reversed the inhibition within 10 min. Phentolamine (10(-3) M), an alpha-adrenergic antagonist, did not alter CBF significantly when used alone, but partially blocked the strong cilioinhibitory effect of xylometazoline. This action of xylometazoline is similar to that of several commercially prepared decongestants that contain potentially ciliotoxic preservatives in addition to alpha-adrenergic agonists and supports the view that alpha-adrenergic agonists act directly on ciliated cells to inhibit ciliary activity.


Otoneurology.

This review on progress in otoneurology focuses on peripheral and central vestibular disorders rather than auditory dysfunction. Recent literature reflects an imbalance between quantity and quality. For instance, several of the numerous papers on Menière's disease contribute little to furthering our knowledge of pathophysiology and treatment. The comparatively few papers on neurotransmitters, otolith function, and central vestibular pathway syndromes illustrate a promising area for scientific and clinical research in the future. Identification of vestibular pathway lesions as the cause of many oculomotor syndromes, such as downbeat and upbeat nystagmus or ocular tilt reaction lesions, will broaden the scope of otoneurology and the clinical responsibility of the neurologist.


Synthesis and trafficking of prion proteins in cultured cells.

Scrapie prions are composed largely, if not entirely, of the scrapie prion protein (PrPSc) that is encoded by a chromosomal gene. Scrapie-infected mouse neuroblastoma (ScN2a) and hamster brain (ScHaB) cells synthesize PrPSc from the normal PrP isoform (PrPC) or a precursor through a posttranslational process. In pulse-chase radiolabeling experiments, we found that presence of brefeldin A (BFA) during both the pulse and the chase periods prevented the synthesis of PrPSc. Removal of BFA after the chase permitted synthesis of PrPSc to resume. BFA also blocked the export of nascent PrPC to the cell surface but did not alter the distribution of intracellular deposits of PrPSc. Under the same conditions, BFA caused the redistribution of the Golgi marker MG160 into the endoplasmic reticulum (ER). Using monensin as an inhibitor of mid-Golgi glycosylation, we determined that PrP traverses the mid-Golgi stack before acquiring protease resistance. About 1 h after the formation of PrPSc, its N-terminus was removed by a proteolytic process that was inhibited by ammonium chloride, chloroquine, and monensin, arguing that this is a lysosomal event. These results suggest that the ER is not competent for the synthesis of PrPSc and that the synthesis of PrPSc occurs during the transit of PrP between the mid-Golgi stack and lysosomes. Presumably, the endocytic pathway features in the synthesis of PrPSc.


Multiple endocrine neoplasia type 2A.

A 40-year-old woman was admitted with complaints of headache, palpitation and diaphoresis. She had undergone right hemithyroidectomy 12 years previously. Histological reexamination of the operative specimen revealed a medullary thyroid carcinoma. Abdominal ultrasonography, CT scan and angiography showed bilateral adrenal tumors. Serum catecholamine levels in both adrenal veins were high. Based on these data, bilateral adrenalectomy was performed. Histological examination confirmed the diagnosis of pheochromocytomas. After operation, serum calcitonin and urinary noradrenaline levels were still high. Further examination by 131I-metaiodobenzylguanidine (MIBG) scintigraphy is planned.


The proliferative kinetics of somatostatin-producing cells in the rat antral mucosa after truncal vagotomy.

The kinetics of somatostatin-producing cells (D-cells) in the rat antral mucosa after truncal vagotomy were studied using double immunostaining for bromodeoxyuridine (BrdU) and somatostatin. Both the concentration of somatostatin and D-cell density in the antral mucosa demonstrated a significant increase on the 3rd day after truncal vagotomy. With the single labeling of BrdU, a few D-cells showed positive immunostaining for BrdU throughout the experimental period in both vagotomized and sham operated rats. With cumulative labeling, the BrdU labeled cells demonstrated a linear increase in an identical number for each experimental time-point in both groups. The labeling index of BrdU in the D-cells increased significantly, beginning on the 3rd day and attaining a maximum level of 41.8% on the 10th day, in the vagotomized group after cumulative labeling. In this group, however, the density of D-cells with no immunoreactive BrdU also increased quickly on the 3rd day with cumulative labeling. The present study indicates that the most important factor involving D-cell hyperplasia observed after truncal vagotomy is the activation of pre-existing D-cells to synthesize and release hormones, together with the rapid replication of progenitor cells and their maturation to D-cells.


A case of duodenal carcinoma presenting as a submucosal tumor.

This paper describes a patient with duodenal carcinoma showing the features of a submucosal tumor, leading to difficulty in making an accurate preoperative diagnosis. A 63-year-old woman was admitted for investigation of a duodenal mass. An examination of the upper gastrointestinal tract revealed a semicircular compression of the stomach and the duodenum. Endoscopy of the stomach and duodenum disclosed a hemispherical tumor with a deep ulcer in the apex. Computer tomography revealed a tumor of about 5 cm in diameter at the same site. Laparotomy was performed under the tentative diagnosis of a submucosal tumor. A tumor was found occupying the duodenum, which compressed the gastric antrum exteriorly, and was also adherent to the head of the pancreas by direct invasion. A curative resection was performed by combining a pancreatoduodenectomy with a transverse colectomy along with regional lymph node clearance. A microscopic examination showed that the tumor contained neoplastic cells growing in a tubular pattern, particularly in its peripheral regions. Thus, this lesion was finally diagnosed as primary adenocarcinoma of the duodenum.


Hormonal treatment of cryptorchidism--hCG or GnRH--a multicentre study.

In a modified, double-blind controlled study, 163 prepubertal boys (aged 1.8-13.0 years) with bilateral and 94 (aged 1.5-13.1 years) with unilateral cryptorchidism were allocated to treatment with either human chorionic gonadotrophin (im), gonadotrophin releasing hormone (intranasally) or placebo (intranasally). In individuals with the bilateral condition treatment with human chorionic gonadotrophin resulted in complete descent of both testes in 23% of patients. Treatment with human chorionic gonadotrophin in unilateral cryptorchidism resulted in complete descent in 19% of patients; all results were significantly better than those obtained with gonadotrophin releasing hormone or placebo. Linear and logistic regression analysis of the results obtained by treatment of bilateral disease showed that all treatments were more successful the younger the age of the boys. The data indicated that bilateral and unilateral cryptorchidism respond differently to hormonal treatment. We suggest that human chorionic gonadotrophin should be the first choice of treatment for prepubertal boys older than one year.


Prevention of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus infected patients: a clinical approach comparing aerosolized pentamidine and pyrimethamine/sulfadoxine.

The incidence of Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis (TE) was analyzed in 83 human immunodeficiency virus (HIV)-infected patients who inhaled aerosolized pentamidine (AP) either for primary prophylaxis (group Ia) or secondary prophylaxis (group IIa) of PCP. These cohorts were compared with two historical groups of patients who took Fansidar (pyrimethamine/sulfadoxine) for primary prophylaxis (group Ib) or secondary prophylaxis (group IIb) of PCP. The follow-up was 3-41 months (median 8 months). PCP did not occur in group Ia but was seen in 1 patient of group Ib (5%). TE was observed in 3 patients of group Ia (7.3%) and in 1 patient of group Ib (5%). PCP relapses were seen in 5 patients of group IIa (11.9%) and in 3 patients of group IIb (6.9%), whereas TE occurred in 13 patients of group IIa (30.9%) and in 1 patient of group IIb (2.3%). 20.3% of patients with CD4+ counts less than or equal to 100/microliters and only 7.7% of those with CD4+ counts greater than 100/microliters developed toxoplasmosis. In conclusion, Fansidar rather than AP prophylaxis should be recommended for patients with a history of PCP or toxoplasmosis and for all HIV-infected patients with CD4+ counts less than or equal to 100/microliters. In patients with CD4+ lymphocyte counts between 100 and 200/microliters, AP prophylaxis appears appropriate.


Gallstones in acromegalic patients undergoing different treatment regimens.

The frequency of gallstones during long-term treatment with the somatostatin analogue octreotide reported in different studies varies from 0% to 50%, the reason for this variation being unknown. Therefore, we examined 58 acromegalic patients undergoing different treatment regimens for the frequency of gallstones. Thirteen were treated with octreotide, 20 with bromocriptine, and 25 had no medical treatment after successful neurosurgery. Also, 58 patients without known gallbladder disease served as controls. The postprandial gallbladder contraction was also investigated in 27 acromegalic patients (10 with octreotide, 10 with bromocriptine, and 7 with no medical therapy). Ten of the 58 acromegalic patients were found to have gallstones, 4 of 25 receiving no medical treatment, 4 of 20 treated with dopamine agonists, and 2 of 13 treated with octreotide. In 9 of the 58 control patients, gallstones were detected. Although in the octreotide group the gallstones were newly formed under therapy, there was no difference in gallstone prevalence between the different treatment regimens and the control group. However, the postprandial gallbladder contraction was significantly more often inhibited during octreotide therapy, and this effect was most pronounced during the first hours following injection. Differences in the timing of injections therefore may be an explanation of the variable incidence of cholelithiasis in the different studies.


Development of ulcerative colitis under the immunosuppressive effect of cyclosporine.

In recent studies, cyclosporine has been used for the treatment of both ulcerative colitis and Crohn's disease. The results of these studies were variable. We report on a patient who was treated for 6 years with cyclosporine after kidney transplantation. He developed chronic distal colitis with all the features of ulcerative colitis. An infectious etiology of the colitis was carefully excluded. High-dose treatment with methylprednisolone was required to induce remission. This report shows that immunosuppressive therapy with cyclosporine did not prevent the development of ulcerative colitis in this patient.


Modulation of the incidence of hamster pulmonary endocrine cell hyperplasia by unilateral collapse of the lung.

We evaluated the effects of the unilateral collapse of the left lung on the formation of pulmonary endocrine cell hyperplasia (PECH) induced by 4-nitroquinoline 1-oxide (4NQO) in Syrian golden hamsters. Ten hamsters were injected subcutaneously with 20 mg/kg body weight of 4NQO, once a week for 4 weeks and treated with injection of silicone rubber into the left thorax at the 8th experimental week. Another 30 animals were divided into three groups: treated with 4NQO only, left lung collapse only, and vehicle only. All animals were sacrificed at the 30th week. The lung tissues were embedded in paraffin; 50 serial sections were made from the tissues of each animal and were studied histologically and immunohistochemically. PECH showed a positive immunostain for calcitonin and/or serotonin. In the uncollapsed right lungs of the animals treated with both 4NQO and unilateral collapse, the mean incidence of PECH was 12.2 x 10(-2)/mm3 lung volume; the incidences of PECH in the animals treated with 4NQO only, collapse only, and vehicle only were 4.1, 3.8, and 1.4 x 10(-2)/mm3, respectively. In the collapsed left lungs, PECH did not form, regardless of 4NQO treatment. This study demonstrates that unilateral collapse of the lung modulates the incidence of PECH induced by 4NQO in hamsters.


The maize auxotrophic mutant orange pericarp is defective in duplicate genes for tryptophan synthase beta.

orange pericarp (orp) is a seedling lethal mutant of maize caused by mutations in the duplicate unlinked recessive loci orp1 and orp2. Mutant seedlings accumulate two tryptophan precursors, anthranilate and indole, suggesting a block in tryptophan biosynthesis. Results from feeding studies and enzyme assays indicate that the orp mutant is defective in tryptophan synthase beta activity. Thus, orp is one of only a few amino acid auxotrophic mutants to be characterized in plants. Two genes encoding tryptophan synthase beta were isolated from maize and sequenced. Both genes encode polypeptides with high homology to tryptophan synthase beta enzymes from other organisms. The cloned genes were mapped by restriction fragment length polymorphism analysis to approximately the same chromosomal locations as the genetically mapped factors orp1 and orp2. RNA analysis indicates that both genes are expressed in all tissues examined from normal plants. Together, the biochemical, genetic, and molecular data verify the identity of orp1 and orp2 as duplicate structural genes for the beta subunit of tryptophan synthase.


Mutations at the Arabidopsis CHM locus promote rearrangements of the mitochondrial genome.

Nuclear recessive mutations at the chloroplast mutator (CHM) locus of Arabidopsis produce a variegated phenotype that is inherited in a non-Mendelian fashion. Molecular analysis of the cytoplasmic genomes of variegated plants from two independent chm mutant lines, using specific chloroplast and mitochondrial probes, showed that the chm mutations reproducibly induce the appearance of specific new restriction fragments in the mitochondrial genome. The presence of these restriction fragments cosegregated with the variegated phenotype in the progeny of crosses between mutant and wild-type plants. Sequence analysis of one of the new restriction fragments found in the variegated plants suggested that it was the product of a rearrangement event involving regions of the mitochondrial genome. Thus, it appears that the CHM locus may encode a protein involved in the control of specific mitochondrial DNA reorganization events.


Pinning down loose ends: mapping telomeres and factors affecting their length.

A degenerately repeated sequence, proximal to the telomere heptanucleotide repeat in maize, contains restriction enzyme sites that permit the separation of telomeres from the rest of the chromosomes. Probing with a telomere-specific oligonucleotide revealed genotype-dependent telomere lengths that vary more than 25-fold in maize among the 22 inbreds that have been surveyed. These lengths were found to segregate reproducibly in a recombinant inbred family where 50% of the variation can be accounted for by three loci. The dynamic control over telomere length in maize appears to act rapidly to achieve new genotypically determined telomere lengths in the F1. Clones of telomere proximal sequences were used to map restriction fragment length loci at the distal ends of eight of 20 chromosome arms.


Differential expression of two MADS box genes in wild-type and mutant petunia flowers.

We isolated and characterized two flower-specific genes from petunia. The protein products of these genes, designated floral binding protein 1 (FBP1) and 2 (FBP2), are putative transcription factors with the MADS box DNA binding domain. RNA gel blot analysis showed that the fbp1 gene is exclusively expressed in petals and stamen of petunia flowers. In contrast, the FBP1 protein was only detectable in petals and not in stamens, suggesting post-transcriptional regulation of the fbp1 gene in these tissues. The fbp2 gene is expressed in petals, stamen, carpels, and at a very low level in sepals but not in vegetative tissues. We analyzed the spatial expression of these fbp genes in floral organs of two homeotic flower mutants. In the blind mutant, whose flower limbs are transformed into antheroid structures on top of normal tubes, identical expression levels of both genes were observed in the antheroid structures as in normal anthers. In the homeotic mutant green petals, the petals are replaced by sepaloid organs in which the expression of fbp1 is strongly reduced but not completely abolished. Our results suggest a regulation of the fbp1 gene expression by the green petals (gp) gene. Expression of the fbp2 gene was not affected in the green petals mutant. In contrast to the proposed models describing floral morphogenesis, our data indicated that homeotic genes can be functional in one whorl only.


[Maternal pulmonary edema as an anesthesia complication after intravenous tocolysis and stimulating of lung maturation].

Maternal lung edema due to the use of beta-mimetic tocolytic agents is a well-documented complication. The risk increases if several other factors are present: infectious diseases, the use of inhaled anesthetics, EPH gestosis, hydramnios, twin gestation and preexisting cardiovascular disease. The complications induced by beta-mimetic tocolytic agents can be reduced by remembering their side effects and contraindications and restricting fluid intake. During obstetric general anesthesia in patients undergoing tocolysis, the infusion of large amounts of saline, as is widely practised today, is strictly contraindicated.


[Contribution of molecular genetics to the understanding of chemoresistance of Plasmodium falciparum].

Resistance to pyrimethamine and proguanil is due to a single point mutation in the gene that codes for dihydrofolate reductase. A single mutation gives rise to resistance to only one of the drugs. Resistance to both drugs results from several mutations. Chloroquine resistance phenotype is due to a rapid efflux of the drug from the parasite's digestive vacuole. This efflux is associated with a transmembrane permeability glycoprotein, or P-gp, which is similar to the protein implicated in the multidrug resistant phenotype of some cancer cells. However, one or several other poorly understood major gene(s) may be involved. Drugs which can inhibit the supposed affinity of P-gp for chloroquine are under study.


Drug-related methods for alleviation of stress in dentistry.

For many patients, dental procedures can cause a great deal of anxiety and fear. These emotions are part of a stress reaction, which, in physiologic terms, can pose a serious risk, particularly to patients with pre-existing cardiopulmonary disorders. In each case the dentist must decide whether anxiolytic stress-reducing treatment is indicated, and which method should be used. Besides certain psychotherapeutic techniques, numerous drugs (neuroleptics, barbiturates, beta-blockers, and benzodiazepines) are available for this purpose. This paper reviews these types of drugs and offers recommendations for their use.


Neuroleptic sensitivity in patients with senile dementia of Lewy body type.

To determine the outcome of administration of neuroleptics to patients with senile dementia of Lewy body type confirmed at necropsy. Retrospective analysis of clinical notes blind to neuropathological diagnosis. Specialist psychogeriatric assessment units referring cases for necropsy to a teaching hospital neuropathology service. 41 elderly patients with diagnosis of either Alzheimer type dementia (n = 21) or Lewy body type dementia (n = 20) confirmed at necropsy. Clinical state including extrapyramidal features before and after neuroleptic treatment and survival analysis of patients showing severe neuroleptic sensitivity compared with the remainder in the group. 16 (80%) patients with Lewy body type dementia received neuroleptics, 13 (81%) of whom reacted adversely; in seven (54%) the reactions were severe. Survival analysis showed an increased mortality in the year after presentation to psychiatric services compared with patients with mild or no neuroleptic sensitivity (hazard ratio 2.70 (95% confidence interval 2.50-8.99); (chi 2 = 2.68, p = 0.05). By contrast, only one (7%) of 14 patients with Alzheimer type dementia given neuroleptics showed severe neuroleptic sensitivity. Severe, and often fatal, neuroleptic sensitivity may occur in elderly patients with confusion, dementia, or behavioural disturbance. Its occurrence may indicate senile dementia of Lewy body type and this feature has been included in clinical diagnostic criteria for this type of dementia.


Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects.

Caffeine is the most widely consumed central-nervous-system stimulant. Three main mechanisms of action of caffeine on the central nervous system have been described. Mobilization of intracellular calcium and inhibition of specific phosphodiesterases only occur at high non-physiological concentrations of caffeine. The only likely mechanism of action of the methylxanthine is the antagonism at the level of adenosine receptors. Caffeine increases energy metabolism throughout the brain but decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion. Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Many of the alerting effects of caffeine may be related to the action of the methylxanthine on serotonin neurons. The methylxanthine induces dose-response increases in locomotor activity in animals. Its psychostimulant action on man is, however, often subtle and not very easy to detect. The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue. Caffeine exerts obvious effects on anxiety and sleep which vary according to individual sensitivity to the methylxanthine. However, children in general do not appear more sensitive to methylxanthine effects than adults. The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.


A68930 is a potent, full agonist at dopamine1 (D1) receptors in renal epithelial LLC-PK1 cells.

The selective dopamine1 (D1) receptor agonists SK&F 82526 (fenoldopam) and A68930 and the mixed D1/D2 agonist SK&F 85174 were tested for their ability to stimulate adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation in the porcine renal epithelial cell line, LLC-PK1. SK&F 82526 and SK&F 85174 were potent stimulators of cyclic AMP accumulation (EC50s 21.4 and 14.5 nM, respectively), but only partial agonists (intrinsic activities 31% and 46% of dopamine respectively). In contrast, A68930 was a potent, full agonist (EC50 12.7 nM, intrinsic activity 102% of dopamine). The stimulatory effects of A68930 and dopamine on cyclic AMP accumulation were not additive, and the stimulation of cyclic AMP accumulation by A68930 was blocked by the D1-selective antagonist, SCH 23390. These properties of A68930 suggest that it may be a useful D1-selective agonist to study renal D1 receptor mechanisms in vitro and in vivo.


Neural development. FESN Study Group.

The FESN-sponsored follow-up meeting on neural development highlighted progress toward understanding several central issues in developmental neurobiology with particular emphasis on investigation into the mechanisms of cell fate determination. In systems as diverse as the HSN neurons of C. elegans, the photoreceptor cells of the Drosophila eye, the wide range of cell types within the vertebrate retina and the neurons of the cerebral cortex, hindbrain and spinal cord, the importance of environment in the determination and maintenance of cell fate was clearly established. Advances in cell marking techniques, including fluorescent dye and retroviral tagging, have enabled the fates of cells in normal and heterotypic environments to be followed and have demonstrated the initial plasticity of the progenitor cell population in many systems. The recent establishment of in vitro systems for studying neural development should further define the precise nature and identity of the environmental signals that act to establish and maintain cell fate. Of course, establishment of cell identity is only the initial phase in the formation of the mature nervous system. Once the fate of individual cells is determined, migration of cells to appropriate locations, extension of axons to appropriate targets and refinement of neuronal circuitry must occur. Both the definition of genes that influence these processes in nematodes and recent advances in imaging techniques that provide a means of observing these later, dynamic processes in 'living' brain slices promise to significantly advance understanding of the complexities of development of functional nervous systems.


Vasoconstriction of guinea-pig submucosal arterioles following sympathetic nerve stimulation is mediated by the release of ATP.

1. The nature of the transmitter mediating vasoconstriction of guinea-pig submucosal arterioles following sympathetic nerve stimulation was studied. 2. Prazosin (0.1 microM) abolished the response to exogenously applied phenylephrine (1 microM) but had no effect on constrictions of submucosal arterioles evoked by nerve stimulation (100 pulses at 10 Hz). 3. Vasoconstrictions and excitatory junction potentials elicited by nerve stimulation were potentiated by idazoxan (0.1 microM). 4. Following reserpine treatment, catecholamine fluorescence was absent in submucosal arterioles but nerve-evoked vasoconstrictions were unaltered. 5. Vasoconstrictions and excitatory junction potentials recorded in response to sympathetic nerve stimulation, as well as constrictions evoked by exogenously applied ATP (3 microM), were abolished by the P2-purinoceptor antagonist, suramin (100 microM). Suramin had no effect on the vasoconstriction in response to noradrenaline (3 microM), or the nicotinic excitatory postsynaptic potentials (e.p.s.ps) and noradrenergic inhibitory postsynaptic potentials (i.p.s.ps) recorded from submucosal neurones. 6. We conclude that postjunctional responses of submucosal arterioles following sympathetic nerve stimulation are mediated solely through the activation of P2X-purinoceptors by ATP or a related purine nucleotide. The function of neurally released noradrenaline is to act through prejunctional alpha 2-adrenoceptors to depress transmitter release.


The role of CD18 in IL-8 induced dermal and synovial inflammation.

1. The intradermal administration of endothelial IL-8 (IL-8(1-77) or monocyte derived IL-8 (IL-8(1-72) to rabbits produced a concentration-dependent increase in plasma extravasation and an accumulation of polymorphonuclear leukocytes (PMNs) when measured over a 3 h time period. When plasma extravasation and PMN accumulation were measured over a 30 min time period no significant increases in PMN accumulation or plasma extravasation were observed in response to IL-8 alone. However, under these conditions, the addition of prostaglandin E2 (100 pmol) produced a significant potentiation of IL-8-induced plasma extravasation. There was no significant difference between the biological activities of IL-8(1-77) and IL-8(1-72). 2. Plasma extravasation and PMN accumulation induced by IL-8 were inhibited in rabbits pretreated with the monoclonal antibody designated IB4 (1 mg kg-1, i.v.) directed against the common beta chain (CD18) of the leukocyte integrins. 3. The intra-articular administration to rabbits of IL-8(1-77) (1 nmol) resulted 24 h later in the appearance of a mixed population of leukocytes (PMNs and mononuclear cells) in synovial lavage fluid. Biochemical analyses revealed the presence of an increased level of sulphated proteoglycans (sPG) and of the metalloproteinase stromelysin. Pretreatment of rabbits with IB4 (3 mg kg-1, i.v.) inhibited the accumulation of PMNs but had no effect on the mononuclear infiltrate nor on the levels of sPG or stromelysin. 4. The intradermal or intra-articular injection of E. coli-derived endotoxin induced similar inflammatory changes to those observed with IL-8.The possibility that the biological activities of IL-8 were attributable to minor contamination with endotoxin is unlikely for two reasons. Firstly, biological effects of endotoxin were observed at levels greater than that contained in the IL-8 preparation. Secondly,reduction of the endotoxin content of the IL-8 preparation by a factor of 10 did not produce a concomitant reduction in the observed biological activity of the IL-8.


The action of palytoxin on the isolated detrusor muscle of the rat.

1. The effects of a coelenterate toxin, palytoxin (PTX) have been studied in the isolated detrusor muscle. of the rat. 2. PTX (1-100 nM) initiated concentration-dependent contractions of the detrusor; the contraction led to an irreversible tachyphylaxis. Muscle desensitized to PTX continued to respond to acetylcholine (ACh) and excess K+ but the contractions were reduced compared to pre-PTX contractions. 3. Contractions evoked by PTX were not affected by the presence of atropine (10 microM), indomethacin (10 microM) or tetrodotoxin (0.5 microM) but were greatly reduced by nifedipine (3 microM) and by the absence of K+. PTX could not evoke contractions in the absence of Ca2+ or in tissues depolarized by exposure to excess K+. 4. PTX abolished the neurogenic contractile responses to electrical field stimulation (EFS). 5. Combined treatment with atropine (10 microM) plus nifedipine (3 microM) abolished contractile responses to EFS and greatly reduced the contractile response to PTX. 6. The contractile response to PTX (100 nM) was reduced following exposure of the muscle to alpha, beta-methylene ATP. 7. Exposure to PTX (100 nM) for 1-3 h reduced both the ACh content of the detrusor (by more than 80%), and the immunoreactivity of neuropeptide Y-containing nerve fibres compared to control. 8. It is concluded that the primary effect of PTX is to promote the release of endogenous motor transmitters, leading to their eventual depletion.


Selective and full beta 1-adrenoceptor agonist action of a catechol derivative of denopamine (T-0509) in the guinea-pig cardiac muscle and trachea: comparison with denopamine, xamoterol and isoprenaline.

1. The pharmacological actions of T-0509, a 3-hydroxy derivative of denopamine, were studied in various guinea-pig tissues; these effects were compared with those of isoprenaline, denopamine and xamoterol. 2. The intrinsic activities of the positive inotropic actions of T-0509, denopamine and xamoterol compared with isoprenaline (= 100%) in the papillary muscle were 99%, 83% and 28%, respectively, while their relative potencies (EC50 agonist EC50 isoprenaline) were 0.23, 33 and 1.4, respectively. The intrinsic activities of T-0509, denopamine and xamoterol as positive chronotropic agents in the right atria were 98%, 69% and 48%, respectively, and their equipotent concentrations (isoprenaline = 1) were 0.24, 50 and 4, respectively. 3. The positive chronotropic actions of T-0509 and denopamine were antagonized by bisoprolol (3 x 10(-8) M), but not by ICI 118,551 (3 x 10(-8) M). 4. The intrinsic activity of T-0509 in histamine-contracted tracheae was similar to that of isoprenaline, but its equipotent concentration was 38; the effects of both agents were antagonized by ICI 118,551 (3 x 10(-8) M), but not by bisoprolol (3 x 10(-8) M). Denopamine and xamoterol did not show any agonist activity on guinea-pig trachea. 5. Denopamine and xamoterol antagonized the positive chronotropic (pA2, denopamine: 6.98, xamoterol: 7.75) and tracheal relaxant (pA2, denopamine: 5.39, xamoterol: 6.25) effects of isoprenaline. 6. Isoprenaline, T-0509 and denopamine, but not xamoterol, contracted the guinea-pig aorta in a decreasing order in the presence of propranolol (10(-6) M).7. Based on the above studies, T-0509 appears to be a highly selective betaI-adrenoceptor agonist with full agonist properties, while denopamine and xamoterol appear to be selective, but partial betaI-adrenoceptor agonists.


The effects of combined angiotensin converting enzyme inhibition and beta-adrenoceptor blockade on plasma renin activity in anaesthetized dogs.

1. The effects of beta-adrenoceptor blockade on the changes in plasma renin activity (PRA) following angiotensin enzyme (ACE) inhibition were investigated in pentobarbitone-chloralose anaesthetized dogs. 2. ACE-inhibition, with enalapril (2 mg kg-1), caused a significant reduction in systemic arterial blood pressure (BP) with little or no effect on cardiac function, and a significant elevation of plasma renin activity (PRA). By contrast beta-adrenoceptor blockade with atenolol (1 mg kg-1), caused a similar reduction in BP but in addition, significantly reduced cardiac function and PRA. 3. A combination of enalapril with atenolol, caused a significant reduction in BP, cardiac function and PRA, hence there was no elevation of PRA, as was seen following ACE-inhibition with enalapril alone. 4. The observations with beta-adrenoceptor blockade alone, show that there is an important homeostatic role for the renal sympathetic innervation, mediated by beta-adrenoceptors, in controlling basal renin levels. Furthermore, the renal sympathetic innervation appears to be an important contributor to the renin release caused by an ACE-inhibitor as the additional presence of a beta-adrenoceptor blocking agent will prevent this release. 5. BW B385C (2 mg kg-1), which combines both ACE-inhibition and beta-adrenoceptor blocking properties, also produced reductions in BP and cardiac function similar to those seen with the enalapril/atenolol combination. In addition, for an equivalent degree of ACE-inhibition by BW 385C, to that seen with enalapril alone, the elevation of PRA was attenuated. 6. A combination of ACE-inhibition and beta-adrenoceptor blocking activity in a single entity, such as BW B385C, therefore also produces a reduced renin release when compared with an ACE-inhibitor, such as enalapril. This provides further confirmation of the importance of the renal sympathetic innervation in the renin response to ACE-inhibition, and supports the concept of combining ACEinhibition with beta-adrenoceptor blockade.


Effects of acute and chronic electroconvulsive shock on noradrenaline release in the rat hippocampus and frontal cortex.

1. Changes in the extracellular content of endogenous noradrenaline (NA) in frontal cortex and hippocampus were determined by in vivo microdialysis following acute and chronic electroconvulsive shock (ECS) in rats anaesthetized with chloral hydrate. 2. Basal release of NA in the frontal cortex (4.9 +/- 0.3 pg/sample) did not differ significantly from that in the hippocampus (4.6 +/- 0.2 pg/sample). 3. A single ECS resulted in an increase of NA release in the hippocampus (21.1 +/- 1.3 pg/sample) and in the frontal cortex (11.6 +/- 1.2 pg/sample). In both brain regions extracellular NA had returned to basal values within 30 min. 4. Animals were treated chronically with ECS (once per day for seven days). Twenty-four h later (day 8), basal release of NA into dialysis samples from the frontal cortex was significantly increased (50%) as compared to chronic sham controls. Basal release in the hippocampus was not significantly different from the sham controls. In the chronic ECS animals the increase in NA released in both brain areas following an ECS on day 8 did not differ from either the chronic sham controls or from animals given acute ECS. 5. Animals were challenged 24 h after eight ECS or sham control treatments (once per day) with the alpha 2-adrenoceptor antagonist, idazoxan (10 mg kg-1, s.c.). Idazoxan increased NA release in the hippocampus in both groups. There was no difference in the magnitude of the response in ECS- and in sham-treated rats.In the frontal cortex, idazoxan increased the extracellular NA content in the chronic sham controls, but the response to idazoxan was significantly attenuated in the chronic ECS animals.6. Chronic but not acute ECS was found to elicit a sustained (>24 h) increase in the release of NA in the frontal cortex, but not in the hippocampus. The idazoxan data suggest that the increase may be due to a downregulation of presynaptic alpha2-adrenoceptors in the frontal cortex. The difference in response of these two brain regions to chronic ECS is discussed in terms of differences in the regulation of extracellular NA content by uptake and autoreceptor activation.


The effects of idazoxan and other alpha 2-adrenoceptor antagonists on urine output in the rat.

1. In normally-hydrated Wistar rats the alpha 2-adrenoceptor antagonist, idazoxan (1, 3, 10 mg kg-1 i.p.), increased urine output during the 6 h following injection. 2. The more selective and specific alpha 2-adrenoceptor antagonist, RX811059 (0.3, 1, 3 mg kg-1 i.p.), and the peripherally-acting alpha 2-adrenoceptor antagonist, L-659,066 (1, 3, 10 mg kg-1 i.p.), had no effect on urine output in normally-hydrated animals. 3. In rats given a 25 ml kg-1 water-load orally, idazoxan (10 mg kg-1, i.p.) produced an initial antidiuretic response which was followed by an increase in urine output which was apparent 4 and 6 h after drug administration. 4. RX811059 (1, 3 mg kg-1 i.p.) and L-659,066 (3, 10 mg kg-1 i.p.) significantly decreased urine output in water-loaded rats in the 2 h after injection. 5. The antidiuretic effects of L-659,066 were attenuated in Brattleboro rats which are deficient in vasopressin; only the highest dose (10 mg kg-1 i.p.) decreased urine output, and this was only a small response in comparison with its virtual abolition of urine output in water-loaded Wistar rats. 6. The results with the selective alpha 2-adrenoceptor antagonists in Wistar and Brattleboro rats suggest that alpha 2-adrenoceptors in the periphery may play a physiological role in the control of water balance through a mechanism which involves vasopressin. 7. The paradoxical diuretic effects of idazoxan contrast with the effects of the other alpha 2-adrenoceptor antagonists and therefore may be attributed to a property of this compound unrelated to alpha 2-adrenoceptor blockade.


Investigations of the subtype of alpha 2-adrenoceptor mediating contractions of the human saphenous vein.

1. We have examined the effects of a series of alpha 2-adrenoceptor antagonists against isometric contractions to noradrenaline in human saphenous vein, and correlated these potencies with affinities for the alpha 2A-ligand binding site of human platelet and the alpha 2B-ligand binding site of rat kidney. 2. The alpha 2B-selective adrenoceptor antagonists, prazosin, ARC 239 and HV 723 showed high, and the alpha 2A-selective antagonist BRL 44408 showed low, potency in human saphenous vein. 3. Potency in human saphenous vein correlated better with affinity for the alpha 2B-ligand binding site (r = 0.71, n = 12, P less than 0.01) than with affinity for the alpha 2A-ligand binding site (r = 0.56, n = 12, non significant). 4. It is concluded that the postjunctional alpha 2-adrenoceptor of human saphenous vein resembles an alpha 2B-ligand binding site more than an alpha 2A-ligand binding site.


Modulation of peristalsis in the guinea-pig isolated small intestine by exogenous and endogenous opioids.

1. A recording method was developed to measure physiological parameters of the preparatory and emptying phases of peristalsis in vitro. This method enabled measurement of: the compliance of the intestinal wall during the preparatory phase (a reflection of the resistance of the wall to distension); longitudinal muscle contraction during the preparatory phase; the threshold volume required to trigger the emptying phase; the maximal ejection pressure and the average power generated during the emptying phase, which reflects the rate at which the intestine performs work. Modulation of these parameters by exogenous and endogenous opioids acting at mu, kappa and delta opioid receptors was investigated. 2. The compliance of the intestinal wall during the preparatory phase was reduced by the mu opioid receptor agonist, [D-Ala2, N-methyl-Phe4, Gly5-ol] enkephalin (DAMGO) but not by the kappa agonist, dynorphin, or the delta agonist, [D-penicillamine2, D-penicillamine5] enkephalin (DPDPE). Reflex contraction of the longitudinal muscle during the preparatory phase was inhibited by DAMGO, dynorphin and DPDPE. The threshold volume required to trigger the emptying phase of peristalsis was increased by DAMGO, dynorphin and DPDPE. 3. The maximal ejection pressure generated during the emptying phase was reduced by dynorphin and DPDPE, but not by DAMGO. The average power generated by the intestine when emptying was not altered by any of the agonists. 4. Electrically stimulated contractions of longitudinal muscle in strips of longitudinal muscle-myenteric plexus were not inhibited by DPDPE. Similarly, DPDPE did not significantly inhibit electrically induced contraction of circular muscle in strips of circular muscle-myenteric plexus.5. Each of the agonist effects on peristaltic parameters was antagonized by the appropriate antagonist:D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) (mu), norbinaltorphimine (nor-BNI) (kappa), naltrindole(delta).6. It is concluded that mu and kappa agonists act primarily on excitatory circular and longitudinal muscle motor neurones. The delta agonist probably acts on enteric neurones presynaptic to excitatory circular and longitudinal muscle motor neurones.7. Antagonists for mu, delta and kappa receptors did not affect any parameters of peristalsis when the intestine emptied against a low resistance. However, when emptying against a high outflow resistance, the average power generated by the intestine was increased by the kappa antagonist, nor-BNI, but not by CTOP or naltrindole.8. It is concluded that endogenous opioids appear to have little role in peristalsis when the intestine is working against a low outflow resistance. However endogenous opioids, acting primarily at kappa receptors,provide a braking mechanism by inhibiting the emptying phase of peristalsis in conditions in which the intestine empties against a higher resistance.


Effect of alpha 2-adrenoceptor agonists on gastric pepsin and acid secretion in the rat.

1. The purpose of the present study was to analyze the effects of the alpha 2-adrenoceptor agonists clonidine, guanabenz, detomidine and medetomidine on pepsin secretion in conscious rats provided with gastric chronic fistula and to compare this with acid secretion. 2. Basal interdigestive gastric secretion, which is mainly neurally driven in the rat, and the secretion directly stimulated by the two main stimulants of chief cells, cholecystokinin octapeptide (CCK8) and methacholine, were studied. 3. Basal secretion of pepsin and acid was inhibited by all four drugs with comparable EC50S. 4. CCK-stimulated pepsin and acid secretion was less sensitive than basal pepsin and acid secretion to alpha 2-adrenoceptor inhibition. 5. Methacholine-stimulated pepsin and acid secretion was not changed by clonidine and guanabenz; methacholine-stimulated acid was even marginally increased by clonidine. 6. These results do not favour the presence of alpha 2-receptors on chief cells in the rat stomach. They rather suggest that pepsin inhibition by alpha 2-adrenoceptor agonists is indirect and due to central or peripheral inhibition of the discharge of nerve fibres activating pepsin secretion.