Clinical features and therapeutic outcomes of 65 patients with acromegaly at Tokyo Women's Medical University.

OBJECTIVE: The purpose of this study was to survey the clinical characteristics, complications, and therapeutic outcome in patients with acromegaly. PATIENTS AND METHODS: The clinical features of 65 patients with acromegaly (31 males, 34 females; mean age: 50+/-2 yr.) who were admitted to Tokyo Women's Medical University between 1990 and 1999 were analyzed retrospectively from medical records. RESULTS: The retrospective analysis revealed that the diagnosis of acromegaly was preceded by approximately 8.1+/-1.1 years of signs and symptoms of the disease. Forty-six of the 65 patients (71%) had macroadenomas, 16 (25%) had microadenomas, and the remaining three had empty sella. The rate of biochemical cure or remission was 81% for microadenoma (13/16), 64% for macroadenoma without extrasellar extension (9/14), and 13% for macroadenoma with cavernous sinus extension (2/15). Eighteen (28%) patients had impaired glucose tolerance (IGT) and 32 (49%) had diabetes mellitus (DM). After treatment for acromegaly, glucose metabolism was analyzed again in 38 patients, and it improved in 26 patients with IGT or DM. Twenty-five of 65 patients (38%) had hypertension. Of 26 patients who underwent barium enema or colonoscopy, 10 had colonic polyps and 4 had colon cancer. CONCLUSION: This study suggests that long-term excessive growth hormone (GH) secretion causes many complications. Therefore, awareness of the early symptoms and signs of acromegaly and long-term careful management of complications, along with therapy to reduce serum GH/insulin-like growth factor (IGF)-I levels, are important for patients with acromegaly.

Separation of perfluoroalkylsulfinic acids and perfluoroalkylsulfonic acids by ion-exclusion chromatography.

Ion-exclusion chromatography has been successfully applied to the separation of a number of perfluoroalkylsulfinic acids and perfluoroalkylsulfonic acids. The separation of various perfluoroalkylsulfinic and perfluoroalkylsulfonic acids, with different alkyl groups, was investigated on a polymethacrylate-based, weakly acidic, cation-exchange resin (TSK gel OApak-A) in the H+-form and using conductimetric detection. When water was used as the eluent, these perfluoroalkylsulfinic and perfluoroalkylsulfonic acids could not be resolved. When an aqueous solution of benzoic acid and o-phthalic acid was used, the separation of each of these acids occurred. In order to improve their separation, the effect of the addition of methanol and 2,2,2-trifluoroethanol, as organic modifiers, was also investigated.

Centrilobular nodules correlate with air trapping in diffuse panbronchiolitis during erythromycin therapy.

BACKGROUND: Low-dose erythromycin therapy improves airflow limitation and airway inflammation in patients with diffuse panbronchiolitis (DPB). However, to our knowledge there has been no study to determine whether physiologic improvement during erythromycin therapy correlates with radiologic findings. STUDY OBJECTIVE: To clarify whether improvement in pulmonary function correlates with specific changes on chest CT. DESIGN: The relationship between five CT findings and five pulmonary function parameters was evaluated before and 3 months after low-dose erythromycin therapy in 24 patients with DPB retrospectively. RESULTS: After erythromycin therapy, the predicted percentage of vital capacity (%VC; 87.0 +/- 3.07% vs 98.9 +/- 3.39%; p = 0.00006) and 50% of the maximum midexpiratory flow rate of FVC (1.41 +/- 0.26 L/s vs 1.61 +/- 0.27 L/s; p = 0.03) significantly increased, and the residual volume/total lung capacity ratio (RV/TLC%; 44.5 +/- 1.93% vs 40.7 +/- 1.83%; p = 0.0019) significantly decreased, but the FEV(1) to FVC ratio and 25% of the maximum expiratory flow rate of FVC did not. In five CT findings, centrilobular nodules (3.7 +/- 0.4 vs 1.5 +/- 0.3; p = 0.0001), peripheral bronchiolar wall thickness (3.8 +/- 0.3 vs 2.6 +/- 0.4; p = 0.0007), and peripheral bronchiolectasis (2.8 +/- 0.3 vs 2.2 +/- 0.4; p = 0.0058) had significantly improved, whereas low attenuation area and central bronchiectasis had not. There were positive correlations of improved scores of centrilobular nodules with improved %VC (r = 0.58, p = 0.0062) and RV/TLC% (r = 0.64, p = 0.0022). CONCLUSIONS: Decreased air trapping in DPB correlates with an improvement of centrilobular nodules, which reflects the obstructive lesions of bronchioles during the erythromycin therapy.

Anxiety-like behavior in elevated plus-maze tests in repeatedly cold-stressed mice.

To clarify the relationship between SART (specific alternation of rhythm in temperature) stress (repeated cold stress) and anxiety, the effects of various types of stress on the behavior of mice were studied in elevated plus-maze tests and then the effects of anxiolytics were evaluated. The percentage of time spent in the open arms of the plus-maze apparatus decreased in mice subjected to SART stress without change in the total number of arm entries. No change was noted in mice subjected to other stresses, such as 1-h, 2-day and 5-day cold stress and 1-h, 15-h and 5 x 15-h restraint stress. The reduction in the percentage of time spent in the open arms caused by SART stress was inhibited by single and repeated administrations of diazepam and alprazolam and by a single administration of buspirone, which have no influence on the percentage of time spent in the open arms in nonstressed mice, but not by flumazenil, WAY-100635 and chronic treatment with buspirone. The effects of diazepam and buspirone were antagonized by flumazenil and WAY-100635, respectively. The behavior of SART-stressed mice in the plus-maze would thus appear to arise from anxiety, to which benzodiazepine and serotonin receptors are related, but the diazepam binding inhibitor, an endogenous anxiogenic protein, is not. Thus SART-stressed animals may be useful for investigating the psychopharmacological and neuropharmacological basis of anxiety.

Blood pressure and heart rate are increased by AF-DX 116, a selective M2 antagonist, in autonomic imbalanced and hypotensive rats caused by repeated cold stress.

Rats exposed to SART (specific alternation of rhythm in temperature) stress, which are ideal animal models for vagotonia-type dysautonomia, show various changes in cardiac and circulatory systems. In this study, attention was directed to cholinergic function in the SART-stressed rat heart and the effects of AF-DX 116, a specific muscarinic M2 antagonist, on blood pressure and heart rate. The results were compared with those obtained for atropine and pirenzepine. In SART-stressed rats, systolic and diastolic blood pressures (SBP and DBP) were lower than in unstressed rats. Oral AF-DX 116 resulted in greater elevation of DBP than SBP in unstressed rats. In stressed rats, greater and more prolonged elevation of SBP than in unstressed rats was noted, particularly at higher doses. A dose-dependent SBP change in stressed rats, caused by intravenous AF-DX 116, was shifted upward in parallel with that in unstressed groups, unlike with oral administration. The positive chronotropic effect of this drug was smaller in stressed rats than in unstressed rats, in contrast to the pressor effect. SART-stressed rats may thus have an enhanced sympathetic tone in the heart, as well as changes in muscarinic M2 receptors at sympathetic nerve endings and at the heart muscle. The effects of AF-DX 116 on blood pressure and heart rate thus may arise from peripheral action and AF-DX 116 may be useful for treating hypotension related to autonomic imbalance of the vagotonia type.

Effects of central and peripheral urocortin on fed and fasted gastroduodenal motor activity in conscious rats.

Since few previous studies have examined the effects of urocortin on physiological fed and fasted gastrointestinal motility, we administered urocortin intracerebroventricularly (icv) or intravenously (iv) in freely moving conscious rats and examined the changes in antral and duodenal motility. Icv and iv injection of urocortin disrupted fasted motor patterns of gastroduodenal motility, which were replaced by fed-like motor patterns. When urocortin was given icv and iv in the fed state, the motor activity remained like the fed patterns but % motor index (%MI) was decreased in the antrum and increased in the duodenum. Increase in the %MI in the duodenum induced by urocortin was shown as a nonpropagated event, since the transit of nonnutrient contents in the duodenum was decreased by icv and iv injection of urocortin. Changes in the gastroduodenal motility induced by icv injection of urocortin were abolished in animals with truncal vagotomy but not altered in animals with mechanical sympathectomy, suggesting that the vagal pathway may mediate the central action of urocortin. Neither urocortin antiserum nor alpha-helical CRF-(9-41) affected fed and fasted gastroduodenal motility, suggesting that endogenous urocortin is not involved in regulation of basal gastroduodenal motility.

Thallium-201 scintigraphy was useful in diagnosing ectopic ACTH syndrome due to bronchial carcinoid.

Abstract. Initial investigations of a 70-year-old woman with clinical Cushing's syndrome, including overnight dexamethasone suppression test, CRH test, and pituitary MRI, suggested the presence of ectopic ACTH production. Thoracic computed tomography (CT) scan revealed a mass measuring 7 mm in the right lung, but it was thought to be an incidental opacity, leaving the source of ectopic ACTH undetermined for several years. During this period, although the size of the lung opacity did not change remarkably, serum cortisol levels became elevated to 43 microg/dl, and the patient's symptoms worsened. Tl-201 SPECT demonstrated intense accumulation in the right lung. The mass was surgically resected using thoracoscopy to investigate it as the focus of ACTH production. Histological and immunohistochemical examination confirmed that the area of intense Tl-201 uptake was an ACTH-producing bronchial carcinoid. Plasma ACTH and cortisol levels decreased immediately after the surgery. In conclusion, this case demonstrated Tl-201 scintigraphy as a useful tool in identifying the location of an ACTH-producing bronchial carcinoid.

Synthetic absorbable film for prevention of air leaks after stapled pulmonary resection.

Staple-line reinforcement buttresses made of bovine pericardium (BP), expanded polytetrafluoroethylene (ePTFE), and so on have been shown to be effective in preventing air leaks after stapled lung volume reduction operations, and some of them have been clinically utilized. However, each buttress suffers at least one disadvantage such as risk of viral infection and chronic inflammation. A new buttress was made using a poly(L-lactic acid-co-epsilon-caprolactone) film (L/C film) and its effectiveness as a staple-line reinforcement was examined by performing lung volume reduction operation on a canine model. Soft tissue responses to the buttress were compared with those to the BP strip and the absorbable behavior was studied. The L/C film buttress was flexible and thin enough to easily cut. Death of dogs, infection, acute and prolonged air leaks, and any complications related to its use were not observed. The tissue responses to the film were more mild and favorable than those to BP. The L/C film was absorbed after the staple line was covered by a connective tissue. The results described above suggest that the buttress made of an L/C film is a promising staple-line reinforcement material.

Outcome of clonal hemophagocytic lymphohistiocytosis: analysis of 32 cases.

We studied the impact of clonality, determined by analysis of Epstein-Barr virus genome termini, T-cell receptor genes and clonal chromosomal abnormality, on the clinical outcome in 32 patients with hemophagocytic lymphohistiocytosis (HLH). Of the cases studied, 23 cases were EBV-clonal, 15 cases were TCR-clonal and 7 cases were cytogenetically clonal. Thirty patients were treated with immuno-chemotherapy and/or multiagents' chemotherapy and 4 received bone marrow transplantation. All 7 cases, in which cytogenetically abnormal clones were identified, were fatal (3-year survival by Kaplan-Meier analysis; 14%, 95%CI: 0-40%). None of these 7 cases received bone marrow transplantation. On the other hand, the 3-year survival of 23 clonal EBV-positive HLH cases including 4 cytogenetically abnormal cases was 64 % (95%CI: 42-84%), while that of 15 TCR-clonal cases was 53% (95%CI: 26-78%). Our observations suggest that cytogenetically abnormal cases are at extremely high risk, requiring intensive immuno-chemotherapy followed by prompt and timely allogeneic bone marrow transplantation.

[Stress-induced anxiety and endogenous anxiogenic substances].

Anxiety observed in animals subjected to stress was stated in relation to anxiety level and biological backgrounds of animals, changes in neurotransmitters and causal stressors. 1. Anxiety is thought to be a negative emotion caused by many kinds of stress such as restraint stress, SART (specific alternation of rhythm in temperature) stress (a repeated cold stress caused by environmental temperature), social stress, etc. 2. Emotional behavior in those stressed animals were attenuated by anxiolytics like diazepam, a benzodiazepine receptor agonist and buspirone, a serotonin (5-HT) 1A agonist. 3. Stressed rats had changed brain levels of a variety of neurotransmitters such as corticotropin-releasing factor (CRF), noradrenaline, 5-HT, dopamine, acetylcholine, histamine, cholecystokinin, etc. The percentage of time spent on the open arms of an elevated plus-maze apparatus decreased in those stressed animals. Abnormal elevated plus-maze behaviors were attenuated by diazepam, buspiron and a CRF antagonist. 4. Anxiety level differs according to the coping strategy of the recipients. Rats of different strain, sex, aging and/or family display different behaviors in elevated plus-maze. 5. Stress-induced anxiety-related behaviors were observed when levels of some neurotransmitters became unbalanced. Thus modulators of unbalanced brain substances are thought to have anxiolytic properties.

Neuropeptide Y induces fasted pattern of duodenal motility via Y(2) receptors in conscious fed rats.

Neuropeptide Y (NPY), a 36-amino acid peptide abundantly expressed in the brain, has been implicated in the regulation of feeding and visceral functions. The present study was designed to investigate whether or not NPY specifically regulates duodenal motility. The manometric method was used to measure duodenal motility in conscious, freely moving rats. The rat duodenum showed phasic contractions mimicking the migrating motor complex in the fasted state that were replaced by irregular contractions after the ingestion of food. NPY powerfully affected the contractile activity after intracerebroventricular (i.c.v.) administration, changing fed (postprandial) patterns into phasic contractions characterized as fasted (interdigestive) patterns. This effect was mediated via receptors with pharmacological profiles similar to rat Y(2) and Y(4) receptors, although neither Y(1) nor Y(5) agonists had any effects on motility despite potent feeding-stimulatory effects. Immunoneutralization with anti-NPY antiserum administered i.c.v. abolished fasted patterns and induced fed-like motor activities. An i.c.v. dose of peptide YY produced a different effect from NPY, with increase in the motor activities of both fed and fasted patterns. These results indicate that fasted and fed motor activities are regulated processes and that NPY induces fasted activity through Y(2), and possibly Y(4), receptors, which may represent an integrated mechanism linked to the onset of feeding behavior.

Cilostazol stroke prevention study: A placebo-controlled double-blind trial for secondary prevention of cerebral infarction.

Cilostazol, an antiplatelet drug that increases the cyclic adenosine monophosphate (AMP) levels in platelets via inhibition of cyclic AMP phosphodiesterase, has been used in chronic arterial occlusive disease. The purpose of the present study was to examine the effects of cilostazol on the recurrence of cerebral infarction using a multicenter, randomized, placebo-controlled, double-blind clinical trial method. Patients who suffered from cerebral infarction at 1 to 6 months before the trial were enrolled between April 1992 and March 1996. Oral administration of cilostazol (100 mg twice daily) or placebo was randomly assigned to the patients and continued until February 1997. The primary endpoint was the recurrence of cerebral infarction. In total, 1,095 patients were enrolled. An analysis based on 1,052 eligible patients (526 given cilostazol and 526 given placebo) showed that the cilostazol treatment achieved a significant relative-risk reduction (41.7%; confidence interval [CI], 9.2% to 62.5%) in the recurrence of cerebral infarction as compared with the placebo treatment (P=.0150). Intention-to-treat analysis of 1,067 patients also showed a significant relative-risk reduction (42.3%; CI, 10.3% to 62.9%, P=.0127). No clinically significant adverse drug reactions of cilostazol were encountered. Long-term administration of cilostazol was effective and safe in the secondary prevention of cerebral infarction.

A report on more than 10,000 vaginal hysterectomies performed without ligation of the paracervical ligaments.

OBJECTIVE: To review 10,016 cases of total vaginal hysterectomy (TVH) performed in our department by a method without ligation of the paracervical ligaments. METHODS: From 1955 to 1997, a total of 10,016 TVHs without ligation of the paracervical ligaments were performed at the Department of Obstetrics and Gynecology, Sapporo Medical University Hospital. RESULTS: Of all 22,509 gynecological operations, 44.5% were TVHs, and 8.7% were total abdominal hysterectomies (TAHs). The operative time of our TVHs ranged from 31-60 minutes in 44.1% of the cases, and from 61-90 minutes in 35.3% of the cases. Blood loss was less than 300 ml in 85% of the cases. Abdominal conversion from the vaginal approach occurred in 110 cases (1%). Operative complications also occurred only in 0.7% (69) of the cases. CONCLUSION: TVH without ligation of the paracervical ligaments is a safe and convenient method that has very few complications and that can be utilized by many gynecologists.

A case of vasospastic angina presenting Brugada-type ECG abnormalities.

An electrophysiological study and a provocative test of coronary artery spasm was attempted in a 68-year-old man who was having syncopal attacks and chest pain. His electrocardiogram had the characteristics of Brugada syndrome and ventricular fibrillation (VF) was induced by programmed electrical stimulation. ST-segment elevation became exaggerated by procainamide, which could not prevent the induction of VF. Coronary angiography revealed no stenotic lesions, and spasm in the left coronary artery was induced by intracoronary administration of acetylcholine with similar chest pain to that experienced before. Under treatment with diltiazem and flecainide, which suppressed the induction of VF, the patient experienced no recurrence of symptoms despite persistent ST-segment elevation. No previous reports have described coronary spasm associated with Brugada-type ECG abnormalities, and patients with syncope should be evaluated carefully.

Depressive state with anxiety in repeated cold-stressed mice in forced swimming tests.

The effects of various types of stress and drugs were studied to assess mouse performance in forced swimming tests, following characterization of SART (specific alternation of rhythm in environmental temperature) stress. Immobility time in the test decreased in mice subjected to SART, acute cold and restraint stress. No change was noted due to chronic cold stress or repeated fasting. The shortened time did not recover even 24 hr after the end of SART and chronic restraint stress. The time in SART-stressed mice finally recovered at 5-7 days. Shortening of immobility time in SART-stressed mice was inhibited by diazepam and repeated imipramine but not by lithium carbonate. In chronic restraint-stressed mice, this time was inhibited by repeated lithium carbonate but not diazepam or imipramine. SART stress would thus appear related to anxiety and depression and may be useful for detecting new types of antidepressants.

Thioperamide, a histamine H3 receptor antagonist, powerfully suppresses peptide YY-induced food intake in rats.

BACKGROUND: Whether or not peptide YY (PYY)-induced hyperphagia is modified by the histaminergic system in the brain is not yet known. METHODS: We investigated the effect on feeding of intracerebroventricular (ICV) administration of a specific histamine H3 receptor antagonist prior to ICV administration of PYY in rats. RESULTS: PYY (1, 3, and 10 micrograms/10 microL) strongly induced feeding behavior in a dose-dependent manner in sated rats. The 4-hour food intake induced by 3 micrograms/10 microL of PYY was equal to that induced by a 16-hour fast. The ICV administration of thioperamide (40.8, 122.4, and 408.5 micrograms/10 microL) did not suppress the 4-hour food intake induced by 16-hour fasting; however, thioperamide produced dose-dependent and strong inhibition of hyperphagia induced by a 3-microgram dose of PYY. CONCLUSIONS: These results suggest that the effect of PYY on appetite is different than that induced by fasting and may involve a histaminergic mechanism.

Biological activities of 1,1,6-trisubstituted indanes: beyond magainin 2.

MSI-78 is a peptide analog of naturally occurring magainin 2 isolated from the skin of Xenopus laevis. The peptide is known to have one of the strongest antibacterial activities in magainin 2 analogs against methicillin-resistant Staphylococcus aureus (MRSA). To find novel compounds superior to MSI-78, we have further designed, synthesizing 1,1-di(4-aminobutyl)-6-benzylindane (PM4) and 1,1-dibenzyl-6-(4-aminobutyl) indane (PM5), and tested their inhibitory ability of the growth of S. aureus. In an in vitro assay, PM4 showed the same antibacterial activity against the bacterium as MSI-78, and non-hemolytic activity against human red blood cells (RBCs) at the MIC (minimum inhibitory concentration) value, in contrast to the latter. On the other hand, PM5 showed stronger antibacterial activity than MSI-78, but being still accompanied with hemolysis at the MIC value. Otherwise, stronger decarboxylase activity for oxaloacetate was observed in PM5, rather than magainin 2 analogs or Oxaldie 1 as a control peptide, but not in PM4.

Insecticidal Activity of α-Methylene-γ-butyrolactone against Several Insect Pests.

α-Methylene-γ-butyrolactone (tulipalin A), which has been found to possess effective insecticidal activity against Thrips palmi (Thysanoptera; Thripinae), was examined on several insect pests. This compound caused high mortality against thrips species such as Frankliniella occidentallis and Frankliniella intonsa. In addition, some mortality was observed against other agricultural pest species. It is considered that α-methylene-γ-butyrolactone has a wide spectrum of insecticidal activity.

Precursor of α-Methylene-γ-butyrolactone Involved in the Insecticidal Activity of Thunberg Spiraea, Spiraea thunbergii.

6-Tuliposide A {6-O-(4-hydroxy-α-methylenebutyryl)-D-glucopyranose} was isolated from thunberg spiraea (Spiraea thunbergii) leaves. Acid-hydrolysis of this compound generated tulipalin A (α-methylene-γ-butyrolactone). This compound is thus considered as a precursor of insecticidal tulipalin A.