Therapeutic action and underlying mechanisms of a combination of two pentacyclic triterpenes, α- and β-amyrin,in a mouse model of colitis

Background and purpose:

α- and β-amyrin are pentacyclic triterpenes found in plants and are known to exhibit pronounced anti-inflammatory effects. Here, we evaluated the effects of a 1:1 mixture of α- and β-amyrin (α,β-amyrin) on an experimental model of colitis in mice.

Experimental approach:

Colitis was induced in Swiss male mice by trinitrobenzene sulphonic acid (TNBS) and followed up to 72 h; animals were treated systemically with α,β-amyrin, dexamethasone or vehicle. Macro- and microscopic damage, myeloperoxidase activity and cytokine levels were assessed in colons. Histological sections were immunostained for cyclooxygenase-2 (COX-2), vascular endothelial growth factor, phospho-p65 nuclear factor-κB (NF-κB) and phospho-cyclic AMP response element-binding protein (CREB)

Key results:

TNBS-induced colitis was associated with tissue damage, neutrophil infiltration and time-dependent increase of inflammatory mediators. Treatment with α,β-amyrin (3 mg·kg⁻¹, i.p.) or dexamethasone (1 mg·kg⁻¹, s.c.) consistently improved tissue damage scores and abolished polymorphonuclear cell infiltration. α,β-Amyrin, like dexamethasone, significantly diminished interleukin (IL)-1β levels and partially restored IL-10 levels in colon tissues 72 h after colitis induction, but only α,β-amyrin reduced vascular endothelial growth factor expression by immunohistochemistry. The colonic expression of COX-2 at 24 h and that of phospho-NF-κB and phospho-CREB (peaking at 6 h) after colitis induction were consistently inhibited by both α,β-amyrin and dexamethasone.

Conclusions and implications:

Systemic administration of α,β-amyrin exerted a marked and rapid inhibition of TNBS-induced colitis, related to the local suppression of inflammatory cytokines and COX-2 levels, possibly via inhibition of NF-κB and CREB-signalling pathways. Taken together, our data suggest a potential use of α,β-amyrin to control inflammatory responses in bowel disease.     

Radiotherapy for nonfunctioning pituitary adenomas: from conventional to modern stereotactic radiation techniques

The initial management of nonfunctioning pituitary macroadenomas (NFAs) is usually surgery; however, a significant proportion of NFAs may require further treatment. Radiotherapy is currently used in patients with residual tumour and achieves excellent long-term control, but there are concerns about potential late toxicity. Stereotactic radiotherapy, both in the form of radiosurgery or fractionated stereotactic radiotherapy, has been developed as a more accurate technique of irradiation with more precise tumour localization and consequently a reduction in the volume of normal tissue, particularly the brain, irradiated to high radiation doses. A review of the literature suggests that new radiation techniques offer safe and effective treatment for recurrent or residual pituitary adenomas; however longer follow-up is necessary to confirm the excellent tumour control and the potential reduction of long-term radiation toxicity. Currently, radiotherapy has an important role in patients with residual or progressive disease after surgery. Patients with small or no residual tumours after surgery may generally continue on a policy of surveillance without immediate irradiation, in order to avoid the potential toxicity of treatment.     

Closed trauma of the spleen. Indications to surgical treatment

The Authors mention the historical evolution that led to consider the splenectomy as the ideal operation in patients with post-traumatic lesions of the spleen. They linger then on the actual knowledges about the physiopathology of this organ that determined a substantial change of mind to a conservative treatment, when possible. By reporting their experience of the last decade, they weigh up how every therapeutic choice must be consequent to an accurate clinical evaluation that suggests the surgical abdomen exploration in urgency or, on the contrary, the monitoring of the patient. They linger particularly on the validity of the investigation and quantization of organ lesions and of the subsequent hemoperitoneum. The Authors end affirming that an accurate diagnostic evaluation and the subsequent therapy must take place in a specialized Trauma Center that ensures intensive monitoring and, if necessary, a timely operation in these patients.     

Surgical Treatment and Clinical Outcome of GH-Secreting Adenomas in Elderly Patients

Summary. Patients older than 65 years represent 3–5% of all acromegalic patients. The old age of the patients and the higher incidence of cardiovascular and metabolic complications related to acromegaly could increase the intra- and peri-operative risk, so that medical treatment is usually recommended as a therapy of choice. The aim of this retrospective study was to investigate the impact of transsphenoidal surgery in a series of 22 elderly patients with active acromegaly, with special regard to anaesthesiological risk, peri-operative complications, and clinical outcome. Despite an increased anesthesiological risk being present in 16/22 patients, no complication occurred during surgery. Similarly, no post-operative mortality or major complications were observed. Biochemical cure, defined at 6 months by glucose-suppressed plasma GH levels below 1 ng/ml and normal age-corrected IGF-I value levels, was achieved in 68% of patients and no recurrence of disease was observed in the subsequent follow-up (mean 5.2±2.1 years). A significant cardiovascular improvement was observed in cured patients, with a decrease of left ventricular mass index (91.3±20.1 vs 115.9±15.0 g/m²; P<0.005), as measured by echocardiography, as well as a slight but significant decrease of systolic and diastolic blood pressure values (130.0±12.1 mmHg vs 137.6±13.5 mmHg P<0.05; and 84.2±6.4 mmHg vs 88.8±7.5 mmHg P<0.05, respectively). A significant post-operative improvement of glucose tolerance was also observed in this group. We conclude that transsphenoidal surgery, if well planned and carefully performed, is safe and able to induce a significant cardiovascular and metabolic improvement even in elderly acromegalic patients.     

Atypical tentorial meningioma 30 years after radiotherapy for a pituitary adenoma

Although the human central nervous system used to be considered relatively resistant to the carcinogenic action of ionizing radiation, several lines of evidence now document a high incidence of secondary tumors in irradiated patients. The numerous reports of radiation-induced cerebral meningiomas generally distinguish those induced by high-dose radiation from those induced by low-dose radiation. We describe the case of patient who underwent subtotal resection of a chromophobe pituitary adenoma at the age of 18 years, who was successively treated by conventional fractionated radiotherapy with gamma rays emitted by a source of ⁶⁰Co until a total dose of 41 Gy. Over the next 30 years the patient experienced all the known late effects of radiation, including panhypopituitarism, cranial-nerve deficits (II, III and VI), massive radiation necrosis involving the left cerebral hemisphere and causing right hemiparesis and aphasia and, ultimately, an atypical tentorial meningioma with early recurrence after total resection. Received: 13 December 2000 / Accepted in revised form: 19 November 2001     

Increasing experience with integrated approach to pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries.

OBJECTIVES: To validate the preliminary surgical results of 'integrated approach' to pulmonary atresia, ventricular septal defect (VSD), and multiple aortopulmonary collateral arteries by retrospective analysis of our center experience. METHODS: Between 01/94 and 03/02, 37 patients aged 22 days to 13 years underwent surgery for pulmonary atresia, VSD, and multiple aortopulmonary collaterals. Case selection was based on preoperative calculation of total neopulmonary arterial index (TNPAI), pulmonary arterial index (PAI), and pulmonary arteries-to-collateral arteries lung segment perfusion ratio (S(pa):S(ca)). The decision for a possible VSD closure during one-stage procedures was based on an intraoperative pulmonary flow study. Twenty-five patients with a TNPAI equal to or greater than 150 mm(2)/m(2) underwent primary unifocalization, irrespective of PAI and S(pa):S(ca). Conversely, 12 patients with a TNPAI less than 150 mm(2)/m(2) and hypoplastic (PAI less than 100 mm(2)/m(2)) dominant (S(pa):S(ca) greater than 1) pulmonary arteries received a first-stage right ventricular outflow tract reconstruction, followed by unifocalization and repair (i.e. VSD closure) in nine cases. RESULTS: Among 34 patients who received total unifocalization, the overall repairability rate was 85% (first instance repairs: n=27; delayed VSD closure: n=2; 95% confidence interval, CI: 73-97%), with a survival rate at 7 years of 81%. Repaired survivors (n=26) are asymptomatic (n=22) or mildly symptomatic (n=4) at a follow-up interval of 43+/-28 months, with a 0.48+/-0.2 mean haemodynamic right ventricular/left ventricular pressure ratio, whereas palliated ones are waiting for either repair (n=3) or catheter study (n=2). Analysis of results has shown the following: (1) 100% (34/34 cases) feasibility of one-stage unifocalization in patients with a preoperative TNPAI equal to or greater than 150 mm(2)/m(2), whereas combined repairability rate was 79% only (95% CI: 65-93%); (2) 100% (12/12 cases) fulfillment of criteria for second-stage repairability (acquired TNPAI greater than 150 mm(2)/m(2)) in all patients treated with right ventricular outflow tract reconstruction; and (3) 93% (95% CI: 83-100%) overall accuracy of intraoperative flow study in predicting either postrepair mean pulmonary arterial pressure (VSD closed: n=23) or balanced pulmonary to systemic blood flow ratio (VSD left open: n=4). CONCLUSIONS: Increasing experience with 'integrated approach' to pulmonary atresia, VSD, and multiple aortopulmonaty collaterals has confirmed the preliminary results of our surgical series. The pulmonary flow study remains the most accurate intraoperative test for successful management of VSD during unifocalization procedures     

Inhibition of cell proliferation with an HLA-A-specific monoclonal antibody

A new mouse IgG2A monoclonal antibody--JD 12--is described, which was selected for its ability to inhibit peripheral blood mononuclear cell (PBMC) proliferation. Serologic, immunoprecipitation and immunoelectrophoretic studies showed JD12 to be monomorphically reactive with HLA-A molecules with an affinity of 10(9) M-1. JD12 was capable of inhibiting growth in resting or stimulated PBMC with an ID50 of 300 ng/ml in a time-dependent and dose-dependent manner without cytotoxicity. IgG, F(ab)2 and F(ab) were active. Growth stimulation by phorbol ester was not inhibited, suggesting that JD12 action occurred prior to protein kinase C activation. DNA and RNA synthesis were both slowed with a resulting G0/G1 block. Analysis of separated PBMC components showed that adherent cells displayed increased activity (clumping and RNA synthesis) upon JD12 binding. In addition, the inhibitory activity of JD12 could be transferred to new cultures by cell-free, IgG-free supernatant from JD12-treated PBMC, suggesting that the antiproliferative effects could be mediated, at least in part, in an indirect manner through an inhibitory factor. Therefore, potent, noncytotoxic inhibition of cell proliferation, DNA and RNA synthesis via MHC molecules can be mediated specifically through effects initiated by binding to HLA-A molecules alone.     

15The effect of Lower Esophageal Sphincter (LES) electrical stimulation on LES pressure

Background: Electrical stimulation (ES) of the stomach has been shown to modulate LESP. Electrical stimulation, using neural high frequency stimulation (NGES) can induce contractions of the smooth muscle of the gut. The purpose of this study was to determine if electrical stimulation of the LES can affect LESP. Methods: Four female hound dogs, weight: 20–25 kg, underwent an esophagostomy that allowed the introduction of a sleeve manometry catheter into the esophagus. They were also implanted with a pair of electrodes along the longitudinal axis of the LES. After 3 weeks of recovery, they underwent esophageal manometry recording during control and ES, performed randomly on separate days, using 4 different stimulations: 1‐Low frequency: freq: 6 cycles/min, pulse: 350 milisec, amp: 5 mAmp; 2 High‐frequency: freq: 50 Hz, pulse: 1 milisec, amp: 5 mAmp; 3‐ NGES: freq: 50 Hz, pulse:20 milisec, amp:10 volts; 4‐ High‐frequency, circular: freq: 20 Hz, pulse:1 milisec, amp:5 mAmp. All recordings were performed 1 hour after consumption of 3 ounces of canned dog food, to prevent fluctuations in LESP and under mild sedation (acepromazine 0.5 mg kg^­1). Tests consisted, during ES days, of 3 periods of 20 minutes each: control , stimulation and post stimulation. The effect of NGES was also tested under anesthesia and following administration of L‐NAME 50 mg kg^­1 IV. and also atropine 0.05 mg kg^­1 IV. Analysis: area under the curve (AUC) and pressure were compared among the 3 periods. Data shown as mean ± SD, ANOVA and t‐test, p < 0.05. Results: Sustained increase in LESP was observed during low frequency stimulation, 32.1 ± 12.8 vs. 42.4 ± 18.0 vs. 50.1 ± 23.6, control vs. stimulation vs. post stimulation respectively, p = 0.013. AUC also significantly increased during and after stimulation, 39,320.3 ± 15,722 vs. 51,294 ± 21,826 vs. 59,823.6 ± 28,198.4 mmHgxsec, control vs. stimulation vs. post stimulation respectively, p = 0.01. There was no significant change with other types of ES. NGES induced an initial rise in LESP followed within few seconds by relaxation with slow resumption of pressure over a 1 minute period. L‐NAME increased LESP and augmented the initial rise in LESP following NGES but markedly diminished or abolished the relaxation phase. Atropine lowered LESP and abolished the initial rise in LESP induced by NGES. Conclusions: Low frequency ES of the LES increases LESP in conscious dogs. NGES has dual effect on LESP: an initial stimulation, cholinergically mediated, followed by relaxation mediated by nitric oxide.     

Safety trial with the 5HT1B/1D agonist avitriptan (BMS-180048) in patients with migraine who have experienced pressure, tightness, and/or pain in the chest, neck, and/or throat following sumatriptan

We investigate whether symptoms of pressure, tightness, and/or pain in the chest, neck, and/or throat after administration of the 5HT_1B/1D agonist avitriptan were associated with objective impairment of the myocardial function on 12-lead electrocardiogram (ECG), continuous ECG (Holter) monitoring, and echocardiography. Migraine sufferers who in two-thirds of alt attacks treated with sumatriptan had experienced chest/throat/neck symptoms were chosen for study. Baseline measures included vital signs, a 12-lead ECG and an echocardiogram. Patients ( n =51) who had no clinically significant abnormality at baseline received a high dose (150 mg) of avitriptan orally outside of a migraine attack. If pressure, tightness, and/or pain in the chest, neck, and/or throat occurred, an ECG was obtained, and a repeat echocardiogram was done while the symptoms were present in order to monitor for impairment of myocardial function. If symptoms of these types did not occur within 60 min after administration of the study drug, a second echocardiogram was obtained. Forty-five patients (88%) reported at least one adverse event and 23 (45%) experienced pressure, tightness, and/or pain in the chest, neck, and/or throat after administration of avitriptan. No clinically significant myocardial abnormalities were observed in any patient, even in those who had experienced the targeted symptoms. No other serious adverse event occurred. We concluded that the typical 5HT_1B/1D agonist-induced chest/throat/neck symptoms are most unlikely to be of cardiovascular origin.     

Efficacy of confrontational counselling for smoking cessation in smokers with previously undiagnosed mild to moderate airflow limitation: study protocol of a randomized controlled trial

Background  

The use of spirometry for early detection of chronic obstructive pulmonary disease (COPD) is still an issue of debate, particularly because of a lack of convincing evidence that spirometry has an added positive effect on smoking cessation. We hypothesise that early detection of COPD and confrontation with spirometry for smoking cessation may be effective when applying an approach we have termed "confrontational counselling"; a patient-centred approach which involves specific communication skills and elements of cognitive therapy. An important aspect is to confront the smoker with his/her airflow limitation during the counselling sessions. The primary objective of this study is to test the efficacy of confrontational counselling in comparison to regular health education and promotion for smoking cessation delivered by specialized respiratory nurses in current smokers with previously undiagnosed mild to moderate airflow limitation.