Cellular morphometric changes in cat hearts subjected to three hours of regional ischaemia

Summary We have studied the histogenesis of malignant lymphoma (ML), small cleaved cell of the B-cell type and intermediate lymphocytic lymphoma (mantle zone lymphoma) by comparing immunophenotypes and ALP-activity of neoplastic cells with those of germinal center cells (follicular center cells) anti mantle zone (MZ) cells of secondary follicles in non-neoplastic lymphoid tissues. The neoplastic cells in 3 cases of ML, follicular, small cleaved cell and 1 case of ML, small cleaved cell expressed the phenotypes similar to those of germinal center (GC) B lymphocytes (SIgM⁺, B1⁺, B2⁺, CALLA⁺, SigD^–, IL-2R^–, Leu-1^– and ALP^–). The neoplastic cells in 2 cases of ML, follicular, small cleaved cell and 12 cases of ML, diffuse, small cleaved cell displayed the characteristic phenotypes of MZ B lymphocytes (SIgM⁺, SIgD⁺, BA-1⁺, IL-2R⁺, Leu-1⁺ and ALP⁺). The phenotypes of 2 cases of mantle zone lymphoma were closely comparable with those of MZ B lymphocytes. These findings indicate that the histogenesis of ML, small cleaved cell of the B-cell type is heterogeneous and can be divided phenotypically into 2 types (GC B lymphocyte origin and MZ B lymphocyte origin). It is also apparent that intermediate lymphocytic lymphoma (mantle zone lymphoma) is derived from MZ B lymphocytes of secondary follicles.This work was supported by a Grant-in-Aid for Cancer Research From the Ministry of Health and Welfare (NO. 61-2)     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

Regional myocardial tissue blood flow during β-adrenergic blockade in cat hearts with acute ischaemia

Summary. Selective β₁ or β₂-adrenergic blockade was achieved by practolol or IPS 339, respectively, in cats with acute ligation of a coronary artery. During blockade, heart rate was kept constant by atrial pacing and blood pressure reduction was prevented by aortic clamping. Regional myocardial blood flow was measured by the distribution of 15 μm labelled microspheres. Practolol slightly reduced epicardial blood flow in ischaemic myocardium, while blood flow in border and normally perfused myocardium remained unchanged. Following IPS 339, myocardial tissue flow increased in normally perfused myocardium, on average by 37% in the endocardium and 30% in the epicardium. No changes occurred in the other regions. The flow changes brought about by IPS 339 were unrelated to haemodynamic changes, and the coronary vascular resistance was reduced. These results are indicative of coronary vasodilation related to β₂-adrenergic receptor blockade and was confined to well-oxygenated areas surrounding the acutely ischaemic zone.     

Regional myocardial tissue blood flow during sequential beta 1- and beta 2-adrenergic blockade in cat hearts with acute ischaemia

beta-Adrenergic blockade was imposed on cats with ischaemic regions of the left ventricle produced by coronary artery occlusion. Ten animals first received a beta 1-blocking agent (atenolol) followed by a beta 2-blocking agent (IPS 339). In ten more animals this sequence was reversed. Combined blockade, obtained after both agents were administered, showed clear reduction of tissue blood flow in all areas of the ventricle, except for the central ischaemic zone. The flow reduction could be ascribed to bradycardia and reduced coronary perfusion pressure. By analysing the sequential changes it was evident that blockade of beta 1-adrenergic receptors was responsible for the haemodynamic changes, and the coronary vascular resistance rose so as to match the quantity of blood flow to the functional state of the ventricle. Blockade of beta 2-receptors by IPS 339, however, showed no evidence of coronary vasoconstriction but rather maintained vascular resistance at an unchanged level despite a weak beta 1-adrenergic blocking effect.     

Reductions in convictions for violent crime during opioid maintenance treatment: a longitudinal national cohort study

Background

Although opioid maintenance treatment (OMT) has been found to reduce crime, less is known about its associations with violent crime. This study investigates changes in violent crime convictions prior to, during, and after OMT, and examines the relationship between violent crime convictions prior to OMT with the risk of violent and non-violent crime convictions during treatment.

Methods

The cohort comprised all who started OMT (n = 3221) in Norway between 1997 and 2003. Treatment data were cross linked with the national Crime Registry. Convictions for violent crime 3 years prior to, during, and after treatment were studied.

Results

Violent crime rates were significantly reduced during OMT compared with before treatment, for both men and women. The rate of convictions for violent crime during OMT was halved amongst those who remained in treatment. The reduction was less pronounced for those who left treatment: for this group, the rate of violent convictions after OMT was higher than before treatment. The risk of convictions for violent and non-violent crime during OMT was highest for those with violent convictions prior to treatment.

Conclusions

Violent crime is reduced during OMT. Screening for violent behaviour and violence risk assessment should be implemented in the treatment system.     

Plants used to treat malaria in Nyakayojo sub-county, western Uganda

Aim of study

We performed an ethnobotanical study of plants used to treat malaria in Nyakayojo sub-county in south western Uganda because malaria in this region, and in Uganda at large, is still the single most important reason for ill health and mortality. Two of the most vulnerable groups affected by malaria are young children and pregnant women and plants are commonly used in their treatment.

Materials and methods

Twenty-eight traditional birth attendants were interviewed about how they used plants to treat malaria. Review of the literature available on all species identified was undertaken.

Results

Altogether 56 plant species were used by the informants, 48 of which have been identified to species level. Thirty-two (67%) of the species used by the respondents are documented for antimalarial use in other studies, and nearly half (44%) have documented anti-plasmodial activity. Fifty-five percent of the species were used by 2 or more of the respondents. The most commonly used species were Vernonia amygdalina, the indigenous Aloe species, Justicia betonica, Vernonia adoensis and Tithonia diversifolia. It was common to use more than one plant in a recipe (43%). The respondents had good knowledge of the symptom of malaria, and fairly good understanding of the causes.

Conclusion

The interviews show that the group of traditional birth attendants has an extensive and diverse knowledge on plants used in the treatment of malaria. The literature survey may indicate a possible explanation for the use of several plants.     

Effects of timolol on adenine nucleotide catabolism in cat hearts with acute regional ischaemia

The effects of the beta-adrenergic blocking agent timolol on cardiac function and adenine nucleotide metabolism were investigated in cats with 45 min of acute ischaemia following coronary occlusion. Regional myocardial blood flow was measured by 15 micron radiolabelled microspheres, and adenine nucleotides and their degradation products were measured by high performance liquid chromatography in 16 tissue regions in each cat. During ischaemia, cats treated with timolol exerted a reduced cardiac performance as judged from reduced heart rate and cardiac contractility; consequently preocclusion tissue blood flow was reduced compared with a control group of cats. The ATP concentration was less severely depleted in ischaemic regions of the left ventricle in cats treated with timolol. The energy charge was reduced to a lesser extent in ischaemic regions, and in intermediate flow ranges the contents of the inosine and hypoxanthine/xanthine were reduced compared with untreated cats. These results indicate that the beta-adrenergic blocking agent timolol might protect the myocardium within a 45 min ischaemic period. The mechanism for this effect is most probably related to the reduction in overall cardiac performance.     

Open tibial fractures treated with Hoffmann external fixation

Thirty-two open fractures of the tibial shaft were treated with external fixation between 1973 and 1981. Early amputation was necessary in one patient. In the remainder, including 14 with extensive soft-tissue lesions, wound healing was obtained within 18 weeks, and the median time until full weight bearing without pain was 32 weeks (range 8-60 weeks). Two deep infections healed during the observation period. Among 26 patients examined 1-9 years after the injury, the result was excellent in six, good in 11, fair in four, and poor in five patients (including the amputation). One fracture had not united during the observation period. Four poor results were due to the stiffness of the ankle and foot after compartment syndrome. In conclusion, alertness for early fasciotomy is necessary even in severe open tibial fractures. The external fixation should not be continued longer than the soft tissue and bone reconstruction make it necessary.     

Prophylaxis of venous thromboembolism by aspirin, warfarin and heparin in patients with hip fracture. A prospective clinical study with cost-benefit analysis

Seven hundred and thirty-four patients were included in a prospective study for incidence of clinical venous thromboembolism under prophylaxis with either heparin, aspirin or warfarin and for the expenditure of hospital resources. Thromboembolic complications were more frequent (P less than 0.02) and hospital costs clearly higher in the low-dose heparin treated patient group compared with the aspirin and warfarin groups. There were no distinct differences between aspirin and warfarin treated patients neither in results nor in costs. However, carefully monitored treatment with warfarin with Thrombotest always less than 0.20, appeared to be the most effective prophylaxis in patients with hip fractures. In conclusion we now use aspirin as general prophylaxis in orthopaedic patients, and warfarin in patients with established risk of thromboembolic complications.