Effect of ABT-627 (A-147627), a potent selective ETA receptor antagonist, on the cardiopulmonary profile of newborn lambs with surgically-induced diaphragmatic hernia

1. Postnatal mortality in isolated congenital diaphragmatic hernia (CDH) is mainly related to the associated pulmonary hypertension (PH) and to right-to-left shunting. 2. Endothelins (ETs) are potent vasoconstrictors and pro-mitogenic peptides. Strong evidences support their participation in CDH and in the etiology of PH via the activation of ET(A) receptors (ET(A)-Rs). 3. Evaluation of the effect of ABT-627, a selective non-peptidic ET(A)-R antagonist, given from -15 to 210 min post-delivery (1 mg kg(-1) bolus +0.01 mg kg(-1) h(-1) infusion, i.v.), was conducted in the lamb model of CDH. 4. Severity of CDH was assessed in comparison to untreated controls (n=5). Untreated CDH lambs (n=7) had a higher mean pulmonary arterial pressure (MPAP; P<0.0001), lower mean blood pressure (MBP; P=0.0004), higher MPAP / MBP ratio (P<0.0001), lower arterial pH (P<0.0001), higher paCO(2) (P<0.0001), lower paO(2) (P<0.0001) and lower post-ductal pulsatile SaO(2) (P<0.0001) than untreated controls. 5. Treated controls (n=7) showed a higher MPAP, lower MBP, higher MPAP/MBP ratio, lower arterial pH, higher paCO(2), lower paO(2), lower post-ductal pulsatile SaO(2) and lower plasmatic ir-ET ratios compared to untreated controls (P<0.0001). 6. Treated CDH lambs (n=8) showed a higher MBP (P<0.0001), lower MPAP / MBP ratio (P<0.0001), higher arterial pH (P<0.0001), lower paCO(2) (P<0.0001), higher paO(2) (P=0.0228), higher post-ductal pulsatile SaO(2) (P=0.0016) and lower plasmatic ir-ET ratios (P=0.0247) when compared to untreated CDH lambs. 7. These observations revealed that, although acute perinatal treatment with a selective non-peptidic ET(A)-R antagonist had some adverse effects in controls, it attenuated the progressive cardiopulmonary deterioration that occurred after birth in CDH lambs.     

Rapid escalation of weekly intramuscular methotrexate for nonmetastatic gestational trophoblastic disease: a Gynecologic Oncology Group study

Patients with postmolar nonmetastatic gestational trophoblastic disease were entered into this Gynecologic Oncology Group study to determine the relationship of efficacy and toxicity to a rapidly escalating dose of weekly intramuscular methotrexate. The treatment was initiated at 40 mg/m2 weekly of intramuscular methotrexate. If no major toxicity was encountered, the weekly dose was escalated 5 mg/m2 at 2-week intervals until a maximum dose of 50 mg/m2 per week was achieved. Complete response was defined as three normal beta-hCG values measured on consecutive weeks. Forty-six of sixty-two (74%) evaluable patients had a complete response to this regimen. Duration of therapy ranged from 3 to 16 weeks with a median of 7 weeks. No major toxicity occurred. Eight patients experienced leukopenia at a median of 3200/microliters (range 2100-3900). Two patients had platelet nadirs of 128,500 and 131,000. Only 50% (8/16) of the nonresponders subsequently responded to second-line 5-day methotrexate every 2 weeks. Fifteen of the sixteen weekly intramuscular methotrexate failures ultimately had complete responses after treatment with subsequent chemotherapy. In this study, second-line therapy results support administration of another agent such as dactinomycin rather than 5-day methotrexate. This higher dose (1.36 relative dose intensity to median complete response) of weekly intramuscular methotrexate therapy (40 mg/m2) is no more effective and of similar toxicity to a lower-dose regimen (30 mg/m2) reported earlier.     

Pulses and lipaemia,short- and long-term effect: potential in the prevention of cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of death in most developed countries. Most CVD deaths are preventable through life-style measures such as diet, exercise and avoidance of cigarette smoking. Decreased intake of saturated fat and cholesterol and increased intake of cholesterol-reducing foods, such as pulses, deserve a high priority for activities designed to prevent CVD. Epidemiological and observational studies indicate that habitual intakes of large amounts of dietary fibre or of vegetables are associated with significantly lower rates of CVD. Studies over four decades document the hypocholesterolaemic effect of pulses and soyabeans. We performed a meta-analysis of eleven clinical trials that examined the effects of pulses (not including soyabeans) on serum lipoproteins. Intake of non-soya pulses was associated with these changes: fasting serum cholesterol, -7.2 %, 95 % CI -5.8, -8.6 %; LDL-cholesterol, -6.2 %, 95 % CI -2.8, -9.5 %; HDL-cholesterol, +2.6 %, 95 % CI +6.3, -1.0 %; triacylglycerols, -16.6 %, 95 % CI -11.8 %, -21.5 %; and body weight, -0.9 %, 95 % CI +2.2 %, -4.1 %. The hypocholesterolaemic effects of pulses appear related, in estimated order of importance, to these factors: soluble dietary fibre, vegetable protein, oligosaccharides, isoflavones, phospholipids and fatty acids, saponins and other factors. Intake of pulses may also reduce risk for CVD by favourable effects on blood pressure, glycaemia and risk for diabetes, and risk for obesity. Overall, the available evidence indicates that regular consumption of pulses may have important protective effects on risk for CVD.     

Modelling normal tissue isoeffect distribution in conformal radiotherapy of glioblastoma provides an alternative dose escalation pattern through hypofractionation without reducing the total dose

The purpose of this study was to prove that by using conformal external beam radiotherapy (RT) normal brain structures can be protected even when applying an alternative approach of biological dose escalation: hypofractionation (HOF) without total dose reduction (TDR). Traditional 2-dimensional (2D) and conformal 3-dimensional (3D) treatment plans were prepared for 10 gliomas representing the subanatomical sites of the supratentorial brain. Isoeffect distributions were generated by the biologically effective dose (BED) formula to analyse the effect of conventionally fractionated (CF) and HOF schedules on both the spatial biological dose distribution and biological dose-volume histograms. A comparison was made between 2D-CF (2.0 Gy/day) and 3D-HOF (2.5 Gy/day) regimens, applying the same 60 Gy total doses. Integral biologically effective dose (IBED) and volumes received biologically equivalent to a dose of 54 Gy or more (V-BED54) were calculated for the lower and upper brain stem as organs of risk. The IBED values were lower with the 3D-HOF than with the 2D-CF schedule in each tumour location, means 22.7+/-17.1 and 40.4+/-16.9 in Gy, respectively (p < 0.0001). The V-BED54 values were also smaller or equal in 90% of the cases favouring the 3D-HOF scheme. The means were 2.7+/-4.8 ccm for 3D-HOF and 10.7+/-12.7 ccm for 2D-CF (p = 0.0006). Our results suggest that with conformal RT, fraction size can gradually be increased. HOF radiotherapy regimens without TDR shorten the treatment time and seem to be an alternative way of dose escalation in the treatment of glioblastoma.     

New methods of intensive therapy in stroke: hemicraniectomy in patients with complete middle cerebral artery infarction and treatment of intracerebral and intraventricular hemorrhage with urokinase

Life-threatening, complete middle cerebral artery infarction occurs in up to 10% of all stroke patients. The "malignant media occlusion" is an infarction occupying more than 50% of middle cerebral artery territory. The malignant, space-occupying supratentorial ischemic stroke is characterised by a mortality rate of up to 80%. Several reports indicate, that hemicraniectomy in this situation can be life-saving. Hemicraniectomy increases cerebral perfusion pressure and optimises retrograde perfusion via the leptomeningeal collateral vessels. A case of a patient is presented, having progressive neurological deterioration due to massive cerebral infarctions. The patient rehabilitation was successful. Decompressive surgery is life saving and can also give acceptable functional recovery. Hemorrhagic stroke is due to stroke in 15% of cases and in 10%, it is "spontaneous" intracerebral hematoma. The intracerebral and intraventricular hemorrhage represents one of the most devastating types of stroke associated with high morbidity and mortality. The 30-day mortality rate is 35% to 50% and most survivors are left with a neurological disability. The value of surgical therapy is debatable. The aspiration and urokinase therapy of the hematoma of intracerebral hemorrhage could improve final neurological outcome. Spontaneous, nontraumatic intraventricular hemorrhage frequently carries a grave prognosis. A large part of morbidity after intraventricular hemorrhage is related to intracranial hypertension from hydrocephalus. One patient presented had intracerebral hemorrhage and another had intraventricular hemorrhage treated with urokinase. Rapid and extensive reduction in the amount of intracerebral and intraventricular blood occurred. Urokinase lysis is safe and can be a potentially beneficial intervention in intracerebral and intraventricular hemorrhage. By performing decompressive craniectomy, the neurologists of stroke departments and intensive care units with the neurosurgeons will have to play major role in the management of stroke patients.     

Experimental stereotactic gamma knife radiosurgery. Vascular contractility studies of the rat middle cerebral artery after chronic survival

In vitro isometric small vessel myograph experiments and pathological investigations were performed on rat middle cerebral arteries. Thirty-four animals provided 68 normal vessels, six further rats had the endothelial layer mechanically removed from their 12 arteries. Eighteen animals received gamma knife irradiation to the middle cerebral arteries. Fifteen of these received 50 Gray, and three 25 Gray dose to the 50% isodose and the contralateral vessels offered 20 Gray and 15 Gray irradiated specimens. Survival times varied from 12 weeks to 18 months. In the acute stage, abolition of potassium-induced relaxation occurred as early as 24 h after irradiation whilst in one year this reaction seemed to recover and remained active to 18 months. The contraction response to prostaglandin F2 alpha was diminished at six weeks in the 50 Gray-irradiated vessels. However, from one year further reduction was seen and by 18 months this response was totally abolished. We demonstrated reduction of contractile capability of the irradiated normal vessels while the vessels remained patent. When using low irradiation dose there were no pathological changes even at 18 months, but marked physiological changes could be demonstrated. Different vessel wall functions appear to have different radiosensitivity, time course and capability for regeneration.     

Analysis of the temporal expression of nestin in human fetal brain derived neuronal and glial progenitor cells

Nestin expression in the developing human brain was examined with the use of unique human specific anti-nestin antibodies. Double immunostaining of cell cultures and tissue sections derived from first and second trimester human fetal brain (HFB) examined the co-expression of nestin with other cell type specific phenotypic markers. The immunocytochemical analysis shows that from first to second trimester, the majority of developing glial cells exhibited a transitional state marked by co-expression of nestin and GFAP. However, the corresponding transitional state for developing neuronal cells, co-expressing nestin and MAP-2, was rarely detected. These results imply different temporal patterns of nestin expression in cells of glial and neuronal lineages. Confocal microscopy of HFB tissue section staining also revealed a similar pattern of nestin co-expression with glial and neuronal markers. Our results suggest that nestin expression alone may not identify an undifferentiated stem cell, and that progenitor cells in glial and neuronal lineages express nestin in different temporal patterns.     

Practice patterns of antiphospholipid syndrome at a tertiary teaching hospital in Lebanon

The objective of the study was to describe the practice patterns of the antiphospholipid syndrome (APS) as compared with consensus guidelines for diagnosis and to determine whether practice patterns correlate with patient demographics and physician specialty. A retrospective medical chart review was conducted at the American University Hospital, in Beirut, Lebanon. All adult and pediatric patients admitted to the hospital between 1 January and 31 December 1998 who underwent either anticardiolipin antibodies (aCL) or lupus anticoagulant (LA) testing were included in the study. Work-up of APS syndrome was compared with: (a) the consensus guidelines for clinical diagnosis; (b) physician specialty; and (c) patient demographics (age, gender, ethnicity, health insurance status). Eighty-seven patients fulfilled at least one clinical criterion for APS; 92% were for work-up of thrombosis and 8% for pregnancy morbidities. Fifty-one percent underwent both aCL and LA. Overall 38% (33) of patients had an abnormal test result, however only 18% (6) underwent retesting, of whom only two satisfied a minimum of 6 weeks between test and retest TheAPS diagnostic work-up was requested by 11 different specialties. Rheumatologists were the most consistent in asking for both tests. APS is seen and diagnosed by a variety of medical specialties. Practice patterns as compared with the latest consensus are sub-optimal, and need to be improved. Interventions to help improve this have been discussed and are being implemented.