Improved results of allogeneic bone marrow transplantation for advanced hematologic malignancy using busulfan, cyclophosphamide and etoposide as cytoreductive and immunosuppressive therapy.

Twenty-four patients between the ages of 8 and 48 years (median 27.5) with high-risk for relapse hematologic malignancy received a marrow transplant from an HLA and MLC compatible sibling donor after chemotherapy with busulfan, 4 mg/kg/day for 4 days by mouth, cyclophosphamide 60 mg/kg/day i.v. for 2 days, and etoposide 60 mg/kg i.v. over 4 h on the first day of cyclophosphamide treatment (BU/CY/VP). Toxicity consisted of mucositis, skin rash, and nausea and vomiting in all patients, transient fever thought to be due to etoposide administration in 16/24 (67%) patients, and clinical veno-occlusive disease (VOD) of the liver in 4/24 (17%). There were nine deaths from causes other than recurrent disease in the first 100 days after transplant and two deaths after day 100, a total transplant mortality of 11/24 (46%). Three patients relapsed, but 10/24 (40%) remain alive and disease free 26-182 weeks (median 60 weeks) from transplant. These results compare favorably with results in a group of 12 similar risk patients treated with total body irradiation (TBI) containing regimens during an overlapping time period. Six of the TBI patients have had persistent or recurrent disease and only two (17%) are currently alive and disease free. The probability of disease persistence or relapse is 67% in the TBI group and 20% in the BU/CY/VP group (p less than 0.02).     

Analysis of resistance to gas flow in nine adult ventilator circuits

We measured the resistance in nine complete ventilator circuits, partial circuits and 7, 8, and 9 mm ID endotracheal tubes at flow rates of 20 to 120 liters per minute. We found a statistically significant (p less than 0.01) increase in resistive pressure with increases in flow rate, as the diameter of the ETT decreased, and as each component of the ventilator circuit was added to the ETT. There was a curvilinear increase in resistive pressure to increase in flow rate. However, when resistances were computed, the Bennett cascade "circuit" created higher resistance at 20 lpm than at flow rates up to 120 lpm. The Bennett cascade humidifier added the greatest resistive pressure, 3.5 to 8.5 cm H2O, the Engstrom Edith, 0.5 to 6.5 cm H2O, and the Conchapak added the least, 0.0 to 2.5 cm H2O at flow rates of 20 to 120 lpm. After all the components of the ventilator circuit were attached to the ETTs, there was approximately a 97 to 450 percent increase in resistive pressure compared to the resistive pressure created by the ETTs alone.     

Anesthetic effects on muscarinic signal transduction

A wealth of pharmacological and physiological evidence has established that anesthetics disrupt synaptic transmission at muscarinic and other synapses. The sequence of molecular events precipitated by agonist binding to the receptors is under intense scrutiny. It appears that at the majority of synapses G proteins serve to mediate the transfer of information from receptors to intracellular mechanisms. The major exception to this scheme is the situation in which an ion channel is incorporated directly in the receptor structure. Binding of an agonist to these receptors produces a conformational change in the receptors which opens an intrinsic ion channel. This situation occurs in nicotinic acetylcholine gamma-amino butyric acid type A (GABAA, and 5-hydroxytryptamine type 3 (5-HT3) receptors). Assays have been developed to evaluate several steps in the cascade of events involved in synaptic signal transduction, and these assays have been employed to determine the step at which anesthetics act to disrupt synaptic transmission. We have demonstrated that several volatile anesthetics alter the interaction of muscarinic receptors with transducer G proteins. Ligand-binding experiments suggest that receptor-G protein complexes are stabilized, thereby disrupting G protein GTPase activity and muscarinic control of cellular activity. This "stabilization" does not appear to involve an inhibition of guanine nucleotide binding, the proximal event in receptor-G protein dissociation. Two possibilities warrant further consideration: (1) that GDP release from inactive G protein trimers, which is normally catalyzed by the receptor, is inhibited, and (2) that receptor-G protein complexes fail to dissociate even in response to GTP binding. We are currently examining these possibilities using purified G proteins and receptors in reconstituted systems.     

Null mutation in human ciliary neurotrophic factor gene confers higher body mass index in males

Ciliary neurotrophic factor (CNTF) administration reduces weight in leptin-resistant mice via the signalling pathway normally activated by leptin. A G>A null mutation in the CNTF gene results in complete absence of protein. We hypothesised that absence of CNTF could lead to diminished initiation of anorectic pathways, with consequent increase in body mass. In 575 Caucasian men aged 59-73 years, the A/A genotype (frequency 1.9%) was associated with a 10 kg increase in weight (P=0.03, 2 df) and 3 kg/m(2) greater BMI (P=0.02, 2 df). There was no effect in women. The CNTF G>A null mutation therefore confers a moderate effect on obesity in males of A/A genotype, who represent 1% of the general population.     

High-performance liquid chromatographic method for quantification of busulfan in plasma after derivatization by tetrafluorothiophenol

A high-performance liquid chromatographic (HPLC) method was developed and validated for the determination of busulfan in plasma. Busulfan was extracted in toluene, derivatized by 2,3,5,6-tetrafluorothiophenol to obtain di-TFTP-butane, the derivatization product was then re-extracted in toluene and injected into the HPLC system with ultraviolet detection (wavelength: 275 nm). Recovery from extraction was 80%, the limit of quantification was 50 ng/ml and linearity ranged from 50 to 2000 ng/ml. In addition, forty-two samples obtained from pediatric patients treated with busulfan were analyzed by the HPLC and GC-MS assays based on the same derivatization procedure. The correlation between the di-TFTP-butane concentrations was highly significant (p<0.0001), demonstrating that the two methods were in good agreement.     

The association between social isolation and musculoskeletal health in older community-dwelling adults: findings from the Hertfordshire Cohort Study

Quality of Life Research - Social isolation has been associated with both physical and psychological adverse outcomes and is prevalent in older adults. We investigated the impact of social...     

Electrochemical lesions in the rat liver support its potential for treatment of liver tumors

BACKGROUND: An effective therapy is needed for patients with surgically unresectable liver tumors who have very limited life expectancy. One possible treatment is electrochemical tumor necrosis. This study investigated the natural history of electrochemical lesions in the normal rat liver. MATERIALS AND METHODS: A direct current generator, connected to platinum electrodes, was used to create controlled areas of liver necrosis. Animals were sacrificed 2 days, 2 weeks, 2 months, and 6 months after treatment and the macroscopic and histological appearance of the necrotic lesions was followed. RESULTS: No animal died as a result of electrolysis; postoperatively, all gained weight normally. Liver enzymes were significantly (P < 0.001) elevated after treatment, but returned to normal after a week. Two days after electrolysis, histology confirmed an ellipsoidal area of coagulative necrosis at the site of the electrode tip and commonly a segment of peripheral necrosis. After 2 weeks there was histological evidence of healing. By 6 months, very little necrotic tissue remained within a small fibrous scar. CONCLUSIONS: Electrolysis is a safe method for creating defined areas of liver necrosis that heal well with no associated mortality. This study supports the potential of electrolysis for treating patients with unresectable liver tumors.     

The safety of electrolytically induced hepatic necrosis in a pig model

BACKGROUND: Electrolysis fulfils the criteria for an ideal treatment of patients with unresectable liver tumours. Previous studies in the rat and pig have shown that controlled necrosis can be safely produced by inserting platinum electrodes into normal liver' parenchyma and liver tumours. As with any new treatment it is mandatory to investigate the 'worst-case scenario' of inadvertent intravascular electrode placement in a large animal model before progressing to clinical trials. METHODS: Under ultrasound control in six pigs, electrodes were inserted into, or immediately adjacent to, an hepatic vein. An electrolytic 'dose' of 100 C was then administered and the evolution of the lesion was monitored using ultrasound. Venous blood was collected before and during the electrolysis to evaluate potential acid/base disturbances and animals were closely monitored during electrolysis and during their recovery until a full autopsy was performed 4-7 days after treatment. RESULTS: Gas bubbles were seen to enter the hepatic veins or interior vena cava during treatment in five of the six animals. There were no major complications as a consequence and all animals recovered and remained in a healthy state until they were killed. At autopsy one animal had complete thrombotic occlusion of the left hepatic vein. Otherwise, findings were normal. CONCLUSION: In the clinical setting, due to the use of ultrasound to guide electrode placement into the centre of a tumour, the electrodes should rarely juxtapose an hepatic vein. Nevertheless, in this extreme situation, electrolysis is surprisingly safe with only one major vascular occlusion and no morbidity or mortality.