Stem cell transplantation for the treatment of Fanconi anaemia using a fludarabine-based cytoreductive regimen and T-cell-depleted related HLA-mismatched peripheral blood stem cell grafts

We have employed a new cytoreductive regimen to transplant two patients with Fanconi anaemia (FA), using T cell-depleted two HLA-allele disparate related peripheral blood stem cell transplants (PBSCTs). Patient 1, a 5-year-old male with FA and aplastic anaemia, initially received an HLA two-antigen mismatched unrelated cord blood transplant and failed to engraft. He received fludarabine (Flu) and cyclophosphamide (Cy), followed by a CD34(+) E-rosette(-) (CD34(+)E(-)), T cell-depleted, granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCT from his HLA B-DRB1 mismatched father. He received anti-thymocyte globulin (ATG), steroids, FK506 and G-CSF after transplant for rejection and graft-versus-host disease (GVHD) prophylaxis. The patient is now 23 months after SCT with no evidence of GVHD and with full haematopoietic and immune reconstitution. Patient 2, a 10-year-old boy with FA and myelodysplastic syndrome, received single-dose total body irradiation (SDTBI), Flu and Cy followed by a CD34(+)E(-), T-cell-depleted, G-CSF-mobilized PBSCT from his HLA B-DRB1 mismatched sister. He also received ATG, steroids, FK506 and G-CSF after transplant. The patient is now 12 months after SCT in complete remission with no evidence of GVHD. Absolute neutrophil counts (ANC) of > 1 x 10(9)/l were achieved on day 11 and day 10 post transplant respectively. Both patients are fully engrafted. In summary, we report two successful T-cell-depleted stem cell transplants from mismatched related donors for the treatment of Fanconi anaemia, using a fludarabine-based cytoreduction. Both patients experienced minimal toxicity, rapid engraftment and no GVHD.     

Enhanced surveillance of campylobacter infection in the North West of England 1997-1999

OBJECTIVES: To identify sources and routes of infection for sporadic cases of campylobacter infection in the North West of England. METHODS: Standard, structured questionnaires were used to gather epidemiological information from cases of campylobacter infection in the North West Region of England between 1997 and 1999. The strains of campylobacter isolated from these cases were identified and typed using serotyping and phage typing methods. Analysis of combined serotype and epidemiological data is presented. RESULTS AND CONCLUSIONS: Human campylobacter infection in the North West is seasonal and a new observation was a peak in cases in March each year. Drinking bird-pecked milk was a highly seasonal exposure that might be an indicator of environmental contamination with campylobacter. A possible environmental basis for seasonality of infection is discussed. Frequencies of risk exposures related to serotypes of cases are described and a potential association was demonstrated between Campylobacter jejuni HS6 and consumption of bird-pecked milk. Also, Campylobacter coli infections were more commonly associated with travel abroad than C. jejuni and a decreased proportion of C. jejuni HS2 and C. jejuni HS11 reported consumption of meat and unpasteurised milk (respectively). Contact with a sick animal may be a significant risk exposure in younger age groups and in those who do not consume poultry or meat. It is clear from this and other studies that the sources and vehicles of human campylobacter infection are numerous and interventions that target a single risk factor are unlikely to impact significantly on the overall burden of disease.     

Progression of myocardial abnormalities in experimental alcoholism

To determine those characteristics of left ventricular functional and metabolic alterations in chronic ethanolism that may be time-dependent, up to 36 percent of total daily calories as ethanol was fed to dogs for an average of 18 months (study group 1) or 52 months (study group 2). The short- and long-term study groups were fed the same diet with vitamin supplements and were compared with simultaneously studied control animals. Left ventricular function was assessed in the intact anesthetized dogs using the thermodilution method for end-diastolic volume and stroke volume determinations. During preload increments with saline solution, a significantly greater increase in end-diastolic pressure was observed in both groups receiving ethanol as compared with the control animals; this increase was associated with reduced end-diastolic and stroke volume. However, the responses were similar in the short- and long-term study groups. Increased left ventricular collagen was the apparent basis for the compliance abnormality, but neither variable differed in the groups receiving ethanol.In contrast, the first derivative of ventricular pressure (dP/dt) normalized for preload and afterload, an index of left ventricular contractility, and the velocity of the contractile element (Vce) were significantly reduced only in the long-term study group while tissue calcium was normal. When chromium-51-EDTA was used as an extracellular marker, accumulation of water and sodium in myocardial cells was observed only in the long-term study group, without a reduction of cell potassium. In view of the dilatation of sarcoplasmic reticulum observed on electron microscopy, It is postulated that distortion of the tubular membranes may limit the rate of calcium availability to contractile protein and thus diminish contractile function in chronic alcoholism.     

Effectiveness of multiple bolus administration of tissue-type plasminogen activator in acute myocardial infarction

The feasibility and possible advantages of intravenous bolus administration of recombinant tissue-type plasminogen activator (rt-PA) were investigated in 26 consecutive patients with early (less than 6 hours) evolving acute myocardial infarction. Either an intravenous infusion of 40 clot-lysis megaunits (cIMU) double-chain rt-PA over 1.5 hours followed by 20 cIMU over 5 hours (infusion group, n = 12) or 4 intravenous bolus injections of 10 cIMU at 20 minute intervals (bolus group, n = 14) were randomly administered. Coronary arteriography was performed before and at regular predefined intervals up to 90 minutes from the start of rt-PA administration, and at 24 hours. Acute recanalization of the infarct-related coronary artery was demonstrated in 7 of 12 patients (58%; 95% confidence interval 28 to 85%) in the infusion group and 11 of 14 patients (79%; 95% confidence interval 49 to 95%) in the bolus group (difference not significant). Two patients in the bolus group had reoccluded by 24 hours. Mean time from the start of rt-PA to patency of the infarct-related coronary artery was 39 +/- 6 (standard error of the mean) minutes in the infusion group and 28 +/- 6 minutes in the bolus group (p = 0.2). There were no significant differences in the minimum infarct-related coronary artery luminal diameter measured by computerized quantitative arteriography between the infusion group and the bolus group at 90 minutes or at 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)     

Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London

OBJECTIVE: To examine the maternal and foetal risks of adverse pregnancy outcome in relation to maternal obesity, expressed as body mass index (BMI, kg/m(2)) in a large unselected geographical population. DESIGN: Retrospective analysis of data from a validated maternity database system which includes all but one of the maternity units in the North West Thames Region. A comparison of pregnancy outcomes was made on the basis of maternal BMI at booking. SUBJECTS: A total of 287,213 completed singleton pregnancies were studied including 176,923 (61.6%) normal weight (BMI 20--24.9), 79 014 (27.5%) moderately obese (BMI 25--29.9) and 31,276 (10.9%) very obese (BMI> or =30) women. MEASUREMENTS: Ante-natal complications, intervention in labour, maternal morbidity and neonatal outcome were examined and data presented as raw frequencies and adjusted odds ratios with 99% confidence intervals following logistic regression analysis to account for confounding variables. RESULTS: Compared to women with normal BMI, the following outcomes were significantly more common in obese pregnant women (odds ratio (99% confidence interval) for BMI 25--30 and BMI> or =30 respectively): gestational diabetes mellitus (1.68 (1.53--1.84), 3.6 (3.25--3.98)); proteinuric pre-eclampsia (1.44 (1.28--1.62), 2.14 (1.85--2.47)); induction of labour (2.14 (1.85--2.47), 1.70 (1.64--1.76)); delivery by emergency caesarian section (1.30 (1.25--1.34), 1.83 (1.74--1.93)); postpartum haemorrhage (1.16 (1.12--1.21), 1.39 (1.32--1.46)); genital tract infection (1.24 (1.09--1.41), 1.30 (1.07--1.56)); urinary tract infection (1.17 (1.04-1.33), 1.39 (1.18--1.63)); wound infection (1.27 (1.09--1.48), 2.24 (1.91--2.64)); birthweight above the 90th centile (1.57 (1.50--1.64), 2.36 (2.23--2.50)), and intrauterine death (1.10 (0.94--1.28), 1.40 (1.14--1.71)). However, delivery before 32 weeks' gestation (0.73 (0.65--0.82), 0.81 (0.69--0.95)) and breastfeeding at discharge (0.86 (0.84--0.88), 0.58 (0.56--0.60)) were significantly less likely in the overweight groups. In all cases, increasing maternal BMI was associated with increased magnitude of risk. CONCLUSION: Maternal obesity carries significant risks for the mother and foetus. The risk increases with the degree of obesity and persists after accounting for other confounding demographic factors. The basis of many of the complications is likely to be related to the altered metabolic state associated with morbid obesity.     

Myocardial ischemia and cell acidosis: Modification by alkali and the effects on ventricular function and cation composition.

Myocardial cell pH was measured with 5, 5 dimethyl-2, 4-oxazolidinedione (DMO) in intact anesthetized dogs by a transient indicator dilution technique. Bolus injections of labeled DMO, vascular, extracellular and water indicators were made into the left anterior descending coronary artery, and blood samples were collected from the great cardiac vein. The steady state distribution of DMO between cells and plasma was calculated from the mean transit times of the indicator. Normal myocardial cell pH averaged 6.94 and changed by 58% of the concomitant alterations in plasma pH after infusions of acid or alkali. Myocardial ischemia induced by inflation of a balloon tip catheter in the left anterior descending coronary artery resulted in progressive decreases in cell pH to 6.59 by 1 hour. Infusions of sodium carbonate diminished intracellular acidosis. Hemodynamic studies during 4 hours of ischemia with blood pH at 7.55 to 7.60 indicated a significantly reduced left ventricular end-diastolic pressure and increased stroke volume by comparison with findings in animals given infusions of saline solution. Ventriculograms revealed improved wall motion in the ischemic segment after infusion of alkali. Precordial mapping showed a significant reduction in the number of leads with S-T segment elevation as well as in the sum of S-T segment elevations, but R wave amplitudes did not differ from those in control studies. Calculations of extracellular space, tissue water and cation content revealed a reduced gain of cell sodium ion and loss of cell potassium ion during ischemia after alkali treatment. The latter may account for the S-T segment responses, whereas enhanced ventricular performance may be related to reduced competition of hydrogen ion with calcium ion for binding sites on contractile protein.     

Influence of fructose on the glycogen synthase and phosphorylase systems in rat liver

Fructose and glucose, when administered as a single, large intravenous dose (500 mg/kg) produced opposite effects on key regulatory enzymes of glycogen metabolism in intact normal fed animals. Glucose rapidly stimulated glycogen synthase phosphatase activity and increased the proportion of glycogen synthase in the active (I) form as expected; fructose reduced synthase phosphatase activity and the proportion of synthase in the I form. Glucose also stimulated a reduction in the proportion of phosphorylase in the active (a) form, whereas fructose stimulated an increase in the proportion of phosphorylase in thea form. The effect of fructose was not mediated by an increase in cyclic adenylate (cAMP) concentration nor by a conversion of phosphorylase kinase b to phosphorylase kinase a. As expected, the concentration of ATP decreased significantly. The increase in proportion of phosphorylase in the a form may be due to stimulation of phosphorylase kinase b activity by a decrease in the intracellular ATP:Mg++ ratio or by increase in intracellular Ca++ concentration. The mechanism of the fructose-induced change in synthase phosphatase activity and in synthase I activity is unknown.