Controversies in the use of the pulmonary artery catheter

The pulmonary artery catheter (PAC) has been in use for more than 30 years. The amount and detail of hemodynamic information provided by the PAC cannot be matched by any other single technology. Whether or not this information makes a difference in the clinical outcomes of critically ill patients is uncertain, however. The Pulmonary Artery Catheter Consensus Conference scrutinized the available research data on the catheter and provided guidelines for clinicians on its use. This article summarizes the controversy and the guidelines available for use of the PAC. It notes the need for further research on patient outcomes.     

Staging and preparation of human fetal striatal tissue for neural transplantation in Huntington's disease

Transplantation of human fetal central nervous system tissue has been shown to be of benefit in Parkinson's disease, and is currently being explored as a therapeutic option in Huntington's disease. The success of a neural transplant is dependent on a number of factors, including the requirement that donor cells are harvested within a given developmental window and that the cell preparation protocols take account of the biological parameters identified in animal models. Although many of the criteria necessary for a successful neural transplant have been defined in animal models, ultimately they must be validated in human studies, and some issues can only ever be addressed in human studies. Furthermore, because neural transplantation of human fetal tissue is limited to small numbers of patients in any one surgical center, largely due to practical constraints, it is crucial that tissue preparation protocols are clearly defined and reproducible, so that (i) multicenter trials are possible and are based on consistent tissue preparation parameters, and (ii) results between centers can be meaningfully analyzed. Here we describe the preparation of human fetal striatum for neural transplantation in Huntington's disease, and report on the validation of a method for estimating the developmental stage of the fetus based on direct morphometric measurements of the embryonic tissue.     

Effect of a calcium and exercise intervention on the bone mineral status of 16-18-y-old adolescent girls

BACKGROUND: Osteoporosis may be prevented or delayed by maximizing peak bone mass through diet modification and physical activity during adolescence. OBJECTIVE: We studied whether increases in calcium intake and physical activity effectively increase the bone mineral status of adolescent girls aged 16-18 y. DESIGN: We conducted a 15.5-mo study of calcium supplementation (1000 mg Ca/d as carbonate) in 144 adolescent girls aged 17.3 +/- 0.3 y ( +/- SD). The subjects were randomly allocated to an exercise (three 45-min exercise-to-music classes/wk during term time) or nonexercise group. Dual-energy X-ray absorptiometry of the whole body, spine, forearm, and hip was performed before and after intervention. RESULTS: The mean (+/- SD) percentage of subjects compliant with supplement taking was 70 +/- 27% and with exercise class attendance was 36 +/- 25%. Baseline calcium intake was 938 +/- 411 mg/d. Calcium supplementation significantly increased size-adjusted bone mineral content. The effect was stronger in subjects with good compliance (percentage difference +/- SE): whole body, 0.8 +/- 0.3% (P < or = 0.01); lumbar spine, 1.9 +/- 0.5% (P < or = 0.001); ultradistal radius, 1.3 +/- 0.6% (P < or = 0.05); total hip, 2.7 +/- 0.6% (P < or = 0.001); femoral neck, 2.2 +/- 0.7% (P < or = 0.001); trochanter, 4.8 +/- 0.9% (P < or = 0.001). Attendance at > 50% of the exercise sessions was significant at the total hip (1.4 +/- 0.7%; P < or = 0.05) and trochanter (2.6 +/- 1.2%; P < or = 0.05). CONCLUSIONS: Calcium supplementation and exercise enhanced bone mineral status in adolescent girls. Whether this is a lasting benefit, leading to the optimization of peak bone mass and a reduction in fracture risk, needs to be determined.     

UK Food Standards Agency Optimal Nutrition Status Workshop: environmental factors that affect bone health throughout life

The UK Food Standards Agency (FSA) convened a group of expert scientists to discuss and review UK FSA- and Department of Health-funded research on diet and bone health. This research focused on the lifestyle factors that are amenable to change and may significantly affect bone health and the risk of osteoporotic fracture. The potential benefits of fruits and vegetables, meat, Ca, vitamins D and K and phyto-oestrogens were presented and discussed. Other lifestyle factors were also discussed, particularly the effect of physical activity and possible gene-nutrient interactions affecting bone health.     

Are women with polycystic ovary syndrome resistant to activated protein C?

Objective: This study was performed to test the hypothesis that an increased prevalence of activated protein C (APC) resistance in women with polycystic ovary syndrome (PCOS) puts them at increased risk of miscarriage and thrombosis.

Design: Case control study.

Setting: A district general hospital in the United Kingdom.

Patient(s): Forty-one women with PCOS and 25 controls.

Intervention(s): Clinical histories, ultrasound scans, and venepunctures.

Main Outcome Measure(s): Diagnosis of PCOS or control, clinical histories, APC resistance according to an activated partial thromboplastin time–based assay.

Result(s): There was no significant difference in the proportion of women with APC resistance in both groups (three women in the PCOS group [7%] vs. one woman in the control group [4%]). The prevalence of APC resistance in the entire study population was 6.5%. In the PCOS group, 29% (12/41) gave a positive family history of thrombosis compared with 8% (2/25) in the control group. None of the women with a positive family history of thrombosis had abnormal antithrombin 111, protein C, or protein S levels.

Conclusion(s): This study suggests that women with PCOS may have the same prevalence of APC resistance as the background population and that APC resistance may not put them at a higher risk of thrombosis or miscarriage compared with the case of the general population.     

Endocervical cancer is associated with an increase in the ligands and receptors for transforming growth factor-beta and a contrasting decrease in p27(Kip1)

OBJECTIVE: The aim of this study was to investigate the relationship between the expression of the TGF-beta ligands and TGF-beta receptors to the expression of p27(Kip1), a TGF-beta-regulated gene, in endocervical cancer. METHODS: To examine the expression of TGF-beta and p27(Kip1) in malignant transformation of the uterine endocervix, a panel of 23 formalin-fixed and paraffin-embedded human cervical specimens, including 8 with benign endocervical glands, 8 with cervical adenocarcinoma in situ, and 7 with cervical adenocarcinomas, was used. Tissues were immunostained with polyclonal antibodies that react specifically with TGF-beta 1, TGF-beta 2, TGF-beta 3, TGF-beta RI, TGF-beta RII, and p27(Kip1). RESULTS: Immunostaining for TGF-beta 1, TGF-beta 2, TGF-beta 3, TGF-beta RI, TGF-beta RII, and p27(Kip1) was detected in normal endocervix, with the TGF-betas showing weak cytoplasmic staining, while p27(Kip1) showed strong nuclear staining. Expression of TGF-beta increased significantly upon neoplastic transformation with the TGF-beta ligands and receptors showing strong cytoplasmic staining in adenocarcinoma in situ compared to normal endocervix. Interestingly, expression of TGF-beta was lower in adenocarcinoma than in adenocarcinoma in situ, but still significantly higher than in normal endocervix. TGF-beta 2 and TGF-beta 3 showed higher levels of immunostaining than TGF-beta 1 in adenocarcinomas. In contrast, p27(Kip1) protein expression decreased with progressive malignancy, with lower p27(Kip1) protein levels detected in adenocarcinoma than in adenocarcinoma in situ, while normal endocervix showed the highest level of p27(Kip1) protein expression. CONCLUSION: Elevated expression of the TGF-beta ligands and receptors is found in both cervical adenocarcinoma in situ and adenocarcinoma compared to normal endocervix. In contrast, a progressive decrease in p27(Kip1) occurs upon neoplastic transformation of the normal endocervix to cervical adenocarcinoma. These results suggest that neoplastic transformation of the endocervix may be related to dysregulation of TGF-beta and p27(Kip1) seen as an elevation of TGF-beta and a reduction of p27(Kip1) expression that may lead to loss of cell cycle control.     

Bilirubin and bile acids may modulate their own metabolism via regulating uridine diphosphate-glucuronosyltransferase expression in the rat

BACKGROUND AND AIMS: Uridine diphosphate (UDP)-glucuronosyltransferase (UGT) is a critical enzyme in the elimination of bilirubin and it also plays a role in the metabolism of bile acids. The aim of this study was to determine whether bilirubin and bile acids could modulate their own metabolism by regulating UGT levels in cultured rat hepatocytes. METHODS AND RESULTS: Incubation of hepatocytes with bilirubin (48 micromol/L) for 24 h significantly increased the mRNA expression of UGT1A1 and UGT1A5, two UGT isoforms responsible for the conjugation of bilirubin. The induction of UGT1A1 and UGT1A5 by bilirubin was concentration and time dependent. Treatment with chenodeoxycholic acid, cholic acid, deoxycholic acid, hyodeoxycholic acid and lithocholic acid at a concentration of 100 micromol/L for 48 h significantly enhanced the mRNA expression of UGT2B1, a UGT isoform responsible for the glucuronidation of bile acids. The UGT2B3 mRNA level was also increased by hyodeoxycholic acid. The regulation of UGT2B1 mRNA by chenodeoxycholic acid and hyodeoxycholic acid was dose and time dependent. CONCLUSION: Our results suggest that bilirubin and bile acids can induce UGT expression and as a result, these compounds may modulate their own metabolism. Such regulation could play a compensatory role in the pathological increased concentrations of these compounds in some hepatobiliary diseases.     

Gene Transfer And Models Of Gene Therapy For The Myocardium

1. Gene transfer into the myocardium can be achieved through direct injection of plasmid DNA or through the delivery of viral vectors, either directly or through the coronary vasculature. Direct DNA injection has proven extremely valuable in studies aimed at characterizing the activities of promoter elements in cardiac tissue and for examining the influence of the pathophysiological state of the myocardium on expression of transferred foreign genes. 2. Viral vectors, in particular adenoviruses and adeno-associated virus, are capable of transfecting genetic material with high transduction efficiencies and have been applied to a range of model systems for in vivo gene transfer. Efficient gene transfer has been achieved into the coronary vessels and surrounding myocardium by intracoronary infusion of adenovirus. 3. Because the immunogenicity of viral vectors can limit transgene expression, much attention has been paid to strategies for circumventing this, including the development of new modified adenovirus and adeno-associated virus vectors that do not elicit significant inflammatory responses. While cellular transplantation may prove valuable for the repair of myocardial tissue, confirmation of its value awaits establishment of a functional improvement in the myocardium following cell grafting. 4. Because gene transfer into the myocardium can now be achieved with high efficiency in the absence of significant inflammatory responses, the ability to regulate foreign gene expression in response to an endogenous disease phenotype will enable the development of new effective viral vectors with direct clinical applicability for specified therapeutic targets.