Prior diabetes mellitus is associated with increased morbidity in cystic fibrosis patients undergoing bilateral lung transplantation: an 'orphan' area? A retrospective case-control study.

BACKGROUND: The aim of this study was to determine whether pre-existing diabetes mellitus increases the risk of rejection, infection and/or death in cystic fibrosis patients undergoing bilateral sequential single-lung transplantation. METHODS: A retrospective audit of 25 consecutive patients with cystic fibrosis who underwent bilateral sequential single-lung transplantation between 1 January 2003 and 31 December 2005 at a tertiary referral hospital was carried out. RESULTS: Although 32% patients had diabetes diagnosed before lung transplantation, 92% had random blood glucose levels > or =11.1 mmol/L requiring insulin during admission. Patients with pre-existing diabetes had increased infection-related (3.9 vs 1.2, P= 0.01) and putative rejection-related (1.4 vs 0.5, P= 0.04) hospital admissions post-transplantation compared with those without diabetes pre-transplant. During the period of observation, four of eight patients with a prior diagnosis of diabetes died compared with none of 17 patients without prior diabetes (P= 0.0055). CONCLUSION: Almost all cystic fibrosis patients develop hyperglycaemia after lung transplantation, but patients with prior diabetes have more complication-related admissions to hospital and a higher mortality rate.

Antiretroviral therapy and the human immunodeficiency virus--improved survival but at what cost?

Patients infected with human immunodeficiency virus are living longer since the introduction of combination antiretroviral therapy more than a decade ago - but at what cost? Highly active antiretroviral therapy has been associated with lipodystrophy and associated metabolic derangements such as dyslipidaemia, insulin resistance and diabetes. These complications are likely to contribute to an increased risk of premature and accelerated atherosclerosis with growing concern about potential cardiovascular consequences.

Localization of the extracellular Ca(2+)-sensing receptor in the human placenta.

We have demonstrated using immunohistochemistry and in situ hybridization that the calcium-sensing receptor (CaR) is expressed in both villous and extravillous regions of the human placenta. CaR expression was detected in both first trimester and term placentas. In the villous region of the placenta, the CaR was detected in syncytiotrophoblasts and at lower levels in cytotrophoblasts. Local expression of the CaR in the brush border of syncytiotrophoblasts suggests a role for maternal Ca(2+) concentration in the control of transepithelial transport between the mother and fetus. In the extravillous region of the placenta, the CaR was detected in cells forming trophoblast columns in anchoring villi, in close proximity to maternal blood vessels and in transitional cytotrophoblasts. Given the importance of extravillous cytotrophoblasts in the process of uterine invasion and maintenance of placental immune privilege, the CaR represents a possible target by which the maternal extracellular Ca(2+) concentration could promote or maintain placentation. Thus, the results support hypotheses that the CaR contributes to the local control of transplacental calcium transport and to the regulation of placental development.

Expression of the parathyroid Ca(2+)-sensing receptor in cytotrophoblasts from human term placenta.

Fura-2-loaded human cytotrophoblasts responded to elevated extracellular Ca2+ concentration ([Ca2+]o) with monophasic or, in the case of large (> 20 microns) extravillous cells, biphasic elevations in intracellular free Ca2+ ion concentration ([Ca2+]i) that returned to baseline levels after restoration of control [Ca2+]o. Large extravillous cytotrophoblasts also responded to elevated [Mg2+]o with transient elevations in [Ca2+]i, consistent with the behaviour of the parathyroid Ca2(+)-sensing receptor. Expression of the parathyroid Ca2(+)-sensing receptor in placental cells was confirmed using Northern blot and reverse transcription (RT)-PCR analysis. However, the major transcript in human placental cells (6.2 kb) differed from that expressed by human parathyroid cells (5.6 kb). RT-PCR analysis and DNA sequencing of key PCR products also revealed the presence of a splice variant in placental and parathyroid cells that lacks exon 3.

Functional heterogeneity of human term cytotrophoblasts revealed by differential sensitivity to extracellular Ca2+ and nucleotides.

We have prepared purified cytotrophoblasts from human term placentas and examined the sensitivity of fura-2 loaded cells to the nucleotides ATP and UTP and to changes in extracellular Ca2+ concentration ([Ca2+]o). Purified cytotrophoblasts were obtained by collagenase digestion and separation according to density using self-generated Percoll gradients. The cytotrophoblast fraction was free of red cell and largely free of white cell contamination (as assessed by uniformly negative staining for vimentin and the failure of > 90% of fura-2 loaded cells to respond to the chemotactic peptide fMet-Leu-Phe). Purified cells secreted progesterone in a linear fashion over several hours in the presence of 25-hydroxycholesterol. The cells ranged in size from approximately 7.5 to 50 microns in diameter as described previously for purified cytotrophoblasts, and an analysis of cells for sensitivity to [Ca2+]o or nucleotides suggested functional heterogeneity within the cytotrophoblast population. Small cells (7.5-10 microns) were negative for cytokeratin-8 and, after loading with fura-2, were insensitive to extracellular nucleotides but sensitive to elevations in [Ca2+]o. Medium-sized cells (12-20 microns) were largely cytokeratin-positive (70% of cells) and sensitive to both ATP and UTP but largely insensitive to [Ca2+]o. Large cells (25-50 microns) were uniformly cytokeratin-positive (100% of cells) and, after fura-2 loading, sensitive to both [Ca2+]o and extracellular ATP or UTP. We examined the likely origin of small, medium and large cytotrophoblasts using an immunomagnetic cell sorting procedure that separates villous cytotrophoblasts (which do not express major histocompatibility class I antigens) from extravillous cytotrophoblasts. This procedure resulted in the selective sedimentation of almost all medium and large cells, leading to the conclusion that the small cells were villous cytotrophoblasts whereas medium and large cells were predominantly extravillous in origin. The data suggest that small, medium and large cytotrophoblasts have distinct roles in the function of the term placenta.

Statistical analysis of defect-caused laser damage in thin films.

An analysis of the statistics of laser-induced damage to thin films is carried out for the commonly assumed single-defect model, in which damage is caused by irradiation of identical, randomly distributed defects in the film. The probability for damage due to a single irradiation with a beam of Gaussian spatial profile is calculated, and it is shown that observed variations with beam size of the intensity required to maintain a constant high probability for damage are accounted for by this expression. The multiple-shot damage probability is then calculated, assuming that irradiation is started at a low value of energy and increased stepwise, for two cases, an N-on-1 experiment where the beam irradiates the same site each time and a 1-on-1 experiment where the beam is moved to a new site with each shot. The damage thresholds, defined to be the median values of the distribution functions for these two cases, are compared to one another and to the thresholdfor a single-shot experiment. Moreover, the dependence of the threshold on the size of the pulse-to-pulse energy increment is determined. Finally, the effect of a second damage mechanism involving damage to the host material is determined by calculating the mean and variance of the probability density function. These results are shown to be in good agreement with prior measurements of the beam-size dependence of threshold.

Dielectric Mirror Damage by Laser Radiation over a Range of Pulse Durations and Beam Radii.

Laser induced damage characteristics have been studied for twelve, multiple-layer dielectric, 95% reflecting mirrors irradiated with single ruby laser pulses of 20 nsec and 20-psec duration and Gaussian beam radii ranging from 0.06 mm to 0.24 mm. During measurements to determine damage threshold the pulse energy, an oscilloscope trace of the pulse, and the beam's transverse energy density profile at the surface being damaged are recorded for each shot. In a separate set of experiments, the temporal development of coating breakup and plasma formation is investigated. The experimental results are discussed in the context of possible damage mechanisms.