Increased glucose excursion in cystic fibrosis and its association with a worse clinical status

BACKGROUND: Abnormal glucose tolerance is a frequent co-morbidity in cystic fibrosis patients (CF), and is associated with a worse prognosis. The objectives are to investigate (a) the relative contribution of insulinopenia and insulin resistance (IR) for glucose tolerance and (b) the association between various glucose parameters and CF clinical status. METHODS: Oral glucose tolerance tests were performed in 114 consecutive CF patients not known to be diabetic as well as 14 controls similar for age and BMI. RESULTS: Abnormal glucose tolerance was found in 40% of patients with CF: 28% had impaired glucose tolerance (IGT) and 12% had new cystic fibrosis related diabetes (CFRD). Compared to control subjects, all CF patients were characterized by an increased glucose excursion (AUC). While reduced early insulin release characterised CF, IGT and CFRD patients also present IR thus both mechanisms significantly contribute to glucose tolerance abnormalities. Increased glucose AUC and reduced early insulin release but not glucose tolerance categories were associated with a reduced pulmonary function (FEV(1)). CONCLUSION: In CF, early insulin secretion defect but also IR contribute to glucose intolerance. Early in the course of the disease, increased glucose AUC and reduced early insulin secretion are more closely associated with a worse clinical status than conventional glucose tolerance categories.     

Sterile surgical technique for shunt placement reduces the shunt infection rate in children: preliminary analysis of a prospective protocol in 115 consecutive procedures

Objective The objective of this study was to evaluate whether the rigid application of a sterile protocol for shunt placement was applicable on a routine basis and allowed the reduction of shunt infections (SI) in children. Materials and methods Since 2001, a rigid sterile protocol for shunt placement in children using neither antibiotic-impregnated catheters nor laminar airflow was prospectively applied at Erasme Hospital, Brussels, Belgium. For assessing the protocol efficacy before continuation, we preliminarily analyzed the results of the first 100 operated children (43 females, 57 males, 49 aged <12 months; 115 consecutive shunt placement/revision procedures). All procedures were performed by the same senior surgeon, one assistant, one circulating nurse, one anesthesiologist. The sterile protocol was rigidly imposed to these four staff members: uniformed surgical technique; limited implant and skin edge manipulation; minimized human circulation in the room; scheduling surgery as first morning operation; avoiding postoperative cerebrospinal fluid (CSF) leak; double gloving; procedures of less than 30-min duration; systemic antibiotics prophylaxis. We analyzed separately: (1) children carrying an increased risk of SI (n = 38) due to preoperative external ventricular drainage, CSF leak, meningitis, glucocorticoids, chemotherapy; (2) children aged <12 months; (3) procedures for shunt revision. Results Errors in protocol application were recorded in 71/115 procedures. They were mainly done by non-surgical staff, decreased with time and were medically justified in some young children. Surprisingly, no SI occurred (follow-up, 4 to 70 months). One child developed an appendicitis with peritonitis (Streptococcus faecalis) after 6 months. No SI was found. After peritonitis was cured, shunt reinsertion was uneventful. Conclusion These preliminary results suggest that a uniform and drastic sterile surgical technique for shunt placement: (1) can be rigidly applied on a routine basis; (2) can lower the early SI rate below 1%; (3) might have a stronger impact to reduce SI than using antibiotic-impregnated catheters and optimizing the operative environment such as using laminar airflow and reducing the non-surgical staff. This last issue will be evaluated further in the present ongoing protocol.     

Differential modification of muscarinic cholinergic receptors in the hippocampus of patients with Alzheimer''s disease: an autoradiographic study

We have used quantitative light microscopic autoradiographic techniques to analyze changes in muscarinic cholinergic receptors in the hippocampus in Alzheimer type dementia (ATD). The density and distribution of muscarinic cholinergic receptors has been correlated with the density of neurons, neuritic plaques and neurofibrillary tangles in the CA1 subfield of the hippocampus of control and ATD patients. The number of pyramidal cells per mm² in the CA1 sector was significantly decreased in ATD cases as compared to controls, although there were large variations among cases. The most marked reductions in cell counts were observed in patients with a history of profound dementia. The densities of muscarinic receptors, as well as the proportions of M₁ and M₂ subtypes, in the CA1 sector and dentate gyrus were not significantly different between ATD and old non-demented patients. Neuritic plaques, even in high numbers, did not affect the density of muscarinic receptors; moreover, the densities of receptors over the neuritic plaques did not differ from the surrounding neuropil. However, in some ATD cases there was a marked decrease in the concentration of these receptors in the CA1 sector and subiculum, with no change in the proportions of muscarinic receptor subtypes. These patients exhibited frequent extracellular remnants of neurofibrillary tangles (ghost tangles), but scarce neuritic plaques, and were those showing severe losses of pyramidal cells. There was a significant positive correlation between the total concentration of muscarinic receptors in the CA1 and the density of pyramidal cells, suggesting that decreases in receptor concentration result from a severe neuronal loss. We observed that the ratio of muscarinic receptors per pyramidal cell was significantly increased in ATD patients. This might indicate a possible upregulatory mechanism for muscarinic receptors in the population of remaining neurons in ATD. However, decreases of receptor numbers following severe neuronal fall out suggest that compensatory mechanisms are no longer possible in such cases. The question is raised whether these differences between cases reflect different diseases or different stages of the same disease.     

Evaluation of the ETS and ADx urine drug screening immunoassay analyzers

The Syva ETS and Abbott ADx urine drug testing immunoassay systems were evaluated for analytical performance, ease of operation, data processing, and time of analysis. Urine specimens were analyzed by each system for six drugs of abuse. Discrepancies in drug detection were due to variations in the cut-off concentrations between ADx and EMIT d.a.u. (ETS) reagents. The ETS was found to have several major advantages over the ADx: greater sample load, more convenient "random access," and real time data processing. When analyzing multiple specimens, the turnaround time for the ETS as compared to the ADx was twice as fast for the six-analyte assay. The ADx assay calibrations were stable for two weeks, while the ETS required daily calibration with verification by cut-off calibrators every eight hours. The ETS was found superior to the ADx for multianalyte urine drug screening.     

Ependymal changes in experimental hydrocephalus

A morphologic investigation of ependyma over gray matter (caudate nucleus) and over periventricular white matter (tapetum) of the rabbit lateral ventricle was performed four months after the induction of experimental hydrocephalus. Ependymal cells over the caudate nucleus are not modified by hydrocephalus. They remain cuboidal and heavily ciliated. Numerous microvilli cover the cell surface. The extracellular space of the neuropil is not expanded. Ependymal cells over the periventricular white matter are markedly modified. The characteristic response of these ependymal cells is to enlarge and to form lacunae in their apical cytoplasm. Their apical, horizontal cytoplasmic processes elongate as adjacent ependymal cells separate. The ex-tracellular space of the neuropil is expanded. It is proposed that the changes seen in ependymal cells over periventricular white matter are a response to enlargement of the ventricular surface permitted by the orientation of neuronal and glial fibers parallel to the ventricular surface. With expansion of the ventricular surface, overlapping apical processes become elongated and modified, containing a terminal web. With further enlargement, sliding of an overlapping apical process of one cell uncovers the apical process of its neighboring cell. By this mechanism, the ventricular surface area of any ependymal cell whose surface has been partially covered by its neighbor is increased. With further progression, this compensation fails and the neuropil is exposed to the ventricular cavity. Over caudate nucleus, expansion of ventricular surface is hindered by the disposition of fascie adherentes along intercellular clefts oriented perpendicular to the ventricular surface. Lateral sliding of horizontal apical processes does not occur as such processes are not found in ependyma over the caudate nucleus. The differential response of the ventricular surface in these two areas characteristically seen in hydrocephalus is; determined by regional differences in the morphology of their ependymal cells and underlying neuropil.     

Characterization of rat hyperplastic bile ductular epithelial cells in culture andin vivo

A novel intrahepatic biliary cell culture/in vivo transplantation system has been developed with an essentially pure population of bile ductular epithelial cells isolated from rat liver 6–12 weeks after bile duct ligation. In primary culture, these cells retain staining strongly for -glutamyltranspeptidase and glutathione S-transferase P. The cytoplasm of cultured bile ductular cells reacts with an anti-laminin antibody, but loses immunoreactivity with a monoclonal anti-cytokeratin 19 antibody. Semiconservative DNA synthesis in the cultured cells was dependent upon the continued presence of 10% fetal calf serum in the medium. Replicating bile ductular cells could be subcultured for a finite number of passages. In addition, freshly isolated bile ductular epithelial cells gave rise to well differentiated bile ductular structures when transplanted into the interscapular fat pads of syngeneic recipient rats.Presented at the Proceedings of the International Meeting on Normal and Neoplastic Growth in Hepatology, Bari, Italy, June 1989.This work was supported by USPHS Grant RO1 CA39225 to Dr. Sirica by the National Cancer Institute, Department of Health and Human Services.     

Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications.

PURPOSE: It has been hypothesized that tumors with high interstitial fluid pressure (IFP) and/or hypoxia respond poorly to chemotherapy (CT) because of poor drug delivery. Preclinical studies have shown that paclitaxel reduces the IFP and improves the oxygenation (pO(2)) of tumors. Our aim is to evaluate the IFP and pO(2) before and after neoadjuvant CT using sequential paclitaxel and doxorubicin in patients with breast cancer tumors of >/= 3 cm. PATIENTS AND METHODS: Patients were randomly assigned, according to an institutional review board-approved phase II protocol, to receive neoadjuvant sequential CT consisting of either four cycles of dose-dense doxorubicin at 60 mg/m(2) every 2 weeks followed by nine cycles of weekly paclitaxel at 80 mg/m(2) (group 1) or vice versa, with paclitaxel administered before doxorubicin (group 2). Patients were re-evaluated clinically and radiologically. The IFP (wick-in-needle technique) and pO(2) (Eppendorf) were measured in tumors at baseline and after completing the administration of the first and second drug. RESULTS: IFP and pO(2) were measured in 54 patients at baseline and after the first CT. Twenty-nine and 25 patients were randomly assigned to groups 1 and 2, respectively. Paclitaxel, when administered first, decreased the mean IFP by 36% (P = .02) and improved the tumor pO(2) by almost 100% (P = .003). In contrast, doxorubicin did not have a significant effect on either parameter. This difference was independent of the tumor size or response measured by ultrasound. CONCLUSION: Paclitaxel significantly decreased the IFP and increased the pO(2), whereas doxorubicin did not cause any significant changes. Tumor physiology could potentially be used to optimize the sequence of neoadjuvant CT in breast cancer.