Toxicity of Calcium Sodium Metaphosphate Fiber: II. Chronic Inhalation and Oncogenicity Study

Male and female Fischer 344 rats (80/sex/group) were exposedto CSM fiber 6 hr/day, 5 days/week at target-exposure levelsof 0, 1, 5, or 25 mg/m³ for 24 months, corresponding to 0, 27,80, and 513 fibers/cc, respectively. Number and size of theairborne fibers were determined during the course of the study.At 3 and 12 months, 10 rats/sex/group were euthanized and at18 and 24 months 5 rats/sex/group were euthanized. In addition,5 rats/ sex/group were removed from exposure at 18 months andmaintained for a 6-month recovery period. All animals survivingat the completion of the exposure period were maintained ina clean environment for up to 5 additional months. Clinicallaboratory examinations were performed on 10 animals/sex/groupat 3, 12, and 24 months. The number of fibers in the lung werealso determined at 3, 12, 18, and 24 months. Body weight andsurvival did not appear to be affected by treatment. There wereno biologically significant effects on clinical parameters.There was a dose-related increase in lung weight during theexposure period which was generally reversible during the recoveryperiods. There also was a dose-related increase in the numberof fibers/ milligram of lung, but no increase in lung fiberburden after the first 3 months. The number of fibers in thelungs of animals exposed to CSM fiber for 18 months and allowed6-month recovery period showed a decrease especially at thehigh dose. No increase in tumors (benign or malignant) was observedin this study. Microscopic changes considered reflective ofan irritant response were observed in the nasal turbinates notablyat the 5 and 25 mg/m³ levels. Histological changes were alsoobserved in the lungs at the 5 and 25 mg/m³ levels. The incidenceand/ or severity of histopathological changes in the 1 mg/m³group was considered to be essentially comparable to controls.     

Necrotizing enterocolitis in a perinatal centre

Thirty-five neonates developed radiologically proven necrotizing enterocolitis (NEC) over a 40 month period. They were 28 +/- 2 weeks gestation, and weighted 1094 +/- 411 g at birth. Eighteen infants (51%) required surgery and three (8.5%) died. The incidence was 6.7% in the very low birthweight (VLBW) infants. A large proportion of NEC (60%) presented beyond 10 days of life. An inverse relationship between gestation and age of onset was observed. The age of presentation was 22 +/- 13 days (range 10-53 days) for the 18 infants less than or equal to 28 weeks compared with 7 +/- 5 days for those over 28 weeks (P less than 0.01). Five NEC infants had bacteraemia which occurred 2-7 days prior to gastrointestinal symptoms of NEC, and four were staphylococcal. Compared with infants controlled for gestation, there was no significant differences observed in perinatal events or feeding history. We concluded that an immature gastrointestinal system is vulnerable to NEC even beyond the early neonatal period.     

Atrial Lead Dysfunction: An Unusual Feature of Hypothyroidism

Hypothyroidism is known to have a multitude of cardiac electrophysiologic effects, including bradycardia, atrioventricular block, prolonged QT interval, and elevated ventricular pacing thresholds. We report the case of a 36‐year‐old woman who presented with isolated dysfunction of her atrial pacemaker lead, which reversed with thyroid hormone replacement.     

Bronchoalveolar lavage in pulmonary tuberculosis: a decision analysis approach

We assessed the utility of bronchoalveolar lavage (BAL) in thediagnosis of pulmonary tuberculosis (PTB) in 50 consecutiveHIV-negative patients with clinical and radiographic findingssuggestive of PTB, but with negative microscopy for acid-fastbacilli (AFB) on sputum smear. Patients were grouped, usinga scoring system, into relative likelihoods of having PTB (I—IV,in descending probability). Patients were started on anti-tuberculosistreatment according to the BAL results. Bacteriological diagnosisof PTB was confirmed in 22/50 BAL; 11 (91.6%), seven (37%) andfour (40%) of groups I–III, respectively. In 13 cases,an early diagnosis of PTB was made by positive microscopy forAFB on BAL; an alternative diagnosis was made in six cases (bacterialpneumonia 4, carcinoma 2). A decision analysis model was createdto assess the overall utility of BAL. This suggested that ina region of high PTB prevalence, and when the clinical diagnosisof PTB is likely, empirical treatment is the best course ofaction, with BAL being reserved for further investigation ofnon-responders. Early BAL should be considered when the diagnosisof PTB is uncertain.     

Functional ENaC Channels Expressed in Endothelial Cells: a New Candidate for Mediating Shear Force

Endothelial cells (ECs) are regulated not only by circulating hormones, but also by mechanical stresses, such as shear force. Ion channels in ECs can signal rapid changes of shear forces and are involved in controling EC permeability, proliferation, and angiogenesis. In this study, we employed patch clamping and molecular biology approaches to clarify whether the epithelial sodium channel (ENaC) is functionally expressed in ECs. The α‐subunit of the ENaC was expressed in cultured human ECs and in intact ECs from a variety of rat arteries. In either inside‐ or outside‐out current recordings, inward currents with a conductance of 4.83 pS were detected in cultured human ECs, where these were sensitive to micromolar amiloride. The right shift of the I‐V curve in the condition of low cytoplasmic Na⁺ implicated that these currents were carried by Na⁺. The currents were mediated by ENaC channels, as confirmed by ENaC knockdown experiments. However, the activity of ENaC was nearly absent in intact ECs, because its activity was greatly inhibited by cellular molecules, partly due to 11,12‐epoxyeicosatrienoic acid. In the outside‐out configuration, laminar flow directly enhanced ENaC opening probability, suggesting a potential role for ENaC in mediating shear force signaling events.     

Canadian Registry of ICD Implant Testing Procedures (CREDIT): Current Practice,Risks, and Costs of Intraoperative Defibrillation Testing

Defibrillation Testing at ICD Implantation. Background: There is uncertainty about the proper role of defibrillation testing (DT) at the time of implantable cardioverter defibrillator (ICD) insertion. Methods: A prospective registry was conducted at 13 sites in Canada between January 2006 and October 2007. Objectives: To document the details of DT, the reasons for not conducting DT, and the costs and complications associated with DT. Results: DT was conducted at implantation in 230 of 361 patients (64%). DT was more likely to be conducted for new implants compared with impulse generator replacements (71% vs 32%, P = 0.0001), but was similar for primary and secondary prevention indications (64% vs 63%, P = NS). Among patients not having DT, the reason(s) given were: considered unnecessary (44%); considered unsafe, mainly due to persistent atrial fibrillation (37%); lack of an anesthetist (20%); and, patient or physician preference (6%). When performed, DT consisted of a single successful shock ≥ 10J below maximum device output in 65% of cases. A 10J safety‐margin was met by 97% of patients, requiring system modification in 2.3%. Major perioperative complications occurred in 4.4% of patients having DT versus 6.6% of patients not having DT (P = NS). ICD insertion was $844 more expensive for patients having DT (P = 0.16), largely due to increased costs ($28,017 vs $24,545) among patients having impulse generator replacement (P = 0.02). Conclusions: DT was not performed in a third of ICD implants, usually due to a perceived lack of need or relative contraindication. (J Cardiovasc Electrophysiol, Vol. 21, pp. 177‐182, February 2010)     

Effect of glycoPEGylation on factor VIIa binding and internalization

Summary. Recombinant coagulation factor VIIa (rFVIIa), which is widely used for treatment of bleeding episodes in haemophilia patients with inhibitors, is cleared from the circulation relatively fast with a plasma half‐life of 2–4 h. PEGylation is an established and clinically proven strategy for prolonging the circulatory life‐time of bio‐therapeutic proteins. The aim of this study was to investigate the effect of glycoPEGylation of rFVIIa on rFVIIa binding to its cellular receptors and its subsequent internalization. rFVIIa and glycoPEGylated rFVIIa were labeled with ¹²⁵I and the radio‐iodinated proteins were used to monitor rFVIIa binding and uptake in endothelial cells and fibroblasts. FVIIa‐TF activity at the cell surface was analyzed by a factor X activation assay. Modification of rFVIIa with PEG impaired rFVIIa binding to both endothelial cell protein C receptor and tissue factor (TF) on cell surfaces. The internalization of PEGylated rFVIIa in endothelial cells and fibroblasts was markedly lower compared to the internalization of rFVIIa in these cells. PEGylated rFVIIa was able to activate factor X on TF expressing cell surfaces at a rate similar to that of unmodified rFVIIa when the cells were not subjected to multiple washings to remove the free ligand. General effects such as steric hindrance or changes in electrostatic binding properties of the modified rFVIIa to its receptors are probably responsible for this impairment rather than a loss of specific recognition of the receptors, which could explain near normal activation of factor X by glycoPEGylated rFVIIa on TF expressing cells while its uptake is reduced.