Familial nephropathic non-neuropathic amyloidosis: clinical features, immunohistochemistry and chemistry.

Classification of familial amyloidosis by the chemical nature of the fibrillar protein has become possible. Most such amyloidogenic proteins so far recognized are variant transthyretins, but two kindreds with the same apolipoprotein AI modification have been reported. We describe the clinical features of another such family in whom petechial skin rash appeared to be a marker for the disease, which was non-neuropathic and of the Ostertag-type. Immunohistochemistry showed the protein to be apolipoprotein AI, but allele-specific DNA amplification indicated that it was not the Arg26 variant previously identified.     

Point-of-care and standard laboratory coagulation testing during cardiovascular surgery: balancing reliability and timeliness

Objective. The use of point-of-care technology has increased faster than efforts to validate its effectiveness compared to standard laboratory testing modalities. To address this issue with a current point-of-care coagulation system (HEMOCHRON® Jr, International Technidyne Corporation (ITC), Edison, NJ), we designed a study to test the hypothesis that data obtained from point-of-care coagulation equipment correlates with data obtained from standard laboratory coagulation equipment. One of the potential advantages gained using point-of-care testing is the ability to obtain more rapid results. To address this issue, turnaround time, defined as the elapsed time (in minutes) from when the sample was acquired from the patient until the investigators knew the results, was also determined. Methods. Following Human Investigation Committee approval and informed consent, a prospective study was conducted to compare results obtained from point-of-care coagulation equipment with those results obtained from standard laboratory coagulation equipment. The study was performed in three groups of patients undergoing cardiovascular surgery, each requiring different levels of anticoagulation. Results. Of the 83 patients who met the inclusion criteria, the correlation (combining data from groups 1–3) between results obtained from point-of-care and standard laboratory prothrombin time was r = 0.867, p < 0.001. The correlation (group 3) between point-of-care and standard laboratory international normalized ratio was r = 0.943, p < 0.001. The correlation (combining data from groups 1 & 2) between point-of-care and standard laboratory activated partial thromboplastin time was r = 0.825, p < 0.001. Median turnaround time for the standard laboratory was 90 minutes, with a mean turnaround time of 74 to 78 minutes, depending upon the group. In contrast, the median turnaround time for point-of-care testing was two minutes and 14 seconds. Conclusions.The results from this study population reveal that data obtained from point-of-care prothrombin time, international normalized ratio and activated partial thromboplastin time results correlate with results obtained from standard laboratory coagulation testing. The value of obtaining reliable results in a timely fashion offers a potential advantage for point-of-care testing in clinical situations, such as in the operating room, where saving time may translate into financial savings.     

The antimalarial drug mefloquine binds to membrane phospholipids.

The new antimalarial drug mefloquine bound with high affinity (Kd approximately 3 X 10-7 M) to membrane lipids of normal mouse erythrocytes and of erythrocytes infected either with chloroquine-susceptible or chloroquine-resistant Plasmodium berghei. Approximately 80 nmol of mefloquine was bound per mg of total lipid. Mefloquine also bound to purified phospholipids with high affinity (Kd approximately 3 X 10-7 M). Phosphatidylinositol and phosphatidylserine bound 300 to 400 nmol of mefloquine per mg. Phosphatidylcholine and phosphatidylethanolamine bound approximately 100 nmol of mefloquine per mg. Mefloquine did not bind to hemoglobin with high affinity, but it bound to free ferriprotoporphyrin IX with a Kd of approximately 3 X 10-7 M. In comparison with mefloquine, chloroquine did not bind effectively to purified phospholipids, although it is known to bind with high affinity to free ferriprotoporphyrin IX. Greater binding to phospholipids may account for the superiority of mefloquine in the treatment of chloroquine-resistant malaria.     

Caring for the caregivers: Innovative program for oncology nurses.

An innovative program, Care for the Professional Caregiver, was designed to provide staff nurses in a cancer program with the opportunity to learn about coping with stress in their practice. The program was evaluated using quantitative and qualitative methods. The findings clearly describe the benefits of the program on both a short- and long-term basis. The value of connecting with other cancer nurses, supporting each other, and sharing stories about their work life experiences resulted in benefits to the nurse as an individual, as a team member, and as a professional practitioner. The program achieved its aims and is recommended for ongoing implementation.     

Oxidative damage and TGF-β differentially induce lung epithelial cell sonic hedgehog and tenascin-C expression: implications for the regulation of lung remodelling in idiopathic interstitial lung disease

Idiopathic interstitial lung diseases (iILDs) are characterized by inflammation, hyperplasia of Type-II alveolar epithelial cells (AECs) and lung remodelling often with progressive fibrosis. It remains unclear which signals initiate iILD and/or maintain the disease processes. Using real-time RT-PCR and immunohistochemistry on archival biopsies of three patterns of iILD (usual interstitial pneumonitis/UIP, non-specific interstitial pneumonitis/NSIP and cryptogenic organizing pneumonia/COP) we investigated whether hedgehog signalling (previously associated with lung damage and repair) was functional and whether the damage associated extracellular matrix protein tenascin-C was present in activated Type-II AECs in all three iILDs. Using tissue culture, protein and mRNA detection we also determined how two signals (oxidative damage and TGF-β) associated with iILD pathogenesis affected Sonic hedgehog (SHH) and tenascin-C production by a Type-II AEC cell line. We report that SHH pathway and tenascin-C mRNA and proteins were found in UIP, NSIP and COP. SHH signalling was most active at sites of immature organizing fibrous tissue (fibroblastic foci) in UIP. In vitro Type-II AECs constitutively secrete SHH but not tenascin-C. Oxidative injury stimulated SHH release whereas TGF-β inhibited it. TGF-β and oxidative damage both upregulated tenascin-C mRNA but only TGF-β induced synthesis and release of a distinct protein isoform. SHH signalling is active in Type-II AECs from three types of ILD and all three express tenascin-C.     

Recent advances in the diagnosis and treatment of pheochromocytoma in children

BACKGROUND: The purpose of this study was to analyze the effects of changes in the diagnosis and treatment of pheochromocytoma in a pediatric population. METHODS: We reviewed the medical records of all children who had resection of pheochromocytoma or paraganglioma at a major children's hospital since 1968. RESULTS: Fifteen children underwent surgery at 11.9 +/- 4.2 years of age. Presenting symptoms included headache, hypertension, and sweating. Three children had a mutation of the succinate dehydrogenase enzyme, and 1 child had nonsyndromic, familial pheochromocytoma. The most sensitive diagnostic modalities included 24-hour urinary and plasma norepinephrine and 24-hour urinary total metanephrines, magnetic resonance imaging, and 123I-meta-iodobenzylguanidine scintigraphy. Laparoscopic cortical-sparing adrenalectomy was performed in 3 patients with von Hippel-Lindau disease. Compared with those with open procedures (n = 7), patients who had laparoscopic resection (n = 5) had a statistically shorter hospital length of stay, and time to eating ambulation. CONCLUSIONS: The addition of 123I-meta-iodobenzylguanidine scanning, genetic testing, and laparoscopic surgery has changed the diagnosis and treatment of pheochromocytoma in children. Laparoscopic cortical-sparing adrenalectomy can be accomplished safely and is the preferred treatment for children at risk for multifocal disease.     

Pemetrexed and Gemcitabine for Biliary Tract and Gallbladder Carcinomas: a North Central Cancer Treatment Group (NCCTG) Phase I and II Trial, N9943

Purpose

To determine the maximum tolerated dose (MTD) and efficacy of pemetrexed and gemcitabine in patients with either biliary tract or gallbladder carcinoma.

Patients and Methods

Patients with unresectable previously untreated biliary tract cancers were eligible for participation. An initial phase I trial was performed to determine the MTD using an every-2-weeks schedule. The MTD was then used in the phase II portion of the trial. The primary end point for the phase II portion was 6-month survival with a planned accrual of 59 patients.

Results

Overall, 63 eligible patients were enrolled. The MTD was established as pemetrexed 500 mg/m² IV over 10 min and gemcitabine 800 mg/m² IV at 10 mg/m² per minute on days 1 and 15 of an every-4-weeks schedule with vitamin B12 and folate supplementation. Fifty-eight patients were included in the phase II portion. Median age was 61 and median follow-up was 18.2 months. A median of three cycles of treatment was given. Six-month survival was 55% and the median survival was 6.6 months (95% confidence interval 5.4–8.7 months) with a median time to progression of 3.8 months (2.4–5.4). Forty-seven (81%) experienced at least one grade 3+ adverse event, and 28 patients (48%) experienced at least one grade 4 adverse event, most of which were due to grade 4 neutropenia.

Conclusion

The addition of pemetrexed to fixed-dose-rate gemcitabine, in a biweekly schedule, did not enhance the activity of gemcitabine in patients with biliary tract or gallbladder carcinoma.     

CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

Spinal cord and brain injuries lead to complex cellular and molecular interactions within the central nervous system in an attempt to repair the initial tissue damage. Many studies have illustrated the importance of the glial cell response to injury, and the influences of inflammation and wound healing processes on the overall morbidity and permanent disability that result. The abortive attempts of neuronal regeneration after spinal cord injury are influenced by inflammatory cell activation, reactive astrogliosis and the production of both growth promoting and inhibitory extracellular molecules. Despite the historical perspective that the glial scar was a mechanical barrier to regeneration, inhibitory molecules in the forming scar and methods to overcome them have suggested molecular modification strategies to allow neuronal growth and functional regeneration. Unlike myelin associated inhibitory molecules, which remain at largely static levels before and after central nervous system trauma, inhibitory extracellular matrix molecules are dramatically upregulated during the inflammatory stages after injury providing a window of opportunity for the delivery of candidate therapeutic interventions. While high dose methylprednisolone steroid therapy alone has not proved to be the solution to this difficult clinical problem, other strategies for modulating inflammation and changing the make up of inhibitory molecules in the extracellular matrix are providing robust evidence that rehabilitation after spinal cord and brain injury has the potential to significantly change the outcome for what was once thought to be permanent disability.     

Patent ductus arteriosus ligation in neonates: preoperative predictors of poor postoperative outcomes

Purpose

The purpose of this study was to identify preoperative predictors of adverse outcomes in infants undergoing surgical ligation of patent ductus arteriosus (PDA).

Methods

Charts of all neonates who underwent PDA ligation at Texas Children's Hospital (Houston, TX) between 2001 and 2006 were retrospectively reviewed with specific attention to preoperative clinical characteristics, echocardiographic details, operative morbidity, and postoperative outcomes. Infants with other cardiac anomalies or right-to-left or bidirectional PDA shunt were excluded.

Results

Eighty-two neonates were included (mean gestational age, 27 weeks; mean birth weight, 1000 g). There were no intraoperative complications. Preoperative symptoms related to respiratory insufficiency, hypotension, apnea, and pulmonary edema improved after ligation (P < .001). Birth weight, age at ligation, and indomethacin use did not correlate with postoperative outcome; however, lower gestational age, lower blood pressure, and lower shunt peak velocity predicted longer time to extubation by multiple analysis techniques (P < .0001). Linear regression (controlling for gestation, birth weight, and mean arterial pressure) showed inverse correlation between peak velocity and postoperative days on the ventilator (95% confidence interval, 47.18 to −12.25; P = .001).

Conclusion

The PDA ligation can be accomplished safely; however, some neonates have prolonged recovery. Lower gestational age and low peak velocity (<2.6 m/s) at the PDA shunt correlate with lengthened ventilator requirement after surgery.