Progressive multifocal leukoencephalopathy during ixazomib-based chemotherapy.

Progressive multifocal leukoencephalopathy (pml) is a rare demyelinating disease of the central nervous system that most often affects immunocompromised individuals. It is caused by the reactivation of the John Cunningham virus (jcv), which is found in latent form in the majority of adults. We describe a 59-year-old man with multiple myeloma who developed severe neurological deficits during treatment with ixazomib-based chemotherapy. A diagnosis of pml was established with gadolinium-enhanced magnetic resonance imaging (mri) and by detection of jcv in the cerebrospinal fluid. Despite cessation of chemotherapy and treatment with mirtazapine, he had an inexorable neurological decline and died two months after presenting to hospital. Multiple myeloma and its treatments can predispose patients to opportunistic infections including pml. Although there have been case reports of pml in patients with multiple myeloma treated with bortezomib (a different proteosome inhibitor), this is, to our knowledge, the first documented case of pml in a patient treated with a regimen that includes ixazomib.

A case of transfusion independence in a patient with myelodysplastic syndrome using deferasirox, sustained for two years after stopping therapy.

Patients with myelodysplastic syndrome (mds) experience clinical complications related to progressive marrow failure and have an increased risk of developing acute myeloid leukemia. Frequent red blood cell transfusion can lead to clinical iron overload and is associated with decreased survival in mds patients. Iron chelation therapy reduces markers of iron overload and prevents end-organ damage. Here, we present the case of a patient with low-risk mds with transfusional iron overload. He was treated for 2 years with an oral iron chelator, deferasirox, and after 12 months of treatment, he experienced a hemoglobin increase of more than 50 g/L, becoming transfusion-independent. He has remained transfusion-independent, with a normal hemoglobin level, for more than 2 years since stopping chelation therapy. Hematologic and erythroid responses have previously been reported in mds patients treated with iron chelation. The durability of our patient's response suggests that iron chelation might alter the natural history of mds in some patients.

Alveolar-capillary adaptation to chronic hypoxia in the fatty lung.

AIM: Obese diabetic (ZDF fa/fa) rats with genetic leptin resistance suffer chronic lipotoxicity associated with age-related lung restriction and abnormal alveolar ultrastructure. We hypothesized that these abnormalities impair adaptation to ambient hypoxia. METHODS: Male fa/fa and lean (+/+) ZDF rats (4-months old) were exposed to 21 or 13% O2 for 3 weeks. Lung function was measured under anaesthesia. Lung tissue was assayed for DNA damage and ultrastructure measured by morphometry. RESULTS: In normoxia, lung volume, compliance and diffusing capacity were lower, while blood flow was higher in fa/fa than +/+ rats. In hypoxia, fa/fa animals lost more weight, circulating hematocrit rose higher, and lung volume failed to increase compared to +/+. In fa/fa, the hypoxia-induced increase in post-mortem lung volume was attenuated (19%) vs. +/+ (39%). Alveolar ducts were 35% smaller in normoxia but enlarged twofold more in hypoxia compared to +/+. Hypoxia induced broad increases (90-100%) in the volumes and surface areas of alveolar septal components in +/+ lungs; these increases were moderately attenuated in fa/fa lungs (58-75%), especially that of type II epithelium volume (16 vs. 61% in +/+). In fa/fa compared to +/+ lungs, oxidative DNA damage was greater with increased hypoxia induced efflux of alveolar macrophages. Harmonic mean thickness of the diffusion barrier was higher, indicating higher structural resistance to gas transfer. CONCLUSION: Chronic lipotoxicity impaired hypoxia-induced lung expansion and compensatory alveolar growth with disproportionate effect on resident alveolar progenitor cells. The moderate structural impairment was offset by physiological adaptation primarily via a higher hematocrit.

Hypoxia imaging predicts success of hypoxia-induced cytosine deaminase/5-fluorocytosine gene therapy in a murine lung tumor model.

Tc-99m-HL91 is a hypoxia imaging biomarker. The aim of this study was to investigate the value of Tc-99m-HL91 imaging for hypoxia-induced cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy in a murine lung tumor model. C57BL/6 mice were implanted with Lewis lung carcinoma cells transduced with the hypoxia-inducible promoter-driven CD gene (LL2/CD) or luciferase gene (LL2/Luc) serving as the control. When tumor volumes reached 100 mm(3), pretreatment images were acquired after injection of Tc-99m-HL91. The mice were divided into low and high hypoxic groups based on the tumor-to-non-tumor ratio of Tc-99m-HL91. They were injected daily with 5-FC (500 mg kg(-1)) or the vehicle for 1 week. When tumor volumes reached 1000 mm(3), autoradiography and histological examinations were performed. Treatment with 5-FC delayed tumor growth and enhanced the survival of mice bearing high hypoxic LL2/CD tumors. The therapeutic effect of hypoxia-induced CD/5-FC gene therapy was more pronounced in high hypoxic tumors than in low hypoxic tumors. This study provides the first evidence that Tc-99m-HL91 can serve as an imaging biomarker for predicting the treatment responses of hypoxia-regulated CD/5-FC gene therapy in animal tumor models. Our results suggest that hypoxia imaging using Tc-99m-HL91 has the predictive value for the success of hypoxia-directed treatment regimens.

Analysis and comparison of sleeping posture classification methods using pressure sensitive bed system.

Pressure ulcers are common problems for bedridden patients. Caregivers need to reposition the sleeping posture of a patient every two hours in order to reduce the risk of getting ulcers. This study presents the use of Kurtosis and skewness estimation, principal component analysis (PCA) and support vector machines (SVMs) for sleeping posture classification using cost-effective pressure sensitive mattress that can help caregivers to make correct sleeping posture changes for the prevention of pressure ulcers.

Recombinant activated factor VII in the treatment of non-haemophilia patients: physician under-reporting of thromboembolic adverse events.

The objective of this study was to determine if clinically important thromboembolic adverse events (TAEs) because of recombinant activated factor VII (rFVIIa) administration are being under-reported. rFVIIa is a potent haemostatic agent with a short half-life of 2.6 h that is increasingly used in 'off-label' situations. Retrospective review of 94 patients who received rFVIIa during 1 January 2003 to 30 June 2007 was carried out at a tertiary care centre. Sixty-nine patients, 32 females and 37 males, mean age 55 years (18-84 years), satisfied study criteria of off-label usage. This was a high-risk population with 33 (48%) deaths. A mean dose of 8.2 mg (2.4-19.2 mg) was administered in two average divided doses. Thirty-six potential TAEs were identified in 29 patients, and of these, 12 patients had TAEs deemed to be rFVIIa related and were identified on average 8.8 days after exposure to rFVIIa. Forty-eight (70%) physician questionnaires were completed; however, no TAEs were reported in these questionnaires or on chart review. Potential clinically significant TAEs are being under-reported by treating physicians. Until further evidence, we suggest the urgent need to develop consensus recommendations for utilization and required follow up to monitor the safety of rFVIIa and that at a minimum, all use of rFVIIa should be regulated through a gate-keeping mechanism that ensures adherence to these policies. Furthermore, prospective registries and trials are necessary to evaluate the efficacy and safety of rFVIIa in off-label settings.

Evaluation of optimal cerebral perfusion pressure in severe traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of death and disability. In the 2000 guidelines, one of the suggestions for TBI treatment was to maintain cerebral perfusion pressure (CPP) < or = 70 mmHg. But in the 2003 guidelines, the suggestion was changed to < or = 60 mmHg. There have been some discrepancies of opinions about this recommendation in recent publications. In this study, we retrospectively reviewed 305 severe TBI (STBI) patients with Glasgow Coma Scales (GCS) < or = 8 between January 1, 2002 and March 31, 2003. The study group was stratified according to use or nonuse of intracranial pressure (ICP) monitoring, ICP levels, ages, and GCS levels in order to test the correlation between CCP and the prognosis. The patients < 50-year-old, with higher GCS level, with ICP monitoring, and with ICP levels < 20 mmHg had lower mortality rates and better prognosis (GOS) (p < 0.05 or 0.001). The patients in the GCS 3-5 subgroup had a significantly lower mortality and better prognosis if the CPP value was maintained higher than 70 mmHg (p < 0.05) The optimal CPP maintained < or = 60 mmHg did not fit in all STBI patients. Our study concludes that it is critical to maintain CPP substantially higher in lower GCS level patients.

Integration of hepatitis B virus containing mutations in the core promoter/X gene in patients with hepatocellular carcinoma.

UNLABELLED: Integration of hepatitis B virus is thought to be an essential step in hepatitis B virus associated hepatocarcinogenesis. Mutations at nucleotides 1762 and 1764 in the hepatitis B virus, within a sequence encoding both the core promoter gene and the X gene, have been found frequently in patients with hepatocellular carcinoma. However, integration of these mutant sequences has not been reported to date. METHODS: A 228-base pair segment of the hepatitis B virus core promoter gene was amplified from hepatocellular carcinomas and adjacent non-tumourous liver tissue by nested PCR and sequenced. Integration of hepatitis B virus into human genomic DNA was investigated using the 'genome walking' method. RESULTS: Point mutations were found in both hepatitis B virus nucleotides 1762 and 1764 in 8 of 14 hepatocellular carcinoma tissues (57%) and in 11 of 14 adjacent non-tumourous liver tissues (79%). Three patients were evaluated using the 'genome walking' method; all were found to have hepatitis B virus DNA integrated in their hepatocellular carcinoma (two patients) and/or in their non-tumourous liver tissue (three patients). Integration occurred in all tissues near host genomic sites that are prone to integration. Hepatitis B virus was integrated at or near the hepatitis B virus DR1 site in all samples, and all contained truncated X gene sequences that have been reported to be capable of producing fusion transcripts with transactivation potential. CONCLUSIONS: Integrated hepatitis B virus DNA containing core promoter mutations at nucleotides 1762 and 1764 was found in hepatocellular carcinoma and/or adjacent non-tumourous liver tissue of three patients. These findings leave open the possibility that insertional mutagenesis or transactivation by fusion transcripts resulting from hepatitis B virus integration could play a role in hepatocarcinogenesis in some patients.

Molecular and serological aspects of HBsAg-negative hepatitis B virus infections in North America.

A few hepatitis B virus (HBV) infections are characterized by the presence of HBV DNA in serum or liver tissue, or both, in the absence of detectable hepatitis B surface antigen (HBsAg) in serum. However, such infections have rarely been described previously in North American patients. In the present study, 31 hepatocellular carcinoma (HCC) patients from the United States and Canada who had no detectable HBsAg in their serum were studied. In these 31 HBsAg-negative HCC patients, HBV DNA was detected in HCC and/or in adjacent nontumorous liver tissue using nested polymerase chain reaction (PCR) in 5/9 (56%) patients from the United States and in 12/22 (55%) from Canada. The 17 HBV DNA-positive/HBsAg-negative patients from the United States and Canada included 9 without any serological markers for HBV and 8 with detectable antibodies to hepatitis B core antigen. In these patients, HBV genotype C was the most prevalent genotype (11/17; 64%). HBV genotypes have not been previously reported in HCC patients from North America. Replicative intermediate forms of HBV (covalently closed circular HBV DNA) were detected in 2/17 (12%) HBV DNA-positive/HBsAg-negative patients, indicating that at least two of these patients had actively replicating HBV infections. The use of tests to detect HBV DNA permitted the identification of HBV infections in HBsAg-negative HCC patients from North America. Among these patients, those with antibody to hepatitis C virus (HCV) would otherwise have been designated "HCV-associated HCCs" based on serological tests alone. These findings provide a new perspective on determining the possible viral etiologies of HCCs in North America.

Pulmonary membrane diffusing capacity and capillary blood volume measured during exercise from nitric oxide uptake.

STUDY OBJECTIVES: To validate lung diffusing capacity for nitric oxide (DLNO) as an index of conductance of the alveolar-capillary membrane during exercise, we compared DLNO to lung diffusing capacity for carbon monoxide (DLCO) and pulmonary membrane diffusing capacity for carbon monoxide (DMCO), and compared pulmonary capillary blood volume (Vc) calculated by two methods. SETTING AND PARTICIPANTS: The study was performed at a university medical center involving 12 nonsmoking healthy volunteers (age range, 23 to 79 years). DLCO, DLNO, cardiac output (c), and lung volume were measured simultaneously at rest and during graded ergometer exercise by a rebreathing technique. Pulmonary membrane diffusing capacity and Vc were compared by (1) the classic technique of Roughton and Forster from DLCO measured at two alveolar oxygen tension (PAO(2)) levels, and (2) from DLNO and DLCO assuming negligible erythrocyte resistance to nitric oxide (NO) uptake, ie, DLNO approximately equal to pulmonary membrane diffusing capacity for nitric oxide. RESULTS: In all subjects, DLNO increased linearly from rest to exercise; age, c, and lung volume were the major determinants of DLNO by stepwise regression analysis. The DLNO/DLCO ratio averaged 3.98 +/- 0.38 (+/- SD) and the DLNO/DMCO ratio averaged 2.49 +/- 0.28 irrespective of exercise intensity. Changing PAO(2) did not alter DLNO. Brief exposure to 40 ppm of inhaled NO during 16 s of rebreathing did not alter either DLCO or c. Estimates of pulmonary membrane diffusing capacity and Vc by the two methods showed a strong correlation. CONCLUSION: Results support DLNO as a direct measure of pulmonary membrane diffusing capacity, allowing the estimation of Vc in a single rebreathing maneuver during exercise. The DLNO-DLCO rebreathing technique can be applied clinically in the investigation of pulmonary microvascular regulation.

Preventing mediastinal shift after pneumonectomy impairs regenerative alveolar tissue growth.

To examine the effects of mechanical lung strain on regenerative growth of alveolar septal tissue after pneumonectomy (PNX), we replaced the right lungs of adult dogs with a custom-shaped inflatable silicone prosthesis. The prosthesis was either inflated (Inf) to maintain the mediastinum at the midline or deflated to allow mediastinal shift. The animals were euthanized approximately 15 mo later, and the lungs were fixed at a constant distending pressure. With the Inf prostheses, lung expansion, alveolar septal tissue volumes, surface areas, and diffusing capacity of the tissue-plasma barrier were significantly lower than with the deflated prostheses; the expected post-PNX tissue responses were impaired by 30-60%. Capillary blood volume was significantly higher with Inf prostheses, consistent with microvascular congestion. Measurements in the Inf group remained consistently and significantly higher than those expected for a normal left lung, indicating persistence of partial compensation. In one dog, delayed deflation of the prosthesis 9-10 mo after PNX led to vigorous lung expansion and septal tissue growth, particularly of type II epithelial cells. We conclude that mechanical lung strain is a major signal for regenerative lung growth; however, other signals are also implicated, accounting for a significant fraction of the compensatory response to PNX.

Adaptation of respiratory muscle perfusion during exercise to chronically elevated ventilatory work.

Pneumonectomy (PNX) leads to chronic asymmetric ventilatory loading of respiratory muscles (RM). We measured RM energy requirements during exercise from RM blood flow (Q) using a fluorescent microsphere technique in dogs that had undergone right PNX as adults (adult R-PNX) or as puppies (puppy R-PNX), compared with dogs subjected to right thoracotomy without PNX as puppies (Sham) and to left PNX as adults (adult L-PNX). Ventilatory work (W) was measured during exercise. RM weight was determined post mortem. After adult and puppy R-PNX, the right hemidiaphragm becomes grossly distorted, but W and right costal muscle mass increased only after adult R-PNX. After adult L-PNX, the diaphragm was undistorted; W and left hemidiaphragm RM Q were elevated, but muscle mass did not increase. Mass of parasternal muscle did not increase after adult R-PNX, despite increased Q. Thus muscle mass increased only in response to the combination of chronic stretch and dynamic loading. There was a dorsal-to-ventral gradient of increasing Q within the diaphragm, but the distribution was unaffected by anatomic distortion, hypertrophy, or workload, suggesting a fixed pattern of neural activation. The diaphragm and parasternals were the primary muscles compensating for the asymmetric loading from PNX.

Preventing mediastinal shift after pneumonectomy does not abolish physiological compensation.

To determine the role of mediastinal shift after pneumonectomy (PNX) on compensatory responses, we performed right PNX in adult dogs and replaced the resected lung with a custom-shaped inflatable silicone prosthesis. Prosthesis was inflated (Inf) to prevent mediastinal shift, or deflated (Def), allowing mediastinal shift to occur. Thoracic, lung air, and tissue volumes were measured by computerized tomography scan. Lung diffusing capacities for carbon monoxide (DL(CO)) and its components, membrane diffusing capacity for carbon monoxide (Dm(CO)) and capillary blood volume (Vc), were measured at rest and during exercise by a rebreathing technique. In the Inf group, lung air volume was significantly smaller than in Def group; however, the lung became elongated and expanded by 20% via caudal displacement of the left hemidiaphragm. Consequently, rib cage volume was similar, but total thoracic volume was higher in the Inf group. Extravascular septal tissue volume was not different between groups. At a given pulmonary blood flow, DL(CO) and Dm(CO) were significantly lower in the Inf group, but Vc was similar. In one dog, delayed mediastinal shift occurred 9 mo after PNX; both lung volume and DL(CO) progressively increased over the subsequent 3 mo. We conclude that preventing mediastinal shift after PNX impairs recruitment of diffusing capacity but does not abolish expansion of the remaining lung or the compensatory increase in extravascular septal tissue volume.

Effects of crocetin on pulmonary gas exchange in foxhounds during hypoxic exercise.

The carotenoid compound crocetin has been hypothesized to enhance the diffusion of O(2) through plasma, and observations in the rat and rabbit have revealed improvement in arterial PO(2) when crocetin is given. To determine whether crocetin enhances diffusion of O(2) between alveolar gas and the red blood cell in the pulmonary capillary in vivo, five foxhounds, two previously subjected to sham and three to actual lobectomy or pneumonectomy, were studied while breathing 14% O(2) at rest and during moderate and heavy exercise before and within 10 min after injection of a single dose of crocetin as the trans isomer of sodium crocetinate (TSC) at 100 microg/kg iv. This dose is equivalent to that used in previous studies and would yield an initial plasma concentration of 0.7-1.0 microg/ml. Ventilation-perfusion inequality and pulmonary diffusion limitation were assessed by the multiple inert gas elimination technique in concert with conventional measurements of arterial and mixed venous O(2) and CO(2). TSC had no effect on ventilation, cardiac output, O(2) consumption, arterial PO(2)/saturation, or pulmonary O(2) diffusing capacity. There were minor reductions in ventilation-perfusion mismatching (logarithm of the standard deviation of perfusion fell from 0.48 to 0.43, P = 0.001) and in CO(2) output and respiratory exchange ratio (P = 0.05), which may have been due to TSC or to persisting effects of the first exercise bout. Spectrophotometry revealed that TSC disappeared from plasma with a half time of approximately 10 min. We conclude that, in this model of extensive pulmonary O(2) diffusion limitation, TSC as given has no effect on O(2) exchange or transport. Whether the original hypothesis is invalid, the dose of TSC was too low, or plasma diffusion of O(2) is not rate limiting without TSC cannot be discerned from the present study.

Regenerative growth of respiratory bronchioles in dogs.

Loss of lung units due to pneumonectomy stimulates growth of the remaining lung. It is generally believed that regenerative lung growth involves only alveoli but not airways, a dissociated response termed "dysanaptic growth." We examined the structural response of respiratory bronchioles in immature dogs raised to maturity after right pneumonectomy. In another group of adult dogs, we also examined the effect of preventing mediastinal shift after right pneumonectomy on the response of respiratory bronchioles. In immature dogs after pneumonectomy, the volume of the remaining lung increased twofold, with no change in volume density, numerical density, or mean diameter of respiratory bronchiole, compared with that in the control lung. The number of respiratory bronchiole segments and branch points increased proportionally with lung volume. In adult dogs after pneumonectomy, prevention of mediastinal shift reduced lung strain at a given airway pressure, but lung expansion and regenerative growth of respiratory bronchiole were not eliminated. We conclude that postpneumonectomy lung growth is associated with proliferation of intra-acinar airways. The proportional growth of acinar airways and alveoli should optimize gas exchange of the regenerated lung by enhancing gas conductance and mixing efficiency within the acinus.

Correlation of immunohistochemical staining and mutations of p53 in human hepatocellular carcinoma.

Mutations of the p53 tumor suppressor gene are common in hepatocellular carcinomas (HCCs). Detection of mutations by sequencing provides more information than immunohistochemical staining, but the equipment needed and the time required make it less practical for use in large-scale studies or in studies in developing countries. The degree of correlation between results obtained with these two methods has been studied in various tumors but has not been well-established in human HCCs. Paraffin sections of HCCs of 28 patients from Qidong, China were immunohistochemically stained using monoclonal antibody to p53. In addition, exons 5-8 of the p53 gene were sequenced in these HCCs. Of the 28 HCCs, nine had 0-9% of nuclei stained for p53, and 19 had 50-95% stained. Mutations in p53 exons 5-8 were found in 17/28 (61%) HCCs, including 15 at codon 249 (exon 7), one at codon 198 (exon 6), and one at codon 175 (exon 5). Among these 17 cases with p53 mutations, 16 cases (94%) had 50-95% of nuclei stained. Among 11 HCCs with no mutations by sequencing, 8 were also negative by immunohistochemistry (0-9% of nuclei stained) (73%) (the five HCCs with no staining whatsoever all had wild-type p53). Immunohistochemical staining to detect p53 mutations in human HCCs detected most mutations that were detected by sequencing (94% sensitivity, 73% specificity), and this method is therefore suitable when sequencing cannot be performed.