Health related quality of life in Friedreich Ataxia in a large heterogeneous cohort.

INTRODUCTION: This study assessed the Health Related Quality of Life (HRQOL) of individuals with Friedreich Ataxia (FRDA) through responses to HRQOL questionnaires. METHODS: The SF-36, a generic HRQOL instrument, and symptom specific scales examining vision, fatigue, pain and bladder function were administered to individuals with FRDA and analyzed by comparison with disease features. Multiple linear regression models were used to study independent effects of genetic severity and age. Assessments were performed at baseline then intermittently after that. RESULTS: Subjects were on average young adults. For the SF36, the subscale with the lowest HRQOL score was the physical function scale, while the emotional well-being score was the highest. The physical function scale correlated with age of onset, duration, and subject age. In assessment of symptom specific scales, bladder control scores (BLCS) correlated with duration and age, while impact of visual impairment scores (IVIS) correlated with duration. In linear regression models, the BLCS, Pain Effect Score, and IVIS scores were predicted by age and GAA length; modified fatigue impact scale scores were predicted only by GAA length. Physical function and role limitation scores declined over time. No change was seen over time in other SF-36 subscores. Symptom specific scales also worsened over time, most notably the IVIS and BLCS. CONCLUSION: The SF-36 and symptom specific scales capture dysfunction in FRDA in a manner that reflects disease status. HRQOL dysfunction was greatest on physically related scales; such scales correlated with disease duration, indicating that they worsen with progressing disease.

Cancer cells suppress p53 in adjacent fibroblasts.

The p53 tumor suppressor serves as a crucial barrier against cancer development. In tumor cells and their progenitors, p53 suppresses cancer in a cell-autonomous manner. However, p53 also possesses non-cell-autonomous activities. For example, p53 of stromal fibroblasts can modulate the spectrum of proteins secreted by these cells, rendering their microenvironment less supportive of the survival and spread of adjacent tumor cells. We now report that epithelial tumor cells can suppress p53 induction in neighboring fibroblasts, an effect reproducible by tumor cell-conditioned medium. The ability to suppress fibroblast p53 activation is acquired by epithelial cells in the course of neoplastic transformation. Specifically, stable transduction of immortalized epithelial cells by mutant H-Ras and p53-specific short inhibitory RNA endows them with the ability to quench fibroblast p53 induction. Importantly, human cancer-associated fibroblasts are more susceptible to this suppression than normal fibroblasts. These findings underscore a mechanism whereby epithelial cancer cells may overcome the non-cell-autonomous tumor suppressor function of p53 in stromal fibroblasts.

Development of a self-emulsifying formulation that reduces the food effect for torcetrapib.

Torcetrapib is a highly lipophilic (Clog P=7.45) and water insoluble cholesteryl ester transfer protein (CETP) inhibitor developed for the treatment of atherosclerosis. Self-emulsifying drug delivery system (SEDDS) formulations have been developed to reduce the food effect observed in early clinical trials using medium chain triglyceride (MCT) softgels and to increase the dose per capsule. MCT/Triacetin/Polysorbate 80/Capmul MCM (20/30/20/30) (MTPC) increased fasted exposure and thus reduced the food effect from 5- to 3-fold in dogs at a dose of 90 mg. Self-emulsifying formulations also accelerated absorption and generally decreased variability. Use of the lipophilic, GRAS cosolvent triacetin allowed a 2-fold increase in the dose per capsule. For the three formulations evaluated in dogs that showed significant differences in absorption, emulsion droplet size did not appear to play a significant role. Absorption did increase with Cremophor RH40 content, and at 50% Cremophor RH40 there was no food effect (at 30 mg). High polar surfactant content also resulted in poor dose proportionality, while there was good dose proportionality for MTPC. Studies of in vitro lipolysis are being conducted to aid in understanding the in vitro/in vivo relationships for torcetrapib SEDDS absorption.

Chromosomal aberrations and gene expression profiles in non-small cell lung cancer.

Alterations in genomic content and changes in gene expression levels are central characteristics of tumors and pivotal to the tumorigenic process. We analyzed 23 non-small cell lung cancer (NSCLC) tumors by array comparative genomic hybridization (array CGH). Aberrant regions identified included well-characterized chromosomal aberrations such as amplifications of 3q and 8q and deletions of 3p21.31. Less frequently identified aberrations such as amplifications of 7q22.3-31.31 and 12p11.23-13.2, and previously unidentified aberrations such as deletion of 11q12.3-13.3 were also detected. To enhance our ability to identify key acting genes residing in these regions, we combined array CGH results with gene expression profiling performed on the same tumor samples. We identified a set of genes with concordant changes in DNA copy number and expression levels, i.e. overexpressed genes located in amplified regions and underexpressed genes located in deleted regions. This set included members of the Wnt/beta-catenin pathway, genes involved in DNA replication, and matrix metalloproteases (MMPs). Functional enrichment analysis of the genes both overexpressed and amplified revealed a significant enrichment for DNA replication and repair, and extracellular matrix component gene ontology annotations. We verified the changes in expressions of MCM2, MCM6, RUVBL1, MMP1, MMP12 by real-time quantitative PCR. Our results provide a high resolution map of copy number changes in non-small cell lung cancer. The joint analysis of array CGH and gene expression analysis highlights genes with concordant changes in expression and copy number that may be critical to lung cancer development and progression.

Do hyperoxaemia and hypocapnia add to the risk of brain injury after intrapartum asphyxia?

BACKGROUND: Episodes of hyperoxaemia and hypocapnia, which may contribute to brain injury, occur unintentionally in severely asphyxiated neonates in the first postnatal hours. OBJECTIVE: To determine whether hyperoxaemia and/or hypocapnia during the first 2 hours of life add to the risk of brain injury after intrapartum asphyxia. METHODS: Retrospective cohort study in term infants with post-asphyxial hypoxic ischaemic encephalopathy (HIE) born between 1985 and 1995. Severe and moderate hyperoxaemia were defined as Pao(2) >26.6 and Pao(2) >13.3 kPa (200 and 100 mm Hg). Severe and moderate hypocapnia were defined as Paco(2) <2.6 and Paco(2) <3.3 kPa (20 and 25 mm Hg). Adverse outcome ascertained by age 24 months was defined as death, severe cerebral palsy, or any cerebral palsy with blindness, deafness, or developmental delay. With outcome as the dependent variable, multivariate analyses were performed including hyperoxaemic and hypocapnic variables, and factors adjusted for initial disease severity. RESULTS: Of 244 infants, 218 had known outcomes, 127 of which were adverse (64 deaths, 63 neurodevelopmental deficits). Multivariate analyses showed an association between adverse outcome and episodes of severe hyperoxaemia (odds ratio (OR) 3.85, 95% confidence interval (CI) 1.67 to 8.88, p = 0.002), and severe hypocapnia (OR 2.34, 95% CI 1.02 to 5.37, p = 0.044). The risk of adverse outcome was highest in infants who had both severe hyperoxaemia and severe hypocapnia (OR 4.56, 95% CI 1.4 to 14.9, p = 0.012). CONCLUSIONS: Severe hyperoxaemia and severe hypocapnia were associated with adverse outcome in infants with post-asphyxial HIE. During the first hours of life, oxygen supplementation and ventilation should be rigorously controlled.

Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy.

BACKGROUND: Multiorgan dysfunction (MOD) is one of four consensus based criteria for the diagnosis of intrapartum asphyxia. The theoretical concept behind MOD is the diving reflex (conservation of blood flow to vital organs at the cost of non-vital organs). OBJECTIVES: To assess the patterns of involvement of each major organ/system and combinations of involvement in infants with post-asphyxial hypoxic-ischaemic encephalopathy (HIE), and to describe this in relation to long term outcome. DESIGN: Retrospective cohort study. SETTING: Regional tertiary neonatal intensive care unit at the Hospital for Sick Children, Toronto, Canada. PATIENTS: Term neonates with post-intrapartal asphyxial HIE assessed for kidney, cardiovascular system, lung, and liver function. OUTCOME: Death and presence or absence of severe neurodevelopmental disability. RESULTS: Out of 130 of 144 eligible infants with outcome data, 80 (62%) had severe adverse outcome and 50 (38%) had good outcome. All infants had evidence of MOD (at least one organ dysfunction in addition to HIE). Renal, cardiovascular, pulmonary, and hepatic dysfunction was present in 58-88% of infants with good outcome and 64-86% of infants with adverse outcome. CONCLUSIONS: MOD was present in all the infants with severe post-asphyxial HIE. However, there was no association between MOD and outcome in these infants. No relation between individual or combinations of organ involvements and long term outcomes was observed.

Recovery of metabolic acidosis in term infants with postasphyxial hypoxic-ischemic encephalopathy.

AIMS: To describe the base deficit (BD) values and the rate of postnatal recovery of the BD of infants with hypoxic ischemic encephalopathy due to intrapartum asphyxia; and to explore the relationships between the rate of recovery of BD, severe adverse outcome and different time patterns (acute total vs prolonged partial) of asphyxia. METHODS: Clinical and laboratory data were collected from the neonatal period (n = 244) and outcome data to a minimal age of 1 y (n = 218). Rates of recovery of BD were described in four 60 min blocks of time. The values of rate of recovery were compared between the outcome groups, ignoring correlation structure within subjects and with adjustment by the generalized estimating equations method. RESULTS: The BD normalized within 4 h of birth in all but 9 of 244 infants. The rates of recovery of BD in infants with good and severe adverse outcome respectively were 0.11 [95% confidence interval (95% CI) 0.07, 0.14] and 0.09 (95% CI 0.07, 0.12) mmol l(-1) min(-1) over the first 4 h after birth. The rates of recovery were similar with or without buffer therapy, and after acute near-total and prolonged partial asphyxia. CONCLUSION: The BD in the great majority of infants with severe intrapartum asphyxia normalizes within 4 h of birth. The BD recovery rate of infants with adverse outcomes was similar to those with relatively good outcome. The different time patterns of asphyxial episode were not associated with differential recovery profiles.

Solution-phase, parallel synthesis and pharmacological evaluation of acylguanidine derivatives as potential sodium channel blockers.

Solution-phase synthesis of various acylguanidine derivatives and the evaluation of a small library of compounds as potential sodium channel blockers are described.

Identification and characterization of a potential ischemia-selective N-methyl-D-aspartate (NMDA) receptor ion-channel blocker, CNS 5788.

The identification and characterization of a potentially ischemia-selective and orally-active sulfoxide based NMDA ion-channel blocker showing good neuroprotective activity, (R)-(+)-N-(2-chloro-5-methylthiophenyl)-N'-(3-methylsulfinylphenyl)-N'-methylguanidine (CNS 5788), is described.

Prognostic value of EEG in neonatal bacterial meningitis.

The contribution of electroencephalogram (EEG) findings early in the course of neonatal bacterial meningitis to the prediction of severe adverse outcome was assessed in a retrospective cohort study. Infants had known outcomes to 1 year of age and an EEG performed during the first week of illness. EEGs were subclassified as follows: overall EEG description, background activity, presence of positive rolandic sharp waves, presence of seizure activity, and presence of focal abnormal activity. EEG patterns predictive of severe adverse outcome were identified by univariate and multivariate analyses. Of 101 infants admitted with bacterial meningitis, 37 had an EEG performed. Of the 37 infants, 21 had adverse outcomes; nine infants died, and 12 infants had moderate or severe disability. EEG background activity and overall EEG description were identified as predictors of adverse outcome; multivariate analysis indicated that the latter was a stronger predictor (sensitivity 88%, specificity 90%). Infants with normal or mildly abnormal EEGs had good outcomes whereas those with moderate to markedly abnormal EEGs died or survived with adverse outcome. The accuracy of predictions increased when EEGs were repeated. In a high-risk population of infants with bacterial meningitis, moderate-to-markedly abnormal EEG reliably predicts adverse outcome.

Synthesis and binding characteristics of N-(1-naphthyl)-N'-(3-[(125)I]-iodophenyl)-N'-methylguanidine ([(125)I]-CNS 1261): a potential SPECT agent for imaging NMDA receptor activation.

N-(1-Naphthyl)-N'-(3-[(125)I]-iodophenyl)-N'-methylguanidine ([(125)I]-CNS 1261) was synthesized as a potential radioligand to image N-methyl-D-aspartate (NMDA) receptor activation. [(125)I]-CNS 1261 was prepared by radioiodination of N-(1-naphthyl)-N'-(3-tributylstannylphenyl)-N'-methylguanidine using Na(125)I and peracetic acid. [(125)I]-CNS 1261 uptake in vivo reflected NMDA receptor distribution in normal rat brain, whereas in ischemic rat brain, uptake was markedly increased in areas of NMDA receptor activation. Radiolabeled CNS 1261 appears to be a good candidate for further development as a single photon emission computed tomography tracer in the investigation of NMDA receptor activation in cerebral ischemia.

Predicting the outcome of neonatal bacterial meningitis.

OBJECTIVE: To build predictive models of severe adverse outcome at various times in the course of neonatal bacterial meningitis. STUDY DESIGN: Retrospective cohort study with follow-up to a minimum age of 1 year of term and near-term infants, admitted between 1979 and 1998 to a regional tertiary care center. Predictors of adverse outcome detectable at 1 year of age (death or moderate or severe neurosensory impairment) were identified by univariate analysis. Independent predictors of adverse outcome were identified by multivariate analysis. Predictive tree models were constructed at 12, 24, 48, and 96 hours after admission and at discharge. RESULTS: Of 101 infants admitted with definitive bacterial meningitis, 13 died and 17 had moderate or severe disability at 1 year of age. Outcomes are known for all patients, to 1 year of age. Twelve hours after admission the important predictors of adverse outcome were presence of seizures, presence of coma, use of inotropes, and leukopenia (sensitivity: 68%; specificity: 100%). At 96 hours the predictors were seizure duration of >72 hours, presence of coma, use of inotropes, and leukopenia (sensitivity: 88%; specificity: 99%). CONCLUSIONS: Most infants at risk for adverse outcome can be identified within 12 hours of admission. Duration of seizures for >72 hours, presence of coma, use of inotropes, and leukopenia were the most important predictors of adverse outcome. Although these models have good predictive accuracy, they need to be validated in a contemporary cohort in large multicenter studies.

Disability outcomes in a worker's compensation population: surgical versus nonsurgical treatment of carpal tunnel syndrome.

A retrospective record review of patients with occupational carpal tunnel syndrome, nerve conduction velocity studies, and a closed Workers' Compensation case was undertaken to compare the outcome of surgical versus nonsurgical treatment with respect to disability and return to work status. Between January 1, 1991, and December 31, 1993, 182 patients who met the inclusion criteria were identified. Surgical release of the carpal tunnel was performed in 57% of patients and the other 43% were treated conservatively. Overall, 82% of patients returned to full work status, whereas 18% had duty modifications. Surgical treatment decreased the rate of duty modifications and disability ratings compared with nonsurgical treatment and reduced the odds of incurring disability. Severity of carpal tunnel syndrome was also a significant factor affecting disability. Despite the generally held belief that the outcome of treatment of occupational carpal tunnel syndrome is poor, the present study shows that both surgical and nonsurgical treatment is effective. However, patients treated with surgery had decreased disability when compared with those who were treated conservatively.

The incidence of joint involvement with adjacent osteomyelitis in pediatric patients.

Sixty-six patients admitted to our institution over an 8-year period with the diagnosis of osteomyelitis were analyzed to determine the incidence of adjacent joint involvement. Patients with osteomyelitis of the hand, foot, spine, and extraarticular pelvis were excluded from this study. The average age was 5.8 years (range, 1 month to 17 years). Forty-two percent of our patients who had osteomyelitis had evidence of adjacent joint involvement (either septic or nonseptic). One third of our patients had evidence of septic joint involvement. The most commonly involved joint was the knee. There was no difference in the incidence of adjacent joint involvement in those patients who were younger than 18 months compared with the incidence in older children. Our study suggests that the incidence of adjacent joint involvement in children who have osteomyelitis is higher than that suggested in the literature. We believe that careful evaluation of the adjacent joint should be an important part of the evaluation of any child who has osteomyelitis.

Ankle fusion in a high risk population: an assessment of nonunion risk factors.

Between July 1992 and April 1996, 88 ankle fusions were performed at our institution. Sixty-seven of these had adequate follow-up for evaluation for union of the fusion, including adequate records and/or radiographs. The average age of patients was 43 years. There were 37 men and 24 women. The charts were reviewed to determine what level of trauma had resulted in posttraumatic arthritis (low energy, high energy, or open fracture). Alcohol use, drug abuse, diabetes, peripheral vascular disease, psychiatric history, smoking, or technical problems were also assessed. A chi-square analysis was used to evaluate the statistical significance. Nineteen of sixty-seven ankle fusions progressed to nonunion (28%). Eighty-five percent of the patients had posttraumatic arthritis. Among 17 patients with a history of open trauma, nine patients developed a nonunion (P < 0.03). A trend toward significance was noted for patients who were smokers, drank alcohol, had diabetes, had a psychiatric disorder, or used illegal drugs. Even with current techniques, this study demonstrates that a high risk population in a trauma center is at risk for nonunion after an ankle fusion caused by multiple risk factors, including a history of open trauma, tobacco use, alcohol use, illegal drug use, a history of psychiatric disorders, or diabetes.

A randomized trial of 72- versus 24-hour intravenous tubing set changes in newborns receiving lipid therapy.

OBJECTIVE: To compare the microbial contamination rate of infusate in the intravenous tubing of newborns receiving lipid therapy, replacing the intravenous delivery system at 72-hour versus 24-hour intervals. DESIGN: Infants requiring intravenous lipid therapy were randomly assigned to have intravenous sets changed on a 72- or a 24-hour schedule, in a 3:1 ratio, in order to compare the infusate contamination rates in an equivalent number of tubing sets. SETTING: A 35-bed, teaching, referral, neonatal intensive-care unit (NICU). PARTICIPANTS: All neonates admitted to the NICU for whom intravenous lipid was ordered. METHODS: Patients were randomized in pharmacy, on receipt of the order for intravenous lipid therapy, to either 72- or 24-hour administration set changes, and followed until 1 week after discontinuation of lipids or discharge from the NICU. Microbial contamination of the infusate was assessed in both groups at the time of administration set changes. Contamination rates were analyzed separately for the lipid and amino acid-glucose tubing sets. Patient charts were reviewed for clinical and epidemiological data, including birth weight, gestational age, gender, age at start of lipid therapy, duration of parenteral nutrition, and type of intravenous access. RESULTS: During the study period, 1,101 and 1,112 sets were sampled in the 72- and 24-hour groups, respectively. Microbial contamination rates were higher in the 72-hour group than the 24-hour group for lipid infusions (39/1,101 [3.54%] vs 15/1,112 [1.35%]; P=.001) and for amino acid infusions (12/1,093 [1.10%] vs 4/1,103 [0.36%]; P=.076). Logistic regression analysis controlling for birth weight, gestational age, and type of venous access showed that only the tubing change interval was significantly associated with lipid set contaminations (odds ratio, 2.69; P=.0013). The rate of blood cultures ordered was higher in the 72- versus the 24-hour group (6.11 vs 4.99 per 100 patient days of total parenteral nutrition; P=.017), and a higher proportion of infants randomized to the 72-hour group died (8% vs 4%; P=.05), although the excess deaths could not clearly be attributed to bacteremia. CONCLUSION: Microbial contamination of infusion sets is significantly more frequent with 72- than with 24-hour set changes in neonates receiving lipid solutions. This may be associated with an increased mortality rate.

Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow autotransplants in newly diagnosed multiple myeloma.

There is controversy whether high-dose therapy and a bone marrow autotransplant or conventional chemotherapy is a better treatment for newly diagnosed multiple myeloma. Data from 1 comparative study and 1 randomized trial provide insufficient subject-level data to advise specific people whether to have an autotransplant. We analyzed appropriate use of high-dose therapy and bone marrow autotransplants in people with newly diagnosed, multiple myeloma using a modified Delphi-panel group judgment process. The panel consisted of 9 myeloma experts from diverse geographic sites and practice settings who reviewed Boolean MEDLINE searches of multiple myeloma and chemotherapy or autotransplants. The panel rated a metric of 64 clinical setting developed by permuting age, performance score, disease-stage and disease-related prognostic variables and response to initial therapy. Each panelist rated appropriateness of high-dose therapy and an autotransplant versus conventional-dose chemotherapy on a 9-point ordinal scale (1, most inappropriate, 9, most appropriate). An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Autotransplants were rated appropriate in persons <55 years old with stage 3 disease and a complete or partial response or stable disease after initial chemotherapy, inappropriate in persons with stage 1 or 2 disease, a performance score <70% and a complete or partial response or stable disease after initial chemotherapy and uncertain in all other settings.

Symptomatic hypoglycemia in otherwise healthy, breastfed term newborns.

Transient symptomatic neonatal hypoglycemia, a diagnosis that is made in the neonatal nursery, is not usually associated with apparently normal infants who have been discharged from hospital. We describe 3 such cases that presented at home on day 3 of life with seizures or life-threatening apneas. We postulate that early discharge of apparently normal infants with marginal nutritional or metabolic adaptation, may expose some infants to postdischarge (but still neonatal) hypoglycemia and its attendant risks.