Head injury serum markers for assessing response to trauma: Design of the HeadSMART study.

BACKGROUND: Accurate diagnosis and risk stratification of traumatic brain injury (TBI) at time of presentation remains a clinical challenge. The Head Injury Serum Markers for Assessing Response to Trauma study (HeadSMART) aims to examine blood-based biomarkers for diagnosing and determining prognosis in TBI. METHODS: HeadSMART is a 6-month prospective cohort study comparing emergency department patients evaluated for TBI (exposure group) to (1) emergency department patients evaluated for traumatic injury without head trauma and (2) healthy persons. Study methods and characteristics of the first 300 exposure participants are discussed. RESULTS: Of the first 300 participants in the exposure arm, 70% met the American Congress of Rehabilitation Medicine criteria for TBI, with the majority (80.1%) classified as mild TBI. The majority of subjects in the exposure arm had Glasgow Coma Scale scores of 13-15 (98.0%), normal head computed tomography (81.3%) and no prior history of concussion (71.7%). CONCLUSION: With systematic phenotyping, HeadSMART will facilitate diagnosis and risk-stratification of the heterogeneous group of individuals currently diagnosed with TBI.

SLE-key(®) rule-out serologic test for excluding the diagnosis of systemic lupus erythematosus: Developing the ImmunArray iCHIP(®).

We describe here the development, verification and validation of the SLE-key(®) rule-out test for a definitive rule-out of a diagnosis of systemic lupus erythematosus (SLE). The test uses the proprietary iCHIP(®) micro-array technology platform (Fattal et al., 2010) to identify discriminating patterns of circulating autoantibodies among SLE patients compared with self-declared healthy individuals. Given the challenges associated with the diagnosis of SLE and the healthcare costs of delayed diagnosis and misdiagnosis, a definitive rule-out test can provide significant clinical benefits to patients and potentially major cost savings to healthcare systems.

Association between offspring intelligence and parental mortality: a population-based cohort study of one million Swedish men and their parents.

BACKGROUND: An inverse association of IQ with mortality has been observed in previous studies. Analyses of associations between offspring's IQ and parental mortality in biological and non-biological family relations may shed light on genetic and environmental influences. METHODS: In a target cohort of 1,235,375 Swedish men, 931,825 (75%) men had complete data on all variables used. IQ of offspring was measured at age 18 and mothers and father were followed, on average, for 21.2 years and 19.7 years, respectively, with respect to all-cause and cause-specific mortality (cardiovascular disease, coronary heart disease, stroke and diabetes). The analyses were conducted by proportional hazards regression with adjustment for parental occupation, education and income. RESULTS: In adjusted analyses using IQ as a continuous variable over a standard nine-point scale, hazards ratio (HR) for all-cause mortality was 0.96 (95% CI 0.96 to 0.96) for fathers and 0.95 (0.95 to 0.95) for mothers. The corresponding HRs were 0.99 (0.97 to 1.00) for step-fathers and 0.97 (0.95 to 0.99) for step-mothers. In adjusted analyses, HRs for CVD mortality among fathers and mothers were 0.97 (0.96 to 0.97) and 0.94 (0.93 to 0.94) respectively. The corresponding HRs for diabetes mortality were 0.91 (0.89 to 0.92) among fathers and 0.85 (0.83 to 0.87) among mothers. CONCLUSIONS: The associations found in non-biological family relationships suggest shared environmental influences and/or assortative mating. Stronger IQ-mortality associations in biological than non-biological relationships suggest genetic influences. Stronger inverse offspring IQ-parental mortality associations in mothers than in fathers might be due to environmental factors or epigenetic mechanisms.

Evaluation of renal function in transplantation.

Kidney dysfunction causes a myriad of adverse influences on posttransplant outcomes necessitating accurate assessment of kidney function for patient management. This evaluation assists in guiding treatment decisions, with the ultimate aim of allaying renal function decline. In clinical practice, renal function is typically estimated from serum creatinine levels, creatinine-based estimation equations or creatinine clearance; however, each of these methods has demonstrated limitations when used in the kidney transplant setting. Equally important is the emerging recognition of the incidence and impact of kidney dysfunction in recipients of nonrenal solid organ transplantation. The performance of commonly used estimation equations and methods for measuring kidney function in renal and liver transplant patients are overviewed here along with their potential roles in clinical transplantation.

The nondirected living donor program: a model for cooperative donation, recovery and allocation of living donor kidneys.

We describe an altruistic nondirected (ND) and live donor/deceased donor list exchange (LE) donor program administered by an organ procurement organization (OPO) in the Washington, DC area. Screening eliminated 25 donors (17 NE; 8 LE) from the 97 donor applications (62 ND; 35 LE) completed. Twenty-one donors (16 ND; 5 LE) failed to follow through with the psychiatric evaluation, which eliminated 13 donors (9 ND; 4 LE). Two donors dropped out and 12 (9 ND; 3 LE) were medically unsuitable after final clinical evaluation. Twenty donor procedures were performed (10 ND; 10 LE) with four pending (2 ND; 2 LE). This resulted in a modest 3-5% increase in the OPO-procured kidney organ pool. The average cold ischemia time of the grafts not transported between transplant centers was 205 +/- 66 min compared with 243 +/- 48 min for transported grafts. With no documented adverse outcomes, donors had a hospital stay of length 2.9 days and at home recuperation of 12.3 days. Three- and 6-month creatinines were 1.44 +/- 1.36 and 1.68 +/- 0.61 for grafts not transported between transplant centers, and 1.6 +/- 0.27 and 1.6 +/- 0.44 for transported grafts. An OPO-administered altruistic donor program can serve as a model for cooperative donation, recovery and allocation of living donor kidneys.

Assessing the antifungal activity and toxicity profile of amphotericin B lipid complex (ABLC; Abelcet) in combination with caspofungin in experimental systemic aspergillosis.

The purpose of this study was to assess the antifungal activity and renal and hepatic toxicity of amphotericin B lipid complex (ABLC; Abelcet) following co-administration of Caspofungin to rats infected with Aspergillus fumigatus. Aspergillus fumigatus inoculum (1.3-2.3 x 10(7) colony forming units [CFU]) was injected via the jugular vein; 48 h later male albino Sprague-Dawley rats (350-400 g) were administered either a single intravenous (i.v.) dose of Fungizone(R) (1 mg AmpB/kg), ABLC (1 or 5 mg AmpB/kg), or an equivalent volume of normal saline (NS) (vehicle control) once daily for 4 days. Rats were further randomized into groups to receive 3 mg/kg Caspofungin or physiologic saline i.v. once daily for 4 days. To assess antifungal activity, brain, lung, heart, liver, spleen, and kidney sections were homogenized with NS (2 mL; 1 g of each tissue/mL) and a 0.1-mL aliquot was spread plated onto a Sabouraud dextrose agar plate. The plates were incubated for 48 h at 37 degrees C, at which time the numbers of CFU were determined and corrected for tissue weight. To assess renal and hepatic toxicity, serum creatinine and aspartate aminotransferase levels were determined. Fungizone and ABLC at a dosing regimen of 1 mg/kg i.v. once daily for four consecutive days and Caspofungin at a dosing regimen of 3 mg/kg i.v. once daily for four consecutive days had similar effectiveness in decreasing the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to non-treated controls. A combination of ABLC (1 mg/kg i.v. x 4 days) and Caspofungin (3 mg/kg i.v. x 4 days) significantly decreased the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to Caspofungin alone and non-treated controls. ABLC at a dosing regiment of 5 mg/kg i.v. once daily for four consecutive days was more effective in decreasing the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to Fungizone or ABLC alone at 1 mg/kg and Caspofungin alone at 3 mg/kg. However, a combination of ABLC (5 mg/kg i.v. x 4 days) and Caspofungin (3 mg/kg i.v. x 4 days) was not more effective than ABLC at 5 mg/kg or the combination of ABLC at 1 mg/kg and Caspofungin 3 mg/kg in reducing the total number of Aspergillus fumigatus CFUs compared to controls. Except for non-treated infected control rats, none of the treatment groups tested displayed a greater than 50% increase in serum creatinine concentrations from baseline. In addition, only ABLC at a dosing regimen of 1 mg/kg i.v. once daily for four consecutive days displayed a greater than 50% increase in AST concentration from baseline. Taken together, these findings suggest that ABLC at 5 mg/kg once daily x 4 days appears to be the best therapeutic choice in this animal model.

Structural design and performance of a rear support walking frame.

Rear support walking frames provide predetermined vertical support for patients with dysfunctional lower limbs that have limited active control; the support is provided through a spring-loaded boom hinged on an upright stanchion mounted at the rear of a wheeled frame within which the patient ambulates. The application of these frames for total-body-involved cerebral palsy patients, in combination with a walking orthosis, has highlighted a number of practical problems that need to be addressed for the system to become fully viable. A composite material prototype walking frame has been developed that permits the patient to be transferred by a single carer without the need to use inappropriate manual handling techniques. The frame has improved structural properties, with stiffness in the sagittal and coronal planes increasing by between 50 and 100 per cent. Evaluation with patients showed that the greater structural stiffness permitted the objective of improved continuity of walking to be achieved. The strength of the frame is such that it can accommodate patients of up to 80 kg, more than twice that possible in the earlier system. Since the structural yield point is approximately twice the maximum working load, the device should not be prone to unacceptable fatigue characteristics. Despite the use of carbon composite materials (which have brittle failure characteristics), the mode of failure is of progressive collapse and is therefore inherently safe. The successful outcome of prototype testing has justified production development. Work is now proceeding on a design that incorporates further improvements in structural performance and ease of manufacture.

Effect of donor factors on early graft survival in adult cadaveric renal transplantation.

Previous studies of the effect of donor factors on renal transplant outcomes have not tested the role of recipient body mass index, donor/recipient weight ratios and age matching, and other factors. We analyzed 20,309 adult (age 16 or older) recipients having solitary cadaveric renal transplants from adult donors from 1 July 1994 to 30 June 1998 in an historical cohort study (the 2000 United States Renal Data System) of death censored graft loss by the Cox proportional hazards models, which corrected for characteristics thought to affect outcomes. The only independently significant findings in Cox Regression analysis were a high donor/ recipient age ratio (> or = 1.10, e.g. a 55-year-old donor given to a recipient age 50years or younger, adjusted hazard ratio (AHR) 3.22, 95% confidence interval (CI) 2.36-4.39) and African American donor kidneys (AHR 1.64, 95% CI, 1.24-2.17). African American recipients and older donors were not at independently increased risk of graft failure in this model. Among donor factors, older donor kidneys given to younger recipients and donor African American kidneys were independently associated with graft loss in recipients of cadaver kidneys. The task for the transplant community should be to find the best means for managing all donor organs without discouraging organ donation.

Induction therapy with monoclonal antibodies specific for CD80 and CD86 delays the onset of acute renal allograft rejection in non-human primates.

CD80 and CD86 (also known as B7-1 and B7-2, respectively) are both ligands for the T cell costimulatory receptors CD28 and CD152. Both CD80 and CD86 mediate T cell costimulation, and as such, have been studied for their role in promoting allograft rejection. In this study we demonstrate that administering monoclonal antibodies specific for these B7 ligands can delay the onset of acute renal allograft rejection in rhesus monkeys. The most durable effect results from simultaneous administration of both anti-B7 antibodies. The mechanism of action does not involve global depletion of T or B cells. Despite in vitro and in vivo evidence demonstrating the effectiveness of the anti-B7 antibodies in suppressing T cell responsiveness to alloantigen, their use does not result in durable tolerance. Prolonged therapy with murine anti-B7 antibodies is limited by the development of neutralizing antibodies, but that problem was avoided when humanized anti-B7 reagents are used. Most animals develop rejection and an alloantibody response although still on antibody therapy and before the development of a neutralizing antibody response. Anti-B7 antibody therapy may have use as an adjunctive agent for clinical allotransplantation, but using the dosing regimens we used, is not a tolerizing therapy in this non-human primate model.

Hepatic decompensation associated with lamivudine: a case report and review of lamivudine-induced hepatotoxicity.

We report a case of a 62-yr-old man with chronic hepatitis B virus (HBV)-related cirrhosis who developed hepatic decompensation after being started on lamivudine requiring liver transplantation. Decompensated liver disease while on lamivudine has been previously reported on two occasions, both HIV coinfected patients on a combination of nucleoside analogues. Our patient is alive and well nearly 2 yr after successful liver transplantation.

Hepatitis C virus seropositivity at the time of renal transplantation in the United States: associated factors and patient survival.

National statistics for patient characteristics and survival of renal transplant recipients positive for hepatitis C virus (HCV+) at the time of renal transplant are presented. A historical cohort analysis of 33479 renal transplant recipients in the United States Renal Data System from 1 July, 1994 to 30 June, 1997 has been carried out. The medical evidence form was also used for additional variables, but because of fewer available values, this was analyzed in a separate model. Outcomes were patient characteristics and survival associated with HCV+. Of 28692 recipients with valid HCV serologies, 1624 were HCV+ at transplant (5.7% prevalence). In logistic regression analysis, HCV+ was associated with African-American race, male gender, cadaveric donor type, increased duration of pre-transplant dialysis, previous transplant, donor HCV+, recipient (but not donor) age, serum albumin, alcohol use, and increased all-cause hospitalizations. Diabetes and IgA nephropathy were less associated with HCV+. Total all-cause, unadjusted mortality was 13.1% in HCV+ vs. 8.5% in HCV- patients (p <0.01 by log rank test). In Cox regression, mortality was higher for HCV+ (adjusted hazard ratio = 1.23, 95% confidence interval = 1.01-1.49, p = 0.04). HCV+ recipients were more likely to be African-American, male, older, and to have received repeat transplants and donor HCV+ transplants. HCV+ recipients also had substantially longer waiting times for transplant. In contrast to recent studies, diabetes did not have an increased association with HCV+, perhaps due to limitations of the database. HCV+ recipients had increased mortality and hospitalization rates compared with other transplant recipients.

Reliability of a physical activity questionnaire in middle-aged men.

Although some items from a questionnaire used to assess occupational and leisure activity in a cohort of male factory workers have reasonable validity, their reliability is unknown. In this study the reliability of this questionnaire was assessed in 54 middle-aged male factory employees by test-retest administration over a 4-6 week period. Kappa statistics for test-retest agreement for individual items on the questionnaire ranged between 0.24 and 0.66. Those items that demonstrated reasonable reliability and validity will subsequently be related to a range of disease endpoints in a prospective cohort study.

Stable binding of human XPC complex to irradiated DNA confers strong discrimination for damaged sites.

Nucleotide excision repair (NER) of DNA damage requires an efficient means of discrimination between damaged and non-damaged DNA. Cells from humans with xeroderma pigmentosum group C do not perform NER in the bulk of the genome and are corrected by XPC protein, which forms a complex with hHR23B protein. This complex preferentially binds to some types of damaged DNA, but the extent of discrimination in comparison to other NER proteins has not been clear. Recombinant XPC, hHR23B, and XPC-hHR23B complex were purified. In a reconstituted repair system, hHR23B stimulated XPC activity tenfold. Electrophoretic mobility-shift competition measurements revealed a 400-fold preference for binding of XPC-hHR23B to UV damaged over non-damaged DNA. This damage preference is much greater than displayed by the XPA protein. The discrimination power is similar to that determined here in parallel for the XP-E factor UV-DDB, despite the considerably greater molar affinity of UV-DDB for DNA. Binding of XPC-hHR23B to UV damaged DNA was very fast. Damaged DNA-XPC-hHR23B complexes were stable, with half of the complexes remaining four hours after challenge with excess UV-damaged DNA at 30 degrees C. XPC-hHR23B had a higher level of affinity for (6-4) photoproducts than cyclobutane pyrimidine dimers, and some affinity for DNA treated with cisplatin and alkylating agents. XPC-hHR23B could bind to single-stranded M13 DNA, but only poorly to single-stranded homopolymers. The strong preference of XPC complex for structures in damaged duplex DNA indicates its importance as a primary damage recognition factor in non-transcribed DNA during human NER.

Damage recognition in nucleotide excision repair of DNA.

Nucleotide excision repair (NER) is found throughout nature, in eubacteria, eukaryotes and archaea. In human cells it is the main pathway for the removal of damage caused by UV light, but it also acts on a wide variety of other bulky helix-distorting lesions caused by chemical mutagens. An ongoing challenge is to understand how a site of DNA damage is located during NER and distinguished from non-damaged sites. This article reviews information on damage recognition in mammalian cells and the bacterium Escherichia coli. In mammalian cells the XPC-hHR23B, XPA, RPA and TFIIH factors may all have a role in damage recognition. XPC-hHR23B has the strongest affinity for damaged DNA in some assays, as does the similar budding yeast complex Rad4-Rad23. There is current discussion as to whether XPC or XPA acts first in the repair process to recognise damage or distortions. TFIIH may play a role in distinguishing the damaged strand from the non-damaged one, if translocation along a DNA strand by the TFIIH DNA helicases is interrupted by encountering a lesion. The recognition and incision steps of human NER use 15 to 18 polypeptides, whereas E. coli requires only three proteins to obtain a similar result. Despite this, many remarkable similarities in the NER mechanism have emerged between eukaryotes and bacteria. These include use of a distortion-recognition factor, a strand separating helicase to create an open preincision complex, participation of structure-specific endonucleases and the lack of a need for certain factors when a region containing damage is already sufficiently distorted.

Isolation, characterization, and biological activity of naphthoquinones from Calceolaria andina L.

Two compounds recognized as responsible for the insecticidal activity of extracts of Calceolaria andina L. (Scrophulariaceae) have been isolated and characterized as 2-(1, 1-dimethylprop-2-enyl)-3-hydroxy-1,4-naphthoquinone and the corresponding acetate, 2-acetoxy-3-(1,1-dimethylprop-2-enyl)-1, 4-naphthoquinone. Their activities against 29 pest species and 9 beneficial species of arthropod from a total of 11 orders have been determined. Activities against homopteran and acarine species are of the same order as those of established pesticides, and, significantly, no cross-resistance is observed for strains resistant to established classes of insecticide. Mammalian toxicities are low.