Aberrant Structural Brain Connectivity in Adolescents with Attentional Problems Who Were Born Prematurely.

BACKGROUND AND PURPOSE: Differences in structural brain connectivity that underlie inattention have been previously investigated in adolescents with attention deficit/hyperactivity disorder, but not in the context of premature birth, which is often associated with attentional problems. The purpose of this study was to identify the neural correlates of attentional problems in adolescents born prematurely and determine neonatal predictors of those neural correlates and attention problems. MATERIALS AND METHODS: The study included 24 adolescents (12.5 ± 1.8 years of age; 12 girls, 12 boys) who were born prematurely and underwent MR imaging of the brain and cognitive assessment, both shortly after birth and as adolescents. Structural connectivity was assessed at adolescence using diffusion tensor imaging and tractography. RESULTS: Of the 24 subjects, 12 had attention deficits. A set of axonal pathways connecting the frontal, parietal, temporal, and occipital lobes had significantly lower fractional anisotropy in subjects with attentional problems. The temporoparietal connection between the left precuneus and left middle temporal gyrus was the most significantly underconnected interlobar axonal pathway. Low birth weight and ventriculomegaly, but not white matter injury or intraventricular hemorrhage on neonatal MR imaging, predicted temporoparietal hypoconnectivity in adolescence. However, neither birth weight nor other neonatal characteristics were associated with attention deficits directly. CONCLUSIONS: We identified an aberrant structural brain connectivity pattern, involving temporoparietal hypoconnectivity, in prematurely born adolescents with attentional problems. We also identified birth weight as a potential neonatal predictor of the temporoparietal hypoconnectivity. These findings add to our understanding of the neural basis and etiology of inattention in adolescents after premature birth.

The curious ability of polyethylene glycol fusion technologies to restore lost behaviors after nerve severance.

Traumatic injuries to PNS and CNS axons are not uncommon. Restoration of lost behaviors following severance of mammalian peripheral nerve axons (PNAs) relies on regeneration by slow outgrowths and is typically poor or nonexistent when after ablation or injuries close to the soma. Behavioral recovery after severing spinal tract axons (STAs) is poor because STAs do not naturally regenerate. Current techniques to enhance PNA and/or STA regeneration have had limited success and do not prevent the onset of Wallerian degeneration of severed distal segments. This Review describes the use of a recently developed polyethylene glycol (PEG) fusion technology combining concepts from biochemical engineering, cell biology, and clinical microsurgery. Within minutes after microsuturing carefully trimmed cut ends and applying a well-specified sequence of solutions, PEG-fused axons exhibit morphological continuity (assessed by intra-axonal dye diffusion) and electrophysiological continuity (assessed by conduction of action potentials) across the lesion site. Wallerian degeneration of PEG-fused PNAs is greatly reduced as measured by counts of sensory and/or motor axons and maintenance of axonal diameters and neuromuscular synapses. After PEG-fusion repair, cut-severed, crush-severed, or ablated PNAs or crush-severed STAs rapidly (within days to weeks), more completely, and permanently restore PNA- or STA-mediated behaviors compared with nontreated or conventionally treated animals. PEG-fusion success is enhanced or decreased by applying antioxidants or oxidants, trimming cut ends or stretching axons, and exposure to Ca(2+) -free or Ca(2+) -containing solutions, respectively. PEG-fusion technology employs surgical techniques and chemicals already used by clinicians and has the potential to produce a paradigm shift in the treatment of traumatic injuries to PNAs and STAs.

Human genome-wide expression analysis reorients the study of inflammatory mediators and biomechanics in osteoarthritis.

A major objective of this article is to examine the research implications of recently available genome-wide expression profiles of cartilage from human osteoarthritis (OA) joints. We propose that, when viewed in the light of extensive earlier work, this novel data provides a unique opportunity to reorient the design of experimental systems toward clinical relevance. Specifically, in the area of cartilage explant biology, this will require a fresh evaluation of existing paradigms, so as to optimize the choices of tissue source, cytokine/growth factor/nutrient addition, and biomechanical environment for discovery. Within this context, we firstly discuss the literature on the nature and role of potential catabolic mediators in OA pathology, including data from human OA cartilage, animal models of OA, and ex vivo studies. Secondly, due to the number and breadth of studies on IL-1ß in this area, a major focus of the article is a critical analysis of the design and interpretation of cartilage studies where IL-1ß has been used as a model cytokine. Thirdly, the article provides a data-driven perspective (including genome-wide analysis of clinical samples, studies on mutant mice, and clinical trials), which concludes that IL-1ß should be replaced by soluble mediators such as IL-17 or TGF-ß1, which are much more likely to mimic the disease in OA model systems. We also discuss the evidence that changes in early OA can be attributed to the activity of such soluble mediators, whereas late-stage disease results more from a chronic biomechanical effect on the matrix and cells of the remaining cartilage and on other local mediator-secreting cells. Lastly, an updated protocol for in vitro studies with cartilage explants and chondrocytes (including the use of specific gene expression arrays) is provided to motivate more disease-relevant studies on the interplay of cytokines, growth factors, and biomechanics on cellular behavior.

Needs assessment to improve neonatal intensive care in Mexico.

BACKGROUND: At the time of the research, Dr Weiss was a clinical fellow in neonatal-perinatal medicine at Baylor College of Medicine, Texas Children's Hospital. Dr Profit was on faculty at Baylor College of Medicine, Texas Children's Hospital, Department of Pediatrics, Section of Neonatology. He held a secondary appointment in the Department of Medicine, Section of Health Services Research and conducted his research at the VA Health Services Research and Development Center of Excellence where he collaborated with Dr Kowalkowski.: Improving the quality of neonatal intensive care is an important health policy priority in Mexico. A formal assessment of barriers and priorities for quality improvement has not been undertaken. AIM: To provide guidance to providers and policy makers with regard to addressing opportunities for better care delivery in Mexican neonatal intensive care units. OBJECTIVE: To conduct a needs assessment regarding improvement of quality of neonatal intensive care delivery in Mexico. METHODS: Spanish-language survey administered to a volunteer sample of Mexican neonatal care providers attending a large paediatric conference in Mexico in June 2011. Survey domains included institutional context of quality improvement, barriers, priorities, safety culture, and respondents' characteristics. Results were analysed using descriptive analyses of frequencies, proportions and percentage positive response (PPR) rates. RESULTS: Of 91 respondents, the majority identified neonatology as their primary specialty (n = 48, 65%) and were physicians (n = 55, 73%). Generally, providers expressed a desire to improve quality of care (PPR 69%) but reported notable deterrents. Respondents (n, %) identified family inability to pay (38, 48%), overcrowded work areas (38, 44%), insufficient financial reimbursement (25, 36%), lack of availability of nurses (26, 30%), ancillary staff (25, 29%), and subspecialists (22, 25%) as the principal barriers. Respiratory care (27, 39%)--reduction of mechanical ventilation and initiation of nasal continuous positive airway pressure--and reduction in frequency of late-onset infections (19, 28%) were selected as top clinical priorities. There were substantial opportunities for improving safety (PPR 48%) and teamwork climate (PPR 58%). CONCLUSION: These findings may guide efforts to improving quality of care delivery in Mexican neonatal intensive care units.

Polyethylene glycol-fused allografts produce rapid behavioral recovery after ablation of sciatic nerve segments.

Restoration of neuronal functions by outgrowths regenerating at ∼1 mm/day from the proximal stumps of severed peripheral nerves takes many weeks or months, if it occurs at all, especially after ablation of nerve segments. Distal segments of severed axons typically degenerate in 1-3 days. This study shows that Wallerian degeneration can be prevented or retarded, and lost behavioral function can be restored, following ablation of 0.5-1-cm segments of rat sciatic nerves in host animals. This is achieved by using 0.8-1.1-cm microsutured donor allografts treated with bioengineered solutions varying in ionic and polyethylene glycol (PEG) concentrations (modified PEG-fusion procedure), being careful not to stretch any portion of donor or host sciatic nerves. The data show that PEG fusion permanently restores axonal continuity within minutes, as initially assessed by action potential conduction and intracellular diffusion of dye. Behavioral functions mediated by the sciatic nerve are largely restored within 2-4 weeks, as measured by the sciatic functional index. Increased restoration of sciatic behavioral functions after ablating 0.5-1-cm segments is associated with greater numbers of viable myelinated axons within and distal to PEG-fused allografts. Many such viable myelinated axons are almost certainly spared from Wallerian degeneration by PEG fusion. PEG fusion of donor allografts may produce a paradigm shift in the treatment of peripheral nerve injuries.

Obesity and preference-weighted quality of life of ethnically diverse middle school children: the HEALTHY study.

To date, studies examining the relation between body mass index percentile (BMI%) categories and health-related quality of life (QOL) measurements have not reported preference-weighted scores among ethnically diverse children. We report the associations between BMI% categories and preference-weighted scores among a large cohort of ethnically diverse sixth grade children who participated in the HEALTHY school-based type 2 diabetes risk factor prevention study. Health Utility Index 2 (HUI2) and Health Utility Index 3 (HUI3) and the feeling thermometer (FT) were the preference-weighted QOL instruments used to measure student's preference scores. Of 6358 consented students, 4979 (78.3%) had complete QOL, height, weight, and covariate data. Mean (SD) preference scores were 0.846 (0.160), 0.796 (0.237), and 0.806 (0.161) for the HUI2, HUI3, and FT, respectively. After adjusting for age, sex, blood glucose and insulin, Tanner stage, race/ethnicity, family history of diabetes, and educational attainment, children with severe obesity (>99%) had significantly lower preference scores compared to normal weight on all three instruments (HUI2 P = 0.013; HUI3 P = 0.025; and FT P < 0.001). Obese and severe obese categories were significantly associated with lower HUI2 functional ratings in the mobility domain and with lower HUI3 functional ratings in the speech domain.

Fibrillar structure and charge determine the interaction of polyglutamine protein aggregates with the cell surface.

The pathogenesis of most neurodegenerative diseases, including transmissible diseases like prion encephalopathy, inherited disorders like Huntington disease, and sporadic diseases like Alzheimer and Parkinson diseases, is intimately linked to the formation of fibrillar protein aggregates. It is becoming increasingly appreciated that prion-like intercellular transmission of protein aggregates can contribute to the stereotypical spread of disease pathology within the brain, but the mechanisms underlying the binding and uptake of protein aggregates by mammalian cells are largely uninvestigated. We have investigated the properties of polyglutamine (polyQ) aggregates that endow them with the ability to bind to mammalian cells in culture and the properties of the cell surface that facilitate such uptake. Binding and internalization of polyQ aggregates are common features of mammalian cells and depend upon both trypsin-sensitive and trypsin-resistant saturable sites on the cell surface, suggesting the involvement of cell surface proteins in this process. polyQ aggregate binding depends upon the presence of a fibrillar amyloid-like structure and does not depend upon electrostatic interaction of fibrils with the cell surface. Sequences in the huntingtin protein that flank the amyloid-forming polyQ tract also influence the extent to which aggregates are able to bind to cell surfaces.

Identification and functional analysis of 9p24 amplified genes in human breast cancer.

Previously, our group identified a novel amplicon at chromosome 9p24 in human esophageal and breast cancers, and cloned the novel gene, GASC1 (gene amplified in squamous cell carcinoma 1, also known as JMJD2C/KDM4C), from this amplicon. GASC1 is a histone demethylase involved in the deregulation of histone methylation in cancer cells. In the current study, we aimed to comprehensively characterize the genes in the 9p24 amplicon in human breast cancer. We performed extensive genomic analyses on a panel of cancer cell lines and narrowed the shortest region of overlap to approximately 2 Mb. Based on statistical analysis of copy number increase and overexpression, the 9p24 amplicon contains six candidate oncogenes. Among these, four genes (GASC1 UHRF2, KIAA1432 and C9orf123) are overexpressed only in the context of gene amplification while two genes (ERMP1 and IL33) are overexpressed independent of the copy number increase. We then focused our studies on the UHRF2 gene, which has a potential involvement in both DNA methylation and histone modification. Knocking down UHRF2 expression inhibited the growth of breast cancer cells specifically with 9p24 amplification. Conversely, ectopic overexpression of UHRF2 in non-tumorigenic MCF10A cells promoted cell proliferation. Furthermore, we demonstrated that UHRF2 has the ability to suppress the expression of key cell-cycle inhibitors, such as p16(INK4a), p21(Waf1/Cip1) and p27(Kip1). Taken together, our studies support the notion that the 9p24 amplicon contains multiple oncogenes that may integrate genetic and epigenetic codes and have important roles in human tumorigenesis.

Protein standard absolute quantification (PSAQ) method for the measurement of cellular ubiquitin pools.

The protein ubiquitin is an important post-translational modifier that regulates a wide variety of biological processes. In cells, ubiquitin is apportioned among distinct pools, which include a variety of free and conjugated species. Although maintenance of a dynamic and complex equilibrium among ubiquitin pools is crucial for cell survival, the tools necessary to quantify each cellular ubiquitin pool have been limited. We have developed a quantitative mass spectrometry approach to measure cellular concentrations of ubiquitin species using isotope-labeled protein standards and applied it to characterize ubiquitin pools in cells and tissues. Our method is convenient, adaptable and should be a valuable tool to facilitate our understanding of this important signaling molecule.

Cognitive function in post-treatment Lyme disease: do additional antibiotics help?

BACKGROUND: It is controversial whether additional antibiotic treatment will improve cognitive function in patients with post-treatment chronic Lyme disease (PTCLD). OBJECTIVE: To determine whether antibiotic therapy improves cognitive function in two randomized double-blind placebo-controlled studies of patients with PTCLD. METHODS: A total of 129 patients with a physician-documented history of Lyme disease from three study sites in the northeast United States were studied. Seventy-eight were seropositive for IgG antibodies against Borrelia burgdorferi, and 51 were seronegative. Patients in each group were randomly assigned to receive IV ceftriaxone 2 g daily for 30 days followed by oral doxycycline 200 mg daily for 60 days or matching IV and oral placebos. Assessments were made at 90 and 180 days after treatment. Symptom severity was measured from the cognitive functioning, pain, and role functioning scales of the Medical Outcomes Study (MOS). Memory, attention, and executive functioning were assessed using objective tests. Mood was assessed using the Beck Depression Inventory and Minnesota Multiphasic Personality Inventory. RESULTS: There were no significant baseline differences between seropositive and seronegative groups. Both groups reported a high frequency of MOS symptoms, depression, and somatic complaints but had normal baseline neuropsychological test scores. The combined groups showed significant decreases in MOS symptoms, higher objective test scores, and improved mood between baseline and 90 days. However, there were no significant differences between those receiving antibiotics and placebo. CONCLUSION: Patients with post-treatment chronic Lyme disease who have symptoms but show no evidence of persisting Borrelia infection do not show objective evidence of cognitive impairment. Additional antibiotic therapy was not more beneficial than administering placebo.

Effects of two frequencies of walking on cardiovascular risk factor reduction in Mexican American women.

The beneficial effects of moderate-intensity exercise on cardiorespiratory fitness and body composition are well documented, with the greatest health benefits reported in sedentary individuals who engage in moderate levels of exercise. The published literature contains no quantification of the threshold of lower limits of beneficial exercise or estimates of benefits derived from lower exercise levels. The specific aim of this study was to compare the effects of two walking frequencies, holding intensity and duration constant, on blood lipids, body composition, and exercise maintenance regimens of Mexican American women. A quasi-experimental design, with two treatment groups and one comparison group, was used to explore the dose-response effects of low-intensity exercise on cardiovascular outcomes. Significant interactions were found between walking and total serum cholesterol and skin-fold sums. This study demonstrated the clinical efficacy of a low-intensity exercise regimen on cardiovascular risk factors and exercise adherence.

Human transferrin G277S mutation: a risk factor for iron deficiency anaemia.

Numerous polymorphisms of the transferrin gene result in a range of electrophoretic variants. We show that one of these mutations has a functional consequence. A G-->A mutation at cDNA nucleotide 829 (G277S) was associated with a reduction in total iron binding capacity (TIBC). In menstruating white women, the G277S genotype was a risk factor for iron deficiency anaemia: iron deficiency anaemia was present in 27% of homozygous G277S/G277S women, 10% of G277G/G277S heterozygous women and 5% of homozygous wild-type G277G/G277G women.

The treatment of allergic rhinitis with immunotherapy: a review of 1,000 cases.

We conducted a 10-year retrospective chart review of 1,000 immunotherapy-treated patients to evaluate the efficacy and safety of serial dilution quantitative intradermal testing in the management of allergic rhinitis. Three months after the initiation of immunotherapy, these patients had been assessed to ascertain whether or not they had experienced any overall improvement in their initial symptoms. Also included in this evaluation were determinations of each patient's use of medications as well as the incidence of adverse reactions to treatment and recurrent sinus infections. We found that 860 patients had achieved complete relief of their symptoms and required no other treatment; the remaining 140 patients experienced a partial improvement and continued to use pharmacotherapy to control breakthrough symptoms. During skin testing, only one patient experienced a systemic reaction, which responded to subcutaneous epinephrine. There were no deaths. We conclude that serial dilution quantitative intradermal testing is safe and that quantification of skin reactivity in evaluating and treating allergic rhinitis with immunotherapy is completely effective in the vast majority of patients.

Efficacy of wrist/palm warming as an EVA countermeasure to maintain finger comfort in cold conditions.

INTRODUCTION: This study explored the effectiveness of local wrist/palm warming as a potential countermeasure for providing finger comfort during extended duration EVA. METHODS: There were six subjects (five males and one female) who were evaluated in a liquid cooling/warming garment (LCWG) wearing modified liquid cooling/warming (LCW) gloves in three different experimental conditions: Condition 1: Stage 1--no LCWG, LCW glove inlet water temperature 33 degrees C; Stage 2--no LCWG, LCW glove inlet water temperature cooled to 8 degrees C; Stage 3--no LCWG, LCW glove inlet water temperature warmed to 45 degrees C; Condition 2: Stage 1--LCWG and LCW glove inlet water temperature 33 degrees C; Stage 2--LCWG inlet temperature cooled to 31 degrees C, LCW gloves, 8 degrees C; Stage 3--LCWG inlet water temperature remains at 31 degrees C, LCW glove inlet water temperature warmed to 45 degrees C; Condition 3: Stage 1--LCWG and LCW gloves 33 degrees C; Stage 2--LCWG inlet water temperature cooled to 28 degrees C, LCW gloves, 8 degrees C; Stage 3--LCWG remains at 28 degrees C, LCW glove water temperature warmed to 45 degrees C. RESULTS: Wrist/palm area warming showed a statistically significant increase in finger temperature (Tfing) in Stage 3 compared with Stage 2. Blood perfusion showed a trend toward a significantly greater value in Stage 3 compared with Stage 2. The LCW gloves were significantly more effective in increasing Stage 3 Tfing in Condition 1 (33 degrees C) compared with Condition 3 (28 degrees C). Across conditions, subjective perception of heat in the hands was significantly greater at Stage 3 than Stage 2; perception of overall body heat showed a trend for higher heat ratings in Stage 3 than Stage 2. CONCLUSIONS: Local wrist/palm warming was effective in increasing blood circulation to the distal upper extremities, suggesting the potential usefulness of this technique for enhancing astronaut comfort during EVA while decreasing power requirements.

Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease.

BACKGROUND: It is controversial whether prolonged antibiotic treatment is effective for patients in whom symptoms persist after the recommended antibiotic treatment for acute Lyme disease. METHODS: We conducted two randomized trials: one in 78 patients who were seropositive for IgG antibodies to Borrelia burgdorferi at the time of enrollment and the other in 51 patients who were seronegative. The patients received either intravenous ceftriaxone, 2 g daily for 30 days, followed by oral doxycycline, 200 mg daily for 60 days, or matching intravenous and oral placebos. Each patient had well-documented, previously treated Lyme disease but had persistent musculoskeletal pain, neurocognitive symptoms, or dysesthesia, often associated with fatigue. The primary outcome measures were improvement on the physical- and mental-health-component summary scales of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36)--a scale measuring the health-related quality of life--on day 180 of the study. RESULTS: After a planned interim analysis, the data and safety monitoring board recommended that the studies be discontinued because data from the first 107 patients indicated that it was highly unlikely that a significant difference in treatment efficacy between the groups would be observed with the planned full enrollment of 260 patients. Base-line assessments documented severe impairment in the patients' health-related quality of life. In intention-to-treat analyses, there were no significant differences in the outcomes with prolonged antibiotic treatment as compared with placebo. Among the seropositive patients who were treated with antibiotics, there was improvement in the score on the physical-component summary scale of the SF-36, the mental-component summary scale, or both in 37 percent, no change in 29 percent, and worsening in 34 percent; among seropositive patients receiving placebo, there was improvement in 40 percent, no change in 26 percent, and worsening in 34 percent (P=0.96 for the comparison between treatment groups). The results were similar for the seronegative patients. CONCLUSIONS: There is considerable impairment of health-related quality of life among patients with persistent symptoms despite previous antibiotic treatment for acute Lyme disease. However, in these two trials, treatment with intravenous and oral antibiotics for 90 days did not improve symptoms more than placebo.

Molecular characterization of a case of atransferrinemia.

Hereditary atransferrinemia is a rare but instructive disorder that has previously been reported in only 8 patients in 6 families. It is characterized by microcytic anemia and by iron loading, and can be treated effectively by plasma infusions. We now report the first case known in the United States. We determined the sequences flanking the exons of the human transferrin gene and sequenced all of the exons and some of the flanking regions of the patient's DNA and that of her parents. The patient's DNA revealed a 10-base pair (bp) deletion, followed by a 9-bp insertion of a duplicated sequence. There was also a G-->C transversion at complementary DNA (cDNA) nt 1429, predicting that a proline was substituted for the alanine in amino acid position 477 (Ala 477 Pro). The latter mutation occurs at an evolutionarily highly conserved site; 704 control alleles were screened and this point mutation was not found. Each of the patient's transferrin genes contains one mutation, ie, the patient is a compound heterozygote for these mutations, because one was found in each of her parents. In addition to these mutations, which we regard to be causative in the patient's atransferrinemia, a silent polymorphism at cDNA 1572 G-->C was found in exon 13 as well as 2 previously unreported polymorphisms at IVS8 + 62 c-->t and IVS14-4 c-->a. The mutation in nt 1572 and that in intron 8 were common in the general population; the intron 14 mutation is rare.

Labor force participation in a sample of substance users.

This paper reviews the microeconomic theory underlying the work/leisure tradeoff and how this tradeoff may be manifested among substance users. The effects of drug use, demographic factors, and income factors on the probability of labor force participation are analyzed in a sample of 687 male and 327 female drug users. The decision not to seek employment appears to be associated primarily with non-job-related sources of income (including illegal sources).

The importance of quantifying skin reactivity in treating allergic rhinitis with immunotherapy.

Therapeutic options for the treatment of allergic rhinitis include environmental modifications to decrease exposure to allergens, pharmacotherapy, and immunotherapy for those patients who do not experience satisfactory relief of their symptoms with medical management. Skin testing is the best established and most sensitive indicator of allergic disease. Several techniques are currently in use to identify pertinent antigens in the treatment of inhalant allergies. We describe the various skin testing techniques that are associated with such inhalant allergies. Quantification of skin reactivity to formulate a successful antigen vial for effective immunotherapy is necessary in the management of allergic disease.

Economics as a factor in models of behavioral motivation and change.

This note first presents a summary of four main behavioral models that are used to explain behavioral motivation and change. Three models are based on psychosocial theory. They are: 1) the Theory of Reasoned Action, 2) the Theory of Planned Behavior, and 3) the Theory of Stages-of-Change. The fourth model is based on economic theory and is known as the Rational Addiction Model. Each model is analyzed for its strengths and weaknesses. The note concludes by arguing for the usefulness of integrating the economic and the psychosocial models to study drug use. Specific examples and suggestions are presented.