Can repetitive transcranial magnetic stimulation of the visual cortex ameliorate the state of patients with visual snow?

AIMS: Visual snow is a neurological condition, for which an effective treatment has not been established.  The aim of this study was to find whether Repetitive Transcranial Magnetic Stimulation (rTMS) can improve the state of patients suffering from visual snow. To our knowledge, no other group has tested this method in the treatment of visual snow. METHODS: We applied rTMS of 10 and 10+1 Hz on the visual cortices of 9 patients with visual snow. Sham stimulation with the vertex as the target site was also tested. As a method of assessment, we used visual evoked potentials, questionnaires and visual snow diaries. For data evaluation, we used the Paired Sample T-test separately for each stimulation type. RESULTS: The Paired Sample T-test revealed a decreased sum of visual snow intensities extracted from visual snow diaries in the week after 10+1 Hz stimulation as compared to the figure in the week before (p=0.02). CONCLUSION: We detected a trend indicating an improvement of patients' condition based on the data from visual snow diaries. Research on a larger group of patients is required to confirm these findings; however, our study provides a framework to build upon (Tab. 4, Fig. 1, Ref. 22).

Establishing and evaluating pediatric thyroid reference intervals on the Roche Modular Analytics E 170 using computational statistics and data-mining techniques.

OBJECTIVES: This study determined age specific, free thyroxine and thyroid stimulating hormone reference intervals for a pediatric population. METHODS: The data set was partitioned into age groups and the Tukey method was used to identify outliers for removal. The Harris and Boyd algorithm was used to determine if groups could be merged. Reference intervals were calculated using both non-parametric and robust methods. Boot-strapping was used to determine the 90% confidence intervals surrounding the upper and lower limits of each reference interval. These population based reference intervals were then compared to the manufactures suggested reference intervals. RESULTS: This study provides non-parametric and robust reference intervals with associated 90% confidence intervals for free thyroxine and thyroid stimulating hormone as measured on the Roche Modular Analytics E 170. CONCLUSIONS: The results emphasize the importance of establishing population-based reference intervals for the clinical laboratory.

Engineers Without Borders Australia--lessons learned from an innovative approach to the upgrade of water supply infrastructure in Tenganan, Indonesia.

The community of Tenganan in eastern Bali, Indonesia, has requested technical assistance from Engineers Without Borders Australia (EWB) to improve the quantity and quality of water delivered through their water supply system. This is a unique development project in which the Tenganan people have identified their own needs and developed their own conceptual solution to the problem. For the first time, EWB is undertaking the design phase for the water system by an off-shore design team and project assistance team (PAT) based in Australia. This allows EWB to draw on resources and experience of EWB members and their employing companies in Australia. It also enables young engineers to develop skills and experience in development work without having to leave the country. However, the innovative approach also presented significant challenges to the project members, particularly in establishing appropriate design criteria and the co-ordination of simultaneous activities across Australia. This paper describes the approach taken by EWB and makes a preliminary assessment of the benefits and limitations inherent in this approach. The overall aim of the project is to produce a successful "bottom-up" development action that will deliver a sustainable solution to the Tenganan community.

Bone Health in Childhood: Usefulness of Biochemical Biomarkers.

Development of the human skeleton begins in early embryonic life and continues through childhood into early adulthood. The acquisition of peak bone mass during these vulnerable periods may impact on skeletal fragility in later adult years. Once the skeleton has reached maturity, bone remodelling continues with periodic replacement of old bone with new at the same location. Bone biomarkers are specifically derived biomarkers that reflect both formation by osteoblasts and resorption by osteoclasts. Children have significantly higher concentrations of bone biomarkers than adults due to both skeletal growth and rapid bone turnover during childhood and adolescence. Biochemical assessment of markers of bone turnover may be important in the diagnosis, prognosis and management of metabolic bone disease. This review will discuss the various serum bone markers used for assessing bone health and the factors that influence their utility.

Inaccuracy of high-performance liquid chromatography estimation of haemoglobin F in the presence of increased haemoglobin A1c.

Increasingly high-performance liquid chromatography is being used for identification and quantification of normal and variant haemoglobins. In many laboratories, the Beta Thal Short programme of the Bio-Rad Variant II instrument is used for this purpose. We noted that a factitious elevation of haemoglobin F was sometimes observed in diabetic patients and therefore carried out a systematic study of this phenomenon. We found discrepant results in 41% of samples from diabetic patients but in no normal volunteers. This factitious elevation could be predicted from a retention time for haemoglobin F of more than 1.15 min, the normal retention time being 1.08-1.15 min. Haemoglobinopathy laboratories need to be alert to the possibility of this erroneous result.

Sweat collection for testing in Canadian Cystic Fibrosis Centers, is it optimal?

OBJECTIVES: The goal of this study was to examine the ability of the current Canadian CF center network to conduct sweat testing, with a particular focus on testing in infants less than 3 months old. METHODS: Surveys were sent to the 37 CF centers in Canada supported by the Canadian CF Foundation, and results were interpreted with respect to their ability to obtain adequate sweat volumes in children less than 3 months and potential factors influencing these results. RESULTS: Ten centers that care for adult patients referred patients to their local pediatric CF center for sweat testing; the remaining 27 centers conducted sweat tests and 26 responded. Insufficient sweat volume results in children <3 months occurred in a median of 18.3% of tests. The corresponding proportion for the remaining population was 4.5% (P < 0.001). 15 of 19 centers had an incidence of >5% of insufficient tests in children <3 months of age, and 9 of 19 had an incidence of <20% in this age group. Six of 19 had an incidence of >5% of insufficient sweat volumes in older children and adults. CONCLUSIONS: Standardization of testing procedures is required to reduce the rates of insufficient sweat volumes in both infants less than 3 months old and children >3 months old. This will decrease the need for repeat testing and delay in diagnosis.

Monitoring of 25-OH vitamin D levels in children with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis are at risk for malabsorption of fat-soluble vitamins, and those with low 25-OH vitamin D levels have a higher risk of low bone mineral density and long-term skeletal complications. It is currently recommended that vitamins A and E be monitored yearly; however, no recommendations exist for 25-OH vitamin D. Because all three vitamins are fat-soluble, the hypothesis in the current study was that low levels of vitamins A and E could identify patients at risk for low 25-OH vitamin D, so that 25-OH vitamin D measurements could be obtained in only selected circumstances. METHODS: Forty (21 girls) patients with CF, age 10.5 +/- 3.9 (SD) years, were assessed in a cross-sectional survey for ideal weight for height (percentage of predicted), spirometry (percentage of predicted FEV1, 33/40 patients), and serum levels of vitamins A, E, 25-OH vitamin D, and cholesterol (37/40 patients). RESULTS: Nine (22.5%) of 40 patients were malnourished (percentage of predicted ideal weight for height <85%), 7 (21.2%) of 33 had moderate to severe lung disease (FEV1 <60%), 4 (10%) of 40 had low levels of vitamin A, 3 (7.5%) of 40 had low vitamin E levels, 4 (10.8%) of 37 low vitamin E/cholesterol levels, and 4 (10%) of 40 had marginal or low levels of 25-OH vitamin D (<40 mmol/l). The patients with low 25-OH vitamin D were older, with no child < 12 years of age having a 25-OH vitamin D level less than 40 mmol/l. They also had lower vitamin E and vitamin E/cholesterol levels than those with normal 25-OH vitamin D levels. The groups did not differ in percentage of predicted ideal weight for height, lung function, or vitamin A levels. The best positive predictor for 25-OH vitamin D less than 40 mmol/l was low vitamin E (66.7%), with a negative predictive value of 94.6%. 25-OH vitamin D levels correlated with vitamin E/cholesterol levels (r = 0.41, P < 0.01) and weakly with vitamin E levels (r = 0.28, P < 0.08), but not with vitamin A levels. CONCLUSIONS: These results suggest that children aged less than 12 years and older children with normal vitamin E levels are especially unlikely to have low 25-OH vitamin D levels, and this measure can therefore be omitted. In contrast, those children with low vitamin E levels may warrant monitoring.

Treatment of obstructive airway disease with a cysteine donor protein supplement: a case report.

Oxidant/antioxidant imbalance can occur in obstructive airways disease as a result of ongoing inflammation. Glutathione (GSH) plays a major role in pulmonary antioxidant protection. As an alternative or complement to anti-inflammatory therapy, augmenting antioxidant protection could diminish the effects of inflammation. We describe a case of a patient who had obstructive lung disease responsive to corticosteroids, and low whole blood GSH levels. After 1 month of supplementation with a whey-based oral supplement designed to provide GSH precursors, whole blood GSH levels and pulmonary function increased significantly and dramatically. The potential for such supplementation in pulmonary inflammatory conditions deserves further study.

Total plasma antioxidant capacity in cystic fibrosis.

Several studies have demonstrated ongoing oxidative stress in cystic fibrosis (CF). With the complexity of the antioxidant network, measurement of individual antioxidants does not necessarily assess how they work in combination. One measure that has been proposed as a gauge of total plasma antioxidant capacity is the Trolox-equivalent antioxidant capacity (TEAC) of plasma. We decided to look at plasma TEAC levels in children with CF, and relate this measure to their nutritional status, lung function, and blood measurements of several known antioxidants. We hypothesized that values in general would be lower than healthy control values, especially during acute pulmonary exacerbations. Twenty-nine children were evaluated, five of whom were during an acute pulmonary exacerbation. Height and weight, expiratory spirometry, and lung volumes were assessed, as were serum concentrations of vitamins A and E, uric acid, albumin, and lymphocyte glutathione (GSH) concentrations. TEAC values for nonhospitalized patients (1.40 +/- 0. 20 mmol/L) were not different from laboratory control values (1.35 +/- 0.11 mmol/L), but greater than values for hospitalized patients (1.09 +/- 0.17 mmol/L). TEAC correlated with anthropometric values (height: r = 0.39, P < 0.03; weight: r = 0.50, P < 0.01; body mass index: r = 0.47, P < 0.01), and pulmonary function (forced expiratory volume in 1 sec: r = 0.43, P < 0.02; residual volume/total lung capacity: r = -0.42, P < 0.03), but not with age. Univariate correlation with blood measurements demonstrated a significant correlation of TEAC with uric acid (r = 0.49, P < 0.02), but not with albumin, vitamins A or E, or lymphocyte GSH. Multiple regression analysis demonstrated a correlation between TEAC and uric acid, albumin, and lymphocyte GSH in the non-hospitalized group (r(2) = 0.38, P < 0.03). We conclude that TEAC appears to represent a mixed antioxidant response, rather than response to a single antioxidant. While being responsive to oxidative stress, the mechanism of the response may differ between clinical situations, such that the clinical significance of changes in plasma TEAC remains to be defined.

Effect of supplementation with a cysteine donor on muscular performance.

Oxidative stress contributes to muscular fatigue. GSH is the major intracellular antioxidant, the biosynthesis of which is dependent on cysteine availability. We hypothesized that supplementation with a whey-based cysteine donor [Immunocal (HMS90)] designed to augment intracellular GSH would enhance performance. Twenty healthy young adults (10 men, 10 women) were studied presupplementation and 3 mo postsupplementation with either Immunocal (20 g/day) or casein placebo. Muscular performance was assessed by whole leg isokinetic cycle testing, measuring peak power and 30-s work capacity. Lymphocyte GSH was used as a marker of tissue GSH. There were no baseline differences (age, ht, wt, %ideal wt, peak power, 30-s work capacity). Follow-up data on 18 subjects (9 Immunocal, 9 placebo) were analyzed. Both peak power [13 +/- 3.5 (SE) %, P < 0.02] and 30-s work capacity (13 +/- 3.7%, P < 0.03) increased significantly in the Immunocal group, with no change (2 +/- 9.0 and 1 +/- 9.3%) in the placebo group. Lymphocyte GSH also increased significantly in the Immunocal group (35.5 +/- 11.04%, P < 0.02), with no change in the placebo group (-0.9 +/- 9.6%). This is the first study to demonstrate that prolonged supplementation with a product designed to augment antioxidant defenses resulted in improved volitional performance.

Lymphocyte glutathione levels in children with cystic fibrosis.

OBJECTIVE: Lung disease in cystic fibrosis (CF) is characterized by a neutrophilic inflammatory response. This can lead to the production of oxidants, and to oxidative stress in the lungs. Glutathione (GSH) represents the primary intracellular antioxidant, and provides an important defense in the epithelial lining fluid. Evidence suggests that lymphocyte GSH reflects lung GSH concentrations, and so could potentially serve as a peripheral marker of lung inflammation. METHODS: We assessed peripheral blood lymphocyte GSH concentrations in 20 children (13 boys) with CF who were in stable condition at the time of evaluation. Values were compared with nutritional status and lung function parameters. RESULTS: Patients were 11.7+/-3.03 years old (mean +/- SD). Their percentage of ideal body weight was 101.8+/-17.92%; FEV1, 79.5+/-19.22% predicted; FEV1/FVC, 75.0+/-10.08%; and residual volume (RV)/total lung capacity (TLC), 31.3+/-10.47%. For the group, the GSH concentration was 1.31+/-0.52 micromol/10(6) lymphocytes, which was not different from laboratory control values. GSH values were correlated with nutritional status (percentage of ideal body weight: r = 0.49, p < 0.03) and the degree of gas trapping (RV/TLC: r = 0.50, p < 0.03), and were correlated inversely with airflow limitation (FEV1, percent predicted: r = -0.45, p < 0.05; FEV1/FVC: r = -0.48, p < 0.04), but not with age, height, or weight (p > 0.1). CONCLUSIONS: We interpret the inverse correlation between lymphocyte GSH concentration and lung function as a reflection of upregulation of GSH production by lung epithelial tissue in response to oxidative stress. We interpret the correlation between lymphocyte GSH concentration and nutritional status as a reflection of the role of cysteine in hepatic glutamine metabolism. Peripheral blood lymphocyte GSH concentration may potentially serve as a convenient marker of lung inflammation. Furthermore, the increased demand for GSH production in the face of ongoing inflammation suggests a potential role for supplementation with cysteine donors.

Specific antibody responses to diphtheria/tetanus revaccination in children evaluated for immunodeficiency.

BACKGROUND: Assaying specific antibody levels against well-defined antigens such as diphtheria (D), tetanus (T), and more recently Haemophilus is used as one indicator of humoral immune reactivity when evaluating patients for immunodeficiency. The nature of the response to booster vaccine in this group of patients is not well defined. OBJECTIVE: To define the response to D/T booster vaccination in patients with nonprotective antibody levels in order to distinguish immunocompetent from immunodeficient children. METHODS: Patients between the ages of 16 months and 17 years referred for possible immunodeficiency were assessed for specific antibody levels as part of a standard immunologic evaluation. Twenty-six previously immunized patients had antibody titers less than or equal to 0.2 IU against D and/or T or another abnormal vaccine response. All of these patients received boosters of diphtheria and tetanus vaccine (D2T5). Diphtheria and tetanus antibody levels were assayed 4 weeks following booster vaccination. RESULTS: Of the twenty-six subjects, a subset of patients (6) failed to show significant elevations in specific-serum antibody titers to diphtheria and/or tetanus and were thus labeled nonresponders. These patients were retrospectively compared with their responder counterparts examining specific antibody titers pre-immunization and post-immunization, serum immunoglobulins, and clinical presentation. The groups showed no significant difference in baseline specific antibody measures but following re-immunization responders showed a 31.34-fold and 22.33-fold increase in D and T antibody levels, respectively. In contrast, nonresponders produced only a 2.62-fold to D and 6.15-fold increase to T (all group comparisons P < .05). Clinical presentation also tended to be more severe in the nonresponder group. CONCLUSIONS: These data stress the importance of specific antibody titers pre-immunization and post-immunization in the assessment of immunodeficiency states, and emphasize the different characteristics of responses between diphtheria and tetanus toxoids. The ability to achieve the minimum protective antibody level does not necessarily denote immune competence. Serum immunoglobulin levels and baseline antibody titers are insufficient for the functional assessment of the immune response. The ability to generate antibody responses following booster vaccination is a more complete measure of overall immune competence and should be considered when evaluating patients for replacement immunoglobulin therapy.

Infusion clearance of subcutaneous iothalamate versus standard renal clearance.

Accurate, timed urine collections for the measurement of glomerular filtration rate (GFR) may be impractical in infants or in patients with urological abnormalities. GFR may be measured without urine collection using a constant subcutaneous infusion of iothalamate. We compare the infusion clearance with conventional renal clearance in 14 children and young adults. The mean clearance ratio (infusion clearance/renal clearance +/- 1 SD) was 0.99 +/- 0.1 and the mean discrepancy between the two methods was 8.5% +/- 4.7%. The 95% limits of agreement for the ratio of the two methods are 0.83-1.23. These data indicate that subcutaneous infusion of iothalamate is a practical method for measuring GFR in children without a urine collection.

Therapeutic drug monitoring in pediatrics: a need for improvement.

Therapeutic drug monitoring (TDM) is practiced for a number of frequently used drugs in infants and children. It is believed that monitoring drug levels will increase the probability of a therapeutic response and minimize the probability of adverse drug sequelae. Dose adjustments are based on measured drug levels interpreted relative to published therapeutic ranges which may or may not reflect the true relationship with either therapeutic or adverse effects. Potential errors derive from many sources, some amenable to solutions based on current knowledge, others awaiting improved understanding of the causes and consequences of unreliable therapeutic ranges.

Insulin-like growth factor II/mannose-6-phosphate receptors are transiently increased in the rat distal intestinal epithelium after resection.

The levels of insulin-like growth factor II/mannose-6-phosphate (IGF-II/Man-6-P) receptor and the insulin-like growth factor I (IGF-I) receptor were measured in the intestinal epithelium after 50% resection of the small intestine. Controls were either pair-fed to match the reduced food intake of the resected group or fed ad libitum. [125I]IGF-II binding was transiently increased 2-fold in the distal segment of the small intestine 3 days after resection compared with the pair-fed control. Receptor levels increased from 2.60 nmol/mg protein (pair-fed) to 4.63 nmol/mg protein (resected; p less than 0.001) with no significant change in affinity of IGF-II binding (Kd = 11.2 vs. 9.8 nmol/l). The increase in IGF-II/Man-6-P receptors coincided with increased activity of thymidine kinase in the distal intestinal segment after the resection. [125I]IGF-I binding remained unchanged after the resection. However, the decreased food intake of the pair-fed and resected groups caused a 2-fold increase in the amount of IGF-I receptors (0.18 nmol/mg protein; p less than 0.001) compared with the control fed ad libitum (0.08 nmol/mg protein). IGF-II/Man-6-P receptors were only moderately increased during restricted food intake (2.60 vs. 1.78 nmol/mg protein; p less than 0.005). These results suggest that the IGF-II/Man-6-P receptor may play a role in the adaptive regenerative response of the intestinal epithelium.