Childhood asthma management guided by repeated FeNO measurements: a meta-analysis

The fraction of exhaled nitric oxide (FeNO) has gained interest as a non-invasive tool to measure airway inflammation in asthma since it reflects allergic inflammation. Recent controlled clinical studies have, however, questioned its role in the management of asthma in children. To assess the clinical value of FeNO in paediatric asthma management, a meta-analysis was performed on the controlled studies of childhood asthma management guided by repeated FeNO measurements, and relevant publications on the confounders of FeNO were reviewed. The data suggests that utilising FeNO to tailor the dose of inhaled corticosteroids in children cannot be recommended for routine clinical practice since there is a danger of excessive inhaled corticosteroid doses in children without meaningful changes in clinical outcomes. Many disease and non-disease related factors (most importantly atopy, height/age and infection) affect FeNO levels which can easily confound the interpretation.     

Why is the age-standardized incidence of low-trauma fractures rising in many elderly populations?

Low-trauma fractures of elderly people are a major public health burden worldwide, and as the number and mean age of older adults in the population continue to increase, the number of fractures is also likely to increase. Epidemiologically, however, an additional concern is that, for unknown reasons, the age-standardized incidence (average individual risk) of fracture has also risen in many populations during the recent decades. Possible reasons for this rise include a birth cohort effect, deterioration in the average bone strength by time, and increased average risk of (serious) falls. Literature provides evidence that the rise is not due to a birth cohort effect, whereas no study shows whether bone fragility has increased during this relatively short period of time. This osteoporosis hypothesis could, however, be tested if researchers would now repeat the population measurements of bone mass and density that were made in the late 1980s and the 1990s. If such studies proved that women's and men's age-standardized mean values of bone mass and density have declined over time, the osteoporosis hypothesis would receive scientific support. The third explanation is based on the hypothesis that the number and/or severity of falls has risen in elderly populations during the recent decades. Although no study has directly tested this hypothesis, a great deal of indirect epidemiologic evidence supports this contention. For example, the age-standardized incidence of fall-induced severe head injuries, bruises and contusions, and joint distortions and dislocations has increased among elderly people similarly to the low-trauma fractures. The fall hypothesis could also be tested in the coming years because the 1990s saw many research teams reporting age- and sex-specific incidences of falling for elderly populations, and the same could be done now to provide data comparing the current incidence rates of falls with the earlier ones.     

Erector spinae SEMG activity during forward flexion and re-extension in ankylosing spondylitis patients

Objective: To compare erector spinae muscle (ESM) activity as measured by surface electromyography (SEMG) in lumbar flexion from the upright position in men with ankylosing spondylitis (AS) and healthy males, and to study associations between pain, lumbar mobility and ESM activity. Methods: Surface EMG was undertaken at the L1-2 and L4-5 levels in 11 men with AS taking part in a rehabilitation course at the Rheumatism Foundation Hospital, and in 10 pain-free male controls, while the subjects were bending forward. Results: During full flexion ESM SEMG activity was significantly greater in patients with AS than in the controls. Relaxation was evident during flexion in all of the controls but in only some patients with AS. Lumbar mobility correlated negatively with ESM activities. No relationship between pain and ESM activity was evident. Some AS patients reported pain while ESM activity was being measured. Conclusion: Decreased lumbar mobility rather than pain explains ESM activity during full flexion in patients with AS.     

Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling

Summary: Bruton's tyrosine kinase (Btk) is encoded by the gene that when mutated causes the primary immunodeficiency disease X‐linked agammaglobulinemia (XLA) in humans and X‐linked immunodeficiency (Xid) in mice. Btk is a member of the Tec family of protein tyrosine kinases (PTKs) and plays a vital, but diverse, modulatory role in many cellular processes. Mutations affecting Btk block B‐lymphocyte development. Btk is conserved among species, and in this review, we present the sequence of the full‐length rat Btk and find it to be analogous to the mouse Btk sequence. We have also analyzed the wealth of information compiled in the mutation database for XLA (BTKbase), representing 554 unique molecular events in 823 families and demonstrate that only selected amino acids are sensitive to replacement (P < 0.001). Although genotype–phenotype correlations have not been established in XLA, based on these findings, we hypothesize that this relationship indeed exists. Using short interfering‐RNA technology, we have previously generated active constructs downregulating Btk expression. However, application of recently established guidelines to enhance or decrease the activity was not successful, demonstrating the importance of the primary sequence. We also review the outcome of expression profiling, comparing B lymphocytes from XLA‐, Xid‐, and Btk‐knockout (KO) donors to healthy controls. Finally, in spite of a few genes differing in expression between Xid‐ and Btk‐KO mice, in vivo competition between cells expressing either mutation shows that there is no selective survival advantage of cells carrying one genetic defect over the other. We conclusively demonstrate that for the R28C‐missense mutant (Xid), there is no biologically relevant residual activity or any dominant negative effect versus other proteins.     

Protein quantity and quality in term and preterm infants: effects on urine creatinine and expression of amino acid excretion data

The effect of dietary protein quantity and quality on the excretion of creatinine in preterm and term neonatal infants has been investigated. Whey protein predominant formulas result in increased creatinine excretion as compared with either casein protein predominant formulas or with pooled human milk in preterm infants (p less than 0.001 by ANOVA). The volume of human milk (170 versus 185 versus 200 ml/kg/day) appears to have little effect in these infants. In term infants, few differences among the feeding groups were observed, although creatinine excretion did increase with time. The pattern of creatinine excretion among feeding groups was similar regardless of whether or not the data were expressed in milligrams per deciliter or in milligrams per 24 hours. Small correlations of creatinine excretion with birth weight were observed, but these appeared to vary, depending on the type of feeding. These diet-induced differences in creatinine excretion indicate the need for caution in expressing other urinary metabolites, such as amino acids, relative to creatinine excretion.     

Selegiline and levodopa in early or moderately advanced Parkinson's disease: a double-blind controlled short- and long-term study

Abstract– Selegiline 10 mg per day was compared to placebo as an adjunct to levodopa treatment in this double-blind study of early or moderately advanced Parkinson's disease. Thirty-eight patients completed an initial cross-over trial comprising two treatment periods, each of eight weeks, with a four weeks'wash-out period between them. Thirty of the patients continued in a long-term, double-blind parallel trial with a mean duration of 16 months (range 6–30 months). Selegiline treatment allowed a significant reduction of the necessary daily levodopa dose in both parts of the study and of the daily dosing frequency in the long-term investigation. In spite of this reduction of levodopa dose, an improvement was noted in tremor during the short-term selegiline periods. The side-effects were slight and related to dopamine effects and disappeared after reduction of levodopa-dose. The results support the use of selegiline as an early adjunctive treatment in Parkinson's disease.     

Gastric air tonometry during laparoscopic cholecystectomy: a comparison of two PaCO2 levels

PURPOSE: Pneumoperitoneum can cause disturbances in acid-base balance and splanchnic perfusion. We studied the effect of ventilation on acid-base balance and gastric mucosal tonometric values in patients undergoing laparoscopic cholecystectomy. METHODS: Twenty-four patients (ASA I-II) were randomly allocated into two groups. In the fixed ventilation group, ventilation was constant allowing free increase in PCO2, while in the constant CO2 group end-tidal PCO2 was fixed with ventilatory adjustment. Intraabdominal pressure was limited to 12 mmHg. Arterial acid-base balance, automated air tonometric variables and gastric mucosal to arterial PCO2 gap were determined frequently from anesthesia induction until three hours postoperatively. RESULTS: During pneumoperitoneum, in the fixed ventilation group arterial PCO2 changed from 5.0 +/- 0.2 to 6.6 +/- 0.4 kPa and pH from 7.43 +/- 0.03 to 7.33 +/- 0.04, tonometric PCO2 from 5.1 +/- 0.5 to 6.9 +/- 0.4 and pH from 7.44 +/- 0.04 to 7.33 +/- 0.04. In the constant CO2 group these variables remained at control levels (P < 0.01 between groups). The PCO2 gap remained unchanged without any differences between the groups. In the recovery room all measured variables were within normal range in both groups. CONCLUSION: Despite inter-group differences in arterial and tonometric PCO2 and pH values during CO2 pneumoperitoneum, the patients did not develop splanchnic hypoperfusion detectable by air tonometric method, as indicated by normal PCO2 gap in both groups throughout the study.     

Effects of repeated bupivacaine administration on sciatic nerve and surrounding muscle tissue in rats

The effects of repeated administration of 0.5% bupivacaine or saline into the sciatic notch of rats were studied by light microscopy, electron microscopy and a neurophysiological technique. Very severe myositis, including local necrosis, developed in six of 12 rats treated twice daily with 1 ml bupivacaine for either 3 or 7 days. A 3-h infusion of 1.5 ml 0.5% bupivacaine resulted in minor injury to muscle tissue. A marked degree of disruption and vacuolization of myelin sheaths was evident in nerves exposed to bupivacaine for 3 days. Lymphocyte accumulation was confined to the area surrounding the nervous tissue in 7 of 10 of the preparations from rats treated for 3 days or by a 3-h infusion. No histological changes were detected in nerve and muscle tissue from the opposite extremity exposed to saline. After a recovery period of 3 weeks, no differences in the nerve or muscle histology were seen between samples from bupivacaine- or saline-treated animals. The amplitude of the compound action potential of sciatic nerves was, however, significantly lower after bupivacaine treatment (7 days, 1 ml twice daily). Thus, impaired function may continue despite the lack of histological intraneural injury.     

Inhibition of acyl coenzyme a-cholesterol acyltransferase: A possible treatment of atherosclerosis?

Our full understanding of atherosclerosis and our ability to prevent its sequellae are incomplete. As a result, further investigation of novel antiatherosclerotic mechanisms and agents continues. Acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibition has been evaluated as a potential mechanism by which the current treatment arsenal may be expanded. ACAT is present in a variety of tissues and is responsible for catalyzing the conversion of free cholesterol to the more readily stored cholesteryl esters. Impressive lipid effects demonstrated in animals have not generally been demonstrated in human clinical trials. Partial ACAT inhibition with specific agents has resulted in lesion regression and decreased progression, whereas complete ACAT inhibition via genetic alterations has led to an exacerbation of cholesterol deposition in tissues in animal models. No ACAT inhibitor has yet been fully evaluated in human clinical trials for its impact on atherosclerotic disease progression. Several hurdles, such as sample size requirements needed to detect effect over background therapy and lack of sensitive surrogate efficacy markers, have served as a deterrent to the development of this class of investigational drug. However, with recent technologic advancements, more sensitive methods of measuring disease progression may be available. Human clinical trials are currently underway, with several agents reported in Phase II clinical trials. Within the next few years, results from these trials may determine whether or not ACAT inhibitors will be added to the list of treatment options for the prevention of atherosclerotic disease progression.