Characterization of cell fusion in an experimental mouse model of endometriosis†.

Cell fusion is involved in the development of some adult organs, is implicated in the pathogenesis of specific types of cancer, and is known to participate in repair/regeneration processes mediated by bone-marrow-derived cells (BMDCs). Endometriosis is a disease characterized by growth of functional endometrial tissue outside of the uterine cavity. Endometriosis shares some molecular properties with cancer and BMDCs home to endometriosis lesions in a mouse model. Our objective was to determine if cell fusion can occur in endometriosis and establish whether bone-marrow-derived cells participate in cell fusion events in lesions. We employed a Cre-Lox system to identify cell fusion events in a mouse model of endometriosis. Fused cells were detected in endometriotic lesions, albeit at a low frequency (∼1 in 400 cells), localized to the stromal compartment, and displayed restricted proliferation. Using 5-fluorouracil-based nongonadotoxic bone marrow transplantation model, we demonstrate that bone marrow cells represent a principal cell source for fusion events in lesions. Cell fusion progeny uniformly lacked expression of selected markers of hematopoietic, endothelial, and epithelial markers, though they expressed the mesenchymal/stromal markers Sca-1 and CD29. This study is the first to describe the phenomenon of cell fusion in endometriosis and points to a mesenchymal population derived from cell fusion events with limited proliferative activity, properties previously attributed to endometrial stem cells. Their putative role in the pathogenesis of the disease remains to be elucidated.

Pulse propagation in the slow and stopped light regime.

Electromagnetic pulse propagation in the slow light regime and near a zero group velocity point is relevant to a plethora of potential applications, and has analogies in numerous other wave systems. Unfortunately, the standard frequency-based formulation for pulse propagation is unsuitable for describing the dynamics in such regimes, due to the divergence of the dispersion coefficients. Moreover, in the presence of absorption, it is not clear how to interpret the propagation dynamics due to the drastic change induced by absorption upon the dispersion curves. As a remedy, we present an alternative momentum-based formulation, which is rapidly converging in these regimes, and naturally suitable for lossy and nonlinear media. It is specialized to a waveguide geometry which provides a significant simplification with respect to existing momentum-based schemes. Doing so, we provide a somewhat alternative, yet intuitive picture of the seeming enhanced absorption and nonlinear response in these regimes, and show that light-matter interactions are not enhanced in the slow/stopped light regimes.

Early glial activation precedes neurodegeneration in the cerebral cortex after SIV infection: a 3D, multivoxel proton magnetic resonance spectroscopy study.

OBJECTIVES: As ∼40% of HIV-infected individuals experience neurocognitive decline, we investigated whether proton magnetic resonance spectroscopic imaging ((1) H-MRSI) detects early metabolic abnormalities in the cerebral cortex of a simian immunodeficiency virus (SIV)-infected rhesus monkey model of neuroAIDS. METHODS: The brains of five rhesus monkeys before and 4 or 6 weeks after SIV infection (with CD8(+) T-cell depletion) were assessed with T2 -weighted quantitative magnetic resonance imaging (MRI) and 16×16×4 multivoxel (1) H-MRSI (echo time/repetition time = 33/1440 ms). Grey matter and white matter masks were segmented from the animal MRIs and used to produce cortical masks co-registered to (1) H-MRSI data to yield cortical metabolite concentrations of the glial markers myo-inositol (mI), creatine (Cr) and choline (Cho), and of the neuronal marker N-acetylaspartate (NAA). The cortex volume within the large, 28 cm(3) (∼35% of total monkey brain) volume of interest was also calculated for each animal pre- and post-infection. Mean metabolite concentrations and cortex volumes were compared pre- and post-infection using paired sample t-tests. RESULTS: The mean (± standard deviation) pre-infection concentrations of the glial markers mI, Cr and Cho were 5.8 ± 0.9, 7.2 ± 0.4 and 0.9 ± 0.1 mM, respectively; these concentrations increased 28% (p ≈ 0.06), 15% and 10% (both p < 0.05), respectively, post-infection. The mean concentration of neuronal marker NAA remained unchanged (7.0 ± 0.6 mM pre-infection vs. 7.3 ± 0.8 mM post-infection; p ≈ 0.37). The mean cortex volume was also unchanged (8.1 ± 1.1 cm(3) pre-infection vs. 8.3 ± 0.5 cm(3) post-infection; p ≈ 0.76). CONCLUSIONS: These results support the hypothesis that early cortical glial activation occurs after SIV infection prior to the onset of neurodegeneration. This suggests HIV therapeutic interventions should potentially target early glial activation in the cerebral cortex.

A safety evaluation of intermittent high-dose inhaled nitric oxide in viral pneumonia due to COVID-19: a randomised clinical study.

High-dose inhaled Nitric Oxide (iNO) has been shown to have anti-inflammatory, vasodilator, and antimicrobial properties, resulting in improved arterial oxygenation as well as a beneficial therapeutic effect on lower respiratory tract infections. This study evaluated the safety and efficacy of 150-ppm intermittent iNO administered with a novel iNO-generator, for treating adults hospitalised for viral pneumonia. In this prospective, open-label, multicenter study, subjects aged 18-80, diagnosed with viral pneumonia received either standard supportive treatment alone (Control-Group) or combined with iNO for 40 min, 4 times per day up to 7 days (Treatment-Group). Out of 40 recruited subjects, 35 were included in the intention-to-treat population (34 with COVID-19). Adverse Events rate was similar between the groups (56.3% vs. 42.1%; respectively). No treatment-related adverse events were reported, while 2 serious adverse events were accounted for by underlying pre-existing conditions. Among the Treatment-Group, oxygen support duration was reduced by 2.7 days (Hazard Ratio = 2.8; p = 0.0339), a greater number of subjects reached oxygen saturation ≥ 93% within hospitalisation period (Hazard Ratio = 5.4; p = 0.049), and a trend for earlier discharge was demonstrated. Intermittent 150-ppm iNO-treatment is well-tolerated, safe, and beneficial compared to usual care for spontaneously breathing hospitalised adults diagnosed with COVID-19 viral pneumonia.

A pilot cohort study of granulocyte colony-stimulating factor in the treatment of unresponsive thin endometrium resistant to standard therapies.

STUDY QUESTION: Is thin endometrium unresponsive to standard treatments expandable by intrauterine perfusion with granulocyte colony-stimulating factor (G-CSF)? SUMMARY ANSWER: This cohort study is supportive of the effectiveness of G-CSF in expanding chronically unresponsive endometria. WHAT IS KNOWN ALREADY: In a previous small case series, we reported the successful off-label use of G-CSF in four consecutive patients, who had previously failed to expand their endometria beyond 6.9 mm with the use of standard treatments. STUDY DESIGN, SIZE AND DURATION: In a prospective observational cohort pilot study over 18 months, we described 21 consecutive infertile women with endometria <7 mm on the day of hCG administration in their first IVF cycles at our center. All previous cycles using traditional treatments with estradiol, sildenafil citrate (Viagra™) and/or beta-blockers had been unsuccessful. G-CSF (Nupogen™) was administered per intrauterine catheter by slow infusion before noon on the day of hCG administration. If the endometrium had not reached at least a 7-mm within 48h, a second infusion was given following oocyte retrieval. Primary and secondary main outcomes were an increase in endometrial thickness and clinical pregnancy, respectively. Endometrial thickness was assessed by vaginal ultrasound at the most expanded area of the endometrial stripe. PARTICIPANTS/MATERIALS, SETTINGS AND METHOD: This study was uncontrolled, each patient serving as her own control in a prospective evaluation of endometrial thickness. The mean ± SD age of the cohort was 40.5 ± 6.6 years, gravidity was 1.8 ± 2.1 (range 0-7) and parity was 0.4 ± 1.1 (range 0-4); 76.2% of women had, based on age-specific FSH and anti-Müllerian hormone, an objective diagnosis of diminished ovarian reserve and had failed 2.0 ± 2.1 prior IVF cycles elsewhere. MAIN RESULTS AND THE ROLE OF CHANCE: With 5.2 ± 1.9 days between G-CSF perfusions and embryo transfers, endometrial thickness increased from 6.4 ± 1.4 to 9.3 ± 2.1 mm (P < 0.001). The Δ in change was 2.9 ± 2.0 mm, and did not vary between conception and non-conception cycles. A 19.1% ongoing clinical pregnancy rate was observed, excluding one ectopic pregnancy. LIMITATIONS AND REASONS FOR CAUTION: Small sample size (but a highly selected patient population) in an uncontrolled cohort study and in unselected first IVF cycles at our center. WIDER IMPLICATIONS OF THE FINDINGS: This pilot study supports the utility of G-CSF in the treatment of chronically thin endometrium and suggests that such treatment will, in very adversely affected patients, result in low but very reasonable clinical pregnancy rates. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Foundation for Reproductive Medicine, New York, New York, USA, a not-for-profit research foundation and intramural grants from the Center for Human Reproduction (CHR)-New York. N.G. and D.H.B. are members of the board of the Foundation for Reproductive Medicine. N.G. is owner of CHR-New York, where the study was conducted. N.G. and D.H.B. have been recipients of research awards, travel grants and speaker honoraria from various pharmaceutical and medical device companies. None of these companies was, however, in any way associated with the materials and the manuscript presented here. N.G. and D.H.B. are listed as co-inventors on a number of awarded and still pending U.S. patents, none related to the materials presented here. N.G. is on the board of a medically related company, not in any way associated with the data presented here.

Self-expandable metal stent for malignant colonic obstruction: outcome in proximal vs. left sided tumor localization.

INTRODUCTION: The aim of this study was to evaluate the outcome of through-the-scope (TTS) implanted self-expanding metal stent (SEMS) comparing left-sided vs. proximal placement with regard to complications and outcome in palliation of malignant colorectal obstruction. MATERIAL AND METHODS: All patients were consecutively retrospectively enrolled to this study between January 2009 and February 2012 due to impending or prevalent complete malignant colorectal obstruction. TTS applicable uncovered nitinol SEMS with unique flexible properties were used (Taewoong Medical, South Korea). Left-sided obstruction (aboral from the left flexure) was compared to proximal (from the ileo-cecal valve to the left flexure) localization. All patients have been discussed in the interdisciplinary tumor conference and the recommendation to treat by endoscopic stent placement was given in consensus. RESULTS: A total of 15 patients was enrolled to this study (10 male and 5 female; mean age 68.3 ± 15.4 years, range 48 - 94), five patients with obstructions located in the proximal hemicolon whereas ten patients had a left-sided malignancy. Technical success was achieved in all cases and there was no early complication noticed. Three late complications included tumor overgrowth (n = 1), stent occlusion (1), and dislocation (1). Stent-in-stent insertion achieved, again, clinical success. The site of SEMS implantation (proximal vs. left colon) had no impact on patient outcome or complication rate. SEMS patency duration was 269.8 ± 175.2 days (range 30 - 570) and mean survival of the patients was 305.1 ± 279.3 days (range 16 - 990). CONCLUSION: TTS application of flexible, non-covered SEMS seems to be safe and effective for palliation of malignant colorectal obstruction independent of localization of the tumor in the colon.

Evaluating the physiological significance of respiratory sinus arrhythmia: looking beyond ventilation-perfusion efficiency.

We conducted a theoretical study of the physiological significance of respiratory sinus arrhythmia (RSA), a phenomenon used as an index of cardiac vagal tone and wellbeing, whereby the heart rate (HR) increases during inspiration and decreases during expiration. We first tested the hypothesis that RSA improves gas exchange efficiency but found that although gas exchange efficiency improved with slow and deep breathing and with increased mean heart rate, this was unrelated to RSA. We then formulated and tested a new hypothesis: that RSA minimizes the work done by the heart while maintaining physiological levels of arterial carbon dioxide. We tested the new hypothesis using two methods. First, the HR for which the work is minimized was calculated using techniques from optimal control theory. This calculation was done on simplified models that we derived from a previously published model of gas exchange in mammals. We found that the calculated HR was remarkably similar to RSA and that this became more profound under slow and deep breathing. Second, the HR was prescribed and the work done by the heart was calculated by conducting a series of numerical experiments on the previously published gas exchange model. We found that cardiac work was minimized for RSA-like HR functions, most profoundly under slow and deep breathing. These findings provide novel insights into potential reasons for and benefits of RSA under physiological conditions.

Neonatal midaortic syndrome and renal artery atresia presenting as malignant hypertension.

We report a case of congenital midaortic syndrome with bilateral renal artery atresia in a premature female neonate born by way of caesarean section secondary to acute onset of decreased fetal movement and polyhydramnios. The infant required cardiopulmonary resuscitation at birth, and initial echocardiogram exhibited normal intracardiac anatomy and mildly depressed left-ventricular systolic function. Within 24 h, the neonate developed severe systemic arterial hypertension and acute renal failure. Ultrasound demonstrated hyperechoic kidneys and a hypoplastic abdominal aorta. Angiography revealed severe suprarenal hypoplasia of the abdominal aorta with bilateral renal artery atresia. Medical support was withdrawn, and the patient died shortly thereafter.

Adenotonsillectomy improves slow-wave activity in children with obstructive sleep apnoea.

The aim of the present study was to estimate slow-wave activity (SWA), a marker of sleep homeostasis, in children with obstructive sleep apnoea (OSA) before and after adenotonsillectomy (AT) compared with untreated OSA children (comparison group). 14 children with OSA (mean ± sd age 6.4 ± 2.5 yrs; apnoea-hypopnoea index (AHI) 10.0 ± 10.3 events·h⁻¹) who underwent AT were consecutively recruited to the study. The comparison group comprised six retrospectively recruited children (age 5.4 ± 2.2 yrs; AHI 9.4 ± 7.6 events·h⁻¹) with OSA that did not undergo treatment. Electroencephalogram (derivation C3/A2) was analysed using spectral and waveform analysis to determine SWA energy and slow-wave slope. The same procedure was repeated 5.4 and 19 months later for the AT and comparison groups, respectively. AT improved respiration without a change in duration of sleep stages. Following AT, >50% elevation of SWA during the first two sleep cycles (p<0.01) and a more physiological decay of SWA across the night (p<0.0001) were noted. The slow-wave slope increased by >30% following AT (p<0.03). No significant changes were found in SWA in the comparison group. Sleep homeostasis is considerably impaired in pre-pubescent children with OSA. AT restores more physiological sleep homeostasis in children with OSA. SWA analysis may provide a useful addition to standard sleep-stage analyses in children with OSA.

Dried leaves of Rosmarinus officinalis as a treatment for streptococcosis in tilapia.

Dietary application of dried Rosmarinus officinalis (rosemary) leaves as a treatment for streptococcal infection was studied in tilapia, Oreochromis sp. Feeding with dried rosemary leaves significantly reduced mortality following infection with Streptococcus iniae: 44% mortality in the group fed 8% rosemary, similar to oxytetracycline treatment (43% mortality), and significantly lower than the control (65%). Dietary administration of 16% rosemary significantly reduced mortality because of Streptococcus agalactiae infection in 44 g fish (62% and 76% in 16% rosemary and control, respectively), but not in a similar experiment conducted with 5.5 g fish. The antibacterial effect of rosemary on S. iniae was studied. Activity of rosemary cultivar Israel was reduced during the winter, but there was no significant change in cultivars Oranit and Star. Storage of powdered rosemary leaves at 50 degrees C resulted in fourfold and eightfold higher MIC(24 h) values after 3 and 4.5 months, respectively. Storage at -20 degrees C, 4 degrees C and 25 degrees C and autoclaving (120 degrees C) each resulted in a twofold increase in MIC(24 h). Repeated exposures of S. iniae to rosemary did not affect minimal inhibitory concentration, suggesting no development of resistance to rosemary.

Development of a 25-plex SNP assay for traceability in cattle.

Single nucleotide polymorphisms (SNPs) are amenable to automation and therefore have become the marker of choice for DNA profiling. SNaPshot, a primer extension-based method, was used to multiplex 25 SNPs that have been previously validated as useful for identity control. Detection of extended products was based on four different fluorochromes and extension primers with oligonucleotide tails of differing lengths, thus controlling the concise length of the entire chromatogram to 81 bases. Allele frequencies for Holstein, Simmental, Limousin, Angus, Charolais and Tux Cattle were estimated and significant positive Pearson-correlation coefficients were obtained among the analysed breeds. The probability that two randomly unrelated individuals would share identical genotypes for all 25 loci varied from 10(-8) to 10(-10) for these breeds. For parentage control, the exclusion power was found to be 99.9% when the genotypes of both putative parents are known. A traceability test of duplicated samples indicated a high genotyping precision of >0.998. This was further corroborated by analysis of 60 cases of parent-sib pairs and trio families. The 25-plex SNaPshot assay is adapted for low- and high-throughput capacity and thus presents an alternative for DNA-based traceability in the major commercial cattle breeds.

Similar levels of mRNA from the W1282X and the delta F508 cystic fibrosis alleles, in nasal epithelial cells.

The effect of nonsense mutations on mRNA levels is variable. The levels of some mRNAs are not affected and truncated proteins are produced, while the levels of others are severely decreased and null phenotypes are observed. The effect on mRNA levels is important for the understanding of phenotype-genotype association. Cystic fibrosis (CF) is a lethal autosomal recessive disease with variable clinical presentation. Recently, two CF patients with mild pulmonary disease carrying nonsense mutations (R553X, W1316X) were found to have severe deficiency of mRNA. In the Jewish Ashkenazi CF patient population, 60% of the chromosomes carry a nonsense mutation, W1282X. Patients homozygous for this mutation have severe disease presentation with variable pulmonary disease. The presence of CF transcripts in a group of patients homozygous and heterozygous for this mutation was studied by reverse transcriptase PCR of various regions of the gene. Subsequent hybridization to specific CF PCR probes and densitometry analysis indicated that the CF mRNA levels in patients homozygous for the W1282X mutation are not significantly decreased by the mutation. mRNA levels were compared for patients heterozygous for the W1282X mutation. The relative levels of mRNA with the W1282X, and the delta F508 or the normal alleles, were similar in each patient. These results indicate that the severe clinical phenotype of patients carrying the W1282X mutation is not due to a severe deficiency of mRNA. In addition, the severity, progression, and variability of the pulmonary disease are affected by other, as yet unknown factors.

A p53-bound enhancer region controls a long intergenic noncoding RNA required for p53 stress response.

Genome-wide chromatin studies identified the tumor suppressor p53 as both a promoter and an enhancer-binding transcription factor. As an enhancer factor, p53 can induce local production of enhancer RNAs, as well as transcriptional activation of distal neighboring genes. Beyond the regulation of protein-coding genes, p53 has the capacity to regulate long intergenic noncoding RNA molecules (lincRNAs); however, their importance to the p53 tumor suppressive function remains poorly characterized. Here, we identified and characterized a novel p53-bound intronic enhancer that controls the expression of its host, the lincRNA00475 (linc-475). We demonstrate the requirement of linc-475 for the proper induction of a p53-dependent cell cycle inhibitory response. We further confirm the functional importance of linc-475 in the maintenance of CDKN1A/p21 levels, a cell cycle inhibitor and a major p53 target gene, following p53 activation. Interestingly, loss of linc-475 reduced the binding of both p53 and RNA polymerase II (RNAPII) to the promoter of p21, attenuating its transcription rate following p53 activation. Altogether, our data suggest a direct role of p53-bound enhancer domains in the activation of lincRNAs required for an efficient p53 transcriptional response.

Metabolic Abnormalities in the Hippocampus of Patients with Schizophrenia: A 3D Multivoxel MR Spectroscopic Imaging Study at 3T.

BACKGROUND AND PURPOSE: Schizophrenia is well-known to be associated with hippocampal structural abnormalities. We used 1H-MR spectroscopy to test the hypothesis that these abnormalities are accompanied by NAA deficits, reflecting neuronal dysfunction, in patients compared with healthy controls. MATERIALS AND METHODS: Nineteen patients with schizophrenia (11 men; mean age, 40.6 ± 10.1 years; mean disease duration, 19.5 ± 10.5 years) and 11 matched healthy controls (5 men; mean age, 33.7 ± 10.1 years) underwent MR imaging and multivoxel point-resolved spectroscopy (TE/TR, 35/1400 ms) 1H-MRS at 3T to obtain their hippocampal GM absolute NAA, Cr, Cho, and mIns concentrations. Unequal variance t tests and ANCOVA were used to compare patients with controls. Bilateral volumes from manually outlined hippocampal masks were compared by using unequal variance t tests. RESULTS: Patients' average hippocampal GM Cr concentrations were 19% higher than that of controls, 8.7 ± 2.2 versus 7.4 ± 1.2 mmol/L (P < .05); showing no differences, concentrations in NAA were 8.8 ± 1.6 versus 8.7 ± 1.2 mmol/L; in Cho, 2.3 ± 0.7 versus 2.1 ± 0.3 mmol/L; and in mIns, 6.1 ± 1.5 versus 5.2 ± 0.9 (all P > .1). There was a positive correlation between mIns and Cr in patients (r = 0.57, P = .05) but not in controls. The mean bilateral hippocampal volume was ∼10% lower in patients: 7.5 ± 0.9 versus 8.4 ± 0.7 cm3 (P < .05). CONCLUSIONS: These findings suggest that the hippocampal volume deficit in schizophrenia is not due to net loss of neurons, in agreement with histopathology studies but not with prior 1H-MR spectroscopy reports. Elevated Cr is consistent with hippocampal hypermetabolism, and its correlation with mIns may also suggest an inflammatory process affecting some cases; these findings may suggest treatment targets and markers to monitor them.

Modeling carbon and nitrogen transformations for adjustment of compost application with nitrogen uptake by wheat.

Environmentally sound management of the use of composts in agriculture relies on matching the rate of release of available N from compost-amended soils to the crop demand. To develop such management it is necessary to (i) characterize the properties of composts that control their rates of decomposition and release of N and (ii) determine the optimal amount of composts that should be applied annually to wheat (Triticum aestivum L.). Carbon and N mineralization were measured under controlled conditions to determine compost decomposition rate parameters, and the NCSOIL model was used to derive the organic wastes parameters that control the rates of N and C transformations in the soil. We also characterized the effect of a drying period to estimate the effects of the dry season on C and N dynamics in the soil. The optimized compost parameters were then used to predict mineral N concentration dynamics in a soil-wheat system after successive annual applications of compost. Sewage sludge compost (SSC) and cattle manure compost (CMC) mineralization characteristics showed similar partitioning into two components of differing ease of decomposition. The labile component accounted for 16 to 20% of total C and 11 to 14% of total N, and it decomposed at a rate of 2.4 x 10(-2) d(-1), whereas the resistant pool had a decomposition rate constant of 1.2 to 1.4 x 10(-4) d(-1). The main differences between the two composts resulted from their total C and N and inorganic N contents, which were determined analytically. The long-term effect of a drying period on C and N mineralization was negligible. Use of these optimization results in a simulation of compost mineralization under a wheat crop, with a modified plant-effect version of the NCSOIL model, enabled us to evaluate the effects of the following factors on the C and N dynamics in soil: (i) soil temperature, (ii) mineral N uptake by plants, and (iii) release of very labile organic C in root exudates. This labile organic C enhanced N immobilization following application, and so decreased the N available for uptake by plants.

Effect of traditional oriental soy products on iron absorption.

The effect of a variety of traditional oriental unfermented and fermented soy products on iron absorption was evaluated in 242 Indian women. When compared with a soy-flour meal containing an equal amount of protein, iron absorption was found to be significantly improved with silken tofu, natto, tempeh, rice miso, barley miso, and soybean miso. This improvement could not be adequately explained except with reference to changes in the protein composition of the products. The protein fraction profiles of the soy products were obtained by size-exclusion high-performance liquid chromatography. An inverse relationship between food iron absorption and the high-molecular-weight fraction of the soy products was demonstrated (r = 0.66, p = 0.01). However, anomalous results obtained with three products (sufu, tempeh, and fully hydrolyzed isolated soy protein) did not make it possible to reach firm conclusions concerning the effect of the protein fraction of soy on iron bioavailability.

Ascorbic acid prevents the dose-dependent inhibitory effects of polyphenols and phytates on nonheme-iron absorption.

The effects of maize-bran phytate and of a polyphenol (tannic acid) on iron absorption from a white-bread meal were tested in 199 subjects. The phytate content was varied by adding different concentrations of phytate-free and ordinary maize bran. Iron absorption decreased progressively when maize bran containing increasing amounts of phytate phosphorous (phytate P) (from 10 to 58 mg) was given. The inhibitory effect was overcome by 30 mg ascorbic acid. The inhibitory effects of tannic acid (from 12 to 55 mg) were also dose dependent. Studies suggested that greater than or equal to 50 mg ascorbic acid would be required to overcome the inhibitory effects on iron absorption of any meal containing greater than 100 mg tannic acid. Our findings indicate that it may be possible to predict the bioavailability of iron in a diet if due account is taken of the relative content in the diet of the major promoters and inhibitors of iron absorption.

Methylprednisolone therapy for acute asthma in infants and toddlers: a controlled clinical trial.

A controlled double-blind trial was carried out to assess the effect of the early introduction of combined corticosteroid and beta-adrenergic drugs for the treatment of acute asthma in infants and toddlers. Seventy-four emergency room patients (aged 7 to 54 months) who were treated for acute asthma were studied. Treatment included, in addition to salbutamol inhalations, a single dose of intramuscular methylprednisolone (4 mg/kg) or normal saline as placebo. The patients were reevaluated 3 hours after initiation of treatment. At that time, patients were either admitted or discharged based on a clinical decision. Only 8 (20%) of 39 patients treated with steroids were admitted, compared with 15 (43%) of 35 in the placebo group (P less than .05). Sequential analysis of 33 pairs, matched by age and severity of symptoms, revealed statistically significant reduced admission rates in patients treated with steroids. In the younger patients (6 to 24 months), admission rate was significantly lower for those treated with steroids (18%) as compared with those treated without steroids (50%) (P less than .05). In the older group (24 to 54 months), the trend was similar but not statistically significant: 23% vs 31% in the steroid and placebo groups, respectively. These data indicate that corticosteroid treatment combined with an adrenergic agent, given early during an acute asthmatic episode, significantly reduces the hospital admission rate of infants and toddlers.

Monitoring theophylline therapy using citric acid-stimulated saliva in infants and children with asthma.

Saliva stimulation is required for measurement of drugs in saliva. Chewing on a piece of paraffin, which is the method usually used for saliva stimulation, requires cooperation of the patient and, thus, is inapplicable in infants and young children. To assess the value of determining theophylline concentrations from noninvasively obtained saliva in this age group, we studied the theophylline plasma to saliva concentration ratio in citric acid-stimulated saliva. Theophylline concentration was measured in 137 simultaneously obtained paired specimens of plasma and saliva from 68 patients 2 1/2 months to 14 years of age treated with theophylline for asthma (dosage 20.8 +/- 5.2 mg/kg/d, mean +/- SD). Saliva secretion was stimulated by placing citric acid crystals on the tongue. A strong and highly significant correlation was observed between both determinations (r = .96; P less than .01). The plasma to saliva ratio was 1.78 +/- 0.22 (mean +/- SD), with theophylline concentrations between 3.1 and 32.1 micrograms/mL of plasma. The ratio of estimated to actual plasma theophylline concentrations was 1.02 +/- 0.12 (mean +/- SD). Interindividual coefficient of variation of plasma to saliva theophylline concentrations ratios was 12.4%; mean intraindividual coefficient of variation was 5.3%. The use of citric acid for saliva stimulation is easily applicable to infants and young children. Compared with blood drawing, stimulation of saliva secretion by citric acid is painless and noninvasive, is more readily accepted to patients, is at least as clinically relevant for theophylline determination, and allows frequent measurements of drug levels for individualization of the dosage with samples taken at home.(ABSTRACT TRUNCATED AT 250 WORDS)

Dexamethasone and salbutamol in the treatment of acute wheezing in infants.

Thirty-two infants, aged 1 to 12 months, hospitalized with acute wheezing, were studied. They were randomly divided into four treatment groups of eight patients each. The treatments were intramuscular dexamethasone or placebo (double-blind), and salbutamol (oral and inhaled), or none (open), in all four possible combinations. The study was carried out as a randomized block design with eight blocks of four infants each, matched by age and clinical score. Average daily improvements, as reflected by changes in the clinical score and length of hospital stay, was essentially the same for infants treated with placebo, salbutamol alone, and dexamethasone alone. However, combined salbutamol-dexamethasone treatment resulted in more than twice the rate of improvement of the other treatments. The difference was statistically highly significant (P less than .01). Furthermore, the response of this combined treatment was observed within 24 hours; none of the ten infants in whom there was no significant improvement within 48 hours and neither of the two patients who developed respiratory failure received the combined salbutamol-dexamethasone treatment. A potentiating effect of corticosteroids on the beta-adrenergic responsiveness is a possible explanation for the advantage of this combined treatment in the management of acute wheezing in infancy.