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How to induce most efficiently severe sensorineural hearing loss in mice using a single coadministration of an aminoglycoside antibiotic and a loop diuretic

To characterize the effects of deafening and subsequent treatment with brain-derived neurotrophic factor (BDNF) on the peripheral processes (PPs) of spiral ganglion cells (SGCs) in guinea pigs.

Arylalkylamine N-acetyltransferase (AANAT) catalyzes the reaction of serotonin with acetyl-CoA to form N-acetylserotonin and plays a major role in the regulation of the melatonin circadian rhythm in vertebrates. In the present study, the human cloned enzyme has been expressed in bacteria, purified, cleaved, and characterized. The specificity of the human enzyme toward substrates (natural as well as synthetic arylethylamines) and cosubstrates (essentially acyl homologs of acetyl-CoA) has been investigated. Peptide combinatorial libraries of tri-, tetra-, and pentapeptides with various amino acid compositions were also screened as potential sources of inhibitors. We report the findings of several peptides with low micromolar inhibitory potency. For activity measurement as well as for specificity studies, an original and rapid method of analysis was developed. The assay was based on the separation and detection of N-[(3)H]acetylarylethylamine formed from various arylethylamines and tritiated acetyl-CoA, by means of high performance liquid chromatography with radiochemical detection. The assay proved to be robust and flexible, could accommodate the use of numerous synthetic substrates, and was successfully used throughout this study. We also screened a large number of pharmacological bioamines among which only one, tranylcypromine, behaved as a substrate. The synthesis and survey of simple arylethylamines also showed that AANAT has a large recognition pattern, including compounds as different as phenyl-, naphthyl-, benzothienyl-, or benzofuranyl-ethylamine derivatives. An extensive enzymatic study allowed us to pinpoint the amino acid residue of the pentapeptide inhibitor, S 34461, which interacts with the cosubstrate-binding site area, in agreement with an in silico study based on the available coordinates of the hAANAT crystal.

In the past year, there has been an increased emphasis on developing improved methods and assessment of inflammatory bowel disease. Although tumor necrosis factor-α may be useful in the evaluation of inflammatory bowel disease in children, some controversy remains. Other serum markers, such as procollagen type I and type III, appear to be useful as early indicators of growth or inhibition of growth with treatment and activity. The use of steroid-sparing drugs continues to be studied, with new reports of pediatric inflammatory bowel disease responding to cyclosporine, 6-mercaptopurine, azathioprine, and alternate-day prednisone. Long-term studies are reported on outcome and recurrence in children with Crohn's disease following surgery, the development of inflammatory bowel disease in the offspring of couples with inflammatory bowel disease, and the psychologic difficulties that arise in children and families of children with inflammatory bowel disease. Other diseases that may be confused with pediatric inflammatory bowel disease are also reviewed.

Studies in the past year have added important information on how new medical and surgical interventions influence the course of pediatric inflammatory bowel disease. Growth-retarded children with Crohn's disease who responded poorly to medical therapy showed significant catch-up growth following surgical intervention in two independent studies. Other investigators reviewed the outcome and quality of life in a large series of patients who underwent ileoanal pull-through procedures for ulcerative colitis. Advances in the medical therapy for inflammatory bowel disease have centered on the recent introduction of immunosuppressive drugs. Azathioprine used in an uncontrolled trial of pediatric patients with either Crohn's disease or ulcerative colitis showed promise in disease refractory to standard medical therapy. A report on the outcome of pregnancies in patients who used azathioprine added important information concerning its safety in the treatment of inflammatory bowel disease.

The kinetics of nalidixic acid (NA) and its two metabolites, 7-hydroxynalidixic acid (HNA) and 7-carboxynalidixic acid (CNA), were studied after a single oral dose and after two doses a day for 7 days. Total unconjugated NA, HNA, and CNA concentrations in plasma and urine samples were assayed by a new high-pressure liquid chromatographic (HPLC) technique. NA was rapidly absorbed and hydroxylated to HNA. Both were rapidly excreted in urine with an apparent elimination half-life (t½) of 6 to 7 hr. CNA was never detected in the plasma, although it accounted for about 25% of total urinary NA and metabolites. No major sex-related differences in the kinetics and the metabolic pattern were observed. During the 7-day treatment there was no significant cumulation of NA and HNA. The study demonstrated that the concentration of the active compounds, unconjugated NA and HNA, was more than five times the minimum bacteria inhibiting concentration for 8 hr after drug and slightly above this concentration during the next 4 hr.Clinical Pharmacology and Therapeutics (1981) 29, 695–698; doi:10.1038/clpt.1981.97

Real-time particle size spectra are being acquired on our research aircraft with relative ease and speed by techniques that make use of the real-time interaction of laser light with aerosols and cloud droplets. The results are, however, sometimes ambiguous, because the optical "signatures" of the particles depend on their refractive indices in addition to physical dimensions. The calibration supplied by the manufacturer is based on instrument response to a specific test aerosol, e.g., latex spheres (refractive index = 1.59). Such a calibration is strictly valid only for sample aerosols of refractive index and shape similar to the test aerosol. Whenever the sample aerosol differs from the test aerosol, a calibration correction is in order. Of concern here is the use of an active scattering spectrometer probe (ASAS-X), to measure sulfuric acid aerosols on high-flying U-2 and ER-2 research aircraft. Correcting the calibration of the ASAS-X for dilute sulfuric acid droplets (refractive index = 1.44) that predominate the stratospheric aerosol changes the inferred sizes by up to 32% per size interval from that determined from the nominal calibration. This results in an average increase in particle surface area and volume of 42 ± 10% and 71 ± 19%, respectively. The calibration correction of the optical spectrometer probe for stratospheric aerosol is validated by independent and simultaneous sampling of the particles with impactors. Sizing and counting of particles on microphotographs of scanning electron microscope images give results on total particle surface areas and volumes. After the calibration correction, the optical spectrometer data (averaged over four size distributions) agree with the impactor results (similarly averaged) to within a few percent. We conclude that the optical properties, or chemical makeup, of the sample aerosol must be known for accurate size analysis by optical aerosol spectrometers.

A computer land reclamation model was developed and applied to a field leaching study of moderately salt‐affected profiles. Leaching was accomplished by ponding 15 cm of water intermittently in 3 m by 3 m basins every 1 to 2 weeks. Computer predictions on the degree of reclamation were compared with measured changes in soluble salts, soluble boron, and SAR to soil depths of 274 cm. The differences between computed and measured field data were no more than the horizontal variations found in salt‐affected lands in this area and elsewhere. Also reported are predicted drainage water quality and a method for computing gypsum requirements of sodium‐affected profiles.

Les pneumopathies interstitielles diffuses (PID) fibrosantes représentent un groupe hétérogène de maladies dont l’épidémiologie est mal connue. Le caractère fibrosant est associé à une morbi-mortalité importante. Ce travail propose d’évaluer leurs prévalences et leurs incidences dans le département de Haute-Garonne (31).

L’étude EPIDemio est une étude observationnelle prospective multicentrique qui a pour but d’estimer la prévalence des pneumopathies interstitielles diffuses (PID) fibrosantes en France dans le département de Haute Garonne (31). Cinquante-cinq pneumologues issus du Centre Hospitalo-Universitaire de Toulouse et de 8 établissements libéraux ont été sollicités pour participer à cette étude. Deux cent cinquante-six cas de PID fibrosantes ont été déclarés (prévalence minimale de 22,8/100 000 et estimée à 30,1/100 000). Les PID idiopathiques représentent 55,8 % des PID fibrosantes, devant les PID associées aux maladies systémiques (24,6 %) et les PID liées à une exposition (11,3 %). La fibrose pulmonaire idiopathique représente 35,9 % des PID fibrosantes, ce qui correspond à une prévalence minimale de 8,2/100 000 et estimée de 11,2/100 000. Les données épidémiologiques obtenues dans le département sont en accord avec les données préalablement mises en évidence en France et en Europe.

This study estimated the proportion of infants on total parenteral nutrition (TPN) who developed cholestasis. Risk factors associated with the development of this disease were identified. Data were abstracted from medical records of 624 infants ≤30 days of age who were treated with TPN. A case of TPN-related cholestasis was defined as an infant whose serum level of direct bilirubin was ≥1.5 mg/dl subsequent to initiation of TPN. Risk factors were assessed using multiple regression logistic analysis. Forty-six of the 624 infants in the cohort (7.4%) were classified as having TPN-related cholestasis. Even though the proportion of infants with TPN-related cholestasis was small, specific risk factors were identified. The multivariable analysis indicated that cholestasis was associated with intracranial hemorrhage (IH) and patent ductus arteriosus (PDA), conditions seen primarily in premature infants, and with sepsis and gastrointestinal (GI) conditions requiring surgery, seen in both term and preterm infants. Two distinct processes appear to have occurred: 1) in infants who experienced PDA or IH (conditions associated with hypoxia) where TPN may be the necessary trigger for the development of cholestasis, and 2) in infants with GI surgical conditions or sepsis, where cholestasis may develop with or without parenteral infusions.

Frequently, infants with chronic diarrhea and failure to thrive require TPN to overcome the intestinal absorptive defect. Weaning from TPN without exacerbation of diarrhea is difficult. We have developed a formula which can be structured to challenge the intestine sequentially with the various nutrient modules and concentrations. The Core formula is composed of whole casein and minerals calculated to deliver adequate electrolytes when used in a concentration cf 3 gms % protein. To this protein Core, fats and sugars can be added as needed and tolerated by the patient. When weaning from TPN, modules are added in 1 gm % increments every 12 hrs. starting with protein, fat and then carbohydrate. When the composition equals 3 gm % Core mix, 3.5 gm % fat and 6 gm % carbohydrate and this is tolerated for 1 week, the patient is switched to a proprietary formula which most closely matches. If a concentration is reached that causes diarrhea, it is maintained or slightly reduced until intestinal tolerance developes. In the past three years, more than 75 patients have been weaned to oral feedings in this manner with no difficulty. Work supported by: Ross Laboratory, David Underwood Trust, USPH RR-00188, and AM-05721-01.

Infants with AMI have chronic acidic diarrhea secondary to malabsorption of all carbohydrates resulting in profound malnutrition. Four patients with AMF were studied by an intestinal perfusion technique. A triple lumen tube with a Pediatric Crosby capsule at the tip was introduced into the jejunum. A 10% glucose solution was infused through a proximal site 30 cm from the collecting point. 1% polyethylene glycol was added as a non-absorbable marker. Samples were obtained every 15 minutes and glucose absorption rate was calculated. After the perfusion, a jejunal biopsy was obtained for histology and disaccharidase assay.Glucose absorption increased from 9.2 to 17.3 mg/min after 1 month rehabilitation. Villous length increased with recovery. Lactase, sucrose and maltose enzymes remained low.A linear relationship exists between glucose absorption and villous length. This implies that impaired glucose absorption is related to decreased mucosal surface area. Work supported by: Ross Laboratory, David Underwood Trust, NASA Contract 90059, USPH RR-00188 and AM-05721-01.

ASDS is a clinical syndrome characterized by frequent, watery stools, rapid onset of dehydration, and lack of response to dietary restriction. The stools are mainly yellowish water and are produced almost continuously. Stool electrolytes show sodium above 70 mEq/L, chloride above 60 mEq/L, and potassium below 30 mEq/L. Diarrhea responsive to dietary restriction usually has sodium, potassium and chloride under 40 mEq/L. Stool volumes in ASDA are over 60 cc/kg/day leading to rapid onset of dehydration, hyponatremia, and shock. Treatment with exclusively I.V. fluids for as long as 8 days has no effect on fecal losses in ASDS. In 1977, 28 cases of ASDS were recognized at Texas Children's Hospital. Oral colistin was of no value in ASDS. Parenteral aminoglycoside therapy was associated with recovery of normal stool patterns in 4 to 5 days. Oral gentamicin was associated with recovery of normal consistency, frequency, and electrolyte concentrations in 24 to 36 hours. Thus, ASDS is characterized by cholera-like stooling, dehydration during the first days of illness, and an elevated stool sodium. This syndrome responds rapidly to oral gentamicin therapy.Supported by Children's Clinical Research Center NIH RR-00188, Kelsey-Seybold Fellowship Fund and Venezuelan National Academy of Sciences.