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[Evaluation of the incidence of nephrotoxicity associated with the use of aminoglycosides in patients with extrahepatic biliary obstruction].

In the present publication we discuss nephrotoxicity (NT) incidence by reviewing all the clinical histories of one year (May 1989-May 1990) with diagnosis of obstructive jaundice or cholangitis. Of a total of 90 patients. 53 were treated with aminoglycosides and 37 received other antibiotics. Nephrotoxicity developed in nine patients of the group that received aminoglycosides (17%), versus only three patients (8%) in the other group. Both groups were comparable regarding sex, age and liver and renal basal functions. Analysis of the variables that could be associated with a higher incidence in the nephrotoxicity group that received aminoglycosides showed that there were no differences regarding age, sex, dosage, duration of treatment, plasmatic levels of aminoglycosides and liver and renal basal functions. Only simultaneous administration o furosemide was significantly associated with the development of nephrotoxicity. Results of this study underline the need of a prospective follow-up of patients with biliary obstruction during treatment with aminoglycosides. Meanwhile the evidence available allows us to recommend the monitoring of renal function in this type of patients.

Aged↗

Protein targeting in the analysis of learning and memory: a potential alternative to gene targeting.

Gene targeting using homologous recombination in embryonic stem (ES) cells offers unprecedented precision with which one may manipulate single genes and investigate the in vivo effects of defined mutations in the mouse. Geneticists argue that this technique abrogates the lack of highly specific pharmacological tools in the study of brain function and behavior. However, by now it has become clear that gene targeting has some limitations too. One problem is spatial and temporal specificity of the generated mutation, which may appear in multiple brain regions or even in other organs and may also be present throughout development, giving rise to complex, secondary phenotypical alterations. This may be a disadvantage in the functional analysis of a number of genes associated with learning and memory processes. For example, several proteins, including neurotrophins--cell-adhesion molecules--and protein kinases, that play a significant developmental role have recently been suggested to be also involved in neural and behavioral plasticity. Knocking out genes of such proteins may lead to developmental alterations or even embryonic lethality in the mouse, making it difficult to study their function in neural plasticity, learning, and memory. Therefore, alternative strategies to gene targeting may be needed. Here, we suggest a potentially useful in vivo strategy based on systemic application of immunoadhesins, genetically engineered fusion proteins possessing the Fc portion of the human IgG molecule and, for example, a binding domain of a receptor of interest. These proteins are stable in vivo and exhibit high binding specificity and affinity for the endogenous ligand of the receptor, but lack the ability to signal. Thus, if delivered to the brain, immunoadhesins may specifically block signalling of the receptor of interest. Using osmotic minipumps, the protein can be infused in a localized region of the brain for a specified period of time (days or weeks). Thus, the location and timing of delivery are controlled. Here, we present methodological details of this novel approach and argue that infusion of immunoadhesins will be useful for studying the role particular receptors play in behavioral and neural plasticity.

Animals↗

Rubella virus nonstructural protein protease domains involved in trans- and cis-cleavage activities.

Rubella virus (RV) genomic RNA contains two large open reading frames (ORFs): a 5'-proximal ORF encoding nonstructural proteins (NSPs) that function primarily in viral RNA replication and a 3'-proximal ORF encoding the viral structural proteins. Proteolytic processing of the RV NSP ORF translation product p200 is essential for viral replication. Processing of p200 to two mature products (p150 and p90) in the order NH(2)-p150-p90-COOH is carried out by an RV-encoded protease residing in the C-terminal region of p150. The RV nonstructural protease (NS-pro) belongs to a viral papain-like protease family that cleaves the polyprotein both in trans and in cis. A conserved X domain of unknown function was found from previous sequence analysis to be associated with NS-pro. To define the domains responsible for cis- and trans-cleavage activities and the function of the X domain in terms of protease activity, an in vitro translation system was employed. We demonstrated that the NSP region from residue 920 to 1296 is necessary for trans-cleavage activity. The domain from residue 920 to 1020 is not required for cis-cleavage activity. The X domain located between residues 834 and 940, outside the regions responsible for both cis- and trans-cleavage activities of NS-pro, was found to be important for NS-pro trans-cleavage activity but not for cis-cleavage activity. Analysis of sequence homology and secondary structure of the RV NS-pro catalytic region reveals a folding structure similar to that of papain.

Amino Acid Sequence↗

Preoperative anal sphincter high pressure zone, maximum tolerable volume, and anal mucosal electrosensitivity predict early postoperative defecatory function after low anterior resection for rectal cancer.

PURPOSE: The aims of this study were to correlate postoperative defecatory function after low anterior resection with clinical factors and physiologic parameters and to explore the possibility of predicting early postoperative defecatory function after low anterior resection. METHODS: Thirty-two patients who underwent low anterior resection for rectal cancer were studied. Anorectal physiologic studies were performed preoperatively and six months postoperatively; maximum resting pressure, maximum squeeze pressure, length of the high pressure zone, neorectal sensory threshold, neorectal maximum tolerable volume, and anal mucosal electrosensitivity were recorded. Preoperative and postoperative defecatory function was scored between 0 (worst) and 6 (best) on the basis of bowel frequency, fecal incontinence, and urgency. RESULTS: In univariate regression analyses, a longer preoperative high pressure zone and a more sensitive anal mucosa were associated with better postoperative defecatory function. Using multiple regression analysis, in which age, gender, the level of anastomosis, and preoperative physiologic parameters were examined as independent variables, a longer preoperative high pressure zone, a larger preoperative maximum tolerable volume, and lower sensory threshold of the anal canal were associated with better postoperative defecatory function. Postoperative function score was found to be predictable using the following formula: 1.47 + 0.496 x high pressure zone (cm) + 0.007 x maximum tolerable volume (ml) - 0.247 x sensory threshold (mA) of the anal canal. CONCLUSION: Early postoperative defecatory function after low anterior resection is predictable from preoperative high pressure zone, maximum tolerable volume, and anal mucosal electrosensitivity.

Aged↗

Selective saccular plasticity under microgravity links peripheral transcriptomic remodeling to postflight vestibular dysfunction.

Long-duration exposure to microgravity disrupts human balance and spatial orientation, yet the molecular mechanisms underlying vestibular adaptation to spaceflight remain poorly understood. Here, we tested the hypothesis that the saccule, the primary gravity-sensing otolith organ, undergoes selective remodeling during spaceflight and contributes to transient postflight postural instability. Using a cross-species approach, we combined transcriptomic analysis of mouse otolith organs with physiological assessments in astronauts. Laser microdissection-based RNA sequencing of mouse otolith sensory epithelia after a 35-d spaceflight revealed pronounced, organ-specific transcriptomic remodeling in the saccule, whereas the utricle remained stable. Principal component and clustering analyses demonstrated that the saccular transcriptome shifted toward an utricle-like profile under microgravity, accompanied by changes in genes related to synaptic and neuronal function. Promoter motif analysis identified NFAT-associated transcriptional networks, suggesting Ca2+-dependent regulation of synaptic plasticity as a potential molecular substrate of gravity-dependent adaptation. In parallel, vestibular testing in astronauts following long-duration missions (157 to 328 d) revealed selective attenuation of saccule-mediated cervical vestibular-evoked myogenic potentials and increased postural sway immediately after return to Earth, while utricle-mediated responses and semicircular canal function were preserved. Both saccular function and postural stability recovered within approximately 10 d. Notably, early postflight postural instability was partially mitigated by noisy galvanic vestibular stimulation, consistent with stochastic resonance-mediated sensory enhancement. Together, these findings identify the saccule as a plastic gravity sensor and establish a mechanistic link between peripheral molecular remodeling and functional balance deficits after spaceflight, providing a framework for developing countermeasures to facilitate vestibular readaptation during human space exploration.

Animals↗

The proteome of Saccharomyces cerevisiae mitochondria.

We performed a comprehensive approach to determine the proteome of Saccharomyces cerevisiae mitochondria. The proteins of highly pure yeast mitochondria were separated by several independent methods and analyzed by tandem MS. From >20 million MS spectra, 750 different proteins were identified, indicating an involvement of mitochondria in numerous cellular processes. All known components of the oxidative phosphorylation machinery, the tricarboxylic acid cycle, and the stable mitochondria-encoded proteins were found. Based on the mitochondrial proteins described in the literature so far, we calculate that the identified proteins represent approximately 90% of all mitochondrial proteins. The function of a quarter of the identified proteins is unknown. The mitochondrial proteome will provide an important database for the analysis of new mitochondrial and mitochondria-associated functions and the characterization of mitochondrial diseases.

Citric Acid Cycle↗

The effect of comorbidity on self-assessed function in patients with a chronic rotator cuff tear.

BACKGROUND: The results of preoperative assessment of factors that might affect the outcome of orthopaedic surgery have rarely been studied. In this study, we evaluated the relationship between the number of medical comorbidities and the preoperative performance on outcome assessment tools in patients with a chronic rotator cuff tear. METHODS: One-hundred and ninety-nine patients (206 shoulders) with a chronic rotator cuff tear who were treated with surgery were evaluated preoperatively with a detailed history (including medical comorbidities), physical examination, and the following outcome instruments: (1) the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, (2) the Simple Shoulder Test, (3) visual analog scales (pain, function, and quality of life), and (4) the Short Form-36 (SF-36). RESULTS: The patients had a mean of 2.07 comorbidities (range, zero to seven comorbidities). With use of univariate regression analysis, a greater number of comorbidities was associated with worse function (DASH [p = 0.0064], Simple Shoulder Test [p = 0.0001 for the best-case scenario and p = 0.0009 for the worst-case scenario], and visual analog scale for function [p = 0.0003] and increased pain [p = 0.05]) and with worse general health status (physical function [p < 0.0001], role-physical [p = 0.0286], general health [p < 0.0001], vitality [p = 0.0014], social function [p = 0.0004], role-emotional [p = 0.0003], and visual analog scale for quality of life [p = 0.0102]). These results were confirmed with significant associations (p < 0.05) between the number of comorbidities and the scores on the Simple Shoulder Test; DASH questionnaire; visual analog scales for function, pain, and quality of life; and seven of the eight items (all but mental health) on the SF-36 in a multivariate regression analysis, which included age, gender, Workers' Compensation status, number of previous operations, smoking history, size of the tear, duration of symptoms, and average patient expectations as possible confounding variables. CONCLUSIONS: Medical comorbidities have a negative impact on patient-reported preoperative baseline pain, function, and general health status associated with chronic rotator cuff tears. We postulate that this effect may ultimately influence the evaluation of the results of surgical treatment of rotator cuff tears and should be considered when treating patients and analyzing outcomes.

Adult↗

Smoking, pulmonary function, and mortality.

The association of pulmonary function (as percent of predicted forced expiratory volume in 1 second [FEV1]) with total and cause-specific mortality over 15 to 18 years was investigated in a large cohort (5924) of prospectively followed Japanese-American men. Among those who never smoked, pulmonary function was found not to be significantly predictive of total mortality in a multivariate model in which adjustment for variables that might confound the results was made. Among past and current smokers, highly significant associations were found (P < 0.0001). The positive relationship of pulmonary function to mortality in smokers was so strong that it overshadowed these differences in nonsmokers in a model including all smoking groups combined, even after adjusting for smoking. A smoking-pulmonary function interaction term added to this model was statistically significant (P < 0.003). This illustrates the need for attention to the potential for complex interactions between biologic variables when carrying out multivariate statistical analysis. Findings for cardiovascular and noncardiovascular mortality were similar. This analysis indicates that while pulmonary function is associated with subsequent mortality, the relationship is significantly associated with smoking history.

Asian↗

The effect of aging on functional decline among older Japanese living in a community: a 5-year longitudinal data analysis.

BACKGROUND AND AIMS: Using longitudinal data analyses, we examined the effects of aging on functional decline, based on activities of daily living (ADL) and instrumental activities of daily living (IADL) during a 5-year follow-up among older people living in a community in Japan. METHODS: The baseline survey in July 1988 involved all elderly residents aged 60 or older in Saku City, Nagano, Japan (N=13418). All survivors of this cohort were asked to participate in follow-up surveys conducted in 1989, 1990, 1991, 1992 and 1993. Five items of ADL and five of IADL were measured on each survey. A generalized estimating equations (GEE) analysis was used to examine the effects of aging on the increase of the proportion of subjects with functional dependence. RESULTS: These results indicated that the proportion of subjects who were dependent in ADL increased during the 5-year period by 2.2 times (p<0.001) and the proportion of those who were dependent in either ADL or IADL increased during the same period by 1.8 times (p<0.001). Gender did not appear to be significantly associated with functional decline. CONCLUSIONS: The GEE analysis in this study identified the statistically significant effect of aging on the increase of the proportion of subjects with functional dependence based on ADL and IADL.

Activities of Daily Living↗

Persistence of psychiatric disorders in a cohort of HIV/AIDS patients in South Africa: a 6-month follow-up study.

BACKGROUND: Psychiatric disorders in HIV/AIDS are common, emerging soon after diagnosis or during the subsequent course of illness. However, there are few prospective studies on the rates of psychiatric disorders in HIV/AIDS, particularly in the context of the developing world. METHODS: Sixty-five patients with recently diagnosed HIV were interviewed on presentation to a hospital-based HIV clinic and then 6 months later. On both interviews, the patients were assessed using the MINI International Neuropsychiatric Interview, the Carver Brief COPE, and the Sheehan Disability Scale. Exposure to negative life events and risk behaviors was also evaluated. RESULTS: The overall prevalence of psychiatric disorders in the follow-up period remained high (56% of patients had at least one psychiatric disorder at baseline, and 48% of patients had at least one psychiatric disorder at 6 months). Depression and posttraumatic stress disorder (PTSD) were the most prevalent disorders at both baseline (34.9% and 14.8%) and follow-up (26% and 20%), respectively. More than half of all patients with depression at baseline improved (16 of 29; 55.1%). However, there was a new onset of both depression (4 of 49; 8.1%) and PTSD (12 of 17; 70.5%) on follow-up. In univariate analysis, depression on follow-up was significantly associated with: (a) disability in work/social/family functioning, (b) greater number of negative life events, and (c) a decline in CD4 lymphocyte count. Univariate analysis also revealed that a diagnosis of PTSD on follow-up was significantly associated with (a) a longer duration of infection and (b) baseline disability in work/social/family functioning. However, in multivariate analysis, only disability scores predicted the diagnoses of major depression and PTSD on follow-up assessment. Persistence of risky sexual behaviour was also noted, with a significantly higher number of participants reporting nonuse of condom on follow-up. There appeared to be a shift from maladaptive coping behaviors to more adaptive coping behaviors over the 6-month period. CONCLUSION: The rate of psychiatric disorders in HIV/AIDS patients was consistent over time. These findings emphasize the importance of regular evaluation for psychiatric disorders in HIV/AIDS patients, not only at the commencement of treatment but also during subsequent follow-up visits.

Acquired Immunodeficiency Syndrome↗

The quantitative analysis of uronic acid polymers by infrared spectroscopy.

I.r. absorption bands associated with the functional groups of carboxylic acid derivatives are useful for the analysis of alginates and pectins. The ester, amide, and uronate contents of pectins and the uronate content of alginates were determined, respectively, from the ester-carbonyl stretching band (1740 cm- minus 1), the amide I band (1650 cm- minus 1), and the carboxylate antisymmetric stretching band (1607 cm- minus 1) obtained from the spectra of solutions in D2O-phosphate buffer. The results are accurate to within plus or minus 2-4%, are self consistent, and agree well with the few reliable results that are available. The method should be applicable for the determination of carboxylic acid derivatives in other polysaccharides.

Alginates↗

Human growth hormone 1 (GH1) gene expression: complex haplotype-dependent influence of polymorphic variation in the proximal promoter and locus control region.

The proximal promoter region of the human pituitary expressed growth hormone (GH1) gene is highly polymorphic, containing at least 15 single nucleotide polymorphisms (SNPs). This variation is manifest in 40 different haplotypes, the high diversity being explicable in terms of gene conversion, recurrent mutation, and selection. Functional analysis showed that 12 haplotypes were associated with a significantly reduced level of reporter gene expression whereas 10 haplotypes were associated with a significantly increased level. The former tend to be more prevalent in the general population than the latter (p<0.01), possibly as a consequence of selection. Although individual SNPs contributed to promoter strength in a highly interactive and non-additive fashion, haplotype partitioning was successful in identifying six SNPs as major determinants of GH1 gene expression. The prediction and functional testing of hitherto unobserved super-maximal and sub-minimal promoter haplotypes was then used to test the efficacy of the haplotype partitioning approach. Electrophoretic mobility shift assays demonstrated that five SNP sites exhibit allele-specific protein binding. An association was noted between adult height and the mean in vitro expression value corresponding to an individual's GH1 promoter haplotype combination (p=0.028) although only 3.3% of the variance of adult height was found to be explicable by reference to this parameter. Three additional SNPs, identified within sites I and II of the upstream locus control region (LCR), were ascribed to three distinct LCR haplotypes. A series of LCR-GH1 proximal promoter constructs were used to demonstrate that 1) the LCR enhanced proximal promoter activity by up to 2.8-fold depending upon proximal promoter haplotype, and that 2) the activity of a given proximal promoter haplotype was also differentially enhanced by different LCR haplotypes. The genetic basis of inter-individual differences in GH1 gene expression thus appears to be extremely complex.

Adult↗

Predictors of defibrillation efficacy in patients undergoing epicardial defibrillator implantation. The Multicenter Pacemaker-Cardioverter-Defibrillator (PCD) Investigators Group.

OBJECTIVES: The objective of this study was to identify predictors of defibrillation threshold in patients undergoing epicardial defibrillator implantation. BACKGROUND: Factors that predict epicardial defibrillation efficacy are poorly defined. METHODS: The data from 375 consecutive adult patients were reviewed. After exclusion of 137 patients in whom defibrillation threshold was not obtained, 238 patients (32 women and 206 men) with a mean age of 58.9 +/- 13.3 years formed the study group. Coronary heart disease was present in 175 patients and the mean left ventricular ejection fraction was 35.8 +/- 15.4%. At device implantation, three epicardial patch sizes were available and shocks could be delivered over one current pathway (two patches) or over two current pathways (three patches with simultaneous or sequential shocks). Defibrillation threshold was defined as the lowest programmed energy that successfully defibrillated the heart, provided there had been an unsuccessful shock at a lower energy level or successful defibrillation at < or = 5 J. RESULTS: The mean defibrillation threshold was 8.6 +/- 5.3 J. With univariate analysis, female gender, sequential shocks with three patches, higher left ventricular ejection fraction and lower New York Heart Association functional class predicted a lower defibrillation threshold. In the multivariate analysis, female gender (coefficient -3.9; 95% confidence interval [CI] -1.9 to -5.0 J), ejection fraction (coefficient -0.6; CI -0.1 to -1.0 J/decile) and sequential shocks (coefficient -2.5; CI -1.0 to -4.0 J) were independently associated with a lower defibrillation threshold. Total epicardial patch conductive surface area normalized to body surface area reached borderline significance (coefficient 0.004; CI 0 to 0.01; p = 0.10). Antiarrhythmic drug use, including amiodarone, did not predict defibrillation threshold. CONCLUSIONS: Female gender, high left ventricular ejection fraction and the use of sequential pulse shocks were important determinants of improved defibrillation efficacy.

Aged↗

Prevalence and outcomes of anemia in geriatrics: a systematic review of the literature.

Anemia is a common concern in geriatric health, but its exact incidence and prevalence are unclear. Several studies have addressed this issue with discrepant results. Estimates of anemia prevalence reported in the articles reviewed here range from 2.9% to 61% in elderly men and from 3.3% to 41% in elderly women. This variability is related to a number of factors, including the setting of the study, the health status of the subject population, and the criteria used to define anemia. The criteria set by the World Health Organization (WHO)--hemoglobin level <120.0 g/L for women and <130.0 g/L for men--are most frequently, but not universally, used. Even so, their appropriateness in older populations may be questioned. Most existing reports indicate that elderly men have higher rates of anemia than do elderly women, but the threshold values are, in general, higher for men than for women. Incidence of anemia rises with age; some studies report a particularly notable increase in prevalence of anemia in the oldest subjects, those > or =85 years of age. Whereas anemia is associated with symptoms ranging from weakness and fatigue to increased falls and depression, and in severe cases can lead to congestive heart failure, few studies have systematically examined functional, clinical, and economic outcomes or patient satisfaction in the elderly with anemia. Future directions for research on anemia should include a more detailed examination of the importance of aging or age-related diseases on the pathogenesis of anemia, an assessment of the importance of anemia on outcomes such as physical function and cognitive function, and an analysis of whether impairments associated with anemia are amenable to correction by improving hemoglobin concentration.

Activities of Daily Living↗

Analysis of the Recalling Processes of Associative Memory by an Integral Representation of the Sign Function.

The recalling processes of associative memory proposed by Amari and Maginu are analyzed without any assumption on asymptotic distributions of noise using an integral representation of the sign function and by introducing extra variables. General procedures for calculating mean of direction cosine a(t) between a certain memory s(1) and the state x(t) at time t are developed and the exact formulas for E[a(t)] are obtained up to t = 3. It is shown explicitly that E[a(3)] involves non-Gaussian effects caused by some self-coherences. In an approximation of neglecting all the self-coherent effects, general formulas for E[a(t)] are obtained. Copyright 1996 Published by Elsevier Science Ltd

Journal Article↗

Negative consequences of hearing impairment in old age: a longitudinal analysis.

To determine whether functional and psychosocial outcomes associated with hearing impairment are a direct result or stem from prevalent comorbidity, we analyzed the impact of two levels of reported hearing impairment on health and psychosocial functioning one year later with adjustments for baseline chronic conditions. Physical functioning, mental health, and social functioning decreased in a dose-response pattern for those with progressive levels of hearing impairment compared with those reporting no impairment. Our results demonstrate an independent impact of hearing impairment on functional outcomes, reveal increasing problems with higher levels of impairment, and support the importance of preventing and treating this highly prevalent condition.

Activities of Daily Living↗

A pharmacological analysis of an associative learning task: 5-HT(1) to 5-HT(7) receptor subtypes function on a pavlovian/instrumental autoshaped memory.

Recent studies using both invertebrates and mammals have revealed that endogenous serotonin (5-hydroxytryptamine [5-HT]) modulates plasticity processes, including learning and memory. However, little is currently known about the mechanisms, loci, or time window of the actions of 5-HT. The aim of this review is to discuss some recent results on the effects of systemic administration of selective agonists and antagonists of 5-HT on associative learning in a Pavlovian/instrumental autoshaping (P/I-A) task in rats. The results indicate that pharmacological manipulation of 5-HT1-7 receptors or 5-HT reuptake sites might modulate memory consolidation, which is consistent with the emerging notion that 5-HT plays a key role in memory formation.

Animals↗

Cloning, functional organization, transcript studies, and phylogenetic analysis of the complete nitrogenase structural genes (nifHDK2) and associated genes in the archaeon Methanosarcina barkeri 227.

Determination of the nucleotide sequence of the nitrogenase structural genes (nifHDK2) from Methanosarcina barkeri 227 was completed in this study by cloning and sequencing a 2.7-kb BamHI fragment containing the 3' end of nifK2 and 1,390 bp of the nifE2-homologous genes. Open reading frame nifK2 is 1,371 bp long including the stop codon TAA and encodes a polypeptide of 456 amino acids. Phylogenetic analysis of the deduced amino acid sequences of the nifK2 and nifE2 gene products from M. barkeri showed that both genes cluster most closely with the corresponding nif-1 gene products from Clostridium pasteurianum, consistent with our previous analyses of nifH2 and nifD2. The nifE gene product is known to be homologous to that of nifD, and our analysis shows that the branching pattern for the nifE proteins resembles that for the nifD product (with the exception of vnfE from Azotobacter vinelandii), suggesting that a gene duplication occurred before the divergence of nitrogenases. Primer extension showed that nifH2 had a single transcription start site located 34 nucleotides upstream of the ATG translation start site for nifH2, and a sequence resembling the archaeal consensus promoter sequence [TTTA(A/T)ATA] was found 32 nucleotides upstream from that transcription start site. A tract of four T's, previously identified as a transcription termination site in archaea, was found immediately downstream of the nifK2 gene, and a potential promoter was located upstream of the nifE2 gene. Hybridization with nifH2 and nifDK2 probes with M. barkeri RNA revealed a 4.6-kb transcript from N2-grown cells, large enough to harbor nifHDK genes and their internal open reading frames, while no transcript was detected from NH4(+)-grown cells. These results support a model in which the nitrogenase structural genes in M. barkeri are cotranscribed in a single NH4(+)-repressed operon.

Base Sequence↗