Long-term upregulation of protein kinase A and adenylate cyclase levels in human smokers

Repeated injections of cocaine and morphine in laboratory rats cause a variety of molecular neuroadaptations in the cAMP signaling pathway in nucleus accumbens and ventral tegmental area. Here we report similar neuroadaptations in postmortem tissue from the brains of human smokers and former smokers. Activity levels of two major components of cAMP signaling, cAMP-dependent protein kinase A (PKA) and adenylate cyclase, were abnormally elevated in nucleus accumbens of smokers and in ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of the catalytic subunit of PKA were correspondingly higher in the ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of other candidate neuroadaptations, including glutamate receptor subunits, tyrosine hydroxylase, and other protein kinases, were within normal range. These findings extend our understanding of addiction-related neuroadaptations of cAMP signaling to tobacco smoking in human subjects and suggest that smoking-induced brain neuroadaptations can persist for significant periods in former smokers.     

Residents report on adverse events and their causes

BACKGROUND: Resident physicians are frontline providers with a unique vantage point from which to comment on patient safety-related events. METHODS: We surveyed trainees at 2 teaching hospitals about experiences with adverse events (AEs), mistakes, and near misses, as well as the potential causes. RESULTS: Responses were obtained from 821 (57%) of 1440 eligible trainees. Analysis was restricted to 689 clinical trainees. More than half (55%) reported ever caring for a patient who had an AE. The most common types of AEs were procedural and medication related. More than two thirds of AEs were considered significant. Of the most recent AEs, 24% were attributed to mistakes. The most common reasons for mistakes, as perceived by residents, were excessive work hours (19%), inadequate supervision (20%), and problems with handoffs (15%). In the last week, 114 respondents (18%) reported having a patient with an AE; of these, 42 (37%) reported AEs involving a mistake for which they considered themselves responsible. In addition, 141 (23%) reported near-miss incidents in the last week for which they considered themselves responsible. In multivariate analyses, significant predictors of AEs in the last week were inpatient rotation, duty hours in the last week, and procedural specialty. Predictors of near-miss errors in the last week were inpatient rotation, days of fatigue in the last month, and postgraduate year 1 status. CONCLUSIONS: These findings support the perception that AEs are commonly encountered by physicians and often associated with errors. Causes of errors in teaching hospitals appear to be multifactorial, and a variety of measures are necessary to improve safety. Eliciting residents' perspectives is important because residents may perceive events, actions, and causal relationships that medical record reviewers or observers cannot.     

Effect of dietary curcumin and dibenzoylmethane on formation of 7,12- dimethylbenz[a]anthracene-induced mammary tumors and lymphomas/leukemias in Sencar mice

Female Sencar mice (6 weeks old) were administered 1 mg of 7,12- dimethylbenz[a]anthracene (DMBA) by oral gavage once a week for 5 weeks. At 20 weeks after the first dose of DMBA, 68% of mice developed mammary tumors (the average 1.08 tumors per mouse) and 45% had lymphomas/leukemias. Feeding 1% dibenzoylmethane (DBM) in AIN 76A diet, starting at 2 weeks before the first dose of DMBA and continuing until the end of the experiment, inhibited both the multiplicity and incidence of DMBA-induced mammary tumor by 97%. The incidence of lymphomas/leukemias was completely inhibited by 1% DBM diet. In contrast, feeding 2% curcumin diet had little or no effect on the incidence of mammary tumors, and the incidence of lymphomas/leukemias was reduced by 53%.      

Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice

Missense mutations in the beta-amyloid precursor protein gene (APP) co- segregate with a small subset of autosomal dominant familial Alzheimer's disease (FAD) cases wherein deposition of the 39-43 amino acid beta-amyloid (A beta) peptide and neurodegeneration are principal neuropathological hallmarks. To accurately examine the effect of missense mutations on APP metabolism and A beta production in vivo, we have introduced yeast artificial chromosomes (YACs) containing the entire approximately 400 kbp human APP gene encoding APP harboring either the asparagine for lysine and leucine for methionine FAD substitution at codons 670 and 671 (APP(K670N/M671L)), the isoleucine for valine FAD substitution at codon 717 (APP(V7171)) or a combination of both substitutions into transgenic mice. We demonstrate that, relative to YAC transgenic mice expressing wild-type APP, high levels of A beta peptides are detected in the brains of YAC transgenic mice expressing human APP(K670N/M671L) that is associated with a concomitant diminution in the levels of apha-secretase-generated soluble APP derivatives. Moreover, the levels of longer A beta peptides (species terminating at amino acids 42/43) are elevated in YAC transgenic mice expressing human APP(V7171). These mice should prove valuable for detailed analysis of the in vivo effects of the APP FAD mutations in a variety of tissues and throughout aging and for testing therapeutic agents that specifically alter APP metabolism and A beta production.      

Transplants of fibroblasts genetically modified to express BDNF promote regeneration of adult rat rubrospinal axons and recovery of forelimb function

Adult mammalian CNS neurons do not normally regenerate their severed axons. This failure has been attributed to scar tissue and inhibitory molecules at the injury site that block the regenerating axons, a lack of trophic support for the axotomized neurons, and intrinsic neuronal changes that follow axotomy, including cell atrophy and death. We studied whether transplants of fibroblasts genetically engineered to produce brain-derived neurotrophic factor (BDNF) would promote rubrospinal tract (RST) regeneration in adult rats. Primary fibroblasts were modified by retroviral-mediated transfer of a DNA construct encoding the human BDNF gene, an internal ribosomal entry site, and a fusion gene of lacZ and neomycin resistance genes. The modified fibroblasts produce biologically active BDNF in vitro. These cells were grafted into a partial cervical hemisection cavity that completely interrupted one RST. One and two months after lesion and transplantation, RST regeneration was demonstrated with retrograde and anterograde tracing techniques. Retrograde tracing with fluorogold showed that approximately 7% of RST neurons regenerated axons at least three to four segments caudal to the transplants. Anterograde tracing with biotinylated dextran amine revealed that the RST axons regenerated through and around the transplants, grew for long distances within white matter caudal to the transplant, and terminated in spinal cord gray matter regions that are the normal targets of RST axons. Transplants of unmodified primary fibroblasts or Gelfoam alone did not elicit regeneration. Behavioral tests demonstrated that recipients of BDNF-producing fibroblasts showed significant recovery of forelimb usage, which was abolished by a second lesion that transected the regenerated axons.     

Spectrum of mutations in the fumarylacetoacetate hydrolase gene of tyrosinemia type 1 patients in northwestern Europe and Mediterranean countries

Hereditary tyrosinemia type 1 (HT1) is a rare metabolic disease caused by a deficient activity of the enzyme fumarylacetoacetase (FAH). To investigate the molecular heterogeneity of tyrosinemia, the geographic distribution and the genotype–phenotype relationship, we have analyzed the FAH genotype of 25 HT1 patients. Mutation screening was performed by PCR amplification of exons 1-14 of the FAH gene, followed by SSCP analysis and direct sequencing of the amplified exons. Fourteen different mutations were found, of which seven were novel, viz. Three missense mutations (G158D, P261L, F405H), a deletion of three nucleotides causing a deletion of serine (DEL366S) and three splice site mutations: IVS2+1(g-t), IVS6-1(g-c), IVS8-1(g-c). The splice site mutations IVS6-1(g-t) and IVS12+5(g-a) were frequently found in countries around the Mediterranean and northerwestern Europe, respectively. No clear correlation between the genotype and the three major HT1 subtypes could be established. Hum Mutat 12:19–26, 1998. © 1998 Wiley-Liss, Inc.     

Assessment of referral patterns for CT KUB in a tertiary setting

The purpose of this study was to assess the referral patterns and the use of unenhanced renal tract CT (CT KUB) for investigating patients presenting with clinically suspected renal colic. We retrospectively reviewed 500 consecutive CT KUB studies requested for suspected renal colic carried out at a single institution between December 2006 and July 2007. Follow‐up radiology reports and discharge summaries on the hospital clinical Intranet were also reviewed. Studies were analysed for characteristics including patient demographics, referring clinical team, time of referral, final diagnosis and requirement for further imaging. The majority of requests were from Emergency (ED) or Urology Departments (49%, 245 out of 500, and 37%, 186 out of 500, respectively). The positive rate for urolithiasis was 67% (337 out of 500), the negative rate was 25% (123 out of 500), and 8% (40 out of 500) of patients had alternative significant findings. Female patients were more likely to have a negative study than male patients (35 versus 20%, P < 0.0001) and more likely to have alternative significant pathology (12 versus 6%, P < 0.0001). Patients referred by specialities other than Urology and ED were more likely to be female and have a negative or alternative finding (P < 0.0001). CT KUB is a widely used first method of investigation for patients with suspected renal colic with a high positive predictive value allowing rapid diagnosis and intervention. However, given the high rate of negative or alternative findings on CT KUB in young women, especially those referred by specialities other than ED or Urology, ultrasound should be considered as an alternative imaging method to minimise unnecessary radiation exposure.     

Ureaplasma Urealyticum or Mycoplasma Hominis Infections and Semen Quality of Infertile Men in Abidjan

Objective To determine the prevalence of U. urealyticum and M. hominis in semen samples collected from men admitted in clinic for infertility, and to compare the quality of these semen samples.
Methods A total of 1 058 semen samples collected were investigated. Sperm semiological assays were performed according to the guidelines of the World Health Organisation （WHO）. Semen were examined by Mycoplasma IST for the detection of mycoplasma. Semen culture on agar media was used to detect other microorganisms. Chlamydia was detected using direct fluorescent assay （DFA） of Clamydia Trachomatis.
Results Among 1 058 semen samples, microorganisms were detected in 638 （60.3%）. The infected sperms consisted of mycoplasma alone in 507 cases （47.9%）, mycoplasma and other microorganisms in 98 （9.3%）, giving in all 605 （57.2%） samples infected with mycoplasma. The last 33 （3.1%） consisted of other microorganisms alone. The frequency of U. urealyticum, M. hominis and mixed genital infections detected in semen samples of infertile men were 39%, 23.8% and 5.6%, respectively. The rates of abnormal semen parameters recorded among patients infected with mycoplasma were for volume （22.2%-25%）, viscosity （29.6%-43.5%）, pH （64.7%-72.9%）, motility （80.8%-93.8%）, morphology （36.3%-47.9%）, sperm concentration （53.3%-58.3%） and leukocyte count （51.4%-58.3%）.
Conclusion Frequency of U. urealyticum infection was higher than that of M. hominis. Mycoplasma infections were associated with disorders of pH, motility and sperm concentration. In addition M. hominis infection affected spermatozoa morphology. Therefore, screening of U. urealyticum clinically relevant in Abidjan. and M. hominis for routine semen analysis is     

A single measure of FEV1 is associated with risk of asthma attacks in long-term follow-up

BACKGROUND: Clinical practice guidelines for asthma care emphasize the use of objective measures of asthma severity, and yet little data exist on the relationship between FEV(1) and asthma outcomes over long-term follow-up. METHODS: We explored the association between measures of FEV(1) percentage of predicted (FEV(1)% predicted) and subsequent asthma attacks over 3-year intervals. Subjects were identified from two longitudinal cohort studies conducted in the United States and the Netherlands. Persons were included in the analysis if they reported ever having an attack of wheezing with associated shortness of breath prior to or during the follow-up period. RESULTS: Over the course of longitudinal follow-up at 3-year intervals, 195 subjects in the Netherlands cohort contributed 510 observations, and 698 subjects in the US cohort contributed 1,268 observations (for each observation, the report of an attack since their last visit was paired with the subject's FEV(1) recorded 3 years prior). Overall, subjects in the Netherlands cohort experienced 114 attacks (22% of the observations) and subjects in the US cohort had 517 attacks (40.6% of the observations). FEV(1)% predicted was significantly associated with risk of an asthma attack over the 3 years following its measurement. After adjusting for current smoking and gender, FEV1% predicted remained an independent predictor of subsequent asthma attacks. CONCLUSIONS: These findings support the use of spirometry as an objective measure of asthma severity and risk of adverse outcomes.