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Nicotine dependence (ND) is one of the worlds leading causes of preventable death. Nicotine addiction and other forms of drug addiction continue to be significant public health problems in the world. Evidence for a genetic influence on smoking behaviour and ND has prompted a search for susceptibility genes. Evidence has recently accumulated that single nucleotide polymorphisms (SNPs) in the genetic region encoding the nicotinic acetylcholine receptor (nAChR) subunits 6, 5, 3, and 4 are associated with smoking and ND. Brain nAChR are a heterogeneous family of ion channels expressed in the various parts of the brain. A number of studies suggest that brain nAChR are critical targets for the development of pharmacotherapy for nicotine and other drug addictions. In this review, we will discuss the nAChR subtypes, their function in response to endogenous brain transmitters, and how their functions are regulated in the presence of nicotine. Additionally, we will provide an overview of the three major pharmacotherapies for smoking cessation (which have demonstrated efficacy) such as: nicotine replacement therapy (NRT), bupropion, and varenicline. An appreciation of the complexity of nAChR and their regulation will be necessary for the development of nAChR modulators as potential pharmacotherapy for drug addiction. Prevention strategies should be tailored to carriers of SNPs located on chromosome 15q and that are strongly associated with nicotine dependence and risk of lung cancer.

Patients dying from primary intracranial malignancy are a potential source of organs for transplantation. However, a perceived risk of tumor transfer to the organ recipient has limited their use. We evaluated the risk of tumor transmission by reviewing the incidence in patients transplanted in the UK. Information from the UK Transplant Registry was combined with that from the national cancer registries of England, Wales and Northern Ireland to identify all organ donors between 1985 and 2001 inclusive with a primary intracranial malignancy and to identify the occurrence of posttransplant malignancy in the recipients of the organs transplanted. Of 11?799 organ donors in the study period, 179 were identified as having had a primary intracranial malignancy, including 33 with high-grade malignancy (24 grade IV gliomas and 9 medulloblastomas). A total of 448 recipients of 495 organs from 177 of these donors were identified. No transmission of donor intracranial malignancy occurred. Organs from patients dying from primary intracranial malignancy, including those with high-grade tumors, should be considered for transplantation and the small risk of tumor transmission should be balanced against the likely mortality for potential recipients who remain on the transplant waiting list.

We used high-throughput Western blotting to identify proteins that are up- or down-regulated by neuronal hypoxia in vitro. Exposure to hypoxia for 24 h produced ≥1.5-fold increases in the expression of 10/700 proteins (1.4%) and decreases in the expression of 16/700 proteins (2.3%). Up-regulated proteins included Arc, doublecortin/calmodulin kinase-like 1, integrin αv, and fibronectin; down-regulated proteins included nuclear autoantigenic sperm protein, protein kinase C–related kinase 2, and E2F transcription factor 1. The prominence of cytoskeleton-related proteins among those showing altered expression highlights the role of the cytoskeleton in neuronal responses to hypoxia.

The aim of this study is to design an effective hydrogel, which has good potential for application in the field of tissue regeneration. Ultimately, the polymeric biomaterial will be used as a bottom, non-cell adhering layer of a polymeric scaffold, which will inhibit the adhesion and proliferation of fibroblast cells. A series of terpolymer hydrogels were prepared from MMA/HPOEM/MePOEM monomers based on varying formulations. The gels were polymerized via free radical polymerization under UV and characterized by TGA, DSC and FTIR studies. Furthermore, the double bond conversion, gel content and swelling properties of the polymer were analyzed and correlated to its crosslinking density, which revealed details about the hydrogel’s character. Finally, cell culture experiments were used to compare the UV-cured polymer to its thermally derived non-functionalized polymer of the same formulation. Inverted optical microscopy was used to demonstrate cell-resistance of both materials with respect to a control Tissue Culture PolyStyrene plate. ©2003 Kluwer Acadamic Publishers

We describe an outbreak of Acinetobacter baumanniiin a neonatal intensive care unit (NICU), and our investigation to determine the source and mode of transmission and identify the population at risk. A case (infected infant) was defined as a patient hospitalized in the NICU during the outbreak period, with clinical signs of sepsis and isolation of A. baumannii. In colonized infants, A. baumanniiwas isolated from body surfaces without signs of infection. Infected infants were separated and treated by a different medical team. Cultures were taken from working surfaces and along the infant's admission passage from the delivery room to the NICU. The outbreak strain was identified by pulsed-field gel electrophoresis (PFGE). Nine cases and eight colonized infants met the definition criteria. Cases were younger than colonized infants with regard to gestational age and age of diagnosis and had lower birthweights (P<0.01). The outbreak strain was only isolated from hygroscopic bandages used on skin under the ventilation tube and umbilical catheters. Discontinuing the use of the bandages put an end to the outbreak. We conclude that a rapid and thorough investigation of the environment during an outbreak of A. baumanniiis essential to finding the source of the infection, and that hygroscopic bandages may be a source of such outbreaks.

We used cDNA microarray gene expression profiling to characterize the transcriptional response to exposure of cultured mouse cerebral cortical neurons to hypoxia for 24 hr. Of 11,200 genes examined, 1,405 (12.5%) were induced or repressed at least 1.5-fold, whereas 26 known genes were induced and 20 known genes were repressed at least 2.5-fold. The most strongly induced genes included genes coding for endoplasmic reticulum proteins (Ero1L/Giig11, Sac1p, Ddit3/Gadd153), proteins involved in ubiquitination (Arih2, P4hb), proteins induced by hypoxia in non-neuronal systems (Gpi1, Aldo1, Anxa2, Hig1), and proteins that might promote cell death (Gas5, Egr1, Ndr1, Vdac2). These findings reinforce the importance of endoplasmic reticulum-based mechanisms and of protein-ubiquitination pathways in the neuronal response to hypoxia.

ABSTRACTDistinctive international clones of penicillin-nonsusceptible and multidrug-resistant Streptococcus pneumoniaeare increasingly being reported. We investigated the spread of these clones in Canada through an active surveillance that was carried out at 11 Canadian pediatric tertiary care centers from 1991 to 1998. All penicillin-nonsusceptible isolates were serotyped, tested for antibiotic susceptibility, and genotyped by pulsed-field gel electrophoresis (PFGE) and random amplified polymorphic DNA (RAPD). Forty-five penicillin-nonsusceptible S. pneumoniaeisolates were evaluated. Eleven serotype 9V isolates and six serotype 14 isolates displayed identical RAPD and PFGE fingerprint profiles. Twelve (70%) of these isolates were encountered in Quebec. The 9V/14 clone and the Spanish-French clone had similar PFGE fingerprint patterns. Eight isolates of serotype 23F and two isolates of serogroup 14 had the same fingerprint profiles and displayed resistance to three or more antibiotic drug classes. This clone was first detected in Calgary (Alberta) and in 1996 appeared simultaneously in various regions of Canada. This clone showed a PFGE fingerprint pattern similar to that of the Spanish-U.S. 23F clone. Our data show the emergence across Canada of two international clones of penicillin-nonsusceptible S. pneumoniae: (i) serotypes 9V and 14 related to the Spanish-French clone and (ii) the 23F Spanish-U.S. clone. The source of the first clone was in Quebec and the second international clone was probably originated from the United States. The exact reasons for the successful spread of these clones within Canada and their contribution to increased resistance to antibiotics have yet to be explored.

We examined the relationship between CSF amyloid beta peptide (Aβ) concentration and AD severity in 31 probable AD patients and explored whether APOEgenotype modifies this relationship.

Negative Income Tax (NIT) research data is not conclusive as to large or small work decreases. This may be due to a structural, analytical bias. A Seattle- Denver project is used to analyze average work reactions. Findings indicate that a regular pattern can be found in NIT filers in any group: as that number increases, a decrease in labor supply also expands. Tables of alternative estimates of labor supply reactions are included.

Examines how the medical fraternity keeps the government from exposing the skeletons in doctors' closets. Congress set up National Practitioner Data Bank in 1986 to record cases of malpractice; American Medical Association (AMA) still lobbying very hard against public access to it.

BACKGROUND AND AIM: Reduction of serum sex steroid levels has been reported to occur after the administration of @b-adrenergic medication. In that @b-adrenergic blockade is a central pathophysiologic feature of asthma, this study was done to explore the possibility of hormonal alteration in asthma. METHODS: Sex steroids obtained from 22 postmenopausal asthmatic and 22 age-matched, postmenopausal, nonasthmatic women were assayed. No subject had received estrogens, progestins, or oral corticosteroids for 120 days before the study. RESULTS: Mean dehydroepiandrosterone sulfate (DHEAS; p < 0.002), dehydroepiandrosterone (DHEA; p < 0.03), estradiol (p < 0.02), and estrone (p < 0.02) levels were lower in asthmatic patients compared with nonasthmatic subjects. Results could not be accounted for by current medication. Patients with asthma demonstrated no decrease in 17-hydroxyprogesterone or cortisol compared with nonasthmatic subjects, limiting findings to the @D^5, and not the @D^4, steroidogenic pathway. In a second phase of the study, DHEAS was measured before and after 3 days of oral @b-agonist stimulation in eight postmenopausal asthmatic women. Serum DHEAS concentration increased in eight of eight subjects, from a mean of 28.6 +/- 19.9 @mg/dl (mean +/- SD) to 40.7 +/- 24.8 @mg/dl (p = 0.002). Serum cortisol concentration was unchanged. CONCLUSION: The results indicate that postmenopausal asthmatic women have lower serum levels of adrenally derived sex steroids than their nonasthmatic peers and that this anomaly may be ameliorated by adrenergic stimulation. (J ALLERGY CLIN IMMUNOL 1996;97:1-8.)

Exposure of C3H 10T1/2 Cl 8 cells, synchronized by release from confluence-induced arest of proliferation, to different concentrations of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 30 min at various points during the cell cycle causes dose-dependent toxicity (decrease in relative colony-forming efficiency or "survival") that increases linearly during the first G1 phase, reaches a maximum in early to middle S phase, and decreases during late S. In the course of the second S phase, toxicity again becomes maximal. The transformation rate (type III foci) increases and decreases with a similar pattern, increasing during the first G1 phase to a maximum during early S phase, subsequently decreasing, and then increasing again during the second S phase. Although periods of maximal toxicity and transformation roughly coincide with some portion of the S phase, the mechanisms underlying these phenomena appear to differ for the following reasons: (a) toxicity is linearly related to dose of MNNG, whereas the latter is linearly related to the logarithm of transformation rate, and (b) the ratio between toxicity and transformation varies with the cycle phase and the dose of MNNG.

An isotopic radiation source 125I was investigated for use in soft tissue radiaography, with particular attention to possible use in mammography for mass screening. Film sensitivities, exposure rates, absorbed doses, contrast and resolution were determined, and compared to conventional x-ray units. It was found that contrast and resolution were comparable to 30 kVp x-rays (W anode) but that surface absorbed dose was reduced by a factor of two with 125I. These results experimentally verified the advantage to be obtained from monoenergetic radiations, which had been predicted from theoretical considerations by others. Duration of exposure was estimated to be between 4 and 12 sec with a 40 Ci source. The 60-day half life of 125I may necessitate its use in conjunction with an image intensification system or electron radiographic techniques, in order to preclude source replacement at inconveniently short intervals.

Promoter and silencer elements of the immediate 5' flanking region of the gene coding for human factor VII were identified and characterized. The major transcription start site, designated as +1, was determined by RACE (rapid amplification of cDNA ends) analysis of human liver cDNA and was found to be located 50 bp upstream from the translation start site. Two minor transcription start sites were found at bp +32 bp and +37. Progressive deletions of the 5' flanking region were fused to the chloramphenicol acetyltransferase reporter gene and transient expression in HepG2 and HeLa cells was measured. Two promoter elements that were essential for hepatocyte-specific transcription were identified. The first site, FVIIP1, located at bp -19 to +1, functioned independently of orientation or position and contributed about one-third of the promoter activity of the factor VII gene. Electrophoretic mobility-shift, competition, and anti-hepatocyte nuclear factor 4 (HNF4) antibody supershift experiments demonstrated that this site contained an HNF-4 binding element homologous to the promoters in the genes coding for factor IX and factor X. The second site, FVIIP2, located at bp -50 to -26, also functioned independent of orientation or position and contributed about two thirds of the promoter activity in the gene for factor VII. Functional assays with mutant sequences demonstrated that a 10-bp G + C-rich core sequence which shares 90% sequence identity with the prothrombin gene enhancer was essential for the function of the second site. Mobility-shift and competition assays suggested that this site also binds hepatic-specific factors as well as the transcription factor Sp1. Two silencer elements located upstream of the promoter region spanning bp -130 to -103 (FVIIS1 site) and bp -202 to -130 (FVIIS2) were also identified by reporter gene assays.

The promoter for the gene coding for human protein C has been characterized as to nucleotide sequences that regulate the synthesis of mRNA. The major transcription start site was found 65 nucleotides upstream from the first intron/exon boundary along with two minor sites. Functional characterization of 1528 base pairs at the 5'-end of the gene was then carried out by chloramphenicol acetyltransferase reporter assays, protection from DNase I digestion, and electrophoretic mobility shift assays employing HepG2 and HeLa cells. One of the upstream regions (nucleotides -25 to +9) contained binding sites for at least two different transcription factors, including a hepatic nuclear factor 1-binding site (-10 to +9) and two overlapping and oppositely oriented hepatic nuclear factor 3-binding sites (-25 to -11). A second major region (PCE1) (+12 to +30) appeared to be a unique, liver-specific regulatory sequence. An Sp1-binding site in exon I (+58 to +65) was also recognized by cotransfection experiments with an Sp1 expression plasmid. Specific mutations in these promoter elements reduced transcriptional activity and abolished the binding of hepatic nuclear proteins. Finally, a strong silencer element (PCS1) (between -162 and -82) and two possible liver-specific enhancer regions (PCE2 and PCE3), which interact coordinately with the promoter elements, were also found (between -1462 and -162).

Article abstract—Both linkage and association studies provide strong evidence that a gene locus on chromosome 6 is involved in the expression of juvenile myoclonic epilepsy (JME), an adolescent-onset form of primary idiopathic generalized epilepsy (IGE). This epilepsy-related gene locus, designated EJM-1, may also influence the expression of other forms of IGE. We report here evidence that at least one form of epilepsy that is similar to JME—pure, adolescent-onset grand mal epilepsy in which the seizures occur at any time during waking—is not linked to the EJM-1locus. However, we also have evidence that another form of pure, adolescent-onset grand mal that occurs on awakeningis linked to the EJM-1locus and may be genetically the same as JME. This work suggests that clinically similar epileptic syndromes may have different genetic bases and underscores the critical importance of careful clinical observations in studying the genetics of the epilepsies.

The implication of highly-selective vancomycin usage on the outcome for infants with positive blood cultures for coagulase-negative staphylococci (CONS) was assessed retrospectively. The analysis was performed on partly prospective collected data from infants under 3 months of age with a least one CONS-positive blood culture in the neonatal intensive care unit at the Soroka University Medical Center between 1990 and 1996. During the study period, 239 episodes of CONS-positive blood cultures were identified from among 64,226 live births (3.7 per 1,000). Vancomycin was administered in 22 (9%) episodes, in all cases only after identification of the bacteria. The remaining 217 episodes were managed either without antibiotics or with continuation or initiation of empiric antibiotic therapy (usually ceftazidime±ampicillin) for suspected sepsis. Severity of the initial illness, subsequent morbidity and mortality were low regardless of the treatment administered. Only a single case of a blood-borne vancomycin resistant gram-positive organism was observed during the study period. The approach to CONS-positive blood cultures in neonates used here was associated with low morbidity and mortality. These findings support a policy of highly selective vancomycin usage in an era of emerging vancomycin resistance.

A diallel cross analysis of gum content in barley (Hordeum vulgare) was made using six cultivars of two-rowed spring barley as parents. A Jinks-Hayman analysis of F2 progeny means showed that gum content was controlled by a simple additive-dominance genetic system and that low gum content was strongly dominant. The analysis suggested that gum content was principally controlled by two or three genes showing a high degree of dominance. Some genotype-environment interaction was detected in a comparison between the F2 and F3 generations which were grown in different years and locations. However, the character was found to be highly heritable both within and between generations, suggesting that the selection and breeding of barleys of reduced gum content should not be difficult.

Autoimmune thyroid disease (AITD) is often familial and serological HLA disease associations have been described in many different populations. However, such HLA disease associations are weak and the precise molecular contribution of HLA antigens to thyroid disease susceptibility remains unknown. Much of the data available are cross-sectional and few studies have explored familial inheritance of AITD at the molecular level. We have, therefore, examined the inheritance of AITD in multiplex and multi-generational families using restriction fragment length polymorphism (RFLP) analysis of DNA digested with the restriction enzyme BamHl and probed with a full length human HLA-DQ beta cDNA probe. Thirty seven subjects in 7 informative families were available for study. Eleven subjects had Graves' disease and 4 were diagnosed as having Hashimoto's thyroiditis. Segregation of polymorphic fragments enabled genotyping of each individual to produce fully informative families. LOD scores were computed, using the LIPED program, for dominant and recessive models of inheritance, for recombination fractions of 0.01 to 0.5 for each sex, and for penetrances of 0.1 to 1.0. The results showed that maximum LOD scores were negative for all of the inheritance models tested. If the primary locus for AITD were in the HLA region, LOD scores would be highly positive. These data. therefore, provide strong evidence against a disease locus for AITD in linkage disequilibrium with the HLA-DQ beta locus.

To test the evolutionary conservation of DNA sequences specifying the developmentally regulated expression of the skeletal muscle actin gene, a recombinant plasmid containing the chicken skeletal muscle actin gene was introduced into rat myogenic cells. In a significant number of isolated clones, the accumulation of chicken actin mRNA increased greatly during differentiation. To test the expression in myogenic cells of a gene that is normally expressed during terminal differentiation of another tissue, rat myogenic cells were transfected with a mouse/human beta-globin chimeric gene. A decrease by a factor of 2-3 in the amount of globin mRNA during differentiation was observed in most clones in which the gene was expressed. The results indicate the conservation of the muscle-specific regulatory DNA sequences for more than 300 Myr.