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A similar pathway is used in Caenorhabditis elegans at multiple steps in development discount female cialis online american express menopause symptoms bleeding, including singling out to facilitate the signaling of transmembrane receptors of precursor cells involved in vulva differentiation (158) purchase female cialis us breast cancer hormone therapy. For the lin-12/Notch family, and human presenilins have been this purpose, two cells that are initially functionally identical shown to complement for Sel-12 function effectively (163). However, presenilin cleavage lin-12/Notch function causes an egg-laying defect that re- does not seem to be essential for functional activity, because sults from failure in vulva induction. Chapter 83: Molecular Genetics of Alzheimer Disease 1207 Proteins Interacting with PS is responsible for ensuring the proper folding of newly syn- thesized proteins (176,177). Presenilins have been found to interact directly with a vari- ety of proteins. Proteins interacting with presenilins include members of the catenin family (165–167). Catenins have ROLE OF APOLIPOPROTEIN E ISOFORMS IN at least two different functions in the cell. First, they are LATE-ONSET AD components of cell–cell adhesive junctions interacting with the cytoskeletal anchors of cadherin adhesion molecules. In addition to the deterministic genetic mutations found Second, there is compelling evidence that -catenin is a key in APP and presenilins, genetic factors modify the risk of effector in the Wingless/Wnt signaling cascade. The APOE gene on chromosome 19 is con- and its vertebrate counterpart Wnt signaling direct many sidered as an important risk factor for the development of crucial developmental decisions in Drosophila and verte- late-onset AD. These lipoproteins regulate plasma lipid -Catenin interact with the large loop of PS1 (165,166). Apo E has been implicated in the (15), which binds to the C-terminus of PS2. Calsenilin was transport of cholesterol and phospholipids for the repair, shown to interact with both PS1 and PS2 in cultured cells growth, and maintenance of membranes that occur during and could link presenilin function to pathways regulating development or after injury (178). Apo E is polymorphic and is encoded by three alleles Several other proteins have been identified that interact (APOE2,3,4) that differ in two amino acid positions. The with presenilins including the cytoskeletal proteins filamin most common isoform, E3, has a Cys residue at position and filamin homologue (168), -calpain (169), Rab11, a 112 and an Arg at position 158. The two variants contain small guanosine triphosphatase belonging to the p21 ras- either two Cys residues (E2) or two Arg residues (E4) at related superfamily (170), G-protein Go (171), and glyco- these positions. In general, it seems that E4 allele increases gen synthase kinase-3b (172). The presence of one or two E4 alleles is associated with earlier onset of dis- Apoptosis and Cell Death ease and an enhanced amyloid burden in brain, but it has There is increasing evidence of causal involvement of pre- little effect on the rate of progression of dementia (182). ALG3, a 103-residue C-terminal frag- Thus, homozygous E4/E4 subjects have an earlier onset ment of PS2, was isolated in death trap assay as rescuing (mean age less than 70 years) than heterozygous E4 subjects a T-cell hybridoma from T-cell receptor and Fas-induced (mean age of onset for E2/E3 is more than 90 years) (183). In PC12 cells, the down-regulation of PS2 The most obvious hypothesis is that APOE polymor- by antisense RNA protects the cells from glutamate toxicity. This hypothesis is supported by observations lation suggest that this C-terminal fragment of PS2 acts as that the subjects with one or more APOE4 alleles have a a dominant negative form of PS2. Expression of mutant higher amyloid burden than do subjects with no APOE4 alleles PS1 (L286V) in PC12 cells enhanced apoptosis on trophic (184). Second, there is evidence that both Apo E and A factor withdrawal or A toxicity (174). The alternative cas- may be cleared through the LRP receptor, and Apo E4 and pase cleavage in the C-terminal fragment of PS1 has been A peptide may compete for clearance through the LRP shown to abrogate the binding of PS1 to -catenin (167) receptor (179). Third, transgenic mice that overexpress APP and could therefore modulate the apoptotic outcome. The knock-in mutation was shown to influences the onset of AD in patients with DS and in those increase ER calcium mobilization and superoxide and mito- with APP mutations but not in families with presenilin mu- chondrial reactive oxygen species production leading to cas- tations (185–187). Evidence shows that mutant PS1 also renders cells less OTHER GENETIC RISK FACTORS IN AD efficient to respond to stress conditions in ER. Mutations in PS1 may increase vulnerability to ER stress by altering In addition to the APOE gene, which has been confirmed the unfolded protein response (UPR) signaling pathway that as a strong risk factor in various studies, polymorphisms in 1208 Neuropsychopharmacology: The Fifth Generation of Progress several other genes have been described to increase suscepti- in AD because of the very high prevalence of the APOE4 bility for AD. Most of these genetic polymorphisms are allele, even though APOE is only a risk factor for AD. These mutations in APP and PS, rare though late-onset AD and the presence of an exon 2 splice acceptor they are, give crucial insight into the molecular process un- deletion in the 2-macroglobulin (A2M) gene on the short derlying all forms of AD. Thus, the APP mutations clearly arm of chromosome 12 (188). Significantly, A2M binds to underscore critical role of APP in disease initiation. The PS a variety of proteins, including proteases (189,190) and A mutations implicate A , and particularly A 42, in disease. In addition, A2M is also present in senile A similar, crucial role for A in sporadic AD is supported plaques and can attenuate A fibrillogenesis and neurotox- by postmortem and tau studies. Moreover, A2M may, through LRP-mediated and A2M may also have their effects by interacting with endocytosis, allow the internalization and subsequent lyso- APP and A. It therefore seems likely that treatments that somal degradation of A (192). The tau are the actual cause of neuronal dysfunction and cogni- candidacy for these genes as AD loci awaits further testing tive decline. Therefore, abrogating deleterious effects of A and confirmatory studies in greater numbers of AD samples. Various cellular and molecular changes take place in the brain during normal REFERENCES aging, among which changes in glucose and energy metabo- lism are of pivotal significance (196). Biochem Biophys Res Commun 1984;120: membrane instability, and reduced energy availability are 885–890. Am J Pathol 1988;133: APP, thereby facilitating A synthesis intracellularly. In a general context, age may be consid- 52:487–501. Dramatic aggregation of related brain disorders such as sporadic dementia of the Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. Amyloid plaque AD has been reported to be in higher prevalence among core protein in Alzheimer disease and Down syndrome. There is evidence suggest- Natl Acad Sci USA 1985;82:4245–4249. Amyloid beta protein the brain (198,199), an antioxidant compound decreasing gene: cDNA, mRNA distribution, and genetic linkage near the the neuronal damage caused by oxidative stress (200,201), Alzheimer locus. Novel precursor tion of estrogen may contribute to developing AD. A new A4 amyloid mRNA contains a domain homologous to serine pro- CONCLUSIONS teinase inhibitors.

Some programs should also receive health counseling and should be referred have considered partner notifcation in a broader context order female cialis 10mg visa menopause chills, for other health services as appropriate 20mg female cialis sale menstruation low blood sugar. Prospective evaluations efectively decreases exposure to STDs and whether it reduces incorporating the assessment of venues, community structure, the incidence and prevalence of these infections in a com- and social and sexual contacts in conjunction with partner munity. Nevertheless, evaluations of partner notification notifcation eforts have improved case-fnding and illustrated interventions have documented the important contribution transmission networks (74,75). While such eforts are beyond this approach can make to case-fnding in clinical and com- the scope of individual clinicians, support of and collaboration munity contexts (65). When partners are treated, index patients with STD programs by clinicians are critical to the success of have reduced risk for reinfection. Terefore, providers should social network-based interventions. Further, tate partner notifcation (76), especially among MSM and providers can ask patients to bring partners with them when in cases where no other identifying information is available, returning for treatment. Time spent with index patients to and many health departments now conduct formal internet counsel them on the importance of notifying partners is associ- partner notifcation (IPN) (http://www. Clinical When patients diagnosed with chlamydia or gonorrhea providers are unlikely to participate directly in IPN. However, indicate that their partners are unlikely to seek evaluation and when discussing partner notifcation approaches with patients, 8 MMWR December 17, 2010 they should be aware of the value of the internet in this type pregnant women and treating those who are infected are of communication and should know where to refer patients vital not only to maintain the health of the patient, but to who are interested in using the internet to notify partners reduce perinatal transmission of HIV through available about their diagnosis. STD/HIV and acquired immunodefciency syndrome should be performed on any woman in labor who has an (AIDS) cases should be reported in accordance with state and undocumented HIV status unless she declines. Syphilis, gonorrhea, chlamydia, HIV test result is positive in these women, antiretroviral chancroid, HIV infection, and AIDS are reportable diseases in prophylaxis should be administered without waiting for every state. Because the requirements for reporting other STDs the results of the confrmatory test (78). Clinicians populations in which the amount of prenatal care deliv- who are unsure of state and local reporting requirements should ered is not optimal, rapid plasma reagin (RPR) card test seek advice from state or local health departments or STD screening (and treatment, if that test is reactive) should programs. In most jurisdictions, such reports are protected by statute Women who are at high risk for syphilis, live in areas from subpoena. Some states require all women to be screened at deliv- ery. Infants should not be discharged from the hospital unless the syphilis serologic status of the mother has Special Populations been determined at least one time during pregnancy and preferably again at delivery. Any woman who delivers a Pregnant Women stillborn infant should be tested for syphilis. Intrauterine or perinatally transmitted STDs can have • All pregnant women should be routinely tested for hepa- severely debilitating efects on pregnant women, their titis B surface antigen (HBsAg) during an early prenatal partners, and their fetuses. Women the possibility of perinatal infections, and provided access to who were not screened prenatally, those who engage in treatment, if needed. Screening should be conducted after the woman be retested at the time of admission to the hospital for is notifed that she will be screened for HIV as part of delivery. Pregnant women at risk for HBV infection the routine panel of prenatal tests, unless she declines also should be vaccinated. For women who decline HIV transient positive HBsAg result during the 21 days after testing, providers should address their objections, and vaccination, HBsAg testing should be performed before when appropriate, continue to encourage testing strongly. Testing including testing of initially reactive specimens with a Vol. When pregnant • Evidence does not support routine screening for women are tested for HBsAg at the time of admission Trichomonas vaginalis in asymptomatic pregnant women. Diagnostic Considerations) during the frst prenatal visit other Concerns (81). Women aged ≤25 years and those at increased risk for chlamydia (e. Women found and that timely and appropriate prophylaxis is provided to have chlamydial infection during the frst trimester for their infants. Screening during the pital in which delivery is planned and to the health-care frst trimester might prevent the adverse efects of chla- provider who will care for the newborn. In addition, mydia during pregnancy, but supportive evidence for household and sex contacts of women who are HBsAg such screening is lacking. Women aged <25 years are at high- should receive information regarding hepatitis B that est risk for gonorrhea infection. Other risk factors for addresses: gonorrhea include a previous gonorrhea infection, other – modes of transmission; STDs, new or multiple sex partners, inconsistent con- – perinatal concerns (e. Pregnant contraindicated); women found to have gonococcal infection during the – prevention of HBV transmission, including the frst trimester should be retested within approximately importance of postexposure prophylaxis for the new- 3–6 months, preferably in the third trimester. Uninfected born infant and hepatitis B vaccination for household pregnant women who remain at high risk for gonococ- contacts and sex partners; and cal infection also should be retested during the third – evaluation for and treatment of chronic HBV trimester. However, all women with Hepatitis C, Diagnostic Considerations) at the frst HCV infection should receive appropriate counseling and prenatal visit. Women at high risk include those with a supportive care as needed (see Hepatitis C, Prevention). Prophylactic cesarean delivery is not indicated for women who do not have active genital other Tests lesions at the time of delivery. Symptomatic women should references: Prenatal screening for HIV: A Review of the evidence be evaluated and treated (see Bacterial Vaginosis). Preventive Services Task Force (86); Revised 10 MMWR December 17, 2010 Recommendations for HIV Testing of Adults, Adolescents, and covered by the health plan (i. Pregnant Women in Health-Care Setting (77); Guidelines for In addition, federal laws obligate notices to benefciaries when Perinatal Care (87); Rapid HIV Antibody Testing During Labor claims are denied, including alerting consumers who need to and Delivery for Women of Unknown HIV Status: A Practical pay for care until the allowable deductable is reached. For STD Guide and Model Protocol (88); Viral Hepatitis in Pregnancy detection- and treatment-related care, an EOB or medical bill (89); Hepatitis B Virus: A Comprehensive Strategy for Eliminating that is received by a parent might disclose services provided Transmission in the United States — Recommendations of and list any laboratory tests performed. Tis type of mandated the Immunization Practices Advisory Committee (ACIP) (4); notifcation breeches confdentiality, and at a minimum, could Screening for Chlamydial Infection: U. Preventive Services Task prompt parents and guardians to question the costs and reasons Force Recommendation Statement (81); Canadian guidelines on for service provision. Preventive Services about sexual behaviors, assess STD risks, provide risk reduc- Task Force Recommendation Statement (85). Te screening recommendations in this oral, anal, or vaginal sex and drug-use behaviors). Screening Recommendations Adolescents Routine laboratory screening for common STDs is indi- In the United States, prevalence rates of many sexually cated for sexually active adolescents. Te following screening acquired infections are highest among adolescents (92,93). Factors on feasibility, efcacy, and cost-efectiveness.

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Hence buy 20mg female cialis womens health warner robins ga, rat PPI an exemplar for the application of modern molecular bio- models can identify antipsychotic effects only if a drug re- logical techniques to the generation and validation of animal verses the effects of a disruption in PPI produced by another models of psychiatric disorders cheap 20mg female cialis mastercard pregnancy symptoms. However, this genetically drug, a lesion, or a developmental manipulation such as related deficit in sensory gating does not extend to studies isolation rearing. In mice, however, it appears that antipsy- of sensorimotor gating as measured by PPI of the startle chotics improve PPI in mice that have not been manipulated response. Thus, mice in which the 7-nicotinic receptors (106). This important difference means that it may be easier have been deleted by genetic engineering exhibit normal to detect antipsychotic effects in mice, but also that it will levels of PPI (99). Nevertheless, other evidence indicates be much more difficult to demonstrate a reversal of a PPI that PPI is regulated by genetic factors. For example, strain- deficit produced by an experimental manipulation. More relevant to the recent indi- date gene approach, genetically modified mice have been cations that PPI deficits are evident in family members of used to test specific hypotheses of relevance to animal schizophrenia patients (101), Ellenbroek et al. For example, although most phar- pharmacogenetic selective breeding to produce strains of macologic evidence in rat had implicated the D2 subtype rats that were either sensitive (APO-SUS) or insensitive of the family of dopamine receptors in the PPI-disruptive (APO-UNSUS) to the effects of apomorphine on gnawing effects of dopamine agonists, gene knockout mice proved behavior. Within either a single generation or after many useful in testing this conclusion more definitively. Ralph et generations of selective breeding, APO-SUS rats and their al. Only the mice lacking the D2 subtype of logic substrates that regulate behavioral sensitivity to apo- receptor failed to show the normal effect of amphetamine morphine (presumably some feature related to dopamine- on PPI. Although knockout manipulations are confounded 698 Neuropsychopharmacology: The Fifth Generation of Progress by developmental adaptations, such a study takes advantage cal Center (MG); and the Veterans Administration National of the specificity that represents the fundamental strength Center for Schizophrenia (BM). Another model with relevance to the etiology and patho- 1. Psychopharmacology: the fourth 1 1 generation of progress. Prog Brain display exaggerated spontaneous locomotion and stereotypy Res 1986;65:259–270. In: estingly, preliminary studies indicate that some of these be- Judd LL, Groves PM, eds. Psychobiological foundations of clinical havioral abnormalities may be ameliorated with a single dose psychiatry. Stimulants: neurochemical, behavioral, and clinical per- of haloperidol or clozapine. Stimulant-induced psychosis: standing of the long-term effects of congenital NMDA- an evaluation of animal models. Nevertheless, its relevance to schizo- W, Sharman DF, et al. Essays in neurochemistry and neuro- phrenia may be questioned by the fact that no evidence has pharmacology. Amphetamine psychosis: a 'model' schizophrenia been found in schizophrenia for abnormalities in genes that mediated by catecholamines. Animal models with construct validity more, these animals, as would be expected, show no behav- for schizophrenia. Schizophrenic patients, on the other hand, exhibit a human and animal model studies. Startle habituation and sensorimotor gat- sure to a single dose of PCP (109) or ketamine (110). Disorders of attention and perception CONCLUSIONS in early schizophrenia. Sensorimotor gating and habituation evoked by electrocutaneous stimulation in Establishing the construct, etiologic, and predictive validity schizophrenia. Habituation of the is limited by the paucity of rigorous experimental data de- blink reflex in first-episode schizophrenia, psychotic depression rived from clinical studies. The major source of validation and non-psychotic depression. Impaired startle prepulse remains the ability of established antipsychotic drugs to inhibition and habituation in schizotypal patients. Am J Psychia- demonstrate efficacy, measured by broadly defined clinical try 1993;150:1862–1867. Startle-response measures of clinical subtypes, clinical course, and symptom-specific of information processing in animals: relevance to schizophre- nia. Animal models of human treatment effects that can be translated into relevant animal emotion and cognition. Washington, DC: APA Books, 1999: models are needed to overcome the limitations inherent in 103–116. The objective study of such measures in sensorimotor gating to study the pathophysiology and new treat- translational research is critical for the eventual identifica- ments of schizophrenia. Schizophrenia and tion of new antipsychotic treatments. Genetic correlation typical antipsychotics but also could help in the treatment of hippocampal auditory evoked response and alpha-bungaro- of the negative and cognitive symptoms that do not appear toxin binding in inbred mouse strains. Neuropsychopharmacoly to be treated adequately even by the newest generation of 1996;15:152–162. Disruption of latent inhibition atypical antipsychotics. Latent inhibition in ACKNOWLEDGMENTS drug-naı¨ve schizophrenics: relationship to duration of illness and dopamine D2 binding using SPET. This work was supported by National Institutes of Health 20. Latent inhibition (NIH) research grants DA02925 (MG), MH42228 (MG), in schizophrenia. Animal models of psychotic distur- the VISN 22 Mental Illness Research, Education, and Clini- bances. In: den Beor JA, Westenberg HGM, van Praag HM, Chapter 50: Animal Models Relevant to Schizophrenia Disorders 699 eds. Long-lasting psychotomimetic John Wiley and Sons, 1995:89–109. What are the functional consequences of neurocog- 1998;281:1349–1352. Cambridge, MA: MIT tioning and time-linked information processing is schizophre- Press, 1998. The effects of ties in the frontal system in schizophrenia: a magnetic resonance clozapine on symptom reduction, neurocognitive function, and imaging study. Neuropsychopharmacology 1996;15: tion of nicotinamide-adenine dinucleotide phosphate-diapho- 361–369. The reduced neuropil hy- phrenia: a review and meta-analysis. Schizophr Bull 1999;25: pothesis: a circuit-based model of schizophrenia.

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