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Providers should emphasize that PEP survivor also might increase the risk for HIV purchase 60 ml rogaine 2 free shipping prostate cancer radiation. Clinical man- the sexual abuse of children is frequently associated with mul- agement of the survivor should be implemented according to tiple episodes of assault and might result in mucosal trauma the following guidelines (78) discount 60 ml rogaine 2 mastercard prostate operation side effects. Specialist consultation on PEP (see Sexual Assault or Abuse of Children). Te sooner PEP reduced risk for acquiring HIV in a study of health-care work- is initiated after the exposure, the higher the likelihood that ers who had percutaneous exposures to HIV-infected blood it will prevent HIV transmission if HIV exposure occurred; (480). On the basis of these results and the results of animal however, distress after an assault also might prevent the survivor studies, PEP has been recommended for health-care workers from accurately weighing exposure risks and benefts of PEP who have occupational exposures to HIV (446). Tese fnd- and from making an informed decision to start such therapy. If HIV exposure has occurred, be ofered a 3–5-day supply of PEP, and a follow-up visit initiation of PEP as soon as possible after the exposure likely should be scheduled several days later to allow for additional increases beneft. Although a defnitive statement of beneft counseling. Te possible beneft §§ Hours of Sexual Assault of PEP in preventing HIV infection also should be discussed • Assess risk for HIV infection in the assailant. Implications of commonly encountered sexually trans- mitted (ST) or sexually associated (SA) infections for diagnosis and provide enough medication to last until the next return reporting of sexual abuse among infants and pre-pubertal children visit; reevaluate the survivor 3–7 days after initial assess- Evidence for ment and assess tolerance of medications. ST/SA confrmed sexual abuse Suggested action • If PEP is started, perform CBC and serum chemistry at † Gonorrhea* Diagnostic Report baseline (initiation of PEP should not be delayed, pend- Syphilis* Diagnostic Report† Human immunodefciency virus§ Diagnostic Report† ing results). Chlamydia trachomatis* Diagnostic Report† • Perform HIV antibody test at original assessment; repeat Trichomonas vaginalis Highly suspicious Report† at 6 weeks, 3 months, and 6 months. Condylomata acuminata Suspicious Report† (anogenital warts)* Genital herpes* Suspicious Report†¶ Sexual Assault or Abuse of Children Bacterial vaginosis Inconclusive Medical follow-up Recommendations in this report are limited to the identif- Source: Adapted from Kellogg N, American Academy of Pediatrics Committee on Child Abuse and Neglect. Te ¶ Unless there is a clear history of autoinoculation. Postnatally acquired gonorrhea; syphilis; ered if no conclusive explanation for nonsexual transmission and nontransfusion, nonperinatally acquired HIV are usually of an STD can be identifed. Sexual abuse should be suspected when genital herpes is diagnosed. Te investigation of sexual Reporting abuse among children who have an infection that could have All U. Although the exact requirements with recommendations by clinicians who have experience and difer by state, if a health-care provider has reasonable cause training in all elements of the evaluation of child abuse, neglect, to suspect child abuse, a report must be made. Te social signifcance of an infection that might providers should contact their state or local child-protection have been acquired sexually and the recommended action service agency regarding child-abuse reporting requirements regarding reporting of suspected child sexual abuse varies by in their states. In all Diseases cases in which an STD has been diagnosed in a child, eforts should be made to detect evidence of sexual abuse, including Examinations of children for sexual assault or abuse should conducting diagnostic testing for other commonly occurring be conducted in a manner designed to minimize pain and STDs (484–486). Collection of vaginal specimens in pre- Te general rule that sexually transmissible infections pubertal children can be very uncomfortable and should be beyond the neonatal period are evidence of sexual abuse has performed by an experienced clinician to avoid psychological exceptions. Te decision to obtain genital trachomatis among young children might be the result of or other specimens from a child to conduct an STD evaluation perinatally acquired infection and has, in some cases, persisted must be made on an individual basis. Genital warts have been diagnosed in place children at high-risk for STDs and constitute a strong children who have been sexually abused, but also in children indication for testing. BV • Te child has or has had symptoms or signs of an STD has been diagnosed in children who have been abused, but its or of an infection that can be sexually transmitted, even presence alone does not prove sexual abuse. In addition, most in the absence of suspicion of sexual abuse. Among the HBV infections in children result from household exposure signs that are associated with a confrmed STD diagnosis to persons who have chronic HBV infection. Cervical specimens are not rec- for other common STDs before the initiation of any treat- ommended for prepubertal girls. For boys with a urethral ment that could interfere with the diagnosis of those other discharge, a meatal specimen discharge is an adequate STDs. Because of the legal and psychosocial consequences substitute for an intraurethral swab specimen. Because of a false-positive diagnosis, only tests with high specifcities of the legal implications of a diagnosis of N. Te potential beneft to the child of a reliable infection in a child, if culture for the isolation of N. Gram stains are inadequate to ers with experience in the evaluation of sexually abused and evaluate prepubertal children for gonorrhea and should assaulted children. Specimens Te scheduling of an examination should depend on the from the vagina, urethra, pharynx, or rectum should be history of assault or abuse. If the initial exposure was recent, streaked onto selective media for isolation of N. A follow-up visit approximately involve diferent principles (e. Isolates should be preserved to a repeat physical examination and collection of additional enable additional or repeated testing.

A recent study examined interhemispheric connectivity in three groups cheap rogaine 2 60 ml overnight delivery mens health awareness month, 1) MDD discount rogaine 2 60 ml without prescription prostate function purpose, 2) bipolar depression and 3) healthy controls. The pathological groups could be distinguished from the healthy controls, but could not be distinguished from each other (Wang et al, 2015). However, in a recent functional (f)MRI study, MDD and bipolar depression patients “could be clearly distinguished” (from each other) “by changes in large-scale networks” (Goya-Maldonado et al, 2016). Cognition Cognition and residual depressive symptoms appear to be two independent sources of variation in the functioning of people with euthymic bipolar disorder (Roux et al, 2017). Treatment Mood stabilizing drugs (with which we attempt to clamp the mood in the euthymic position, neither too high nor too low) are central to the treatment of bipolar disorder. They include lithium carbonate, the anticonvulsants carbamazepine, sodium valproate, and lamotrigine, and some atypical antipsychotics, including olanzapine, quetiapine and perhaps others. Last modified: November, 2017 12 Antidepressants appear able to trigger manic swings in people with bipolar disorder. Thus, there is reluctance to treat bipolar depression with an antidepressant without first commencing a mood stabilizer. When treating bipolar depression, some experts (R M Post, personal communication) first add a second mood stabilizer. If there is little response, an antidepressant is then added. In patients known to have been catapulted into mania by antidepressants in the past, other choices include making the patient as comfortable as possible and waiting for natural resolution of the episode, or moving to TMS or ECT. The NMDAR antagonist, ketamine, has been administered intravenously for rapid remission of bipolar depression – apparently with good effect (Wohleb et al, 2016) – but more work is needed at this point in time. PERSISTENT DEPRESSIVE DISORDER There are no blood or other objective tests for the mental disorders. Objective tests would be particularly useful in the area between normal sadness and major depressive disorder. Persistent depressive disorder is diagnosed when some symptoms of MDD (but not sufficient for a diagnosis of MDD) have persisted for 2 years. This condition may represent a mild form of MDD, or incomplete remission from MDD. The prognosis of major depressive disorder is less than ideal; 30-50% of patients will still have substantial residual symptoms after adequate first-line treatment, and a poor outcome occurs in at least 25% of patients at 12-year follow-up (Surtees & Barkley, 1994). Personality is the constellation of behaviour/reactions which make us different from each other. Just as individuals differ in their capacity for honesty and generosity, so too, do they differ in their capacity for cheerfulness, optimism and energy. Those who by nature/make-up are at the low end of the cheerfulness scale may satisfy the diagnosis of persistent depressive disorder. Treatment Somewhat surprisingly, given that psychotherapy is said to be indicated in “mild to moderate depression”, psychotherapy as the sole treatment of persistent depressive disorder yields relatively poor results (Markowitz, 1994). Most are treated with a combination of an SSRI and cognitive-behaviour orientated therapy (to assist with self-esteem and adjustment). Last modified: November, 2017 13 HAMILTON DEPRESSION RATING SCALE Many different scales are used in the assessment of depression. The Hamilton Depression Rating Scale (HDRS, or HAM-D (D for depression); Hamilton also created an anxiety scale) has been widely used for more than 5 decades (Hamilton, 1960). The HDRS is not used to make a diagnosis, but to rate severity. A diagnosis must be made before the HDRS is applied. Serial ratings over time reflect change (hopefully, improvement). Because it relies on many vegetative symptoms, the HDRS is not applicable when there is a concurrent severe medical disorder. The original HDRS consisted of 21 items, however, shorter versions are available. Even though the HDRS is not used for diagnosis, many researchers have come to equate the 17-item score of 8, and the 6-item score of 4 with remission. To ensure subjects have at least moderate depression, many studies require a 17-item entry score 18. A COPY OF THE HDRS FOLLOWS THE REFERENCES MONTGOMERY ASBERG DEPRESSION RATING SCALE The Montgomery Asberg Depression Rating Scale (MADRS; Montgomery & Asberg 1979) is another important depression scale. It followed almost two decades after the HDRS, but has been widely used over the last quarter of a century. In contrast to the HDRS, the MADRS is less strongly focused on the somatic symptoms of depression, and more strongly on items such as concentration difficulties, tension, lassitude, pessimistic and suicidal thoughts. The initial hope was that being less focused on somatic symptoms, the MADRS would be more sensitive to change than the HDRS. COPIES OF THE HDRS AND MADRS FOLLOW THE REFERENCES Pridmore S. Last modified: November, 2017 14 References Afridi M, Hima M, Qureshi I, Hussain M.

Neuropsychological assessment of atten- 1738 Neuropsychopharmacology: The Fifth Generation of Progress tion problems in pathological gamblers rogaine 2 60 ml sale prostate 5 2. Gradients of mono- personality and pathological gambling discount 60 ml rogaine 2 prostate xray. J Gambling Behav 1989; amine metabolites and cortisol in cerebrospinal fluid of psychiat- 5:137–152. Tapping time influences con- and pathological gambling. Functional magnetic tiates impulsive from non impulsive violent behavior. Life Sci resonance imaging of human brain activation during cue- 1983;33:2609–2614. Relationship patients with affective and personality disorders: correlates with between subjective effects of cocaine and dopamine transporter suicidal and impulsive aggressive behavior. Trends Pharmacol Sci 1992;13: changes in Pachinko players: beta-endorphin, catecholamines, 177–184. Psychiatry Res (mCPP) interactions with neurotransmitter receptors in the 1981;4:21–29. Functional correlates of serotonin 5–HT1 recogni- onstration of monoamine oxidase B in brain astrocytes and sero- tion sites. Suicide attempts, ioural effects mediated by the 5HT1C receptor. Br J Pharmacol platelet monoamine oxidase and the average evoked response. Personality traits mCPP and TFMPP requires 5HT1C and 5HT1B receptors: and platelet MAO activity in alcohol and drug abusing teenage hypophagia induced by RU 24969 requires only 5HT1B recep- boys. Serotonergic responsivity and activity in sensation seekers. Ethanol like properties and bulimia patients and in healthy controls. Acta Psychiatr of the serotonergic partial agonist m-chlorophenylpiperazine in Scand 1990;81:73–77. Altered CSF 5–HIAA disposition in amine oxidase activity in pathological gambling. Variation in epineph- Arch Gen Psychiatry 1989;46:679–681. Miami Beach, FL: Society for Impact Study Commission: final report to Congress. Reinforcing effects of morphine mi- linked to a dysfunctional orbitofrontal cortex, revealed in alco- croinjection on to the ventral tegmental area. Society for Neuroscience Annual Con- chem Behav 1980;12:965–968. Drug abusers show one on thresholds of ventral tegmental electrical self-stimula- impaired performance in a laboratory test of decision making. Orbitofrontal cortex and alcoholics and normal controls. Psychiatry Res 1990;33: human drug abuse: functional imaging. Familial influences on gam- pathological gamblers, and normal controls: a negative report. Diazepam-binding inhibitor DSM-III-R drug abuse and dependence: a study of 3,372 twin and corticotropin-releasing hormone in cerebrospinal fluid. Lower CSF taurine levels in male patho- dopamine D2 receptor gene in pathological gambling. Evidence for striatal role of the dopamine D1 receptor gene in addictive behaviors. Genetic association tional Conference on Problem Gambling. Suggested minimal polymorphism at the D4 receptor gene. Pharmacogenetics 1997; effective dose of risperidone based on PET-measured D2 and 7:345–348. Conflict monitoring DNA polymorphism at the serotonin transpoter gene (5HTT) versus selection-for-action in anterior cingulate cortex. Limbic activation repeat polymorphism of the DRD4 gene in impulsive, compul- during cue-induced cocaine craving. Am J Psychiatry 1999;156: sive, addictive behaviors: Tourette syndrome, ADHD, patho- 11–18.

It is also possible to use gel electrophoresis to sepa- duction via GPCRs is the actual number of receptors present rate proteins according to relative charge order rogaine 2 60 ml amex man health report, a property that in target tissues and discount 60 ml rogaine 2 free shipping prostate yellow sperm, in particular, the number of receptors is modified predictably by certain modifications such as present in the plasma membrane of individual cells. These types of separation can be com- disturbances in the regulation of receptor number and/or bined in the use of two-dimensional gel electrophoresis, distribution may be of primary importance in the patho- 22: G-Protein–Coupled Receptors 283 physiology of certain neuropsychiatric disorders. For exam- which antibodies recognizing the native receptor are not ple, long-term administration of dopamine receptor antago- available. In either case the general scheme is as follows: nists can induce upregulation of specific receptors, which Cells or tissues expressing the receptor of interest are fixed may contribute to the apparent supersensitivity of dopamine using standard histologic methods. The fixed cells or tissue receptors associated with tardive dyskinesia (46). This phenomenon is termed bodies recognizing the receptor of interest. Studies using ra- tive epitopes in the specimen (typically several hours), the dioligand binding and subcellular fractionation techniques specimens are washed extensively to remove nonspecifically provided early evidence that multiple mechanisms are capa- associated antibodies. The directly visualizing the subcellular localization of GPCRs secondary antibody is typically coupled to a fluorochrome and for performing biochemical studies of specific receptor (such as fluorescein), a recognizable particle (such as colloi- trafficking mechanisms. GPCRs can be detected in situ in cell or tissue preparations using immunochemical techniques and receptor-specific an- Biochemical Methods to AssaySpecific tibodies. Antibodies that recognize the native receptor pro- Receptor Trafficking Processes tein can be used to examine the localization of endogenously expressed receptors, whereas epitope-tagging methods (see Whereas microscopic imaging can readily provide a great above) can be used to detect mutated versions of the receptor deal of qualitative information about GPCR localization protein or as a means to detect recombinant receptors for and trafficking, it can be quite challenging to quantitiate A B FIGURE 22. Visualization of HA epitope-tagged dopamine D1 receptors in transfected cells, using a fluorochrome-labeled secondary antibody and fluorescence microscopy. The ability of this receptortoundergoregulatedinternalizationis indicatedbythedopamine-inducedredistribution of immunoreactive receptors from the plasma membrane (visualized as linear staining at the cell periphery) to endocytic vesicles (visualized as punctate structures located throughout the cytoplasm). In addition to being extremely a specific subcellular localization or to measure accurately useful for examining posttranslational modifications of the rate or extent of specific trafficking processes. The im- GPCRs, in some cases it is possible to use these techniques portance of these processes has motivated the development to isolate receptor-containing complexes that presumably of biochemical methods for examining GPCR trafficking. The In addition to their utility for receptor localization, antibod- basic idea is to immunopurify a specific GPCR from cell ies specifically recognizing GPCRs facilitate biochemical or tissue extracts (or from a partially purified subcellular studies of GPCR trafficking using techniques adapted from fraction prepared from a cell or tissue lysate) using an anti- other areas of cell and molecular biology. For example, one body recognizing the native receptor or an engineered epi- method that has been extremely useful for quantitative stud- tope tag, and then to analyze proteins specifically associated ies of GPCR endocytosis is cell-surface biotinylation cou- with this complex using a different antibody. In general, pled with immunoprecipitation of receptors. Proteins pres- this is accomplished by immunoprecipitation of the receptor ent in the plasma membrane of cells can be specifically followed by analysis of associated proteins in the complex labeled by incubating intact cells in the presence of biotin by immunoblotting with the appropriate additional anti- coupled to an activated ester, which is membrane-imper- body. In some cases, the protein complexes are sufficiently meant and therefore forms a covalent bond only with ex- stable that they remain associated through the initial immu- posed amine moieties present in plasma membrane proteins. In other cases this is not true, In general, biotinylation in this manner does not adversely and the complexes dissociate before the receptor can be affect GPCR function, allowing biotinylation to be used as purified from the extract. In this case, various chemical a chemical tag for surface receptors. Using variations of this basic biochemistry, it is possi- teraction with heterotrimeric G proteins (52) and with - ble to measure a wide variety of membrane trafficking pro- arrestins (53), and to examine the regulation of these protein cesses. For example, internalization of GPCRs has been interactions by ligand-induced activation of the receptor. Recent studies provide strong support for this idea and, specifically, provide evidence for homo- and heterodimeri- Methods for Examining Specific Protein zation of individual GPCRs in vivo. This principle is per- Interactions Involved in GPCR Function haps best established for receptor tyrosine kinases, where it and Regulation is well established that oligomerization of receptors is re- A salient lesson emerging from recent cell biological studies quired for appropriate ligand-dependent signal transduction is that GPCR signal transduction can be viewed, in essence, (54). A relatively early hint that GPCRs may also undergo as a dynamically regulated network of protein–protein in- oligomerization came from studies of the 2-adrenergic re- teractions that occur in specific subcellular locations. There- ceptor using epitope-tagging techniques, where it was ob- fore, an important goal of current and future research is to served that receptors tagged with one epitope could specifi- define these critical protein interactions and elucidate their cally coimmunoprecipitate receptors tagged with a distinct temporal and spatial regulation in intact cells and tissues. More recently, evidence for oligomerization of many Coimmunoprecipitation Techniques to GPCRs has been reported. A particularly compelling exam- Examine Defined Protein Interactions ple of this is the recent observation that distinct subtypes with GPCRs in Intact Cells of GABA-B receptor hetero-oligomerize in cells, and that As discussed above, it is possible to rapidly purify GPCRs oligomerization is essential for the formation of recombi- from cell or tissue extracts using receptor-specific antibodies nant receptors possessing the functional properties charac- 22: G-Protein–Coupled Receptors 285 teristic of native GABA-B receptors observed in vivo interactions. A cDNA library prepared from a tissue of inter- (57,58). Both the bait and prey expressed opioid receptors (59). In a recently published study transcription of the reporter gene. However, if the fused (60), glutathione S-transferase (GST)-fusion proteins en- bait and prey polypeptides form a sufficiently stable pro- coding the C-terminal tail of the D5 receptor were shown tein–protein interaction, they bring their corresponding to interact with the GABA-A receptor present in rat hippo- DNA binding and transcriptional activation domains into campal extracts. Additionally, using an antibody recogniz- close proximity, thus reconstituting transcriptional activa- ing the dopamine D5 receptor, it was possible to coimmu- tion of the reporter gene. Transformed yeast cells containing noprecipitate the GABA-A receptor from cell extracts. In addition to known proteins that mediate and regulate Protein interactions suggested to occur by the yeast two- GPCR signaling (heterotrimeric G proteins, GRKs, ar- hybrid system can be examined using various in vitro bio- restins), which were originally identified by functional as- chemical techniques, such as affinity chromatography facili- says using biochemical purification, cDNA cloning meth- tated by GST-fusion proteins.

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