A paradigm for single nucleotide polymorphism analysis: the case of the acetylcholinesterase gene

Acetylcholinesterase (AChE) plays a crucial physiological role in termination of impulse transmission at cholinergic synapses through rapid hydrolysis of acetylcholine. It is a highly conserved molecule, and only a few naturally occurring genetic polymorphisms have been reported in the human gene. The goal of the present study was to make a systematic effort to identify natural single nucleotide polymorphisms (SNPs) in the human ACHE gene. To this end, the genomic coding sequences for acetylcholinesterase of 96 unrelated control individuals from three distinct ethnic groups were analyzed. A total of 13 ACHE SNPs were identified, 10 of which are newly described, and five that should produce amino acid substitutions [c.101G>A (p.Arg34Gln), c.169G>A (p.Gly57Arg), c.1031A>G (p.Glu344Gly), c.1057C>A (p.His353Asn), and c.1775C>G (p.Pro592Arg)]. Population frequencies of 11 of the 13 SNPs were established in four different populations: African Americans, Ashkenazi Jews, Sephardic Jews, and Israeli Arabs; 15 haplotypes and five ethnospecific alleles were identified. The low number of SNPs identified until now in the ACHE gene is ascribed to technical hurdles arising from the high GC content and the presence of numerous repeat sequences, and does not reflect its intrinsic heterozygosity. Among the SNPs resulting in an amino acid substitution, three are within the mature protein, mapping on its external surface: they are thus unlikely to affect its catalytic properties, yet could have antigenic consequences or affect putative protein-protein interactions. Furthermore, the newly identified SNPs open the door to a study of the possible association of AChE with deleterious phenotypes-such as adverse drug responses to AChE inhibitors employed in treatment of Alzheimer patients and hypersensitivity to pesticides.     

Permanent Cardiac Pacing in Octogenarians

A significant percentage of patients in need of a permanent pacemaker are older than 80 years. The implantation policy may be determined either by the patient's physical activity or by chronologic age. The trend in pacemaker implantation in patients over 80 during the last 10 years in our institution was evaluated and compared with the trend in the patients younger than 80 at the time of implantation. Of 519 patients who had primary pacemaker implantation, 152 (29%) were older than 80 at the time of the procedure. Another 189 patients had second implantation procedures, and 80% of them were older than 80 years. Complete atrioventricular block was the indication for pacing in 44 ?+/- 11% and sick sinus syndrome in 25 ?+/- 7%. The tendency to implant dual-chamber pacemakers increased from 0% during 1985 to 76% in 1994, including 69% DDD and 31% DDDR, but the transition was faster in the younger group. By 1994, there was no difference in the incidence of advanced pacing systems in the 2 age groups. During 1985, only VVI pacemakers were replaced, and during 1994, less than 10% were replaced with simple ventricular pacing units. Pacing system upgrading was frequent during the second half of the decade. The success and complication rate of implantation did not differ in the 2 groups.     

The validity of DSM-IV alcohol abuse: drunk drivers versus all others

OBJECTIVE: Prior research in a community sample indicated that almost half the individuals receiving a diagnosis of DSM-IV alcohol abuse did so on the basis of only one symptom, driving after drinking too much. While this is certainly unwise behavior, it may not be a psychiatric disorder. Therefore, we investigated the differential validity of this subgroup of abuse cases by testing the association of a set of external validating criterion variables with three groups: those who met criteria for abuse just for drinking-driving, those who met criteria by other means and those with no alcohol diagnosis. Present status of past cases of abuse was also investigated. METHOD: Subjects were 22,204 U.S. household residents (a subset of a national probability sample) interviewed in 1992 with the Alcohol Use Disorders and Associated Disabilities Interview Schedule. The generalized logit model was the principal means of analysis. RESULTS: Subjects who met criteria for DSM-IV alcohol abuse just for drinking-driving differed from subjects with no diagnosis on about half the variables tested, while those who met criteria for abuse in other ways differed from subjects with no diagnosis on all variables tested. The two abuse groups differed from each other on some but not all variables. Past cases of abuse for drinking-driving and past cases of other abuse were equally likely to have remitted in the last 12 months, and slightly less likely to meet criteria for current dependence. CONCLUSIONS: Further conceptual and empirical work is needed to resolve the difficulties with the DSM-IV alcohol abuse category.     

The Spanish Alcohol Use Disorder and Associated Disabilities Interview Schedule (AUDADIS): reliability and concordance with clinical diagnoses in a Hispanic population

OBJECTIVE: The study reports the process of translation into Spanish and adaptation to the Hispanic culture of the Alcohol Use Disorder and Associated Disabilities Schedule (AUDADIS). This instrument is a structured diagnostic interview schedule specifically developed for the assessment of substance-related disorders and their comorbid disorders and disabilities. METHOD: A random sample (N = 169) of adults from a primary health care clinic in Puerto Rico was selected. The test-retest reliability of the instrument was examined across time and across interviewers, and the validity was assessed by comparing computer-derived diagnoses obtained through the administration of lay interviewers with best estimate diagnoses given by board-certified psychiatrists. RESULTS: For most diagnoses and symptoms studied, as well as for most of the alcohol consumption measures, the test-retest reliability of the Spanish AUDADIS was consistent with results reported in other national and international studies using this instrument. Good to excellent test-retest reliability was obtained for the diagnoses of alcohol dependence and major depression. Similarly, good to excellent agreement was obtained between the lay administered AUDADIS and best estimate diagnoses for most diagnostic categories, with the exception of dysthymia. As in other studies, the reliability and validity of the substance abuse category was poor. When agreement for this category was estimated independent of lifetime dependence, both the reliability and validity coefficients were considerably improved. CONCLUSIONS: The Spanish AUDADIS generally demonstrates good to excellent levels of reliability and validity that are comparable to findings reported for this instrument in other national and international studies.     

DSM-IV alcohol abuse: investigation in a sample of at-risk drinkers in the community

OBJECTIVE: Although a category for alcohol abuse has been included in the major nomenclatures since DSM-III, many questions have been raised about the definitions and validity of this category. METHOD: We investigated DSM-IV alcohol abuse in 628 at-risk drinkers residing in households who never met criteria for DSM-IV alcohol dependence at the time of a baseline interview. Cross-sectional and prospective longitudinal information were used. RESULTS: Subjects most often met criteria for abuse with the single criterion, recurrent hazardous use (usually driving after drinking too much, on average 4.5 times per year). Younger and white subjects were more likely to receive the abuse diagnosis at baseline, as were drug users and those who drank five or more drinks per occasion frequently. Very few subjects received a diagnosis of DSM-IV alcohol dependence at follow-up, and those who did were equally likely to come from the abuse and non-abuse baseline groups. A current abuse diagnosis at baseline strongly and significantly predicted an abuse diagnosis at follow-up, although a past-only (remitted) abuse diagnosis at baseline was not clearly predictive of abuse at follow-up. CONCLUSIONS: The DSM-IV alcohol abuse category has some predictive validity. However, given the manner in which respondents met criteria for the disorder, its merits as a diagnostic category remain in question. Researchers should be cautious about combining alcohol dependence and abuse into the same category.     

When acute-stage psychosis and substance use co-occur: differentiating substance-induced and primary psychotic disorders

Substances such as alcohol, cocaine, amphetamine, and cannabis can produce psychotic reactions in individuals who are otherwise free of serious mental illness. However, persons with primary psychotic disorders, such as schizophrenia and bipolar disorder, who use these substances often present for treatment with signs and symptoms similar to those whose psychosis resulted from the use of drugs alone. While it is often difficult to distinguish substance-induced from primary psychoses, especially early in the course of treatment, this differential diagnosis has important implications for treatment planning. To help clinicians distinguish these two types of presentations, the authors first review the types of psychotic symptoms that can co-occur with substance use. They discuss the prevalence and patterns of substance use that have been found in patients with schizophrenia and other primary psychotic disorders and review the negative outcomes associated with substance use in this population. The prevalence of and types of symptoms and problems associated with psychotic symptoms that occur as a result of substance use alone are also reviewed. The authors describe assessment procedures for differentiating substance-induced and primary psychotic disorders. They stress the importance of accurately establishing the temporal relationship between the substance use and the onset and continuation of psychotic symptoms in making a differential diagnosis, as well as the importance of being familiar with the types of psychological symptoms that can occur with specific substances. The authors review the utility and limitations of a number of diagnostic instruments for assessing patients with co-occurring psychosis and substance use problems, including The Addiction Severity Index, The Michigan Alcohol Screening Test, and diagnostic interviews such as the Schedule for Affective Disorders and Schizophrenia and the Structured Clinical Interview for DSM. They then discuss the Psychiatric Research Interview for Substance and Mental Disorders (PRISM), an instrument that has been developed to address the lack of a diagnostic interview that is suitable for assessing the comorbidity of substance use and psychiatric disorders. The article concludes with a discussion of the importance of an appropriate match between diagnosis and treatment and the current state of our knowledge concerning the most appropriate types of treatment interventions for patients with substance-induced psychosis and those with dual diagnoses.     

Assessment of specific drug disorders in a sample of substance abuse patients: a comparison of the DIS and the SADS-L procedures

Both the DIS and the SADS-L interviews offer researchers a procedure for assessing the presence of drug disorders categorized by drug class, as defined by psychiatric nomenclatures. In this study, the performance of the drug section of each interview was compared in a sample of hospitalized substance abuse patients. The classes of drug disorders assessed by both instruments and reported here include narcotics, amphetamines, sedatives and tranquilizers, cannabis, cocaine, and hallucinogens. On a group level, the DIS and SADS-L agreed fairly well for all drug classes except hallucinogens. A within-DIS comparison of DSM-III and Research Diagnostic Criteria (RDC) diagnoses followed the same pattern, except with higher agreement. Distinctions between drug abuse and dependence within a drug class were not as reliable as overall assessments. On only a small proportion of patients did the instruments agree completely for all drug classes within an individual. Implications of the findings for research on drug problems are discussed.     

Real-Time Monitoring of High-Intensity Focused Ultrasound Thermal Therapy Using the Manifold Learning Method

High-intensity focused ultrasound (HIFU) induces thermal lesions by increasing the tissue temperature in a tight focal region. The main ultrasound imaging techniques currently used to monitor HIFU treatment are standard pulse-echo B-mode ultrasound imaging, ultrasound temperature estimation and elastography-based methods. The present study was carried out on ex vivo animal tissue samples, in which backscattered radiofrequency (RF) signals were acquired in real time at time instances before, during and after HIFU treatment. The manifold learning algorithm, a non-linear dimensionality reduction method, was applied to RF signals which construct B-mode images to detect the HIFU-induced changes among the image frames obtained during HIFU treatment. In this approach, the embedded non-linear information in the region of interest of sequential images is represented in a 2-D manifold with the Isomap algorithm, and each image is depicted as a point on the reconstructed manifold. Four distinct regions are chosen in the manifold corresponding to the four phases of HIFU treatment (before HIFU treatment, during HIFU treatment, immediately after HIFU treatment and 10-min after HIFU treatment). It was found that disorganization of the points is achieved by increasing the acoustic power, and if the thermal lesion has been formed, the regions of points related to pre- and post-HIFU significantly differ. Moreover, the manifold embedding was repeated on 2-D moving windows in RF data envelopes related to pre- and post-HIFU exposure data frames. It was concluded that if mean values of the points related to pre- and post-exposure frames in the reconstructed manifold are estimated, and if the Euclidean distance between these two mean values is calculated and the sliding window is moved and this procedure is repeated for the whole image, a new image based on the Euclidean distance can be formed in which the HIFU thermal lesion is detectable.