A look into the future? Patients' and health care staff's perception and evaluation of genetic information and the right not to know.

The progress of medical genetics leads to a significant increase in genetic knowledge and a vast expansion of genetic diagnostics. However, it is still unknown how these changes will be integrated into medical practice and how they will change patients' and healthy persons' perception and evaluation of genetic diagnoses and genetic knowledge. Therefore, we carried out a comprehensive questionnaire survey with more than 500 patients, clients seeking genetic counseling, health care staff, and healthy persons (N = 523). The questionnaire survey covered detailed questions on the value of genetic diagnoses for the different groups of study participants, the right to know or not to know genetic diagnoses, possible differences between genetic and other medical diagnoses, and the practical use and implications of genetic knowledge with a special focus on hereditary neuropsychiatric diseases. A huge majority of the participants (90.7%) stated to have a right to learn every aspect of her or his genetic make-up. Similarly, study participants showed high interest (81.8%) in incidental health care findings-independent of whether the diseases are treatable or not. One can derive from the data outcome that study participants did not follow the implications of a "genetic exceptionalism" and often considered genetic findings as equivalent in relation to other medical diagnoses.

Genomic information and a person's right not to know: A closer look at variations in hypothetical informational preferences in a German sample.

In clinical practice and in research, there is an ongoing debate on how to return incidental and secondary findings of genetic tests to patients and research participants. Previous investigations have found that most of the people most of the time are in favor of full disclosure of results. Yet, the option to reject disclosure, based on the so-called right not to know, can be valuable especially for some vulnerable subgroups of recipients. In the present study we investigated variations in informational preferences in the context of genetic testing in a large and diverse German sample. This survey examined health care professionals, patients, participants of genetic counseling sessions and members of the general population (N = 518). Survey participants were assessed regarding their openness to learning about findings under various hypothetical scenarios, as well as their attitudes about the doctor-patient-relationship in a disclosure situation and about informational transfer to third parties. While the majority of participants wanted to learn about their findings, the extent of support of disclosure varied with features of the hypothetical diagnostic scenarios (e.g., controllability of disease; abstract vs. concrete scenario description) and demographic characteristics of the subjects. For example, subjects with higher levels of education were more selective with regards to the kind of information they want to receive than those with lower levels of education. We discuss implications of these findings for the debate about the right not to know and for the clinical practice of informed consent procedures.

Psychiatric comorbidity and additional abuse of drugs in maintenance treatment with L- and D,L-methadone.

Sixty D,L- or L-methadone treated patients in maintenance therapy were interviewed for additional drug abuse and psychiatric comorbidity; 51.7% of the entire population had a comorbid Axis-I disorder, with a higher prevalence in females (P=0.05). Comorbid patients tended to have higher abuse of benzodiazepines, alcohol, cannabis, and cocaine, but not of heroin. They had received a significantly lower D,L- (P<0.05) and L-methadone dose than non-comorbid subjects. The duration of maintenance treatment showed an inverse relationship to frequency of additional heroin intake (P<0.01). Patients with additional heroin intake over the past 30 days had been treated with a significantly lower L-methadone dosage (P<0.05) than patients without. Axis-I comorbidity appears to be decreased when relatively higher dosages of D,L- (and L-methadone) are administered; comorbid individuals, however, were on significantly lower dosages. Finally, L-, but not D,L-methadone seems to be more effective in reducing additional heroin abuse.

Follow-up of 180 alcoholic patients for up to 7 years after outpatient treatment: impact of alcohol deterrents on outcome.

OBJECTIVE: (1) To perform a 9-year study of abstinence, lapse, and relapse in 180 chronic alcoholic patients, participants of the Outpatient Longterm Intensive Therapy for Alcoholics (OLITA); (2) To investigate the role of supervised alcohol deterrents (AD) in relapse prevention and as an adjunct for maintenance of long-term abstinence. METHOD: This prospective open treatment study evaluates the long-term course of drinking outcomes and AD use of 180 chronic alcoholics consecutively admitted from 1993 to 2002. Subsamples are compared for (1) sham-AD versus verum-AD (disulfiram/calcium carbimide), (2) coped lapses versus finally detrimental lapses versus malignant relapses, and (3) AD use for 13 to 20 versus >20 months. RESULTS: In this 9-year study, the cumulative probability of not having relapsed was 0.52, and that of not having consumed any alcohol was 0.26. Despite long-term use, disulfiram/calcium carbimide was well tolerated. Patients on sham-AD (due to contraindications to verum-AD) showed higher cumulative abstinence probability than patients on verum (S = 0.86 vs. S = 0.49, p = 0.03). Detrimental lapses and malignant relapses occurred earlier than successfully coped lapses (p < 0.001); patients with detrimental lapse and with malignant relapse had fewer days of AD intake and less subsequent days without AD than patients with coped lapse (p < 0.001). The cumulative abstinence probability was S = 0.75 for patients with long-term intake compared with S = 0.50 for patients who stopped AD between months 13 and 20 (p < 0.001). CONCLUSIONS: An abstinence rate of >50% in this 9-year study strongly supports the concept of comprehensive, long-term outpatient treatment of alcoholics. Supervised, guided intake of AD, also over extended periods, can be used as a predominantly psychologically acting ingredient of successful alcoholism therapy.

Preserved vasopressin response to osmostimulation despite decreased basal vasopressin levels in long-term abstinent alcoholics.

BACKGROUND: Basal arginine vasopressin (AVP) plasma levels in alcoholic patients are persistently decreased over months of controlled alcohol abstinence. As a potential explanation of this phenomenon, a reduction of AVP immunoreactive neurons was described in the hypothalamus of alcohol-dependent humans and rodents. This study was therefore designed to examine whether long-term abstinent alcoholics have a compromised response of AVP to osmostimulation. METHODS: Fifteen male alcoholics, aged 42 +/- 2 years, were examined (1) over 12 months of strictly controlled abstinence (longitudinal study) and (2) during an osmostimulation test (5% NaCl infusion at 0.06 ml/kg/min over 2 hr) and were compared with 15 healthy male subjects, aged 41 +/- 2 years. AVP and routine laboratory parameters, including electrolytes and osmolality, were measured. RESULTS: Starting from lower basal concentrations, alcoholics showed increases similar to those of controls in AVP and plasma osmolality after osmostimulation. The first sensation of thirst was announced significantly later by alcoholics than by controls. Twenty-hour-posttest urine volume and sodium excretion were reduced in alcoholics compared with controls. CONCLUSIONS: Despite their persistently decreased basal AVP plasma levels, long-term abstinent alcoholics have a well preserved AVP response to osmostimulation. This finding indicates a peripheral suppression of AVP levels that is most likely due to a regulatory set-point shift toward hypotonic hyperhydration, rather than to a reduced central capacity of AVP secretion.

Substantial decrease of psychiatric comorbidity in chronic alcoholics upon integrated outpatient treatment - results of a prospective study.

It is far from clear how comorbidity changes during alcoholism treatment. This study investigates: (1) the course of comorbid Axis I disorders in chronic alcoholics over 2 years of controlled abstinence in the outpatient long-term intensive therapy for alcoholics (OLITA) and (2) the effect of comorbid Axis I and II disorders in this group of patients on subsequent drinking outcome over a four-year follow-up. This prospective treatment study evaluates psychiatric variables of 89 severely affected chronic alcohol dependent patients on admission (t(1)), month 6 (t(2)), 12 (t(3)) and 24 (t(4)). Drinking outcomes have been analyzed from 1998 to 2002. On admission, 61.8% of the patients met criteria for a comorbid Axis I disorder, 63.2% for a comorbid personality disorder. Axis I disorders remit from t(1) (59.0% ill), t(2) (38.5%), t(3) (28.2%) to t(4) (12.8%) (p < 0.0001). Anxiety disorders remit more slowly from t(1) (43.6%) to t(3) (20.5%, p = 0.0086), whereas mood disorders remit early between t(1) (23.1%) and t(2) (5.1%, p = 0.0387) with a slight transient increase at t(3) (10.3%). During the four-year follow-up, the cumulative probability of not having relapsed amounts to 0.59. Two predictors have a strong negative impact on abstinence probability: number of inpatient detoxifications (p = 0.0013) and personality disorders (p = 0.0106). The present study demonstrates a striking remission of comorbid Axis I disorders upon abstinence during comprehensive long-term outpatient alcoholism treatment. The presence of an Axis II rather than an Axis I disorder on admission strongly predicts drinking outcome over a four-year follow-up.

Therapeutic drug monitoring of mirtazapine and its metabolite desmethylmirtazapine by HPLC with fluorescence detection.

A selective and sensitive HPLC method is described for therapeutic drug monitoring of the antidepressant drug mirtazapine and its active metabolite desmethylmirtazapine. Liquid/solid extraction with C18 cartridges was used for cleanup of plasma samples. The chromatographic separation was carried out on a phenylhexyl column. No interference from other coadministered antidepressants has been observed in 234 samples from 184 patients. The calibration range used was from 1 ng/mL to 100 ng/mL. The analytic method has proven robust and well suited for therapeutic drug monitoring. In addition to qualitative and quantitative validation data for the assay method, concentration measurements in samples from patients on mirtazapine therapy and the relevant dosing information are presented. Median drug levels after a 15-mg dose were 37 ng/mL mirtazapine and 20 ng/mL desmethylmirtazapine. When a 60-mg dose was administered, median concentrations of 83 ng/mL mirtazapine and 65 ng/mL desmethylmirtazapine were found.

Persistent alterations of vasopressin and N-terminal proatrial natriuretic peptide plasma levels in long-term abstinent alcoholics.

BACKGROUND: During alcohol withdrawal and early abstinence, severe alterations of electrolyte and water homeostasis and their regulating hormones are well recognized. Almost nothing is known about regeneration of these functions with long-term abstinence. This cohort study was designed to monitor determinants of electrolyte and water balance over 280 days of abstinence in alcohol-dependent men compared with healthy controls. METHODS: Vasopressin (AVP), N-terminal proatrial natriuretic peptide, aldosterone, angiotensin II, and electrolytes, together with major parameters of kidney and liver function, were monitored in 35 male alcoholics aged 44 +/- 8 years. Of these, 21 could be followed up to 280 days of strictly controlled abstinence due to their participation in the Outpatient Long-Term Intensive Therapy for Alcoholics. The control group comprised 20 healthy male volunteers aged 39 +/- 7 years. RESULTS: Basal AVP levels were found to be suppressed over the whole study period. In contrast, N-terminal proatrial natriuretic peptide remained increased over all 280 days. No persistent alterations were found for aldosterone or angiotensin II. Sodium and potassium in plasma and urine returned to normal within a few weeks. Creatinine clearance, urea nitrogen in plasma and urine, urinary osmolality, hematocrit, and hemoglobin remained low as compared with controls over the entire study. CONCLUSIONS: Chronic alcohol abuse causes severe and persistent alterations in the hormonal regulatory systems of electrolyte and water balance. The suppressed basal secretion of AVP may reflect a dysregulation in the brain that influences the hypothalamic-pituitary-adrenal axis function, mood, memory, addiction behavior, and craving during alcohol abstinence. These findings may provide a ground for future therapeutic approaches to stable abstinence.

Erythropoietin therapy for acute stroke is both safe and beneficial.

BACKGROUND: Erythropoietin (EPO) and its receptor play a major role in embryonic brain, are weakly expressed in normal postnatal/adult brain and up-regulated upon metabolic stress. EPO protects neurons from hypoxic/ ischemic injury. The objective of this trial is to study the safety and efficacy of recombinant human EPO (rhEPO) for treatment of ischemic stroke in man. MATERIALS AND METHODS: The trial consisted of a safety part and an efficacy part. In the safety study, 13 patients received rhEPO intravenously (3.3 X 10(4) IU/50 ml/30 min) once daily for the first 3 days after stroke. In the double-blind randomized proof-of-concept trial, 40 patients received either rhEPO or saline. Inclusion criteria were age <80 years, ischemic stroke within the middle cerebral artery territory confirmed by diffusion-weighted MRI, symptom onset <8 hr before drug administration, and deficits on stroke scales. The study endpoints were functional outcome at day 30 (Barthel Index, modified Rankin scale), NIH and Scandinavian stroke scales, evolution of infarct size (sequential MRI evaluation using diffusion-weighted [DWI] and fluid-attenuated inversion recovery sequences [FLAIR]) and the damage marker S100ss. RESULTS: No safety concerns were identified. Cerebrospinal fluid EPO increased to 60-100 times that of nontreated patients, proving that intravenously administered rhEPO reaches the brain. In the efficacy trial, patients received rhEPO within 5 hr of onset of symptoms (median, range 2:40-7:55). Admission neurologic scores and serum S100beta concentrations were strong predictors ofoutcome. Analysis of covariance controlled for these two variables indicated that rhEPO treatment was associated with an improvement in follow-up and outcome scales. A strong trend for reduction in infarct size in rhEPO patients as compared to controls was observed by MRI. CONCLUSION: Intravenous high-dose rhEPO is well tolerated in acute ischemic stroke and associated with an improvement in clinical outcome at 1 month. A larger scale clinical trial is warranted.

Mortalidad y causa de muerte en adicciones / Mortality and cause of death in addictions

Se ha investigado la mortalidad y causas de muerte en un grupo de 2.631 pacientes adictos en el curso de 20 años. El pronóstico más favorable (definido por la abstinencia) es el de las adicciones por medicamentos, el peor, el de las adicciones a drogas ilegales. Todas las adicciones estudiadas (abuso y dependencia de alcohol, medicamentos y drogas ilegales) se asocian con un aumento de la mortalidad. El aumento de la mortalidad relativa es muy alto con las drogas ilegales, alto en el alcoholismo y bajo en pacientes adictos a medicamentos. La adicción combinada a alcohol y medicamentos se acompaña de un aumento moderado de la mortalidad, pero de una baja proporción de abstinencia. El aumento de la mortalidad es constante a través de los años. Este incremento es menor si se logra la abstinencia. Los accidentes (incluyendo intoxicaciones) y el suicidio son en todas las adicciones causas de muerte más frecuentes que en la población general

Dependencia a benzodiazepinas / Benzodiazepine dependency

En los últimos años se han puesto en duda las afirmaciones tradicionales sobre el bajo poder adictivo de las benzodiazepinas, sugiriéndose en cambio que el riesgo es mayor que lo previamente estimado, que para la producción de la adicción no es indispensable el uso del fármaco en grandes dosis por tiempo prolongado y que el fenómeno no se da sólo en sujetos proclives a hacerse dependientes. En el presente trabajo se mencionan algunas investigaciones que apoyan esta posición y la carencia de antecedentes suficientes que permitan suponer un potencial adictivo diferente entre diversas benzodiazepinas