Neural and computational mechanisms of postponed decisions

We consider the mechanisms that enable decisions to be postponed for a period after the evidence has been provided. Using an information theoretic approach, we show that information about the forthcoming action becomes available from the activity of neurons in the medial premotor cortex in a sequential decision-making task after the second stimulus is applied, providing the information for a decision about whether the first or second stimulus is higher in vibrotactile frequency. The information then decays in a 3-s delay period in which the neuronal activity declines before the behavioral response can be made. The information then increases again when the behavioral response is required. We model this neuronal activity using an attractor decision-making network in which information reflecting the decision is maintained at a low level during the delay period, and is then selectively restored by a nonspecific input when the response is required. One mechanism for the short-term memory is synaptic facilitation, which can implement a mechanism for postponed decisions that can be correct even when there is little neuronal firing during the delay period before the postponed decision. Another mechanism is graded firing rates by different neurons in the delay period, with restoration by the nonspecific input of the low-rate activity from the higher-rate neurons still firing in the delay period. These mechanisms can account for the decision making and for the memory of the decision before a response can be made, which are evident in the activity of neurons in the medial premotor cortex.     

Alcohol and non-fatal drug overdoses

The purpose of this study was to explore to what extent alcohol is a factor in non-fatal overdoses on the basis of records of ambulance emergencies, and to what extent this varies across gender and age. Furthermore, we wanted to investigate whether alcohol intake, in relation to an overdose, is associated with the risk of recurrent overdoses, and if so, whether such an association varies across gender and age. To investigate the role of alcohol intake in non-fatal overdoses, analyses were conducted both at the event level and at the individual level. Bivariate associations were explored in table analyses and by comparisons of means. To determine whether alcohol intake was associated with experiencing recurrent overdoses, survival analyses were conducted applying Kaplan-Meier estimation and Cox regression models. Furthermore, a linear regression model was estimated to assess the impact of gender age and number of overdoses on the proportion of overdoses in which alcohol was involved. Between groups of clients who had overdosed once, several times or many times, we found that there was a U-shaped relationship. The proportion of overdoses with alcohol involved was highest among those who had overdosed once and those who had overdosed more than ten times. The probability for a recurrent overdose was higher among those who were reported with no alcohol intake in the first overdose. Being female and having alcohol involved in the first overdose registered during our observation period reduced the risk for a recurrent overdose. However, age seemed to be a gradient with respect to alcohol's association with recurrent overdoses. While alcohol was associated with a significantly lower risk for recurrence in the two youngest age groups, this is not the case in the oldest age group. A possible explanation might be that it is a change in the pattern of drug use as an effect of aging where infrequent heroin use in combination with frequent alcohol intake increases with increasing age. For this type of drug users the individual's risk of recurrent overdoses may be lower due to fewer events of heroin intake.     

Postvagotomy unmasking of nontropical sprue.

Adult celiac disease which became clinically evident after exophagectomy and vagotomy is described. The diagnosis was suggested by small bowel roentgenography and confirmed by intestinal biopsy and response to a gluten-free diet. The possibility that vagotomy unmasks asymptomatic adult celiac disease is discussed.     

Neural correlates of a postponed decision report

Depending on environmental demands, a decision based on a sensory evaluation may be either immediately reported or postponed for later report. If postponed, the decision must be held in memory. But what exactly is stored by the underlying memory circuits, the final decision itself or the sensory information that led to it? Here, we report that, during a postponed decision report period, the activity of medial premotor cortex neurons encodes both the result of the sensory evaluation that corresponds to the monkey''s possible choices and past sensory information on which the decision is based. These responses could switch back and forth with remarkable flexibility across the postponed decision report period. Moreover, these responses covaried with the animal''s decision report. We propose that maintaining in working memory the original stimulus information on which the decision is based could serve to continuously update the postponed decision report in this task.     

Isolated dysphagia unmasking bulbar neurosarcoidosis and pulmonary sarcoidosis

Dysphagia is a rare manifestation of sarcoidosis. It is more commonly the result of esophageal compression by enlarged mediastinal lymph nodes rather than direct esophageal involvement and rarely secondary to neurosarcoidosis and oropharyngeal dysphagia. We report a 54 year old female presenting with a six month history of worsening dysphagia. She denied respiratory symptoms. Physical exam was normal. ESR was 61 mm/hr. Serum ACE level was 65 mcg/L. Chest X-ray was normal. Esophagram revealed a large amount of contrast pooling in pharyngeal recesses with intermittent laryngeal aspiration. Swallow videofluorography showed a decreased retraction of the base of the tongue, limited laryngeal elevation, and a large amount of contrast pooling in pharyngeal recesses with intermittent laryngeal aspiration. EGD showed a normal opening of the upper esophageal sphincter and the cricopharyngeus appeared normal. Proximal esophageal biopsies were normal. Brain MRI with gadolinium was normal. Lumbar puncture was performed. CSF showed a moderate pleocytosis, a WBC count of 19 with 97% lymphocytes, an elevated total protein level of 85 mg/dl (15–60). Neck CT scan showed no oropharyngeal tissue thickening or infiltration, no masses or enlarged lymph nodes. Chest CT scan showed enlarged intrathoracic lymph nodes and no esophageal compression. Bronchoscopy showed the vocal cords to be intact, and the CD4/CD8 ratio in BAL was 5.3. Subcarinal lymph node EBUS biopsy revealed non caseating granulomas. The patient was started on IV methylprednisolone. Three days later, the swallow videofluorography showed a near complete response to steroids. The patient tolerated regular consistency diet with thin liquids, and she was discharged on a slow taper of prednisone over a period of three months. A unique case of isolated dysphagia unmasking bulbar neurosarcoidosis and pulmonary sarcoidosis is herein reported.     

Assessing the validity of potential alcohol-related non-fatal injury indicators

AIM: To assess critically the face validity of the World Health Organization's (WHO's) International Guide for Monitoring Alcohol Consumption and Related Harm (MACRH) for deriving indicators, for the purposes of developing non-fatal alcohol-related injury indicators in New Zealand. DESIGN: MACRH's five solutions for deriving indicators are: (i) use only alcohol-specific cases; (ii) identify subsets of events known to be highly alcohol-related; (iii) utilize control indicators that are rarely alcohol-related; (iv) estimate alcohol attributable fractions (AAFs) and adjust indicators accordingly; and (v) develop composite indicators. These were assessed in terms of their face validity with particular reference to New Zealand. FINDINGS: There are significant face validity issues with each of the five options. Solution 4 offers the greatest promise, provided that: (i) valid AAFs can be derived and they are updated regularly; and (ii) appropriate adjustment is made for extraneous influences on the estimates of alcohol-related harm. To date, the latter has not been carried out. CONCLUSIONS: Most potential sources of data on alcohol-related harm are subject to extraneous influences, which vary over time and space. While the attempt by WHO to offer solutions to this problem is laudable, the solutions do not address the problem adequately. MACRH guidelines need to be revised to include criteria for a valid outcome indicator.     

Use of inhaled corticosteroids and the risk of non-fatal acute myocardial infarction

BACKGROUND: Use of inhaled corticosteroids may reduce the risk of acute myocardial infarction (MI) through reductions in systemic inflammation and C-reactive protein. OBJECTIVES: To examine the association between the use of inhaled corticosteroids and the risk of non-fatal acute MI. METHODS: In the Dutch PHARMO record linkage system database, we conducted a case-control study (2476 MI cases), nested in a cohort of antihypertensive drug users. The use of inhaled corticosteroids 100 days before the index date was compared with never use. We adjusted the analyses for the severity of the underlying respiratory disease and general drug and disease history. RESULTS: We found that the use of inhaled corticosteroids was not associated with a decreased risk of non-fatal MI in antihypertensive drug users after adjustment for the underlying respiratory disease severity, adjusted odds ratio (OR) 1.24, 95% confidence interval (CI) 0.97-1.57. A higher daily dose (adjusted OR 1.82, 95% CI 0.80-4.13) and longer duration of use (adjusted OR 1.28, 95% CI 0.90-1.81) were not associated with a decreased risk of non-fatal MI. An inhaled corticosteroid dispensing in the 30 days before the index date was not protective but resulted in a 1.7-fold increased risk of non-fatal MI. CONCLUSION: Our results do not support the hypothesis that inhaled corticosteroids protect against the risk of non-fatal MI by a reduction of systemic inflammation.     

Environmental effects on age-dependent mortality: a test with a perennial plant species under natural and protected conditions

Most experimental studies of senescence have been done with short-lived organisms under controlled laboratory conditions and it is not clear whether the insights gained from these studies can be broadly generalized. This study was designed to detect senescence in a natural population and to compare the patterns of mortality for a single species in natural and protected conditions. It was done with Plantago lanceolata, a perennial plant for which the demography of a large population of individuals in their natural environment is relatively straightforward. An initial cohort of 10,000 individuals was established in the natural field environment. In order to separate the effects of environment- and age-dependent factors on mortality, an additional cohort was planted in the field one year later. To study the demography of mortality under protected conditions, a population of 1000 individuals was established in the greenhouse. The results of the comparative analysis of two different-aged cohorts in the field and of the field and greenhouse populations show that senescence patterns can be very plastic. The results show that senescence in the natural environment is caused by an increased vulnerability of older individuals to environmental stress. Under the protected environmental conditions of the greenhouse senescence was negligible.     

Role of sodium and calcium channel block in unmasking the Brugada syndrome

OBJECTIVE: We hypothesized that a combination of I(Na) and I(Ca) blockade may be more effective in causing loss of the epicardial action potential (AP) dome and precipitating the Brugada syndrome (BS). The present study was designed to test this hypothesis in an in vitro model of BS. BACKGROUND: The Brugada syndrome is characterized by an ST segment elevation in the right precordial ECG leads and a high risk of sudden death. The ECG sign of BS is often concealed, but can be unmasked with potent sodium channel blockers. Using canine right ventricular (RV) wedge preparations, we previously developed an experimental model of BS using flecainide to depress the AP dome in RV epicardium. METHODS: Intracellular APs and a transmural ECG were simultaneously recorded from canine RV wedge preparations. RESULTS: Terfenadine (5-10 microM)-induced block of I(Ca) and I(Na) caused heterogeneous loss of the epicardial AP dome, resulting in ST segment elevation, phase 2 reentry (12/16), and spontaneous polymorphic VT/VF (6/16). Flecainide (相似文献   

Acute and postponed action of adriamycin on the contractile function and antioxidant status of the myocardium

Functional, biochemical and morphological studies of rat cardiac muscle after single injection of adriamycin (2.2 mg/kg) were carried out. The myocardium was taken for studies in 2 hours and in 2-3 weeks after adriamycin injection. The isolated heart was perfused retrogradely with Krebs solution and left ventricular isovolumic pressure and perfusion pressure were continuously monitored. Two-fold increase in perfusion rate was accompanied by raised developed pressure, heart rate and perfusion pressure which in the given conditions reflected a tone of coronary vessels. The cardiac contractile function of rats that received adriamycin 2 hours before, remained unaltered as compared to control group, however, perfusion pressure was raised by 26%. These hearts responded to H2O2 introduction (100 microM) into coronary vessels by more profound fall in developed pressure, which fell to 31 +/- 8% after 40 minutes vs. 61 +/- 5% in the control group (p<0.01). In two-three weeks after adriamycin injection, both cardiac contractile function and its responsiveness to oxidative stress induced by H2O2 introduction did not differ from the control, however, perfusion pressure remained elevated and this was accompanied by slowed myocardial relaxation. The myocardial concentration of malonic dialdehyde was moderately increased in adriamycin-treated group in both terms while the activity of antioxidant enzymes (SOD, GPHx and catalase) remained unaltered. Results showed an absence of the direct connection between myocardial antioxidant status and the contractile function changes at adriamycin action.     

Early and postponed percutaneous coronary interventions in acute period of myocardial infarction

Aim of the study was elaboration of indications to the application of postponed percutaneous coronary interventions (PCI) in acute period of myocardial Infarction (Ml) in patients without prior thrombolytic therapy. We fulfilled comparative assessment of efficacy of 3 strategies of treatment of 810 patients admitted to the N.V. Sklifosovsky Institute of Urgent Aid from 2003 to 2007: primary PCI carried out within first 12 hours (n=32), postponed PCI in acute period because of initially elevated risk (n=90), conservative treatment without reperfusion therapy (n=688). Elevated risk of death according to TIMI score was used as the basis for establishment of indications for postponed interventions. Right ventricular involvement and repeat MI were considered as additional predictors. The data obtained indicate that elevated risk of death allows to detect patients with high rate of persisting occlusions and subtotal stenoses in infarct related artery. Reperfusion therapy appears to be the main component of treatment of such patients. Necessity to perform primary PCI within first 12 hours does not exclude possibility of its later use in acute period of MI. Both strategies allow to substantially lower rates of complications and lethal outcomes. Shortening of terms of application of reperfusion therapy gives an opportunity to prevent most of unfavorable outcomes. Success of postponed interventions in acute period of MI opens opportunities of their active use in patients from other hospitals.     

Endocrinology in the 21st century: unmasking the mysteries of biology

The traditional concept of endocrinology has provided a model, that enabled to understand and treat endocrine diseases. Molecular and (patho)physiological differentiations of this concept will further improve the treatment of complex endocrine and metabolic diseases. Nature has lifted a tip of her veil, reveiling a number of orphan receptors, which may reflect presently unknown physiological pathways and may be important targets for drug development. Although the integrative function of hormones and receptors can be further elucidated by approaches like reverse endocrinology and functional genomics, the structural interaction between bench (basic science) and bedside (clinical endocrinology) will remain instrumental for the progress of endocrinology.     

Lack of age-dependent cisplatin nephrotoxicity

Cisplatin nephrotoxicity was evaluated by serial pretreatment and post-treatment 24-hour creatinine clearance determinations in 43 patients who received 295 monthly infusions of 60 mg/m2 of this drug. An aggressive standard hydration protocol was used without diuretic administration. Fourteen of these patients had a single kidney. Older patients and patients with a single kidney had lower pretreatment creatinine clearances when compared with younger persons with two functioning kidneys. Older and younger patients with two kidneys had an equal, progressive, dose-related deterioration of renal function. Renal function did not decline in persons with a single kidney but did so markedly in those with two kidneys. When administered at 60 mg/m2, cisplatin dose or schedule modification is not indicated on the basis of advancing age or decreased renal function secondary to the surgical loss or total ureteral obstruction of one kidney.