Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung

Small cell lung cancer (SCLC) is one of the most lethal human malignancies. To investigate the cellular origin(s) of this cancer, we assessed the effect of Trp53 and Rb1 inactivation in distinct cell types in the adult lung using adenoviral vectors that target Cre recombinase to Clara, neuroendocrine (NE), and alveolar type 2 (SPC-expressing) cells. Using these cell type-restricted Adeno-Cre viruses, we show that loss of Trp53 and Rb1 can efficiently transform NE and SPC-expressing cells leading to SCLC, albeit SPC-expressing cells at a lesser efficiency. In contrast, Clara cells were largely resistant to transformation. The results indicate that although NE cells serve as the predominant cell of origin of SCLC a subset of SPC-expressing cells are also endowed with this ability.     

Prognostic value of various markers of inflammation in ST-elevation myocardial infarction

We measured levels of several parameters of immune inflammation (interleukins [IL] 1, 6, 8, 10, 12, tumor necrosis factor [TNF], serum neopterin, C-reactive protein) on days 10-14 after onset of ST segment elevation myocardial infarction (MI) and related them to results of 12 months follow up. Elevated titers of IL-12 and neopterin were significantly associated with unfavorable events (repetitive MI, progression of angina, stroke, decompensation of chronic heart failure) (=0.001 and =0.003, respectively). After adjustment for initial severity of MI only IL-12 retained its prognostic value (=0.05). Regression analysis identified IL-12 level >108.7 g/ml and TIMI score > 3 as independent predictors of combined end point formation. Prognostic value of IL-12 level was significant both among patients with TIMI scores <3 and more or equal 4.     

Experiences in the management of brainstem hematomas

The purpose of this study was to present our experience in the management of spontaneous brainstem hematomas (BSH). Records of 58 consecutive patients were reviewed, including demographic data, symptoms, Glasgow Coma Scale, treatment, intraoperative findings (in surgical cases), and outcome according to the Glasgow Outcome Scale. Fifteen patients were comatose (GCS 4 or less): 11/15 patients were treated conservatively. Four patients with accompanying acute occlusive hydrocephalus were treated by placement of an external ventricular drainage. None survived. In nine patients (60%), arteriosclerosis and/or long-standing arterial hypertension were known and arteriopathic BSH was suspected. Forty-three patients were not comatose: 37 patients showed no impairment of consciousness (GCS 15), 6 patients presented with mild disturbance of conscious state (GCS 13), progressing to coma (GCS 8) in 1. In the majority (36/43) of the non-comatose patients (83.7%) cavernoma could be revealed and removed surgically. In six patients (14%), an atypically located arteriopathic BSH was assumed and treated medically. One patient had an underlying brainstem arteriovenous malformation and was treated radiosurgically. Many arteriopathic BSH cause immediate coma indicating direct and irreversible damage of midpontine structures. Thus, we suggest not to proceed to surgery, even if the bleeding is accompanied by acute hydrocephalus. The majority of BSH not resulting in immediate coma are caused by underlying cavernomas. In these cases surgery should be considered.     

Neurocognitive test performance predicts functional recovery from acute exacerbation leading to hospitalization in bipolar disorder

OBJECTIVE: Bipolar disorder (BPD) is associated with significant functional morbidity at a rate which is particularly elevated among patients discharged from hospital. The aim of this study was to examine the degree to which neurocognitive test performance, measured following hospitalization for an acute affective episode, is predictive of functional recovery 1 year later. METHODS: Seventy-eight Zucker Hillside Hospital patients aged 18-59 years and having Structured Clinical Interview for DSM-IV diagnosis of bipolar I disorder (BPD I), bipolar II disorder (BPD II) or BPD not otherwise specified (NOS) confirmed through a rigorous diagnosis consensus procedure, underwent a comprehensive neurocognitive test battery after initial stabilization (baseline) and were followed for at least 12 months (follow-up). Hamilton Depression Rating Scale (HAM-D) and Clinician-Administered Rating Scale for Mania (CARS-M) ratings were made at baseline and follow-up. At follow-up, functionality was assessed using the Multidimensional Scale for Independent Functioning (MSIF). Logistic regression was used to examine the predictive value of each of six validated neurocognitive domains for determining functionality (MSIF) at follow-up. Baseline and follow-up HAM-D and CARS-M were entered as covariates as was number of days between baseline and follow-up. RESULTS: Attention and Ideational Fluency were significantly predictive of functional recovery 12 months later. Residual mania but not depression was associated with 12-month MSIF rating. Lithium and benzodiazepine treatment at the time of neurocognitive testing did not affect the results. CONCLUSIONS: This is the first study examining the predictive value of neurocognitive deficits, independent of residual mania or depression, for long-term functional recovery following hospitalization. Selective neurocognitive deficits are predictive of long-term functional recovery and, as such, should be candidate targets in treatment and rehabilitation programs.     

Prevention and education to decrease patient falls due to syncope

This article describes a fall reduction program implemented by the University of Wisconsin Medical Foundation in its 50+ clinic sites and departments located across 5 counties in Southern Wisconsin. The fall reduction program specifically targeted falls due to faints in the clinic setting. To reduce the organization's main reason for patient falls, guidelines were developed and mandatory education was given to staff working in high-risk areas.     

Human striatal activation reflects degree of stimulus saliency

Salient stimuli are characterized by their capability to perturb and seize available cognitive resources. Although the striatum and its dopaminergic inputs respond to a variety of stimuli categorically defined as salient, including rewards, the relationship between striatal activity and saliency is not well understood. Specifically, it is unclear if the striatum responds in an all-or-none fashion to salient events or instead responds in a graded fashion to the degree of saliency associated with an event. Using functional magnetic resonance imaging, we measured activity in the brains of 20 participants performing a visual classification task in which they identified single digits as odd or even numbers. An auditory tone preceded each number, which was occasionally, and unexpectedly, substituted by a novel sound. The novel sounds varied in their ability to interrupt and reallocate cognitive resources (i.e., their saliency) as measured by a delay in reaction time to immediately subsequent numerical task-stimuli. The present findings demonstrate that striatal activity increases proportionally to the degree to which an unexpected novel sound interferes with the current cognitive focus, even in the absence of reward. These results suggest that activity in the human striatum reflects the level of saliency associated with a stimulus, perhaps providing a signal to reallocate limited resources to important events.