Caspase-cleaved tau accumulation in neurodegenerative diseases associated with tau and α-synuclein pathology

Alzheimers disease (AD), Picks disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) are diseases associated with the accumulation of tau or -synuclein. In AD, -amyloid (A)-associated caspase activation and cleavage of tau at Asp⁴²¹ (Tau) may be an early step in neurofibrillary tangle (NFT) formation. To examine whether Tau accumulates in other diseases not characterized by extracellular A accumulation, we examined PiD, PSP, and CBD cases in comparison to those without extensive tau accumulation including frontotemporal lobar degeneration without Pick bodies (FTLD) and control cases. Additionally, we studied Tau accumulation in DLB cases associated with intracellular -synuclein. Tau was observed in all disease cases except non-PiD FTLD and controls. These results demonstrate that the accumulation of Tau may represent a common pathway associated with abnormal accumulation of intracellular tau or -synuclein and may be relatively less dependent on the extracellular accumulation of A in non-AD dementias.     

Impact of noise on retinal coding of visual signals

Neural noise introduces uncertainty about the signals encoded in neural spike trains. Because of the uncertainty neurons can reliably transmit a limited amount of information. This amount is difficult to quantify for neurons that combine signals and noise in a complex manner, as many trials would be needed to estimate the joint probability distribution of stimulus and neural response accurately. The task is experimentally tractable, however, for neurons that combine signals with additive Gaussian noise. For such neurons, the joint probability distribution is well defined and information transmission rates can be computed from estimates of signal-to-noise ratio. Here we use power spectral analysis to specify the contributions of signal and noise to retinal coding of visual information. We show that in the spike trains of cat ganglion cells noise power is minimal and constant at temporal frequencies from 0.3 to 20 Hz and that it increases at higher frequencies to a plateau level that generally depends on stimulus contrast. We also show that trial-to-trial fluctuations in noise amplitude at different frequencies are uncorrelated and normally distributed. Although the contrast dependence indicates that noise at high temporal frequencies contributes nonlinearly to ganglion cell spike trains, cells in the primary visual cortex are not known to respond to stimulus modulations >20 Hz. Hence, noise in the retinal output would appear additive, white, and Gaussian from their perspective. This greatly simplifies analysis of information transmission from the eye to the primary visual cortex and perhaps other regions of the brain.     

Intraoperative frozen section of sentinel nodes: a formal decision analysis

In the absence of data from randomized trials, a formal decision analysis was undertaken to quantify the relative value of the patients' quality of life with regard to performing intraoperative frozen section (FS) versus permanent section (PS) analysis of the sentinel lymph node (SLN) for breast cancer. Assumptions for this analysis were based on data from 203 nodal basins where the prevalence of nodal metastasis was 26.1 per cent; the FS sensitivity was 68 per cent and FS false-positive rate was 0.7 per cent. DATA 4.0 was used to model the decision analysis. The two branches of the tree represent the two surgical options of either FS analysis intraoperatively, accompanied by immediate axillary dissection for positive nodes versus PS analysis followed by reoperative axillary dissection. The expected utility (EU) with the FS strategy is 0.9736; the EU for PS is 0.9732, suggesting no definite preference for either procedure. Overall, the toss-up is very robust. The decision to choose FS versus PS should be based on individual patient risk and preference because the decision analysis indicated that these two options are equivalent with respect to patient quality of life.     

The impact of major trauma: quality-of-life outcomes are worse in women than in men, independent of mechanism and injury severity

BACKGROUND: The importance of gender differences in quality of life and psychologic morbidity after major trauma is a newly recognized focus of trauma outcomes research. The Trauma Recovery Project is a large, prospective, epidemiologic study designed to examine multiple outcomes after major trauma, including quality of life (QoL), and psychologic sequelae such as depression and early symptoms of acute stress reaction (SASR). The specific objectives of the present report are to examine gender differences in QoL outcomes and the early incidence of combined depression and SASR after injury, controlling for injury severity, specific body area injured, and mechanism. METHODS: Between December 1, 1993, and September 1, 1996, 1,048 eligible trauma patients triaged to four participating trauma center hospitals in the San Diego Regionalized Trauma System were enrolled in the study. The enrollment criteria for the study included age 18 years and older, admission Glasgow Coma Scale score of 12 or greater, and length of stay greater than 24 hours. QoL outcome after trauma was measured after injury using the Quality of Well-being scale, a sensitive index to the well end of the functioning continuum (range, 0 = death to 1.000 = optimum functioning). Depression was assessed using the Center for Epidemiologic Studies scale. SASR was assessed using the Impact of Events scale. Patient outcomes were assessed at discharge and at 6, 12, and 18 months after discharge. RESULTS: Women (n = 313) were significantly more likely to have poor QoL outcomes at follow-up than men (n = 735) (women vs. men: 12-month follow-up odds ratio [OR] = 2.2, p < 0.001; 18-month follow-up OR = 2.0, p < 0.001). Quality of Well-being scores at each of the 6-, 12-, and 18-month follow-up time points were markedly and significantly lower in women compared with men, independent of injury severity, serious and moderate injury status, lower extremity injury, intentional or unintentional injury type, and blunt or penetrating injury. Women were also significantly more likely to develop early combined depression and SASR at discharge (OR = 1.7, p < 0.01) and to have continuous depression throughout the 18-month follow-up period (OR = 2.3, p < 0.001). CONCLUSION: These analyses provide further important and more detailed evidence that women are at risk of worse QoL outcomes and early psychologic morbidity after major trauma than men, independent of mechanism and injury severity. A better understanding of the impact of major trauma in men and women will be an important component of efforts to improve trauma care and long-term outcome in mature trauma systems.     

The epidemiology of serious and fatal injury in San Diego County over an 11-year period

BACKGROUND: Analysis of the mechanism and severity of injury over time may permit a more focused planning of acute care and trauma prevention programs. METHODS: A retrospective, population-based study examining severe traumatic injury in a single county was undertaken. Three overlapping data sets were used to form a composite injury data set. RESULTS: There were 55,664 patients included in the study. A total of 40,897 (73.5%) patients survived and 14,767 (26.5%) died. Of those patients who died, 8,910 (60.3%) died in the field and were not transported to a trauma center. There was an increase in the mean age of all trauma victims (3 years) and an increase of 5 years in fatally injured patients. The mean Injury Severity Score decreased from 14.7 to 11.6 (p < 0.01); however, Injury Severity Score for fatal patients remained constant (39.7). The overall injury rate remained unchanged (195 per 10(5)), whereas the fatal injury rate decreased by 22% (45.9 per 10(5)) over the 11-year study period. The leading cause of injury was motor vehicle crash, followed by assault. The leading cause of fatal injury was suicide, followed by homicide. CONCLUSION: A combination of three independent injury data sources generated a composite data set of serious and fatal injury. This regional injury analysis was the most comprehensive overview of injury in our region. Important observations included the following: there has been no change in the overall incidence of severe injury within our county; the incidence of fatal traumatic injury has significantly decreased; the leading causes of nonfatal injury do not correlate with the rank order of fatal injury; intentional injury was the leading cause of injury deaths; and scene fatalities represent a poorly studied group of patients who may benefit from primary prevention and injury control research.     

Intramedullary spinal cord metastasis in breast cancer: clinical features, diagnosis, and therapeutic consideration

Intramedullary spinal cord metastases (ISCMs) are very rare, but can cause devastating complications from underlying breast cancer. We report the case of a woman with known metastatic breast cancer and progressive neurologic deterioration caused by an ISCM. The epidemiology, pathogenesis, clinical presentation, diagnostic considerations, and therapeutic options are discussed.     

Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses

With increasing age, the ability to produce protective antibodies in response to immunization declines, leading to a reduced efficacy of vaccination in the elderly. To examine the effect of age on the cognate function of CD4 T cells, we have used a novel adoptive transfer model that allows us to compare identical numbers of antigen-specific naive T cells from young and aged TCR transgenic (Tg) donors. Upon transfer of aged donor CD4 T cells to young hosts, there was significantly reduced expansion and germinal center (GC) differentiation of the antigen-specific B cell population after immunization. This reduced cognate helper function was seen at all time points and over a wide range of donor cell numbers. In hosts receiving aged CD4 cells, there were also dramatically lower levels of antigen-specific IgG. These age-related defects were not due to defects in migration of the aged CD4 T cells, but may be attributable to reduced CD154 (CD40L) expression. Furthermore, we found that there was no difference in B cell expansion and differentiation or in IgG production when young CD4 T cells were transferred to young or aged hosts. Our results show that, in this model, age-related reductions in the cognate helper function of CD4 T cells contribute significantly to defects in humoral responses observed in aged individuals.