Plasma endothelin levels and outcome in patients undergoing repair of ruptured infrarenal abdominal aortic aneurysm

BACKGROUND: Endothelin-1 (ET-1) is the most potent known vasoconstrictor. Elevated plasma levels have been demonstrated in patients with myocardial infarction, cardiogenic and septic shock, and respiratory, heart, and kidney failure, as well as in those undergoing elective abdominal aortic aneurysm (AAA) repair. However, endothelin levels have not previously been examined in patients undergoing repair of ruptured AAA. We hypothesized that hemorrhagic shock, lower torso ischemia, and reperfusion associated with ruptured AAA repair lead to increased synthesis and secretion of ET-1, which, in turn, predispose to organ failure, one of the principal causes of death in this condition. METHODS: Fourteen patients were studied. Plasma levels of big ET-1 and ET-1 were measured immediately before operation and immediately before, 5 minutes, and 6 hours after aortic clamp release. RESULTS: All patients survived for at least 24 hours after operation. Big ET-1 levels were above the normal range at one or more sample points in all patients, and the ET-1 levels were above the normal range in all survivors and four of five nonsurvivors. Five patients who died of organ failure had significantly lower big ET-1 levels at all sample points and significantly lower ET-1 levels after 5 minutes of reperfusion when compared with survivors. Preoperative ET-1 levels were significantly lower in eight patients who subsequently developed kidney failure than in six patients who did not. CONCLUSION: Contrary to our original hypothesis, these novel data demonstrate that patients with ruptured AAA in whom fatal postoperative organ failure develops have significantly lower perioperative endothelin levels than survivors.     

Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis

There is mounting pathological, biochemical and genetic evidence that the metabolism and aggregation of the 43-kDa transactive response (TAR)-DNA-binding protein (TDP-43) play a crucial role in the pathogenesis of sporadic and some forms of familial amyotrophic lateral sclerosis (ALS). Recently, it was reported using an ELISA system that elevated levels of TDP-43 were detected in plasma samples from patients with Alzheimer’s disease and frontotemporal dementia, compared to healthy controls. To determine whether quantification of TDP-43 in cerebrospinal fluid (CSF) is potentially informative in the diagnosis of ALS, we measured the concentration, by a similar ELISA method, of TDP-43 in CSF from 30 patients with ALS (diagnosed according to the revised El Escorial criteria) and 29 age-matched control patients without any neurodegenerative disease. We found that, as a group, the ALS patients had significantly higher levels of TDP-43 in their CSF than the age-matched controls (6.92 ± 3.71 ng/ml in ALS versus 5.31 ± 0.94 ng/ml in controls, p < 0.05), with levels of TDP-43 in CSF elevated beyond 95% upper confidence level for the control group in six (20%) of the patients with sporadic ALS. All the six patients with higher levels of CSF TDP-43 were examined within 10 months of the onset of illness. The patients examined within 10 months of onset showed significantly higher levels of CSF TDP-43 (8.24 ± 4.72 ng/ml) than those examined after 11 months or more of onset (5.41 ± 0.66 ng/ml, p < 0.05). These results suggest that the levels of TDP-43 in CSF may increase in the early stage of ALS. We also confirmed the existence of the TDP-43 protein in CSF from some patients with ALS, and a control subject, by western blotting of proteins immunocaptured from the CSF samples. Raised TDP-43 levels in the CSF may preempt the formation of TDP-43 pathology in the central nervous system, or correlate with early-stage TDP-43 pathology, and accordingly be a biomarker for the early stage of ALS.     

An unusual case of diffuse Merkel cell carcinoma successfully treated with low dose radiotherapy

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine carcinoma of the skin. MCC should be included in the diagnosis of a rapidly growing infiltrating mass and histology as well as laboratory investigations such as Merkel cell polyoma virus (MCPyV) detection are valuable in its diagnosis. We present an unusual case of giant MCC‐positive MCPyV in a Greek woman located on the lower leg. Our patient is very unusual in terms of her extensive MCC and her rapid and complete response to radiotherapy.     

ErbB receptor signaling directly controls oligodendrocyte progenitor cell transformation and spontaneous remyelination after spinal cord injury

We recently discovered a novel role for neuregulin-1 (Nrg1) signaling in mediating spontaneous regenerative processes and functional repair after spinal cord injury (SCI). We revealed that Nrg1 is the molecular signal responsible for spontaneous functional remyelination of dorsal column axons by peripheral nervous system (PNS)-like Schwann cells after SCI. Here, we investigate whether Nrg1/ErbB signaling controls the unusual transformation of centrally derived progenitor cells into these functional myelinating Schwann cells after SCI using a fate-mapping/lineage tracing approach. Specific ablation of Nrg1-ErbB receptors in central platelet-derived growth factor receptor alpha (PDGFRα)-derived lineage cells (using PDGFRαCreERT2/Tomato-red reporter mice crossed with ErbB3fl/fl/ErbB4fl/fl mice) led to a dramatic reduction in P0-positive remyelination in the dorsal columns following spinal contusion injury. Central myelination, assessed by Olig2 and proteolipid protein expression, was unchanged. Loss of ErbB signaling in PDGFRα lineage cells also significantly impacted the degree of spontaneous locomotor recovery after SCI, particularly in tests dependent on proprioception. These data have important implications, namely (a) cells from the PDGFRα-expressing progenitor lineage (which are presumably oligodendrocyte progenitor cells, OPCs) can differentiate into remyelinating PNS-like Schwann cells after traumatic SCI, (b) this process is controlled by ErbB tyrosine kinase signaling, and (c) this endogenous repair mechanism has significant consequences for functional recovery after SCI. Thus, ErbB tyrosine kinase receptor signaling directly controls the transformation of OPCs from the PDGFRα-expressing lineage into PNS-like functional remyelinating Schwann cells after SCI.     

Reconstitution of a Calcium Pump Using Defined Membrane Components

A (Mg(2+) + Ca(2+))ATPase (ATP phosphohydrolase, EC 3.6.1.3) has been purified from sarcoplasmic reticulum using a single step centrifugation procedure. The preparation is >95% pure by weight and contains only 25-30% of the lipid associated with the enzyme in native sarcoplasmic reticulum. The purified enzyme is unable to accumulate Ca(2+). Using a sedimentation-substitution technique, >98% of the lipid associated with the purified enzyme can be replaced by dioleoyl lecithin without grossly affecting the ATPase activity of the enzyme. The Ca(2+) pump can be restored to this dioleoyl lecithin-substituted enzyme by addition of excess sarcoplasmic reticulum lipids in the presence of cholate. Removal of the cholate by dialysis generates a system which accumulates Ca(2+) at a rate and to a level comparable to native sarcoplasmic reticulum. Significant reconstitution of the Ca(2+) pump can also be achieved using excess dioleoyl lecithin, but since the full expression of the capacity to accumulate Ca(2+) requires the presence of oxalate, these vesicles would appear to be more leaky than those reconstituted with an excess of sarcoplasmic reticulum lipids. Of about 90 lipid molecules which are associated with one molecule of ATPase in native sarcoplasmic reticulum, an average of less than one lipid molecule remains in these reconstituted systems. We have therefore achieved a fully functional Ca(2+) pump containing essentially a single protein and exogenous lipid.     

Left mid-ventrolateral prefrontal cortex: underlying principles of function

There is a growing body of evidence indicating that the mid-ventrolateral prefrontal cortex in the left hemisphere is involved in some aspect of controlled verbal memory retrieval. Its precise role, however, remains unclear. We tested the hypothesis that when stimuli in memory are related to each other in multiple ways, and therefore familiarity, strong constant stimulus–stimulus links or contextual cues are not sufficient for successful retrieval, control processing emanating from the mid-ventrolateral prefrontal cortex is required to disambiguate and select the appropriate information among memory traces. We refer to this type of retrieval as active retrieval to distinguish it from automatic retrieval which depends on the simple reactivation of memory traces. Normal human subjects were scanned with functional magnetic resonance imaging while they performed three memory tasks that varied in their demands on active retrieval of verbal information. As the demands on active retrieval increased, there was an increase in the activity within the mid-ventrolateral prefrontal cortex, bilaterally, but with more prominent activity in the left hemisphere. These activity increases correlated with activity in the posterior temporal region which, in the left hemisphere, is involved in language processing. No significant activity increases were observed in any other prefrontal region. Furthermore, for the retrieval of well-learned verbally cued conditional motor associations, there were no activity increases in the mid-ventrolateral prefrontal cortex. The present findings provide strong support for the hypothesis that the mid-ventrolateral prefrontal cortex, particularly in the left hemisphere, plays a major role in the active retrieval of information from verbal memory.     

卒中医疗体系之急诊医疗服务的实施策略——美国心脏协会／美国卒中协会急诊医疗服务体系专家组和卒中委员会的政策声明

尽管卒中的预防、诊断、治疗和康复已取得一些进展，但卒中在美国仍然是第三大死亡原因和长期残疾的主要原因。每年约有70万人新发或复发卒中。在过去10年里，急性卒中诊治的一些进展，包括纤溶和其他短期疗法的引入，     

Mediators of the association between psychotic experiences and future non-suicidal self-injury and suicide attempts: results from a three-wave,prospective adolescent cohort study

European Child & Adolescent Psychiatry - Psychotic experiences (PEs) are robustly associated with subsequent non-suicidal self-injury (NSSI) and suicide attempts, but questions remain as to the...     

TDP-43 protein in plasma may index TDP-43 brain pathology in Alzheimer’s disease and frontotemporal lobar degeneration

Autopsy studies have shown that about 55% of patients with frontotemporal lobar degeneration (FTLD) and 25% of patients with Alzheimer's disease (AD) harbour TDP-43 immunoreactive pathological changes in their brains. Using ELISA, we investigated whether we could detect the presence, or increased amounts, of TDP-43 in plasma of patients with FTLD and AD compared to normal control subjects. We detected elevated levels of TDP-43 protein in plasma of 46% patients with FTLD with clinical frontotemporal dementia (FTD) and 22% patients with AD, compared to 8% of control subjects. The proportions of patients with FTD and AD showing raised plasma TDP-43 levels correspond closely to those proportions known from autopsy studies to contain TDP-43 pathological changes in their brains. Raised TDP-43 plasma levels may thereby index TDP-43 pathology within the brain. Plasma TDP-43 levels may be a biomarker that can provide a laboratory test capable of identifying the presence of TDP-43 brain pathology in neurodegenerative disease during life. It may help to distinguish those cases of FTLD with ubiquitin/TDP-43 pathology in their brains from those with tauopathy. As a predictive test, plasma TDP-43 level may have great practical value in directing therapeutic strategies aimed at preventing or removing tau or TDP-43 pathological changes from the brain in FTLD and AD.     

TDP-43 pathological changes in early onset familial and sporadic Alzheimer��s disease, late onset Alzheimer��s disease and Down��s Syndrome: association with age, hippocampal sclerosis and clinical phenotype

TDP-43 immunoreactive (TDP-43-ir) pathological changes were investigated in the temporal cortex and hippocampus of 11 patients with autosomal dominant familial forms of Alzheimer's disease (FAD), 169 patients with sporadic AD [85 with early onset disease (EOAD) (i.e before 65 years of age), and 84 with late onset after this age (LOAD)], 50 individuals with Down's Syndrome (DS) and 5 patients with primary hippocampal sclerosis (HS). TDP-43-ir pathological changes were present, overall, in 34/180 of AD cases. They were present in 1/11 (9%) FAD, and 9/85 (10%) EOAD patients but were significantly more common (p = 0.003) in LOAD where 24/84 (29%) patients showed such changes. There were no demographic differences, other than onset age, between AD patients with or without TDP-43-ir pathological changes. Double immunolabelling indicated that these TDP-43-ir inclusions were frequently ubiquitinated, but were only rarely AT8 (tau) immunoreactive. Only 3 elderly DS individuals and 4/5 cases of primary HS showed similar changes. Overall, 21.7% of AD cases and 6% DS cases showed hippocampal sclerosis (HS). However, only 9% FAD cases and 16% EOAD cases showed HS, but 29% LOAD cases showed HS. The proportion of EOAD cases with both TDP-43 pathology and HS tended to be greater than those in LOAD, where nearly half of all the cases with TDP-43 pathology did not show HS. The presence of TDP-43-ir changes in AD and DS may therefore be a secondary phenomenon, relating more to ageing than to AD itself. Nevertheless, a challenge to such an interpretation comes from the finding in AD of a strong relationship between TDP-43 pathology and cognitive phenotype. Patients with TDP-43 pathology were significantly more likely to present with an amnestic syndrome than those without (p < 0.0001), in keeping with pathological changes in medial temporal lobe structures. HS was also associated more commonly with an amnestic presentation (p < 0.005), but this association disappeared when TDP-43-positive cases were excluded from the analysis. TDP-43 may, after all, be integral to the pathology of AD, and to some extent determine the clinical phenotype present.