Citations

Screened for by all state newborn screening (NBS) programs in the United States, mitochondrial acetoacetyl-coenzyme A thiolase (T2), or β-ketothiolase, deficiency is a rare autosomal recessive disorder that causes ketoacidosis and hypoglycemia/hyperglycemia. Outcomes vary from normal development to severe cognitive impairment or even death after an acute episode of ketoacidosis. The classical biochemical profile of T2 deficiency is a result of null mutations in both alleles of the ACAT1 gene and consists of persistently increased urinary excretion of ketones, characteristic organic acids, and tiglylglycine as well as abnormal blood or plasma acylcarnitine profiles in acute and stable conditions. Early diagnosis and aggressive management can prevent further episodes of ketoacidosis and lead to normal development. We report the cases of 3 children, all subsequently found to have mutations predicted to be associated with no residual T2 enzymatic activity, but only 1 was identified by NBS in Minnesota since 2001. To our knowledge, this is the first description of compound heterozygotes for null mutations associated with no enzymatic activity exhibiting normal urinary organic acid, blood, and plasma acylcarnitine profiles when clinically well, thereby explaining the false-negative NBS results. We suggest that T2 deficiency may be underrecognized, because the incidence of T2 deficiency in Minnesota, on the basis of these 3 cases, is 1 in 232 000, higher than the reported <1 in 1 million incidence. Our cases emphasize that T2 deficiency must be considered in patients who present with ketoacidosis disproportionately severe to the triggering illness despite normal NBS results or nonspecific biochemical findings in blood and urine during asymptomatic periods.

Purpose: To review the outcomes of retrograde supra-aortic vessel stent (RSAS) placement combined with open carotid or subclavian artery revascularization. Methods: Retrospective review of all consecutive patients between 1995 and 2010, excluding transfemoral procedures or isolated retrograde stent placement. Results: There were 11 patients (9 females, mean age 65 years). Open revascularization included carotid endarterectomy in 6 patients, carotid-subclavian bypass in 3, and carotid-carotid bypass in 2 patients. There were no operative deaths or neurological events. All symptomatic patients improved. Over a mean follow-up of 24 months, One patient developed common carotid artery (CCA) in-stent dissection and symptomatic restenosis treated with subclavian-carotid bypass. Another 3 patients had asymptomatic restenosis of the carotid bifurcation but required no intervention. Conclusions: Retrograde stenting of the common carotid or innominate artery is a safe and effective method to provide inflow in selected patients with severe supra-aortic vessel disease who require concomitant open carotid or subclavian artery reconstructions.

Spontaneous, nontraumatic intracerebral hemorrhage (ICH) is defined as bleeding within the brain parenchyma. Intracranial hemorrhage includes bleeding within the cranial vault and encompasses ICH, subdural hematoma, epidural bleeds, and subarachnoid hemorrhage (SAH). This review will focus only on ICH. This stroke subtype accounts for about 10% of all strokes. The hematoma locations are deep or ganglionic, lobar, cerebellar, and brain stem in descending order of frequency. Intracerebral hemorrhage occurs twice as common as SAH and is equally as deadly. Risk factors for ICH include hypertension, cerebral amyloid angiopathy, advanced age, antithrombotic therapy and history of cerebrovascular disease. The clinical presentation is “stroke like” with sudden onset of focal neurological deficits. Noncontrast head computerized tomography (CT) scan is the standard diagnostic tool. However, newer neuroimaging techniques have improved the diagnostic yield in terms of underlying pathophysiology and may aid in prognosis. Intracerebral hemorrhage is a neurological emergency. Medical care begins with stabilization of airway, breathing function, and circulation (ABCs), followed by specific measures aimed to decrease secondary neurological damage and to prevent both medical and neurological complications. Reversal of coagulopathy when present is of the essence. Blood pressure management can be key and continues as an area of debate and ongoing research. Surgical evacuation of ICH is of unproven benefit though a subset of well-selected patients may have improved outcomes. Ventriculostomy and intracranial pressure (ICP) monitoring are interventions also used in this patient population. To date, hemostatic medications and neuroprotectants have failed to result in clinical improvement. A multidisciplinary approach is recommended, with participation of vascular neurology, vascular neurosurgery, critical care, and rehabilitation medicine as the main players.

Abstract Unlike BCR and secreted Ig, TCR expression is not thought to occur in a bivalent form. The conventional monovalent model of TCR/CD3 is supported by published studies of complexes solubilized in the detergent digitonin, in which bivalency was not observed. We revisited the issue of TCR valency by examining complexes isolated from primary αβ T cells after solubilization in digitonin. Using immunoprecipitation followed by flow cytometry, we unexpectedly observed TCR/CD3 complexes that contained two TCRs per complex. Standard anti-TCR Abs, being bivalent themselves, tended to bind with double occupancy to bivalent TCRs; this property masked the presence of the second TCR per complex in certain Ab binding assays, which may partially explain why previous data did not reveal these bivalent complexes. We also found that the prevalence of bivalency among fully assembled, mature TCR/CD3 complexes was sufficient to impact the functional performance of immunoprecipitated TCRs in binding antigenic peptide/MHC-Ig fusion proteins. Both TCR positions per bivalent complex required an Ag-specific TCR to effect optimal binding to these soluble ligands. Therefore, we conclude that in primary T cells, TCR/CD3 complexes can be found that are physically and functionally bivalent. The expression of bivalent TCR/CD3 complexes has implications regarding potential mechanisms by which Ag may trigger signaling. It also suggests the possibility that the potential for bivalent expression could represent a general feature of Ag receptors.

AbstractBackgroundPancreatic cancer is a common digestive cancer with high mortality, and surgical resection is the only potential curative treatment option. Pancreatic head cancer is usually accompanied by biliary obstruction, which potentially increases surgical complications following pancreaticoduodenectomy. Thus, preoperative biliary drainage has long been advocated.MethodsA review of the literature using Medline, Embase and Cochrane databases was undertaken.ResultsEndoscopic or percutaneous biliary stent placement is technically successful in most patients. The use of routine preoperative biliary drainage in the setting of pancreatic cancer with biliary obstruction is controversial. Prospective studies have shown that complications related to preoperative biliary drainage using endoscopic placement of traditional plastic endoprostheses increase the overall morbidity compared to pancreaticoduodenectomy alone. Placement of self‐expandable metal stents could reduce stent‐related complication rates such as early occlusion because of prolonged patency, especially when surgery is delayed.ConclusionPancreatic cancer patients with deep jaundice and expected delay prior to curative intent surgery are potential candidates for temporary biliary drainage. Cholangitis remains a formal indication for early, urgent preoperative biliary decompression for patients with pancreatic cancer.

Background and Purpose— There is uncertainty whether warfarin-treated patients (despite international normalized ratio <1.7) have increased risks of symptomatic intracerebral hemorrhage after intravenous thrombolysis. Methods— Vascular risk factors, stroke subtype, and outcome measures were compared between warfarin- and nonwarfarin-treated patients undergoing acute thrombolysis within 3 hours of symptom onset. Results— From 212 patients (mean age, 74±14 years; 50% men) studied, 14 (6.5%) had prior warfarin use. After adjusting for age, baseline National Institutes of Health Stroke Scale, and stroke subtype, warfarin-treated patients had significantly increased risks of developing symptomatic intracerebral hemorrhage (adjusted OR, 14.7; 95% CI, 1.3 to 54.3). A trend for poorer stroke recovery and increased mortality was observed in warfarin-treated patients on univariate, but not on multivariable, analyses. Conclusions— Warfarin-treated patients with stroke have increased risks of symptomatic intracerebral hemorrhage after thrombolytic treatment. These data raise safety concerns of thrombolytic treatment in warfarin-treated patients with subtherapeutic international normalized ratio.

Length adaptation in airway smooth muscle (ASM) is attributed to reorganization of the cytoskeleton, and in particular the contractile elements. However, a constantly changing lung volume with tidal breathing (hence changing ASM length) is likely to restrict full adaptation of ASM for force generation. There is likely to be continuous length adaptation of ASM between states of incomplete or partial length adaption. We propose a new model that assimilates findings on myosin filament polymerization/depolymerization, partial length adaptation, isometric force, and shortening velocity to describe this continuous length adaptation process. In this model, the ASM adapts to an optimal force-generating capacity in a repeating cycle of events. Initially the myosin filament, shortened by prior length changes, associates with two longer actin filaments. The actin filaments are located adjacent to the myosin filaments, such that all myosin heads overlap with actin to permit maximal cross-bridge cycling. Since in this model the actin filaments are usually longer than myosin filaments, the excess length of the actin filament is located randomly with respect to the myosin filament. Once activated, the myosin filament elongates by polymerization along the actin filaments, with the growth limited by the overlap of the actin filaments. During relaxation, the myosin filaments dissociate from the actin filaments, and then the cycle repeats. This process causes a gradual adaptation of force and instantaneous adaptation of shortening velocity. Good agreement is found between model simulations and the experimental data depicting the relationship between force development, myosin filament density, or shortening velocity and length.