Stroke etiology and collaterals: atheroembolic strokes have greater collateral recruitment than cardioembolic strokes.

BACKGROUND AND PURPOSE: Chronic hypoperfusion from athero-stenotic lesions is thought to lead to better collateral recruitment compared to cardioembolic strokes. It was sought to compare collateral flow in stroke patients with atrial fibrillation (AF) versus stroke patients with cervical atherosclerotic steno-occlusive disease (CASOD). METHOD: This was a retrospective review of a prospectively collected endovascular database. Patients with (i) anterior circulation large vessel occlusion stroke, (ii) pre-treatment computed tomography angiography (CTA) and (iii) intracranial embolism from AF or CASOD were included. CTA collateral patterns were evaluated and categorized into two groups: absent/poor collaterals (CTA collateral score 0-1) versus moderate/good collaterals (CTA collateral score 2-4). CT perfusion was also utilized for baseline core volume and evaluation of infarct growth. RESULTS: A total of 122 patients fitted the inclusion criteria, of whom 88 (72%) had AF and 34 (27%) CASOD. Patients with AF were older (P < 0.01) and less often males or smokers (P = 0.04 and P < 0.01 respectively). Baseline National Institutes of Health Stroke Scale and Alberta Stroke Program Early CT Score were comparable between groups. Collateral scores were lower in the AF group (P = 0.01) with patients having poor collaterals in 28% of cases versus 9% in the CASOD group (P = 0.03). Mortality rates (20% vs. 0%; P = 0.02) were higher in the AF patients whilst rates of any parenchymal hemorrhage (6% vs. 26%; P < 0.01) were higher in the CASOD group. On multivariable analysis, CASOD was an independent predictor of moderate/good collaterals (odds ratio 4.70; 95% confidence interval 1.17-18.79; P = 0.03). CONCLUSIONS: Atheroembolic strokes seem to be associated with better collateral flow compared to cardioembolic strokes. This may in part explain the worse outcomes of AF-related stroke.

Effect of relative humidity on the aerosolization and total inflammatory potential of fungal particles from dust-inoculated gypsum boards.

The aim of this study was to investigate the effect of relative humidity (RH) on the aerosolization and total inflammatory potential (TIP) of microbial particles released from gypsum boards inoculated with dust samples from homes. After microbial colonization, the gypsum boards were incubated at either high or low RH. The aerosolized particles (0.54-19.8 µm), culturable fungi, ß-glucan and the TIP of the aerosolized particles were quantified. Despite the colonization of several fungal groups, Penicillium dominated the aerosolized fraction. Higher emission rates of particles and culturable fungi were found from low RH compared with high RH in both the inhalable and particulate matter <1 µm (PM1 ) fractions, and the TIP was accordingly higher. However, for the aerosolized fractions, the TIP or concentration ß-glucan relative to the number of fungi or particles present was higher from high RH compared with low RH. Despite the low number of culturable fungi in PM1 , this fraction showed a high TIP, and the concentration of ß-glucan correlated strongly with the TIP of this fraction. The individual particles of the aerosolized PM1 fraction were more inflammatory than the larger particles of the inhalable fraction, and ß-glucan may be an important contributor to the inflammatory potential of the aerosolized particles.

Comparison of sampling methods for the assessment of indoor microbial exposure.

UNLABELLED: Indoor microbial exposure has been related to allergy and respiratory disorders. However, the lack of standardized sampling methodology is problematic when investigating dose-response relationships between exposure and health effects. In this study, different sampling methods were compared regarding their assessment of microbial exposures, including culturable fungi and bacteria, endotoxin, as well as the total inflammatory potential (TIP) of dust samples from Danish homes. The Gesamtstaubprobenahme (GSP) filter sampler and BioSampler were used for sampling of airborne dust, whereas the dust fall collector (DFC), the electrostatic dust fall collector (EDC), and vacuum cleaner were used for sampling of settled dust. The GSP assessed significantly higher microbial levels than the BioSampler, yet measurements from both samplers correlated significantly. Considerably higher levels of fungi, endotoxin, and TIP were found in the EDC compared with the DFC, and regarding fungi, the EDC correlated more strongly and significantly with vacuumed dust than the DFC. Fungi in EDC and vacuum dust correlated most strongly with airborne dust, and in particular, the measurements from the EDC associated well with those from GSP. Settled dust from the EDC was most representative of airborne dust and may thus be considered as a surrogate for the assessment of indoor airborne microbial exposure. PRACTICAL IMPLICATIONS: Significant discrepancies between sampling methods regarding indoor microbial exposures have been revealed. This study thus facilitates comparison between methods and may therefore be used as a frame of reference when studying the literature or when conducting further studies on indoor microbial exposure. Results also imply that the relatively simple EDC method for the collection of settled dust may be used as an alternative to otherwise tedious and time-consuming airborne dust sampling.

Evolution of public response to the energy crisis.

There is a wide range of technical measures to improve the efficiency of fuel use in industry. The economic justification for adopting these measures can, as a rule, be readily established. If one can resolve the nontechnoeconomic constraints which affect the adoption of these measures, one can look forward to substantial reductions in the fuel required to operate many important industrial processes.

Cutaneous Adnexal Cylindroma of Breast: Epithelial Immunoreactivities for GATA-3, Mammaglobin, and E-Cadherin Do Not Equate to a Mammary Ductal Neoplasm.

Cylindromas are benign epithelial neoplasms derived from cutaneous eccrine adnexal structures. These tumors are most commonly encountered on the head, neck, and scalp of older women. In rare instances, solitary cylindromas may arise at other body sites. In the current case, a cylindroma of the skin of the breast was diagnosed by complete excision. Immunohistochemical studies confirmed the tumor cells to be immunoreactive with cytokeratin AE1/3, cytokeratin 5/6, cytokeratin 7, p63, and SOX10. The neoplastic cells were also noted to be immunoreactive with markers typically expected to be positive in ductal epithelium of the breast including GATA3, mammaglobin, and E-cadherin. The case emphasizes the importance of correlating clinical setting, imaging studies, patient history, and careful microscopic evaluation in arriving at an accurate diagnosis. This case also illustrates the point that not all "breast" tumors that are confirmed to be positive for GATA3, mammaglobin, and E-cadherin are derived from mammary ducts.

Intrasteric inhibition of ATP binding is not required to prevent unregulated autophosphorylation or signaling by the insulin receptor.

Receptor tyrosine kinases may use intrasteric inhibition to suppress autophosphorylation prior to growth factor stimulation. To test this hypothesis we made an Asp1161Ala mutant in the activation loop that relieved intrasteric inhibition of the unphosphorylated insulin receptor (IR) and its recombinant cytoplasmic kinase domain (IRKD) without affecting the activated state. Solution studies with the unphosphorylated mutant IRKD demonstrated conformational changes and greater catalytic efficiency from a 10-fold increase in k(cat) and a 15-fold-lower K(m ATP) although K(m peptide) was unchanged. Kinetic parameters of the autophosphorylated mutant and wild-type kinase domains were virtually identical. The Asp1161Ala mutation increased the rate of in vitro autophosphorylation of the IRKD or IR at low ATP concentrations and in the absence of insulin. However, saturation with ATP (for the IRKD) or the presence of insulin (for the IR) yielded equivalent rates of autophosphorylation for mutant versus wild-type kinases. Despite a biochemically more active kinase domain, the mutant IR expressed in C2C12 myoblasts was not constitutively autophosphorylated. However, it displayed a 2.5-fold-lower 50% effective concentration for insulin stimulation of autophosphorylation and was dephosphorylated more slowly following withdrawal of insulin than wild-type IR. In tests of the regulation of the unphosphorylated basal state, these results demonstrate that neither intrasteric inhibition against ATP binding nor suppression of kinase activity is required to prevent premature autophosphorylation of the IR. Finally, the lower rate of dephosphorylation suggests invariant residues of the activation loop such as Asp1161 may function at multiple junctures in cellular regulation of receptor tyrosine kinases.

Even Small Decreases in Blood Pressure during Conscious Sedation Affect Clinical Outcome after Stroke Thrombectomy: An Analysis of Hemodynamic Thresholds.

BACKGROUND AND PURPOSE: The adverse effects of general anesthesia in stroke thrombectomy have been attributed to intraprocedural hypotension, yet optimal hemodynamic targets remain elusive. Identifying hemodynamic thresholds from patients without exposure to general anesthesia may help separate the effect of hypotension from the effect of anesthesia in thrombectomy outcomes. Therefore, we investigated which hemodynamic parameters and targets best correlate with outcome in patients treated under sedation with monitored anesthesia care. MATERIALS AND METHODS: We performed a retrospective analysis of a prospectively collected data base of patients with anterior circulation stroke who were successfully reperfused (modified TICI ≥ 2b) under monitored anesthesia care sedation from 2010 to 2015. Receiver operating characteristic curves were generated for the lowest mean arterial pressure before reperfusion, both as absolute values and relative changes from baseline. Cutoffs were tested in binary logistic regression models of poor outcome (90-day mRS > 2). RESULTS: Two-hundred fifty-six of 714 patients met the inclusion criteria. In a multivariable model, a ≥10% mean arterial pressure decrease from baseline had an OR for poor outcome of 4.38 (95% CI, 1.53-12.56; P < .01). Other models revealed that any mean pressure of <85 mm Hg before reperfusion had an OR for poor outcome of 2.22 (95% CI, 1.09-4.55; P = .03) and that every 10-mm Hg drop in mean arterial pressure below 100 mm Hg had an OR of 1.28 (95% CI, 1.01-1.62; P = .04). CONCLUSIONS: A ≥10% mean arterial pressure drop from baseline is a strong risk factor for poor outcome in a homogeneous population of patients with stroke undergoing thrombectomy under sedation. This threshold could guide hemodynamic management of patients during sedation and general anesthesia.

cbl-b inhibits epidermal growth factor receptor signaling.

The role of cbl-b in signaling by the epidermal growth factor receptor (EGFR) was studied and compared with c-cbl. We demonstrate in vivo, that cbl-b, like c-cbl, is phosphorylated and recruited to the EGFR upon EGF stimulation and both cbl proteins can bind to the Grb2 adaptor protein. To investigate the functional role of cbl proteins in EGFR signaling, we transfected cbl-b or c-cbl into 32D cells overexpressing the EGFR (32D/EGFR). This cell line is absolutely dependent on exogenous IL-3 or EGF for sustained growth. 32D/EGFR cells overexpressing cbl-b showed markedly inhibited growth in EGF compared to c-cbl transfectants and vector controls. This growth inhibition by cbl-b was the result of a dramatic increase in the number of cells undergoing apoptosis. Consistent with this finding, cbl-b overexpression markedly decreased the amplitude and duration of AKT activation upon EGF stimulation compared to either vector controls or c-cbl overexpressing cells. In addition, the duration of EGF mediated MAP kinase and Jun kinase activation in cells overexpressing cbl-b is shortened. These data demonstrate that cbl-b inhibits EGF-induced cell growth and that cbl-b and c-cbl have distinct roles in EGF mediated signaling.

Conformational changes in the activation loop of the insulin receptor's kinase domain.

Low catalytic efficiency of basal-state protein kinases often depends on activation loop residues blocking substrate access to the catalytic cleft. Using the recombinant soluble form of the insulin receptor's kinase domain (IRKD) in its unphosphorylated state, activation loop conformation was analyzed by limited proteolysis. The rate of activation loop cleavage by trypsin is slow in the apo-IRKD. Bound Mg-adenine nucleoside di- and triphosphates increased the cleavage rate with half-maximal effects observed at 0.4-0.9 mM nucleotide. Adenosine monophosphate at concentrations up to 10 mM was not bound appreciably by the IRKD and had virtually no impact on activation loop cleavage. Amino-terminal and carboxy-terminal core-flanking regions of the IRKD had no statistically significant impact on the ligand-dependent or -independent activation loop cleavages. Furthermore, the core-flanking regions did not change the inherent conformational stability of the active site or the global stability of the IRKD, as determined by guanidinium chloride-induced denaturation. These measurements indicate that the intrasterically inhibitory conformation encompasses > or =90% of the ligand-free basal state kinase. However, normal intracellular concentrations of Mg-adenine nucleotides, which are in the millimolar range, would favor a basal-state conformation of the activation loop that is more accessible.

Clinical deterioration following improvement in the NINDS rt-PA Stroke Trial.

BACKGROUND AND PURPOSE: Little is known in regard to cerebral arterial reocclusion after successful thrombolysis. In the absence of arteriographic information, the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial investigators prospectively identified clinical deterioration following improvement (DFI) as a possible surrogate marker of cerebral arterial reocclusion after rt-PA-induced recanalization. Also, we identified any significant clinical deterioration (CD) even if not preceded by improvement. This observational analysis was designed to determine the incidence of DFI and CD in each treatment group, to identify baseline or posttreatment variables predictive of DFI or CD, and to determine any relationship between DFI, CD, and clinical outcome. METHODS: DFI was defined as any 2-point deterioration on the NIH Stroke Scale after an initial 2-point improvement after treatment. CD was defined as any 4-point worsening after treatment compared with baseline. All data were collected prospectively by investigators blinded to treatment allocation. A noncontrast brain CT was mandated when a 2-point deterioration occurred. All cases were validated by a central review committee. RESULTS: DFI was identified in 81 of the 624 patients (13%); 44 were treated with rt-PA and 37 were treated with placebo (P:=0.48). DFI occurred more often in patients with a higher baseline NIH Stroke Scale score. CD within the first 24 hours occurred in 98 patients (16% of all patients); 43 were given rt-PA and 55 were given placebo (P:=0.19). Baseline variables associated with CD included a less frequent use of prestroke aspirin and a higher incidence of early CT changes of edema or mass effect or dense middle cerebral artery sign. Patients with CD had higher rates of increased serum glucose and fibrin degradation products, and they also had higher rates of symptomatic intracranial hemorrhage and death. Patients who experienced either DFI or CD were less likely to have a 3-month favorable outcome. CONCLUSIONS: We found no association between DFI, CD, and rt-PA treatment, and no clinical evidence to suggest reocclusion. Deterioration was strongly associated with stroke severity and poor outcome and was less frequent in patients whose stroke occurred while they were on aspirin.

Finding the most powerful measures of the effectiveness of tissue plasminogen activator in the NINDS tPA stroke trial.

BACKGROUND AND PURPOSE: We sought to identify the most powerful binary measures of the treatment effect of tissue plasminogen activator (tPA) in the National Institute of Neurological Disorders and Stroke (NINDS) rTPA Stroke Trial. METHODS: Using the Classification and Regression Tree (CART) algorithm, we evaluated binary cut points and combination of binary cut points with the 4 clinical scales and head CT imaging measures in the NINDS tPA Stroke Trial at 4 times after treatment: 2 hours, 24 hours, 7 to 10 days, and 3 months. The first analysis focused on detecting evidence of "early activity" of tPA with the use of outcome measures derived from the 2-hour and 24-hour clinical and radiographic measures. The second analysis focused on longer-term outcome and "efficacy" and used outcome measures derived from 7- to 10-day and 3-month measures. After identifying the cut points with the ability to classify patients into the tPA and placebo groups using part I data from the trial, we then used data from part II of the trial to validate the results. RESULTS: Of the 5 most powerful outcome measures for early activity of tPA, 4 involved the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours or changes in the NIHSS score from baseline to 24 hours. The best overall single outcome measure was an NIHSS score

Gilles de la Tourette syndrome and the neurological basis of obsessions and compulsions.

Gilles de la Tourette syndrome (GTS) is a chronic neurological disorder manifested by involuntary motor tics and vocalizations. Many GTS patients also suffer from obsessions and compulsions. The clinical similarities between GTS and obsessive-compulsive disorder (OCD), their occurrence among members of the same families, and the fact that both can be observed as symptoms of known basal ganglia disturbances suggest that GTS and OCD share common neurological mechanisms. It is hypothesized that the tics and vocalizations of GTS are aberrant manifestations of simple motor programs that are spontaneously generated by the basal ganglia and that obsessions and compulsions represent more complex motor plans initiated by similar anomalous activities.

New data on lithium and haloperidol incompatibility.

The authors describe a case of combined lithium and haloperidol toxicity characterized by hyperpyrexia, severe rigidity, mutism, and development of irreversible tardive dyskinesia. This case is similar to four other cases described in the literature and to the neuroleptic malignant syndrome. The authors postulate that two types of combined lithium-neuroleptic toxicity occur: a neuroleptic malignant extrapyramidal syndrome and a lithium toxicity that occurs in combination with phenothiazines, primarily thioridazine. Possible mechanisms and preventive measures are discussed.

Cerebral hemodynamics in preeclampsia and eclampsia.

OBJECTIVE: To test further the hypothesis that preeclampsia and eclampsia are associated with cerebral vasospasm. DESIGN: Prospective case study. SETTING: Inpatient obstetrics service of an urban public hospital. PATIENTS AND METHODS: Eleven women with eclampsia (mean gestational age, 32 weeks), preeclampsia (mean gestational age, 36 weeks), or normotensive pregnancy (mean gestational age, 35 weeks). Middle cerebral artery (MCA) velocity was measured bilaterally in all patients by means of transcranial Doppler ultrasonography. RESULTS: Eclamptic patients (n = 3) had significantly higher mean flow velocities and lower average pulsatility indexes than did normotensive patients (n = 4) (average MCA-mean flow velocity, 165 vs 79 cm/s [P = .007]; average MCA pulsatility index, 0.51 vs 1.1 [P < .001]). Compared with normotensive pregnant women, preeclamptic patients (n = 4) had lower average pulsatility indexes (0.76, P = .003), but similar mean flow velocities (average MCA-mean flow velocity, 82 cm/s; P = .8). CONCLUSION: Significantly higher MCA velocities in eclamptic, but not preeclamptic, women compared with those in normotensive pregnant women suggests that moderate to severe vasospasm is associated with eclampsia.

Human immunodeficiency virus infection and stroke in young patients.

OBJECTIVE: To determine the association between human immunodeficiency virus (HIV) infection and stroke among young persons. DESIGN: Retrospective case-control study. SETTING: Large, inner-city public hospital. PARTICIPANTS: All patients aged 19 to 44 years with a diagnosis of stroke, whose HIV status was determined, admitted from January 1990 through June 1994. Controls matched for age and sex were selected from patients who were admitted during the same period for status asthmaticus whose HIV status was known. MAIN OUTCOME MEASURE: The associations of HIV infection with all strokes and with cerebral infarction, after adjustment for other cerebrovascular risk factors, were evaluated by Mantel-Haenszel stratified analyses. The subtypes and causes of stroke in HIV-infected patients were compared with HIV-seronegative patients. RESULTS: The HIV infection was associated with stroke (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.0-5.3) and cerebral infarction (OR, 3.4; 95% CI, 1.1-8.9), after adjustment for other cerebrovascular risk factors. Among patients with stroke, cerebral infarction was more frequent in HIV-infected patients than in HIV-seronegative patients (20 [80%] of 25 vs 48 [56%] of 88, P = .04). The frequency of cerebral infarctions associated with meningitis (P < .001) and protein S deficiency (P = .06) was higher in HIV-infected patients than in seronegative patients. CONCLUSIONS: Our study suggests that HIV infection is associated with an increased risk of stroke, particularly cerebral infarction in young patients. This risk is probably mediated by increased susceptibility of HIV-infected patients to meningitis and protein S deficiency.

Neuro-ophthalmic abnormalities in Tourette's syndrome: functional and anatomic implications.

Neuro-ophthalmic findings in 29 patients with Gilles de la Tourette's syndrome are described. Twenty-eight patients had blepharospasm, and 19 had other eye tics that included forced staring and involuntary gaze deviation. These neuro-ophthalmic abnormalities and ocular disturbances are similar to those found in known basal ganglia disorders.

The human Klüver-Bucy syndrome.

Twelve patients with the Klüver-Bucy syndrome (KBS) are described. The syndrome occurred in head trauma, Alzheimer's disease, Pick's disease, and following herpes encephalitis. KBS was transient after head trauma but was a persistent feature of the postencephalitic syndrome. In all cases KBS was combined with aphasia, amnesia, or dementia. Human KBS resembles the monkey syndrome, but in humans there is a more elaborate complex of behavioral disturbances. The behavioral manifestations are produced by bilateral temporal lobe dysfunction. Partial expression of the syndrome may have localizing validity.

Biopsy-proven cerebral vasculitis associated with cocaine abuse.

We report cerebral vasculitis in 2 cocaine users who developed symptoms (transient blindness and persistent headache) while smoking "crack," followed by progressive widespread cerebral dysfunction with focal signs over the next few weeks. One patient had smoked crack exclusively, and the other also used cocaine intravenously. Sedimentation rates were elevated and HIV titers negative. Arteriography was normal in 1 patient and in the other showed multiple large-vessel occlusions without beading. Brain biopsy showed vasculitis involving small vessels in both patients. Multinucleated cells were present in the neuropil, but there were no granulomas or evidence of infection. One patient improved significantly with corticosteroid treatment, and made a good recovery. The other died despite corticosteroid and cyclophosphamide treatment.

Thrombolysis in patients with transient neurologic deficits.

What is the risk of thrombolysis in patients with acute stroke who might recover without treatment? In the National Institute of Neurological Disorders and Stroke rt-PA for Acute Stroke Trial, 2.6% of patients taking placebo showed spontaneous 24-hour recovery, compared to 11.5% of recombinant tissue-type plasminogen activator (rt-PA)-treated patients (p < 0.001). There were no symptomatic ICH in the patients taking placebo; one hypertensive, rt-PA-treated patient hemorrhaged. Assuming the National Institute of Neurological Disorders and Stroke protocol is followed rigorously, patients with acute stroke rarely recover spontaneously and the thrombolytic risk is low.