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•GPVI is a key player in LPS-induced pulmonary thrombo-inflammation by promoting PNC formation, neutrophil recruitment, and NETosis.•Anti-GPVI treatment protects mice from LPS-induced ALI and respiratory failure.

Hintergrund: Patient*innen, die an einem akuten Atemnotsyndrom leiden, erhalten als letztmögliche Therapie eine extrakorporale Membranoxygenierung (ECMO). Am Universitätsklinikum Tübingen werden diese Patient*innen während dieser Phase durch ein speziell geschultes Team physiotherapeutisch behandelt, um einer körperlichen Dekonditionierung entgegenzuwirken. Ziel der Arbeit: In dieser Arbeit wurde das Risiko einer Blutung im Bereich der Kanüleneinstichstelle während der physiotherapeutischen Mobilisation untersucht und eine Einschätzung der Sicherheitsaspekte beschrieben. Methodik: Auf der anästhesiologischen Intensivstation des Universitätsklinikums Tübingen wurden in dem Zeitraum von 2013–2018 n= 83 Patient*innen behandelt, die den Einschlusskriterien entsprachen. Die Datensätze wurden mittels einer Fall-Kontroll-Studie retrospektiv analysiert. Die Patient*innen wurden nach ihrem erreichten Mobilisationsstand in eine passive Kontrollgruppe und in eine aktive Interventionsgruppe unterteilt. Blutungsereignisse, Implantationsdauer der ECMO und weitere Aspekte wurden in dieser Analyse besonders betrachtet. Ergebnisse und Schlussfolgerung: Es traten sowohl in der passiven als auch in der aktiven Gruppe jeweils 2 Blutungsereignisse auf, die jedoch nicht im Zusammenhang mit der physiotherapeutischen Mobilisation standen. Die Implantationsdauer der ECMO variiert insgesamt zwischen einem und 77 Tagen. Eine physiotherapeutische Mobilisation durch ein speziell geschultes Team erhöhte das Blutungsrisiko im Kanülenbereich nicht.

Three-dimensional (3D) right ventricular (RV) strain analysis is not routinely performed perioperatively. Although 3D RV strain adds incrementally to outcome prediction in various cardiac diseases, its role in the perioperative setting is not sufficiently understood. The aim of this study was to investigate the association between 3D RV strain measured on RV meshes created from 3D transesophageal echocardiographic data and short-term outcomes among patients undergoing cardiac surgery.

Thromboembolic events are frequently reported in patients infected with the SARS-CoV-2 virus. The exact mechanisms of COVID-19-associated hypercoagulopathy, however, remain elusive. Recently, we observed that platelets (PLTs) from patients with severe COVID-19 infection express high levels of procoagulant markers, which were found to be associated with increased risk for thrombosis. In the current study, we investigated the time course as well as the mechanisms leading to procoagulant PLTs in COVID-19. Our study demonstrates the presence of PLT-reactive IgG antibodies that induce marked changes in PLTs in terms of increased inner-mitochondrial transmembrane potential (Δψ) depolarization, phosphatidylserine (PS) externalization, and P-selectin expression. The IgG-induced procoagulant PLTs and increased thrombus formation were mediated by ligation of PLT Fc-γ RIIA (FcγRIIA). In addition, contents of calcium and cyclic-adenosine-monophosphate (cAMP) in PLTs were identified to play a central role in antibody-induced procoagulant PLT formation. Most importantly, antibody-induced procoagulant events, as well as increased thrombus formation in severe COVID-19, were inhibited by Iloprost, a clinically approved therapeutic agent that increases the intracellular cAMP levels in PLTs. Our data indicate that upregulation of cAMP could be a potential therapeutic target to prevent antibody-mediated coagulopathy in COVID-19 disease.

Thromboembolic events are frequently reported in patients infected with the SARS-CoV-2 virus. The exact mechanisms of COVID-19-associated hypercoagulopathy, however, remain elusive. Recently, we observed that platelets (PLTs) from patients with severe COVID-19 infection express high levels of procoagulant markers, which were found to be associated with increased risk for thrombosis. In the current study, we investigated the time course as well as the mechanisms leading to procoagulant PLTs in COVID-19. Our study demonstrates the presence of PLT-reactive IgG antibodies that induce marked changes in PLTs in terms of increased inner-mitochondrial transmembrane potential (Δψ) depolarization, phosphatidylserine (PS) externalization, and P-selectin expression. The IgG-induced procoagulant PLTs and increased thrombus formation were mediated by ligation of PLT Fc-γ RIIA (FcγRIIA). In addition, contents of calcium and cyclic-adenosine-monophosphate (cAMP) in PLTs were identified to play a central role in antibody-induced procoagulant PLT formation. Most importantly, antibody-induced procoagulant events, as well as increased thrombus formation in severe COVID-19, were inhibited by Iloprost, a clinically approved therapeutic agent that increases the intracellular cAMP levels in PLTs. Our data indicate that upregulation of cAMP could be a potential therapeutic target to prevent antibody-mediated coagulopathy in COVID-19 disease.

The pathophysiology of COVID-19–associated thrombosis seems to be multifactorial. We hypothesized that COVID-19 is accompanied by procoagulant platelets with subsequent alteration of the coagulation system. We investigated depolarization of mitochondrial inner transmembrane potential (ΔΨm), cytosolic calcium (Ca2+) concentration, and phosphatidylserine (PS) externalization. Platelets from COVID-19 patients in the intensive care unit (ICU; n = 21) showed higher ΔΨm depolarization, cytosolic Ca2+, and PS externalization compared with healthy controls (n = 18) and non-ICU COVID-19 patients (n = 4). Moreover, significant higher cytosolic Ca2+and PS were observed compared with a septic ICU control group (ICU control; n = 5). In the ICU control group, cytosolic Ca2+and PS externalization were comparable with healthy controls, with an increase in ΔΨm depolarization. Sera from COVID-19 patients in the ICU induced a significant increase in apoptosis markers (ΔΨm depolarization, cytosolic Ca2+, and PS externalization) compared with healthy volunteers and septic ICU controls. Interestingly, immunoglobulin G fractions from COVID-19 patients induced an Fcγ receptor IIA–dependent platelet apoptosis (ΔΨm depolarization, cytosolic Ca2+, and PS externalization). Enhanced PS externalization in platelets from COVID-19 patients in the ICU was associated with increased sequential organ failure assessment score (r= 0.5635) and D-dimer (r= 0.4473). Most importantly, patients with thrombosis had significantly higher PS externalization compared with those without. The strong correlations between markers for apoptosic and procoagulant platelets and D-dimer levels, as well as the incidence of thrombosis, may indicate that antibody-mediated procoagulant platelets potentially contributes to sustained increased thromboembolic risk in ICU COVID-19 patients.

The pathophysiology of COVID-19–associated thrombosis seems to be multifactorial. We hypothesized that COVID-19 is accompanied by procoagulant platelets with subsequent alteration of the coagulation system. We investigated depolarization of mitochondrial inner transmembrane potential (ΔΨm), cytosolic calcium (Ca2+) concentration, and phosphatidylserine (PS) externalization. Platelets from COVID-19 patients in the intensive care unit (ICU; n = 21) showed higher ΔΨm depolarization, cytosolic Ca2+, and PS externalization compared with healthy controls (n = 18) and non-ICU COVID-19 patients (n = 4). Moreover, significant higher cytosolic Ca2+ and PS were observed compared with a septic ICU control group (ICU control; n = 5). In the ICU control group, cytosolic Ca2+ and PS externalization were comparable with healthy controls, with an increase in ΔΨm depolarization. Sera from COVID-19 patients in the ICU induced a significant increase in apoptosis markers (ΔΨm depolarization, cytosolic Ca2+, and PS externalization) compared with healthy volunteers and septic ICU controls. Interestingly, immunoglobulin G fractions from COVID-19 patients induced an Fcγ receptor IIA–dependent platelet apoptosis (ΔΨm depolarization, cytosolic Ca2+, and PS externalization). Enhanced PS externalization in platelets from COVID-19 patients in the ICU was associated with increased sequential organ failure assessment score (r = 0.5635) and D-dimer (r = 0.4473). Most importantly, patients with thrombosis had significantly higher PS externalization compared with those without. The strong correlations between markers for apoptosic and procoagulant platelets and D-dimer levels, as well as the incidence of thrombosis, may indicate that antibody-mediated procoagulant platelets potentially contributes to sustained increased thromboembolic risk in ICU COVID-19 patients.

The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, we treated 2 patients with defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved during treatment. Moreover, coagulation parameters indicating hypofibrinolysis and complement activation normalized. The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, 2 patients received defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved and hypofibrinolysis/complement activation normalized during treatment.

•Sema7A controls neutrophil chemotaxis in vitro and the formation of platelet-neutrophil complexes in vivo.•Sema7A influences the early phase of inflammation, which is relevant to the outcome in murine experimental sepsis.

Acute kidney injury (AKI) is a common and often severe complication after major surgery. Postoperative AKI is associated with a considerable increase in morbidity and mortality. As no specific treatments exist, prevention of AKI is of high importance.

In critically ill patients infected with SARS-CoV-2, early leukocyte recruitment to the respiratory system was found to be orchestrated by leukocyte trafficking molecules accompanied by massive secretion of proinflammatory cytokines and hypercoagulability. Our study aimed to explore the interplay between leukocyte activation and pulmonary endothelium in different disease stages of fatal COVID-19. Our study comprised 10 COVID-19 postmortem lung specimens and 20 control lung samples (5 acute respiratory distress syndrome, 2 viral pneumonia, 3 bacterial pneumonia, and 10 normal), which were stained for antigens representing the different steps of leukocyte migration: E-selectin, P-selectin, PSGL-1, ICAM1, VCAM1, and CD11b. Image analysis software QuPath was used for quantification of positive leukocytes (PSGL-1 and CD11b) and endothelium (E-selectin, P-selectin, ICAM1, VCAM1). Expression of IL-6 and IL-1β was quantified by RT-qPCR. Expression of P-selectin and PSGL-1 was strongly increased in the COVID-19 cohort compared with all control groups (COVID-19:Controls, 17:23, P< .0001; COVID-19:Controls, 2:75, P< .0001, respectively). Importantly, P-selectin was found in endothelial cells and associated with aggregates of activated platelets adherent to the endothelial surface in COVID-19 cases. In addition, PSGL-1 staining disclosed positive perivascular leukocyte cuffs, reflecting capillaritis. Moreover, CD11b showed a strongly increased positivity in COVID-19 compared with all controls (COVID-19:Controls, 2:89; P = .0002), indicating a proinflammatory immune microenvironment. Of note, CD11b exhibited distinct staining patterns at different stages of COVID-19 disease. Only in cases with very short disease course, high levels of IL-1β and IL-6 mRNA were observed in lung tissue. The striking upregulation of PSGL-1 and P-selectin reflects the activation of this receptor–ligand pair in COVID-19, increasing the efficiency of initial leukocyte recruitment, thus promoting tissue damage and immunothrombosis. Our results show that endothelial activation and unbalanced leukocyte migration play a central role in COVID-19 involving the P-selectin–PSGL-1 axis.

Critical conditions such as sepsis following infection or traumatic injury disturb the complex state of homeostasis that may lead to uncontrolled inflammation resulting in organ failure, shock and death. They are associated with endogenous mediators that control the onset of acute inflammatory response, but the central problem remains the complete resolution of inflammation. Omega-3 enriched lipid emulsions (?-3+LEs) were used in experimental studies and clinical trials to establish homeostasis, yet with little understanding about their role on the resolution of inflammation and tissue regeneration. Here, we demonstrate that ?-3 lipid emulsions (LEs) orchestrate inflammation-resolution/regeneration mechanism during sterile peritonitis and murine polymicrobial sepsis. ?-3+LEs recessed neutrophil infiltration, reduced pro-inflammatory mediators, reduced the classical monocyte and enhanced the non-classical monocytes/macrophages recruitment and finally increased the efferocytosis in sepsis. The actions of ?-3+LE were 5-lipoxygenase (5-LOX) and 12/15-lipoxygenase (12/15-LOX) dependent. ?-3+LEs shortened the resolution interval by 56%, stimulated the endogenous biosynthesis of resolution mediators lipoxin A4, protectin DX and maresin 1 and contributed to tissue regeneration. ?-3+LEs protected against hypothermia and weight loss and enhanced survival in murine polymicrobial sepsis. We highlighted a role of ?-3+LEs in regulating key mechanisms within the resolution terrain during murine sepsis. This might form the basis for a rational design of sepsis specific clinical nutrition.

Aortic arch reconstruction surgery represents a challenge for the whole team involved in the treatment of these complex patients, especially in neonates and infants.

Supplemental Digital Content is available in the text.New surgical techniques aim for less-invasive implantation of left ventricular assist devices (LVADs) viasmall surgical incision sites. Echocardiography plays an important role during patient selection and guidance of the procedure. The surgical incision site can be identified preoperatively by transthoracic echocardiography. Intraoperative identification of left ventricular apex, de-airing, and monitoring heart function is performed by transesophageal echocardiography. This article highlights special echocardiographic considerations during less-invasive LVAD implantation surgeries.

Resolution of inflammation is now recognized as a biosynthetically active process involving pro-resolving mediators. Here, we show in zymosan-initiated peritoneal inflammation that the vagus nerve regulates local expression of netrin-1, an axonal guidance molecule that activates resolution, and that vagotomy reduced local pro-resolving mediators, thereby delaying resolution. In netrin-1+/− mice, resolvin D1 (RvD1) was less effective in reducing neutrophil influx promoting resolution of peritonitis compared with Ntn1+/+. Netrin-1 shortened the resolution interval, decreasing exudate neutrophils, reducing proinflammatory mediators, and stimulating the production of resolvins, protectins, and lipoxins. Human monocytes incubated with netrin-1 produced proresolving mediators, including resolvins and lipoxins. Netrin-1 and RvD1 displayed bidirectional activation in that they stimulated each other’s expression and enhanced efferocytosis. These results indicate that the vagus nerve regulates both netrin-1 and pro-resolving lipid mediators, which act in a bidirectional fashion to stimulate resolution, and provide evidence for a novel mechanism for local neuronal control of resolution.

During a systemic inflammatory response endothelial-expressed surface molecules have been strongly implicated in orchestrating immune responses. Previous studies have shown enhanced extracellular nucleotide release during acute inflammatory conditions. Therefore, we hypothesized that endothelial nucleotide receptors could play a role in vascular inflammation. To address this hypothesis, we performed screening experiments and exposed human microvascular endothelia to inflammatory stimuli, followed by measurements of P2Y or P2X transcriptional responses. These studies showed a selective induction of the P2Y6 receptor (> 4-fold at 24 hours). Moreover, studies that used real-time reverse transcription–polymerase chain reaction, Western blot analysis, or immunofluorescence confirmed time- and dose-dependent induction of P2Y6 with tumor necrosis factor α or Lipopolysaccharide (LPS) stimulation in vitro and in vivo. Studies that used MRS 2578 as P2Y6 receptor antagonist showed attenuated nuclear factor κB reporter activity and proinflammatory gene expression in human microvascular endothelial cells in vitro. Moreover, pharmacologic or genetic in vivo studies showed attenuated inflammatory responses in P2Y6−/− mice or after P2Y6 antagonist treatment during LPS-induced vascular inflammation. These studies show an important contribution of P2Y6 signaling in enhancing vascular inflammation during systemic LPS challenge and implicate the P2Y6 receptor as a therapeutic target during systemic inflammatory responses.

During a systemic inflammatory response endothelial-expressed surface molecules have been strongly implicated in orchestrating immune responses. Previous studies have shown enhanced extracellular nucleotide release during acute inflammatory conditions. Therefore, we hypothesized that endothelial nucleotide receptors could play a role in vascular inflammation. To address this hypothesis, we performed screening experiments and exposed human microvascular endothelia to inflammatory stimuli, followed by measurements of P2Y or P2X transcriptional responses. These studies showed a selective induction of the P2Y6receptor (> 4-fold at 24 hours). Moreover, studies that used real-time reverse transcription–polymerase chain reaction, Western blot analysis, or immunofluorescence confirmed time- and dose-dependent induction of P2Y6with tumor necrosis factor α or Lipopolysaccharide (LPS) stimulation in vitro and in vivo. Studies that used MRS 2578 as P2Y6receptor antagonist showed attenuated nuclear factor κB reporter activity and proinflammatory gene expression in human microvascular endothelial cells in vitro. Moreover, pharmacologic or genetic in vivo studies showed attenuated inflammatory responses in P2Y6−/−mice or after P2Y6antagonist treatment during LPS-induced vascular inflammation. These studies show an important contribution of P2Y6signaling in enhancing vascular inflammation during systemic LPS challenge and implicate the P2Y6receptor as a therapeutic target during systemic inflammatory responses.

Extracellular adenosine has been implicated in vascular adaptation to hypoxia. Based on the observation that increases in intracellular adenosine can effectively elevate extracellular adenosine, we studied the contribution of adenosine kinase (AK, intracellular conversion of adenosine to adenosine monophosphate [AMP]) to vascular adenosine responses. Initial in vitro studies of ambient hypoxia revealed prominent repression of endothelial AK transcript (85% ± 2% reduction), protein, and function. Transcription factor binding assays and hypoxia inducible factor 1-α (HIF-1α) loss- and gain-of-function studies suggested a role for HIF-1α in transcriptional repression of AK. Moreover, repression of AK by ambient hypoxia was abolished in conditional HIF-1α mutant mice in vivo. Studies of endothelial barrier function revealed that inhibition or siRNA repression of AK is associated with enhanced adenosine-dependent barrier responses in vitro. Moreover, in vivo studies of vascular barrier function demonstrated that AK inhibition with 5′-iodotubericidin (1 mg/kg prior to hypoxia) significantly attenuated hypoxia-induced vascular leakage in multiple organs and reduced hypoxia-associated increases in lung water. Taken together, our data reveal a critical role of AK in modulating vascular adenosine responses and suggest pharmacologic inhibitors of AK in the treatment of conditions associated with hypoxia-induced vascular leakage (eg, sepsis or acute lung injury).

Extracellular adenosine has been implicated in vascular adaptation to hypoxia. Based on the observation that increases in intracellular adenosine can effectively elevate extracellular adenosine, we studied the contribution of adenosine kinase (AK, intracellular conversion of adenosine to adenosine monophosphate [AMP]) to vascular adenosine responses. Initial in vitro studies of ambient hypoxia revealed prominent repression of endothelial AK transcript (85% ± 2% reduction), protein, and function. Transcription factor binding assays and hypoxia inducible factor 1-α (HIF-1α) loss- and gain-of-function studies suggested a role for HIF-1α in transcriptional repression of AK. Moreover, repression of AK by ambient hypoxia was abolished in conditional HIF-1α mutant mice in vivo. Studies of endothelial barrier function revealed that inhibition or siRNA repression of AK is associated with enhanced adenosine-dependent barrier responses in vitro. Moreover, in vivo studies of vascular barrier function demonstrated that AK inhibition with 5′-iodotubericidin (1 mg/kg prior to hypoxia) significantly attenuated hypoxia-induced vascular leakage in multiple organs and reduced hypoxia-associated increases in lung water. Taken together, our data reveal a critical role of AK in modulating vascular adenosine responses and suggest pharmacologic inhibitors of AK in the treatment of conditions associated with hypoxia-induced vascular leakage (eg, sepsis or acute lung injury).

Extracellular levels of adenosine increase during hypoxia. While acute increases in adenosine are important to counterbalance excessive inflammation or vascular leakage, chronically elevated adenosine levels may be toxic. Thus, we reasoned that clearance mechanisms might exist to offset deleterious influences of chronically elevated adenosine. Guided by microarray results revealing induction of endothelial adenosine deaminase (ADA) mRNA in hypoxia, we used in vitro and in vivo models of adenosine signaling, confirming induction of ADA protein and activity. Further studies in human endothelia revealed that ADA-complexing protein CD26 is coordinately induced by hypoxia, effectively localizing ADA activity at the endothelial cell surface. Moreover, ADA surface binding was effectively blocked with glycoprotein 120 (gp120) treatment, a protein known to specifically compete for ADA-CD26 binding. Functional studies of murine hypoxia revealed inhibition of ADA with deoxycoformycin (dCF) enhances protective responses mediated by adenosine (vascular leak and neutrophil accumulation). Analysis of plasma ADA activity in pediatric patients with chronic hypoxia undergoing cardiac surgery demonstrated a 4.1 ± 0.6-fold increase in plasma ADA activity compared with controls. Taken together, these results reveal induction of ADA as innate metabolic adaptation to chronically elevated adenosine levels during hypoxia. In contrast, during acute hypoxia associated with vascular leakage and excessive inflammation, ADA inhibition may serve as therapeutic strategy.

Extracellular levels of adenosine increase during hypoxia. While acute increases in adenosine are important to counterbalance excessive inflammation or vascular leakage, chronically elevated adenosine levels may be toxic. Thus, we reasoned that clearance mechanisms might exist to offset deleterious influences of chronically elevated adenosine. Guided by microarray results revealing induction of endothelial adenosine deaminase (ADA) mRNA in hypoxia, we used in vitro and in vivo models of adenosine signaling, confirming induction of ADA protein and activity. Further studies in human endothelia revealed that ADA-complexing protein CD26 is coordinately induced by hypoxia, effectively localizing ADA activity at the endothelial cell surface. Moreover, ADA surface binding was effectively blocked with glycoprotein 120 (gp120) treatment, a protein known to specifically compete for ADA-CD26 binding. Functional studies of murine hypoxia revealed inhibition of ADA with deoxycoformycin (dCF) enhances protective responses mediated by adenosine (vascular leak and neutrophil accumulation). Analysis of plasma ADA activity in pediatric patients with chronic hypoxia undergoing cardiac surgery demonstrated a 4.1 ± 0.6-fold increase in plasma ADA activity compared with controls. Taken together, these results reveal induction of ADA as innate metabolic adaptation to chronically elevated adenosine levels during hypoxia. In contrast, during acute hypoxia associated with vascular leakage and excessive inflammation, ADA inhibition may serve as therapeutic strategy.

Background: Alcohol abuse may involve an altered neuroendocrine response that mediates lymphocyte‐derived proopiomelanocortin (POMC) production and inflammation. We investigated POMC messenger RNA (mRNA) expression in human lymphocytes ex vivo and their relation to plasma ACTH and immunoreactive β‐endorphin (IR‐β‐EP) after intravenous injection of human corticotropin releasing factor (hCRF) in chronic alcoholics (n= 12) and nonalcoholics (n= 12) before surgery. Lipopolysaccharide‐stimulated interleukin (IL)‐1 receptor antagonist (IL‐1 Ra) as a marker for chronic inflammation was determined.

From the physician's perspective, the laboratory diagnosis of learning disabilities is essentially corroborative of history and physical examination. However, since many psychologists and educators tend to think of these disorders in terms of test scores, it is especially important for the physician to understand the common test instruments. The distinctions between aptitude and achievement, between general and specific aptitudes, and between age equivalents and grade equivalents are among those essential to proper interpretation of test scores. An understanding of what physiologically oriented laboratory tests do and do not contribute to diagnosis will help the physician adopt sensible criteria for ordering these tests.

Management of a case of learning disability is nearly always the task of a team of which the physician is but one member. Because consultation to the physician is often of the nature of “second opinion,” diplomacy is critical. It is helpful for all to understand that the biological perspective is only 1 of several. The physician has a role not only in evaluation, but also in follow-up over the long term. An especially important distinction is that between remedial instruction and curriculum support.

Neurologists are called upon with increasing frequency to provide advice to children and adults who are having difficulty coping with academic challenges. An understanding of specific handicaps to academic function (learning disabilities) is essential to this task. The nature of learning and learning ability (intelligence) must first be grasped, especially the distinction between aptitude and skill. Specific learning disabilities must then be understood as restricted deficits in aptitude for learning.

The teratogenicity of maternal epilepsy has been attributed to several factors, including the antiepileptic drugs taken to prevent seizures during pregnancy, the occurrence of seizures during pregnancy, and the factors in the mother that caused her to have epilepsy. We have addressed the hypothesis that the children of women who have a history of epilepsy (seizure history), but who took no antiepileptic drugs (AED) and had no tonic-clonic seizures in pregnancy, have an increased risk of malformations and diminished intelligence. The frequency of cognitive dysfunction was determined in 57 seizure history and 57 matched control children aged 6–l6 years. The masked evaluation of the children included a physical and neurologic examination and testing with the Wechsler Intelligence Scale for Children-Revised (WISC-R) and a systematic physical examination for the features of the fetal AED syndrome. The evaluation of both parents of each child included a test of reasoning (Ravens Progressive Matrix) and a physical examination. There were no differences between the two groups of children in either IQ scores or physical features; none of the seizure history children was judged to have the “anticonvulsant face” or digit hypoplasia. This study had 80% power to rule out a difference of seven or more IQ points between the two groups, based on a two-sided test at a 5% level of significance. Our confidence in concluding that there was no difference between seizure history and control infants was strengthened by the fact that no statistically significant differences were observed with respect to multiple outcomes, including eight related measures of intelligence. Thirty (53%) of the seizure history mothers resumed taking AED after the birth of the child we evaluated. Additional studies are needed to address the teratogenicity of the antiepileptic drugs as monotherapy. Teratology 61:196–202, 2000. © 2000 Wiley-Liss, Inc.

Utilizing computerized brain tomography, left-right morphologic asymmetries of the parietooccipital region were judged in 16 autistic patients, 44 mentally retarded patients, and 100 miscellaneous neurological patients. In 57% of the autistic patients the right parietooccipital region was wider than the left, while this pattern of cerebral asymmetry was found in only 23% of the mentally retarded patients and 25% of the neurological patients. It is suggested that unfavorable morphologic asymmetries of the brain near the posterior language zone may contribute to the difficulties autistic children experience in acquiring language.

Deficits in visual discrimination were examined in 30 combat soldiers with head wounds, 20 of whom had unilateral lesions (10 right and 10 left) of the posterior cerebral hemispheres and 10 of whom had frontal lobe wounds, left, right or bilateral. Seven of the patients with posterior lesions, but none with frontal lesions, showed visual spatial disorientation as demonstrated by a shift in the peak of the stimulus generalization gradient of an experimentally conditioned sensory discrimination. The peak shift occurred to the side opposite the cerebral lesion in all cases, and the deficit did not occur when the task was presented as a match to sample.

Certain clinical tests of widely reputed importance to reading disability have been applied, together with semi-automated visual sample-matching tasks, to a randomly selected school population of good and poor readers. Those performance deficits found with significant frequency among the poor readers of normal intelligence include laterality awareness of body parts (although not laterality preference), and visual sample-matching with three-letter words where the match involved only the order of letters within the word. Coincidence of these two findings suggests that further study might elucidate some more general deficit of laterality awareness in significant portions of the total population of normally intelligent poor readers.

THE SUBJECT of this report suffered a stroke at the age of 14, and the available evidence suggests extensive damage to the left (dominant) cerebral hemisphere. During the two years since onset of his illness we have carried out a series of behavioral studies relevant to the general problem of interhemispheric relations, with particular reference to language function.Clinical tests indicated that the patient was unable to write single letters to dictation, or even to select a dictated letter from several available visual choices. He was, however, able to deal fairly effectively with simple words on these tasks. It was this apparent discrepancy which prompted us to seek through special testing techniques a more precise delineation of his behavioral deficits.An additional, although not secondary, purpose of this report is to describe an investigative methodology. As is so often the case, our patient's almost complete lack of oral speech

Four subjects with partial or episodic complete urinary retention and bladder hypotonicity with large urinary residuals underwent "habituation" treatment. Results indicated an exponential decrease in urinary residuals to 0 ml and disappearance of partial or complete urinary retention within 20 weeks. This study is presented as an example of how conditioning therapy may be applied to the treatment of certain neurological disorders.(JAMA 232:1264-1266, 1975)

• The computerized brain tomograms of 24 patients with developmental dyslexia were analyzed for cerebral asymmetry. Ten patients showed a reversal of the pattern of asymmetry regularly observed in normal right-handed individuals so that the right parietooccipital region was wider than the left. The ten dyslexic patients with this reversal of cerebral asymmetry had a lower mean verbal IQ than the other 14 dyslexic patients in this study. The reversal of cerebral asymmetry that occurred in ten of the dyslexic patients may result in language lateralization to a cerebral hemisphere that is structurally less suited to support language function and thus act as a risk factor for the development of reading disability.