Early in vivo MR spectroscopy findings in organophosphate-induced brain damage-potential biomarkers for short-term survival

Organophosphates are highly toxic substances, which cause severe brain damage. The hallmark of the brain injury is major convulsions. The goal of this study was to assess the spatial and temporal MR changes in the brain of paraoxon intoxicated rats. T2‐weighted MRI and ¹H‐MR‐spectroscopy were conducted before intoxication, 3 h, 24 h, and 8 days postintoxication. T2 prolongation mainly in the thalami and cortex was evident as early as 3 h after intoxication (4–6% increase in T2 values, P < 0.05). On spectroscopy, N‐acetyl aspartate (NAA)/creatine and NAA/choline levels significantly decreased 3 h postintoxication (>20% decrease, P < 0.005), and 3 h lactate peak was evident in all intoxicated animals. On the 8 th day, although very little T2 changes were evident, NAA/creatine and choline/creatine were significantly decreased (>15%, P < 0.05). Animals who succumbed had extensive cortical edema, significant higher lactate levels and a significant decrease in NAA/creatine and NAA/choline levels compared to animals which survived the experiment. Organophosphates‐induced brain damage is obvious on MR data already 3 h postintoxication. In vivo spectroscopic changes are more sensitive for assessing long‐term injury than T2‐weighted MR imaging. Early spectroscopic findings might be used as biomarkers for the severity of the intoxication and might predict early survival. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.     

Lack of correlation between disease activity and decreased stimulated secretion of IL-10 in lymphocytes from patients with celiac disease

BACKGROUND: Celiac disease (CD) is commonly believed to be a predominantly Th1 disease. However, the exact balance between the Th1 and Th2 arms, as well as the correlation to clinical parameters, remains unclear. The aim was to assess the Th1/Th2 cytokine profile and its correlation to clinical parameters in active and non-active CD patients. METHODS: Peak, total secretion and secretory pattern of the Th1 cytokines (IFN-gamma and IL-2) and Th2 cytokines (IL-4 and IL-10) were determined in resting and stimulated peripheral blood mononuclear cells (PBMC) from 19 CD patients with active and non-active disease and 20 normal controls. RESULTS: Peak and total secretion of IL-10 were significantly reduced in CD patients compared with normal controls. This was due to a persistently flat secretory pattern of IL-10 over time in CD patients. In addition, IFN-gamma/IL-10 and the IL-2/IL-10 ratios of peak and total secretion were higher in patients than in controls. In contrast, peak, total secretion and secretory pattern of IL-2, IFN-gamma and IL-4 were comparable in patients and controls as well as the IL-2/IL-4 and IFN-gamma/IL-4 ratios. No difference in the cytokine secretion or Th1/Th2 ratio was found between active and non-active patients or between pediatric and adult patients. CONCLUSIONS: These data indicate that the Thl/Th2 balance in CD is shifted towards Th1 cytokines because of a down-regulated IL-10 secretion. The aberrant profile of cytokine secretion of these patients is not associated with clinical parameters and suggests an inherent defect in IL-10 secretion in CD.     

Acute myocardial infarction as the presenting symptom of acute myeloblastic leukemia with extreme hyperleukocytosis

This case report deals with an unusual leukostatic complication in a 56-year-old woman with acute myeloblastic leukemia (AML) and extreme hyperleukocytosis (316 x 10(9)/L) who presented with acute myocardial infarction (MI). After leukopheresis the patient achieved hemodynamic stabilization and rapid neurologic recovery of encephalopathy that had also developed after the infarction. Considering the central role of WBC in the remodeling of post MI myocardial tissue, it was obvious that administration of chemotherapy with its subsequent inevitable pancytopenia could impose an increased risk for further cardiac complications including myocardial rupture. Nevertheless, cytarabine-based induction chemotherapy was initiated 3 days after admission, and she achieved prolonged complete remission. Coronary angiography disclosed segmental atherosclerosis, but the only significant obstruction was in the right coronary artery. The patient died with relapsed leukemia 7 years later without recurrence of any cardiac symptoms or signs. Autopsy disclosed segmental coronary atherosclerosis involving the LAD (60% obstruction), suggesting that atherosclerosis was a predisposing risk factor. Additional compromise to blood perfusion due to leukostasis had led to this unusual complication of AML involving a major vessel. This is the first documented case of leukostasis causing coronary artery occlusion as well as the first report of successful induction chemotherapy for AML during a myocardial infarction.     

Laser ablation of the mouse zona pellucida for blastomere biopsy

Purpose A xenon-chloride non-contact laser system was evaluated for opening the mouse zona pellucida prior to embryo biopsy.Methods A 308 nm beam was directed into the rear inlet of an inverted microscope, and exited to the target through a 100 X quartz objective. Following laser opening of the zona, blastomere removal was performed.Results Eight-cell mouse embryos (n = 611) were isolated for this study. Ninety-one percent of laser biopsy embryos proceeded to the blastocyst stage compared to 94% for acidified Tyrode's biopsied embryos and 83% for zona-intact controls. Many of the laser exposed embryos, however, exhibited morphologic aberrations such as isolated blastomere arrest and embryo growth delay. Thirtyfour percent of the laser biopsy embryos implanted compared with 47% and 37% for acid biopsied and control embryos, respectively. A significant decrease in fetal development following laser zona opening, however, was noted.Conclusions Though this laser system does allow for blastocyst formation and implantation following biopsy, the possible detrimental effects on embryonic and fetal development should be further evaluated.     

GSK3β regulates physiological migration of stem/progenitor cells via cytoskeletal rearrangement

Regulation of hematopoietic stem and progenitor cell (HSPC) steady-state egress from the bone marrow (BM) to the circulation is poorly understood. While glycogen synthase kinase-3β (GSK3β) is known to participate in HSPC proliferation, we revealed an unexpected role in the preferential regulation of CXCL12-induced migration and steady-state egress of murine HSPCs, including long-term repopulating HSCs, over mature leukocytes. HSPC egress, regulated by circadian rhythms of CXCL12 and CXCR4 levels, correlated with dynamic expression of GSK3β in the BM. Nevertheless, GSK3β signaling was CXCL12/CXCR4 independent, suggesting that synchronization of both pathways is required for HSPC motility. Chemotaxis of HSPCs expressing higher levels of GSK3β compared with mature cells was selectively enhanced by stem cell factor–induced activation of GSK3β. Moreover, HSPC motility was regulated by norepinephrine and insulin-like growth factor-1 (IGF-1), which increased or reduced, respectively, GSK3β expression in BM HSPCs and their subsequent egress. Mechanistically, GSK3β signaling promoted preferential HSPC migration by regulating actin rearrangement and microtubuli turnover, including CXCL12-induced actin polarization and polymerization. Our study identifies a previously unknown role for GSK3β in physiological HSPC motility, dictating an active, rather than a passive, nature for homeostatic egress from the BM reservoir to the blood circulation.     

Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association

The plasma glycoprotein von Willebrand factor (VWF) exhibits fivefold antigen level variation across the normal human population determined by both genetic and environmental factors. Low levels of VWF are associated with bleeding and elevated levels with increased risk for thrombosis, myocardial infarction, and stroke. To identify additional genetic determinants of VWF antigen levels and to minimize the impact of age and illness-related environmental factors, we performed genome-wide association analysis in two young and healthy cohorts (n = 1,152 and n = 2,310) and identified signals at ABO (P < 7.9E-139) and VWF (P < 5.5E-16), consistent with previous reports. Additionally, linkage analysis based on sibling structure within the cohorts, identified significant signals at chromosome 2q12–2p13 (LOD score 5.3) and at the ABO locus on chromosome 9q34 (LOD score 2.9) that explained 19.2% and 24.5% of the variance in VWF levels, respectively. Given its strong effect, the linkage region on chromosome 2 could harbor a potentially important determinant of bleeding and thrombosis risk. The absence of a chromosome 2 association signal in this or previous association studies suggests a causative gene harboring many genetic variants that are individually rare, but in aggregate common. These results raise the possibility that similar loci could explain a significant portion of the “missing heritability” for other complex genetic traits.     

Traumatic injuries to the teeth in young individuals with cerebral palsy

Abstract –  The purpose of the study was to assess the characteristics of dental trauma in individuals with cerebral palsy (CP). The study group consisted of 68 individuals (36 boys and 32 girls) who visit daily a school dedicated for children with CP. Their age ranged between 7 and 21 years with a mean age of 12.6 years. The majority (74%) required a wheel chair for mobility, 13% used a walker and the others were able to walk with crutches or without aid. The parents were asked to complete a questionnaire regarding their child's age, gender, medical history, and history of dental trauma. The teeth were evaluated clinically for evidences of past injuries to the teeth, enamel defects in the permanent incisors, scars on the chin and size of overjet. Thirty-nine individuals (57%) had signs of trauma to the permanent teeth. Sixty-eight teeth, mostly the maxillary central incisors, were injured. Boys were slightly less affected than girls, 56% (20/36) and 59% (19/32), respectively. Fracture of enamel and dentine was the most common type of injury (62%). Scars on the chin were detected in 28% of the individuals but only one had fractures of the molar (primary) teeth. The overjet ranged between −3.0 and +14 mm but no correlation could be found between the size of the overjet and tendency to injure the teeth. Localized enamel defects were detected on the labial surface of 13 teeth in nine individuals, probably due to luxation injuries to the primary incisors. The prevalence of dental injuries in a group of individuals with CP was found to be much higher than that of healthy populations despite the fact that CP individuals do not take part in violent sport activities as healthy children do. This should alert caregivers to carry out a profound investigation of the events that result in dental injuries in disabled individuals and suggest methods to reduce this type of morbidity.     

Homonymous hemianopia caused by occipital lobe infarction in heparin-induced thrombocytopenia and thrombosis syndrome.

A 73-year-old woman developed mental confusion and finger pain after treatment with enoxaparin following arthroplasty. A platelet count was 163,000/microL. Because digital embolism was suspected, she was emergently treated with heparin and recombinant tissue plasminogen activator (rTPA). During rTPA infusion, she reported sudden hemifield loss, so the infusion was aborted. Brain CT disclosed a non-hemorrhagic occipital infarct. Platelets had fallen to 63,000 over eight days, and antibodies against a complex of heparin and platelet factor 4 were detected. These findings led to the diagnosis of heparin-induced thrombocytopenia and thrombosis syndrome (HITTS), an immune-mediated disorder in which venous and arterial thromboses occur. Right lower extremity deep venous thromboses were later diagnosed, and an MRI disclosed multiple cerebral infarcts of recent onset but different ages. Previous reports have documented brain arterial strokes in HITTS, mostly in the distribution of the middle cerebral artery, but clinical documentation is sparse, and there have been no imaging reports. This is the first report to document the clinical and imaging features of a HITTS stroke and the first to describe a stroke presumptively caused by a low molecular weight heparin. It emphasizes that HITTS may cause stroke even when the platelet count is normal. Diagnosis of HITTS should prompt immediate cessation of heparin treatment and substitution of a direct thrombin inhibitor or fondaparinux.