In vivo characterization of emerging white matter microstructure in the fetal brain in the third trimester

The third trimester of pregnancy is a period of rapid development of fiber bundles in the fetal white matter. Using a recently developed motion‐tracked slice‐to‐volume registration (MT‐SVR) method, we aimed to quantify tract‐specific developmental changes in apparent diffusion coefficient (ADC), fractional anisotropy (FA), and volume in third trimester healthy fetuses. To this end, we reconstructed diffusion tensor images from motion corrected fetal diffusion magnetic resonance imaging data. With an approved protocol, fetal MRI exams were performed on healthy pregnant women at 3 Tesla and included multiple (2–8) diffusion scans of the fetal head (1–2 b = 0 s/mm² images and 12 diffusion‐sensitized images at b = 500 s/mm²). Diffusion data from 32 fetuses (13 females) with median gestational age (GA) of 33 weeks 4 days were processed with MT‐SVR and deterministic tractography seeded by regions of interest corresponding to 12 major fiber tracts. Multivariable regression analysis was used to evaluate the association of GA with volume, FA, and ADC for each tract. For all tracts, the volume and FA increased, and the ADC decreased with GA. Associations reached statistical significance for: FA and ADC of the forceps major; volume and ADC for the forceps minor; FA, ADC, and volume for the cingulum; ADC, FA, and volume for the uncinate fasciculi; ADC of the inferior fronto‐occipital fasciculi, ADC of the inferior longitudinal fasciculi; and FA and ADC for the corticospinal tracts. These quantitative results demonstrate the complex pattern and rates of tract‐specific, GA‐related microstructural changes of the developing white matter in human fetal brain.     

Fear of sexual intercourse in patients with coronary artery disease: a pilot study of associated morbidity

IntroductionSexual fear is a known cause for avoidance of intercourse, especially in patients with chronic conditions.AimGiven the significant impact of fear of intercourse on the quality of life, we herein report our pilot results regarding the differences in the demographic, clinical, marital, and psychological characteristics of coronary artery disease (CAD) patients with and without sexual fear.MethodsIn this cross-sectional study conducted in Baqyiatallah Hospital, Tehran, Iran, in 2006, 87 married CAD patients were assessed for the presence of sexual fear. Subjects with and without sexual fear were compared for demographic and clinical data as well as for Hospital Anxiety and Depression Scale (HADS) and Revised-Dyadic Adjustment Scale (R-DAS) scores.Main Outcome MeasureDemographic and clinical data, sexual fear (Relationship and Sexuality Scale), symptoms of anxiety and depression (HADS), and marital relation quality (R-DAS).ResultsTwenty-nine subjects were reported to have some degrees of fear of sexual intercourse and a lower frequency of sexual intercourse. Age, socioeconomic status, education level, tobacco smoking, and history of myocardial infarction were significantly different between those with and the ones without sexual fear. Body mass index, extent of coronary involvement, chronic obstructive pulmonary disease, hypertension, stroke, hyperlipidemia, history of diabetes, and the use of beta-blockers were not statistically different in the two groups. The subjects with sexual fear reported higher HADS depressive and R-DAS scores but not higher HADS anxiety scores.ConclusionAmong different nonmodifiable and modifiable correlates of fear of sexual intercourse in CAD patients, marital relationship and depressive symptoms should be highlighted in future interventional studies with the aim of allaying such fears. Kazemi-Saleh D, Pishgou B, Assari S, and Tavallaii SA. Fear of sexual intercourse in patients with coronary artery disease: A pilot study of associated morbidity.     

Effects of hemodynamic instability on brain death-induced prepreservation liver damage

BACKGROUND: Brain death (BD) is an important multifactorial variable contributing to donor-specific liver damage. Our study aimed at assessing the specific effects of hemodynamic instability on systemic and hepatic parameters of perfusion, bowel ischemia, and oxidative stress in a porcine model of BD. METHODS: BD was induced in 16 pigs (German Landrace, 18-28 kg) in two groups (hypotension-BD [HYPO-BD], n=8; normotension-BD [NORM-BD], n=8), which were compared with control animals/living donors (n=6) for a period of 2 hr. We analyzed systemic hemodynamic parameters, bowel ischemia (intramucosal pH in the stomach and colon, plasma endotoxin levels, and endotoxin-neutralizing capacity [ENC]), and oxidative stress (total glutathione levels in erythrocytes) and compared the findings with hepatic parameters of perfusion (hepatic arterial flow, portal venous flow, and microperfusion) and liver oxidative stress (reduced glutathione and oxidized glutathione levels in the liver). RESULTS: Independent of the hemodynamic stability, liver macrocirculation and microcirculation decreased (HYPO-BD, 79+/-6 to 69+/-10 mL/100 g/min; NORM-BD, 81+/-10 to 73+/-7 mL/100 g/min; P<0.05). Hepatocellular damage (aspartate aminotransferase: NORM-BD, 49+/-20 units/L; HYPO-BD, 170+/-140 units/L; P<0.01) and hepatic oxidative stress (reduced glutathione in the liver/oxidized glutathione in the liver: NORM-BD, 29.4+/-2.3 to 13.0+/-1.3; HYPO-BD, 29.4+/-2.3 to 9.05+/-0.81; P<0.001) increased in both BD groups. With dependence on systemic hemodynamic parameters, bowel ischemia increased (intramucosal pH in the colon, 7.22+/-0.01, P<0.01; ENC, 75+/-14 endotoxin-neutralizing units/mL, P<0.01; endotoxin levels, 7+/-2 to 43+/-10 pg/mL, P<0.01) in the HYPO-BD group but not in the NORM-BD group or the living donor group. Furthermore, systemic oxidative stress was increased in the HYPO-BD group only (total glutathione levels in erythrocytes, 2.65+/-0.25 to 0.15+/-0.25 mM; P<0.01). CONCLUSIONS: During BD, liver-specific parameters (portal venous flow, microperfusion, aspartate aminotransferase activity, ENC, and hepatic oxidative stress) were compromised, independent of the hemodynamic status. Therefore, the systemic hemodynamic status does not reflect the functional status of the liver during BD.     

Breast Fibroblasts Modulate Early Dissemination,Tumorigenesis, and Metastasis through Alteration of Extracellular Matrix Characteristics

A wealth of evidence has now demonstrated that the microenvironment in which a tumorigenic cell evolves is as critical to its evolution as the genetic mutations it accrues. However, there is still relatively little known about how signals from the microenvironment contribute to the early events in the progression to malignancy. To address this question, we used a premalignant mammary model to examine how fibroblasts, and the extracellular matrix (ECM) proteins they secrete, influence progression to malignancy. Their effect on metastatic malignant cells was also assessed for comparison. We found that carcinoma-associated fibroblasts, and the distinct aligned ECM they deposit, can cause both premalignant and malignant mammary epithelial cells to assume a mesenchymal morphology that is associated with increased dissemination and metastasis, while benign reduction mammoplasty fibroblasts favor the maintenance of an epithelial morphology and constrain early dissemination, tumor growth, and metastasis. Our results suggest that normalizing the organization of the ECM could be effective in limiting systemic dissemination and tumor growth.     

Orthostatic Headaches in the Syndrome of the Trephined: Resolution Following Cranioplasty

Objective.— To draw attention to the syndrome of the trephined as a potential cause for orthostatic headaches without cerebrospinal fluid (CSF) leak. Background.— Orthostatic headaches typically result from CSF leaks but sometimes may occur in conditions without any evidence of CSF leakage. Methods.— A 37‐year‐old right‐handed woman became comatose after a motor vehicle accident with cerebral contusions and massive left cerebral edema. A large frontoparietal craniectomy was carried out. In 5 months, she made good neurologic recovery. Freeze‐preserved bone flap was placed back. In several weeks she was functionally near normal. Two years later, she began to complain of orthostatic headache and gradually additional manifestations appeared including progressive gait unsteadiness, imprecise speech, cognitive difficulties, and an increasing left hemiparesis along with progressive sinking of the skull defect and shift of the midline and ventricular distortion. She underwent removal of resorptive sinking bone flap and construction of an acrylic cranioplasty. Results.— At 6‐month follow‐up, there was complete resolution of the orthostatic headaches, remarkable neurologic improvement along with resolution of midline shift and ventricular distortion. Conclusion.— The syndrome of the trephined is yet another cause of orthostatic headaches without CSF leak.     

Hyperthermia induces differentiation without apoptosis in permissive temperatures in human erythroleukaemia cells.

PURPOSE: The aim of the present study was to investigate whether induction of differentiation by hyperthermia is accompanied by apoptosis and necrosis to further evaluate the benefits of using hyperthermia as a differentiation inducing physical modality. MATERIALS AND METHOD: Differentiation was evaluated in K562 erythroleukaemia cells by measuring haemoglobin synthesis and flow cytometric measurement of glycophorin A expression. Apoptosis was measured by Annexin-V-FITC and Propidium Iodide (PI) double staining assay. Apoptosis and necrosis was also evaluated morphologically using staining with acridine orange/ethidium bromide (AO/EtBr) by fluorescence microscopy. Heat shock protein 70 (HSP70) level was measured by ELISA kit. RESULTS: Hyperthermia (43 degrees C) induced differentiation as judged by increased haemoglobin synthesis and glycophorin A expression. No sign of apoptosis or necrosis could be detected at this temperature. Cell viability did not change due to heat treatment, and cellular proliferation was reduced in a dose (heating time) dependent manner. At 45 degrees C, hyperthermia induced apoptosis and necrosis with minimal or no sign of differentiation. HSP70 level was significantly increased at 43 degrees C along with differentiation of leukaemic cells, while at 45 degrees C no significant effect on HSP70 production could be observed. CONCLUSIONS: The encouraging results obtained here indicate that by heat treatment at 43 degrees C, hyperthermia can be used alone or in combination with other modalities as a differentiation inducing agent without any detectable apoptotic activity. Positive correlation between HSP70 production and induction of differentiation and lack of apoptosis by hyperthermia confirm the possible role of HSP70 in the heat-induced differentiation and apoptosis in leukaemic cells.     

2-Chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide (CMV423), a new lead compound for the treatment of human cytomegalovirus infections

Human cytomegalovirus (HCMV) remains one of the major pathogens in immunocompromised patients (AIDS and transplants) and the main cause for congenital infections leading from slight cognitive defects up to severe mental retardation. The drugs that are currently available for the treatment of HCMV infections, i.e. ganciclovir, foscarnet and cidofovir, are all acting at the level of the viral DNA polymerase. Here we describe an entirely new molecule, the 2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide (CMV423), that shows very potent in vitro activity against HCMV. CMV423 is highly active against HCMV reference strains and clinical isolates, but also against those strains, isolated from patients or emerging after in vitro selection, that are resistant to either ganciclovir, foscarnet or cidofovir. CMV423 also showed activity in two ex vivo models, that are both highly relevant for the pathophysiology of HCMV, the retinal pigment epithelial and the bone marrow stromal cell assays. Viral antigen expression analysis by flow cytometry, as well as time of addition experiments, confirmed that CMV423 acts on a step of the viral replicative cycle that precedes the DNA polymerase step and, most likely, coincides with the immediate early (IE) antigen synthesis. Finally, CMV423 combined with either ganciclovir, foscarnet or cidofovir in checkerboard experiments demonstrated a highly synergistic activity.     

Ionizing radiation induces heritable disruption of epithelial cell interactions

Ionizing radiation (IR) is a known human breast carcinogen. Although the mutagenic capacity of IR is widely acknowledged as the basis for its action as a carcinogen, we and others have shown that IR can also induce growth factors and extracellular matrix remodeling. As a consequence, we have proposed that an additional factor contributing to IR carcinogenesis is the potential disruption of critical constraints that are imposed by normal cell interactions. To test this hypothesis, we asked whether IR affected the ability of nonmalignant human mammary epithelial cells (HMEC) to undergo tissue-specific morphogenesis in culture by using confocal microscopy and imaging bioinformatics. We found that irradiated single HMEC gave rise to colonies exhibiting decreased localization of E-cadherin, beta-catenin, and connexin-43, proteins necessary for the establishment of polarity and communication. Severely compromised acinar organization was manifested by the majority of irradiated HMEC progeny as quantified by image analysis. Disrupted cell-cell communication, aberrant cell-extracellular matrix interactions, and loss of tissue-specific architecture observed in the daughters of irradiated HMEC are characteristic of neoplastic progression. These data point to a heritable, nonmutational mechanism whereby IR compromises cell polarity and multicellular organization.