Characterization of volumetric flow rate waveforms in the normal internal carotid and vertebral arteries

Knowledge of normal cerebrovascular volumetric flow rate (VFR) dynamics is of interest for establishing baselines, and for providing input data to cerebrovascular model studies. Retrospectively gated phase contrast magnetic resonance imaging was used to measure time-resolved VFR waveforms from the two internal carotid arteries (ICA) and two vertebral arteries (VA) of 17 young, normal volunteers (16M:1F) at rest in a supine posture. After normalizing each waveform to its respective cycle-averaged VFR, the timing and amplitude of feature points from the individual waveforms were averaged together to produce archetypal ICA and VA waveform shapes. Despite significant inter-individual differences in cycle-averaged VFR within the ICA compared to VA (275+/-52 versus 91+/-18 mL min-1), the respective waveform shapes were qualitatively similar overall. The VA waveform shape did, however, exhibit significantly higher amplitudes (e.g., peak:average VFR of 1.78+/-0.30 versus 1.66+/-0.16; p<0.05) and significantly higher variability both between and within subjects. A significant correlation was observed between peak and cycle-averaged VFR, suggesting that the representative waveform shapes presented here-when scaled by an individual's cycle-averaged VFR-may be used to characterize normal ICA and VA flow rate dynamics. This capability may be of particular utility for studies where cerebrovascular flow dynamics are required, but only average flow rates are available.     

The human multidrug resistance protein MRP5 transports folates and can mediate cellular resistance against antifolates

Members of the multidrug resistance protein family, notably MRP1-4/ABCC1-4, and the breast cancer resistance protein BCRP/ABCG2 have been recognized as cellular exporters for the folate antagonist methotrexate (MTX). Here we show that MRP5/ABCC5 is also an antifolate and folate exporter based on the following evidence: (a) Using membrane vesicles from HEK293 cells, we show that MRP5 transports both MTX (KM = 1.3 mmol/L and VMAX = 780 pmol per mg protein per minute) and folic acid (KM = 1.0 mmol/L and VMAX = 875 pmol per mg protein per minute). MRP5 also transports MTX-glu2 (KM = 0.7 mmol/L and VMAX = 450 pmol per mg protein per minute) but not MTX-glu3. (b) Both accumulation of total [3H]MTX and of MTX polyglutamates were significantly reduced in MRP5 overexpressing cells. (c) Cell growth inhibition studies with MRP5 transfected HEK293 cells showed that MRP5 conferred high-level resistance (>160-fold) against the antifolates MTX, GW1843, and ZD1694 (raltitrexed) in short-term (4 hours) incubations with high drug concentrations; this resistance was proportional to the MRP5 level. (d) MRP5-mediated resistance (8.5- and 2.1-fold) was also found in standard long-term incubations (72 hours) at low concentrations of ZD1694 and GW1843. These results show the potential of MRP5 to mediate transport of (anti)folates and contribute to resistance against antifolate drugs.     

Germline mosaicism in Cornelia de Lange syndrome

Cornelia de Lange syndrome (CdLS) is a genetic disorder associated with delayed growth, intellectual disability, limb reduction defects, and characteristic facial features. Germline mosaicism has been a described mechanism for CdLS when there are several affected offspring of apparently unaffected parents. Presently, the recurrence risk for CdLS has been estimated to be as high as 1.5%; however, this figure may be an underrepresentation. We report on the molecularly defined germline mosaicism cases from a large CdLS database, representing the first large case series on germline mosaicism in CdLS. Of the 12 families, eight have been previously described; however, four have not. No one specific gene mutation, either in the NIPBL or the SMC1A gene, was associated with an increased risk for germline mosaicism. Suspected or confirmed cases of germline mosaicism in our database range from a conservative 3.4% up to 5.4% of our total cohort. In conclusion, the potential reproductive recurrence risk due to germline mosiacism should be addressed in prenatal counseling for all families who have had a previously affected pregnancy or child with CdLS.     

Indirect flight of an African bat to Israel: an example of the potential for zoonotic pathogens to move between continents

The transmission of harmful pathogens during commercial air flights is an increasing health concern. A potential, yet relatively overlooked source of zoonotic infectious diseases involves collisions of birds and bats with aircraft and long distance transport of their carcasses. We report a case of aerial transportation of the remains of an African fruit bat over three continents, following a collision with an aircraft, and demonstrate the relative ease with which zoonotic pathogens, such as rabies virus or other viruses associated with bats, may cross national boundaries and continents even. Improper handling and disposal of animal remains by airport personnel, may lead to exposure of both humans and local fauna to exotic pathogens. This in turn may trigger an epidemic with potentially devastating results.     

Segmental colitis associated with diverticular disease and other IBD look-alikes

Segmental colitis associated with diverticular disease is an inflammatory disorder that bears close clinical and histopathologic similarities to idiopathic inflammatory bowel disease. Comparison with other inflammatory bowel disease-like disorders, such as blind-ended pouches in ulcerative colitis, chronic granulomatous appendicitis, and delayed-surgery appendicitis, affords intriguing analogies and potential clues to its pathogenesis.     

The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity

NK cell cytotoxicity is controlled by numerous NK inhibitory and activating receptors. Most of the inhibitory receptors bind MHC class I proteins and are expressed in a variegated fashion. It was recently shown that TIGIT, a new protein expressed by T and NK cells binds to PVR and PVR-like receptors and inhibits T cell activity indirectly through the manipulation of DC activity. Here, we show that TIGIT is expressed by all human NK cells, that it binds PVR and PVRL2 but not PVRL3 and that it inhibits NK cytotoxicity directly through its ITIM. Finally, we show that TIGIT counter inhibits the NK-mediated killing of tumor cells and protects normal cells from NK-mediated cytoxicity thus providing an “alternative self” mechanism for MHC class I inhibition.     

Mothers' dopamine receptor polymorphism modulates the relation between infant fussiness and sensitive parenting

We determined whether the combination of the 48‐bp variable number tandem repeat polymorphism of the dopamine (DRD4) gene and infants' (fussy‐difficult) temperament predicted parenting sensitivity. The sample was comprised of 147 mothers and their 6‐month olds. Sensitive parenting was assessed by coding filmed interactions between mothers and infants. Infant temperament was assessed by parents' reports on a standard questionnaire. Moderated regressions models, with maternal education and infants' interactive behavior as controls, were used to test our hypotheses. Results showed no main effects of either temperament or DRD4, though the maternal DRD4 × infant temperament interaction was significant. Probes indicated that parents with a DRD4 7‐repeat allele behaved more sensitively to fussier infants and less sensitively to less fussy infants compared to parents without the 7‐repeat allele. Among those parents, sensitivity did not vary with infant temperament. This pattern of results indicates that mothers are differentially susceptible to infant fussiness, dependent on the presence of the 7‐repeat DRD4 allele. © 2010 Wiley Periodicals, Inc. Dev Psychobiol 52:149–157, 2010