EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era.

EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based allo-SCT is a relatively uncommon and challenging clinical problem but has not received detailed study in a large cohort. Quantitative-PCR (qPCR) monitoring for EBV reactivation post allo-SCT is now commonplace but its diagnostic and predictive value remains unclear. Sixty-nine patients with PTLD following Alemtuzumab-based allo-SCT were studied. Marked clinicopathological heterogeneity was evident; lymphadenopathy was frequently absent, whereas advanced extranodal disease was common. The median viral load at clinical presentation was 49 300 copies/mL (50-65 200 000 copies/mL) and, notably, 23% and 45% of cases, respectively, had 10 000 and 40 000 copies/mL. The overall response rate to rituximab as first-line therapy was 70%. For rituximab failures, chemotherapy was ineffectual but DLIs were successful. A four-parameter prognostic index predicted response to therapy (OR 0.30 (0.12-0.74); P=0.009] and PTLD mortality (hazard ratio (HR) 1.81 (1.12-2.93) P=0.02) on multivariate analysis. This is the largest detailed series of EBV-associated PTLD after allo-SCT. At clinical presentation, EBV-qPCR values are frequently below customary thresholds for pre-emptive therapy, challenging current paradigms for monitoring and intervention. A four-point score identifies a proportion of patients at risk of rituximab-refractory disease for whom alternative therapy is needed.

Survey of transportation procedures, management practices, and health assessment related to quality, quantity, and value for market beef and dairy cows and bulls.

This survey consisted of data collected from 23 beef harvest plants to document transportation procedures, management practices, and health assessments of market beef and dairy cows and bulls (about n ≅ 7,000 animals). Gooseneck/bumper-pulled trailers were used more often to transport dairy cattle than beef cattle to market whereas tractor-trailers were used more often to transport beef cattle than dairy cattle. All loads (n = 103) met the American Meat Institute Foundation guidelines for spacing. Loads where more than 3% of the cattle slipped during unloading were observed in 27.3% of beef loads and 29.0% of the dairy loads. Beef loads had numerically greater usage of electrical prods (32.4%) versus dairy loads (15.4%) during unloading and were more likely to have a variety of driving aids used more aggressively on them. Fewer cattle had horns, brands, and mud/manure contamination on hides than in the previous survey in 1999. The predominant hide color for beef cows was black (44.2%) whereas the predominant color for dairy cows was the Holstein pattern (92.9%). Fewer cattle displayed evidence of bovine ocular neoplasia (2.9%) than in previous surveys in 1994 (8.5%) and 1999 (4.3%). Knots on live cattle were found less in the round (0.5%) and more in the shoulder region (4.6%) than in 1999 (1.4% and 0.4%, respectively). Dairy cows were more frequently lame in 2007 (48.7%) than 1999 (39.2%) whereas beef cows had numerically less lameness (16.3% vs. 26.6%, respectively). Most beef cows (62.3%) and dairy cows (68.9%) received midpoint body condition scores (3, 4, and 5 for beef; 2 and 3 for dairy). Beef cows had higher numerical percentages of no defects present (72.0%) versus dairy cows (63.0%) when evaluated for a variety of reproductive, health, or management conditions. Continued improvements in several key factors related to transportation, management, and health were observed in this survey, which could result in increased value in market beef and dairy cows and bulls.

A once-a-day dosage form for the delivery of insulin through the nasal route: in vitro assessment and in vivo evaluation.

An in situ thermogelling, mucoadhesive formulation based on N-trimethyl chitosan chloride has been evaluated for its potential to affect the transmucosal delivery of insulin via the nasal route. In vitro studies at a physiologically relevant temperature (ca. 35 °C) have shown that the formulation releases most of its insulin load (ca. 70%) in a non-Fickian manner during the timescale over which the sol-to-gel transition (ca. 8 min) takes place, and also that, once gelation is complete, the release of the remainder of the therapeutic content follows first order kinetics over at least sixty minutes. Investigations on the effects of the application of the same formulation to a modelled nasal mucosa (Calu-3 cell monolayer) have indicated the capability of the formulation to induce the transient opening of tight junctions. Cytotoxic investigations have shown that the formulation exhibits negligible detrimental effects to the integrity of these monolayers. The in vivo potential of the nasal formulation to act as a once-a-day dosage form for the intranasal delivery of insulin has been demonstrated in a diabetic-rat model.

Long lifetimes of quantum-dot intersublevel transitions in the terahertz range.

Carrier relaxation is a key issue in determining the efficiency of semiconductor optoelectronic device operation. Devices incorporating semiconductor quantum dots have the potential to overcome many of the limitations of quantum-well-based devices because of the predicted long quantum-dot excited-state lifetimes. For example, the population inversion required for terahertz laser operation in quantum-well-based devices (quantum-cascade lasers) is fundamentally limited by efficient scattering between the laser levels, which form a continuum in the plane of the quantum well. In this context, semiconductor quantum dots are a highly attractive alternative for terahertz devices, because of their intrinsic discrete energy levels. Here, we present the first measurements, and theoretical description, of the intersublevel carrier relaxation in quantum dots for transition energies in the few terahertz range. Long intradot relaxation times (1.5 ns) are found for level separations of 14 meV (3.4 THz), decreasing very strongly to approximately 2 ps at 30 meV (7 THz), in very good agreement with our microscopic theory of the carrier relaxation process. Our studies pave the way for quantum-dot terahertz device development, providing the fundamental knowledge of carrier relaxation times required for optimum device design.

Transition from rolling to jamming in thin granular layers.

We study the granular jamming transition for sheared layers of spherical beads ranging in thickness from 1 to 3 times the grain diameter d. As the layer thickness increases slightly above d, the measured friction jumps discontinuously from 0.02 to >0.1, marking the transition from rolling to jamming. Above a critical layer thickness for jamming, the effective granular pressure displays a power law increase with thickness. For thin layers, friction and P increases as the packing fraction decreases near the jamming transition, in contrast to expectations for bulk granular matter.

Characterisation and protein expression profiling of annexins in colorectal cancer.

The annexins are family of calcium-regulated phospholipid-binding proteins with diverse roles in cell biology. Individual annexins have been implicated in tumour development and progression, and in this investigation a range of annexins have been studied in colorectal cancer. Annexins A1, A2, A4 and A11 were identified by comparative proteomic analysis to be overexpressed in colorectal cancer. Annexins A1, A2, A4 and A11 were further studied by immunohistochemistry with a colorectal cancer tissue microarray containing primary and metastatic colorectal cancer and also normal colon. There was significant increase in expression in annexins A1 (P=0.01), A2 (P<0.001), A4 (P<0.001) and A11 (P<0.001) in primary tumours compared with normal colon. There was increasing expression of annexins A2 (P=0.001), A4 (P=0.03) and A11 (P=0.006) with increasing tumour stage. An annexin expression profile was identified by k-means cluster analysis, and the annexin profile was associated with tumour stage (P=0.01) and also patient survival. Patients in annexin cluster group 1 (low annexin expression) had a better survival (log rank=5.33, P=0.02) than patients in cluster group 2 (high annexins A4 and A11 expression). In conclusion, this study has shown that individual annexins are present in colorectal cancer, specific annexins are overexpressed in colorectal cancer and the annexin expression profile is associated with survival.

The impetus for family-centred early childhood intervention.

In this article, the current climate of early intervention is considered, advocating the necessity for it to remain a cutting-edge service that attends to the changing needs profiles of children and their families. The article reviews the difficulties experienced by families in the UK, where, as the government acknowledges, life chances are still unequal. It emphasises that early interventions can increase the likelihood of the family being able to engage or re-engage with mainstream societal services, thus reducing the long-term costs to society. It discusses the past and present UK policy context from 2004, when Sohns reported that the UK was the only country without a national policy of infrastructure in relation to early childhood intervention, until the present when, a raft of legislation is in place acknowledging its importance and the need for priority. Central to many effective early intervention programmes is the goal of establishing shared communication in the infant-key carer dyad, using alternative communication and therapy-based interventions. The article discusses parent-inclusive programmes which meet the needs of both parents and children, and receive endorsement from parents. Finally, the article considers evaluation of early childhood services, and the necessity of increasing the centrality of the family in service delivery in order to provide services which are integrated, relevant and efficacious.

Characterization and over-expression of chaperonin t-complex proteins in colorectal cancer.

The chaperonins are key molecular complexes, which are essential in the folding of proteins to produce stable and functionally competent protein conformations. One member of the chaperonin group of proteins is TCP1 (chaperonin containing t-complex polypeptide 1, or CCT), but little is known about this protein in tumours. In this study, we used comparative proteomic analysis to show that t-complex protein subunits TCP1 beta and TCP1 epsilon are over-expressed in colorectal adenocarcinomas. Monoclonal antibodies to these proteins were developed and the expression and cellular localization of these two proteins in colorectal cancer were analysed by immunohistochemistry on a colorectal cancer tissue microarray. In colorectal cancer, TCP1 beta cellular localization was exclusively cytoplasmic, whereas TCP1 epsilon staining was seen in both the nucleus and the cytoplasm. Both cytoplasmic TCP1 beta and cytoplasmic TCP1 epsilon were significantly over-expressed (p < 0.001 for each protein) in primary colorectal cancer and also showed increased expression with advancing Dukes' stage (p = 0.018 for TCP1 beta and p = 0.045 for TCP1 epsilon). A trend was also identified between over-expression of cytoplasmic TCP1 beta and reduced patient survival (p = 0.05). These results show that both TCP1 beta and TCP1 epsilon are over-expressed in colorectal cancer and indicate a role for TCP1 beta and TCP1 epsilon in colorectal cancer progression.

Heterogeneous nuclear ribonucleoprotein K is over expressed, aberrantly localised and is associated with poor prognosis in colorectal cancer.

Heterogeneous ribonucleoprotein K (hnRNP K) is a member of the hnRNP family which has several different cellular roles including transcription, mRNA shuttling, RNA editing and translation. Several reports implicate hnRNP K having a role in tumorigenesis, for instance hnRNP K increases transcription of the oncogene c-myc and hnRNP K expression is regulated by the p53/MDM 2 pathway. In this study comparing normal colon to colorectal cancer by proteomics, hnRNP K was identified as being overexpressed in this type of cancer. Immunohistochemistry with a monoclonal antibody to hnRNP K (which we developed) on colorectal cancer tissue microarray, confirmed that hnRNP K was overexpressed in colorectal cancer (P<0.001) and also showed that hnRNP K had an aberrant subcellular localisation in cancer cells. In normal colon hnRNP K was exclusively nuclear whereas in colorectal cancer the protein localised both in the cytoplasm and the nucleus. There were significant increases in both nuclear (P=0.007) and cytoplasmic (P=0.001) expression of hnRNP K in Dukes C tumours compared with early stage tumours. In Dukes C patient's good survival was associated with increased hnRNP K nuclear expression (P=0.0093). To elaborate on the recent observation that hnRNP K is regulated by p53, the expression profiles of these two proteins were also analysed. There was no correlation between hnRNP K and p53 expression, however, patients who presented tumours that were positive for hnRNP K and p53 had a poorer survival outcome (P=0.045).

The cost of steroid-free protocols in primary cadaver kidney transplantation.

Steroid-free immunosuppression regimens have been enjoying recent success in clinical transplantation. The use of antibodies required for such protocols can be an economic burden. We proposed to study their cost in our center. This retrospective study involved 147 consecutive patients subjected to 4 protocols of immunosuppression. The first received triple therapy. The second group received induction with basiliximab, whereas the third received Basiliximab plus cyclosporine (CSA) plus mycophenolate mofetil (MMF), and the fourth received Thymoglobulin plus CSA plus MMF in conjuction with only 4 days of steroid. Rejection episodes were treated with Solumedrol. Six-month charges were obtained from computerized records of the finance department, the in-house laboratories, and the transplantation service registry. All charges were expressed in 2004 dollars. Statistical analyses were obtained using chi-square, analysis of variance (ANOVA) and Kaplan-Meier tests. The 4 groups were similar with regard to donor and/or recipient gender, race, panel reactive antibodies, cold ischemia, dialysis requirements length of stay and readmission, graft survival, and function. Charges were significantly higher in the last 2 groups as compared with triple therapy.

Multicenter linkage study of schizophrenia loci on chromosome 22q.

The hypothesis of the existence of one or more schizophrenia susceptibility loci on chromosome 22q is supported by reports of genetic linkage and association, meta-analyses of linkage, and the observation of elevated risk for psychosis in people with velocardiofacial syndrome, caused by 22q11 microdeletions. We tested this hypothesis by evaluating 10 microsatellite markers spanning 22q in a multicenter sample of 779 pedigrees. We also incorporated age at onset and sex into the analysis as covariates. No significant evidence for linkage to schizophrenia or for linkage associated with earlier age at onset, gender, or heterogeneity across sites was observed. We interpret these findings to mean that the population-wide effects of putative 22q schizophrenia susceptibility loci are too weak to detect with linkage analysis even in large samples.

Characterization of mouse urea transporters UT-A1 and UT-A2.

Specialized transporter proteins that are the products of two closely related genes, UT-A (Slc14a2) and UT-B (Slc14a1), modulate the movement of urea across cell membranes. The purpose of this study was to characterize the mouse variants of two major products of the UT-A gene, UT-A1 and UT-A2. Screening a mouse kidney inner medulla cDNA library yielded 4,047- and 2,876-bp cDNAs, the mouse homologues of UT-A1 and UT-A2. Northern blot analysis showed high levels of UT-A mRNAs in kidney medulla. UT-A transcripts were also present in testes, heart, brain, and liver. Immunoblots with an antiserum raised to the 19 COOH-terminal amino acids of rat UT-A1 (L194) identified immunoreactive proteins in kidney, testes, heart, brain, and liver and showed a complex pattern of differential expression. Relative to other tissues, kidney and brain had the highest levels of UT-A protein expression. In kidney sections, immunostaining with L194 revealed immunoreactive proteins in type 1 (short) and type 3 (long) thin descending limbs of the loop of Henle and in the middle and terminal inner medullary collecting ducts. Expression in Xenopus laevis oocytes showed that, characteristic of UT-A family members, the cDNAs encoded phloretin-inhibitable urea transporters. Acute application of PKA agonists (cAMP/forskolin/IBMX) caused a significant increase in UT-A1- and UT-A3-, but not UT-A2-mediated, urea transport.

meso-1,2-bis(methylazo)-1,2-diphenylethane.

The title compound, meso-1,2-bis(methyldiazenyl)-1,2-diphenylethane, C16H18N4, is arranged in a disordered manner around an inversion point. The N-N atom distances in the azo group of 1.192 (8) and 1.195 (8) A, and the C-C atom distances in the ethylene moiety at 1.512 (8) and 1.503 (8) A in the two models [refined to 51.7 (6) and 48.3 (6)% occupancies] were not significantly different.

Attachment bonds between adult daughters and their older mothers: associations with contemporary caregiving.

This study examined associations between attachment bonds and the care that daughters were providing to their community-dwelling mothers. Adult daughters (40 African American, 40 European American) completed assessments of adult attachment, instrumental and emotional caregiving, and caregiver burden. The author performed hierarchical linear regressions to examine the relationships between attachment dimensions (Security and Anxiety) and the provision of instrumental and emotional care. Both attachment dimensions were unrelated to the provision of instrumental care. In contrast, high scores on the Security dimension and low scores on the Anxiety dimension were associated with the provision of more emotional care to mothers. A final analysis revealed that high scores on the Security dimension were associated with less caregiver burden. These results suggest that practical care that daughters provide to their mothers may be independent of attachment patterns within the child-parent relationship, whereas affective, discretionary care may be promoted or hindered by attachment patterns. Moreover, the stress of caregiving may be mediated by a more secure attachment bond. The potential impact of adult attachment patterns has implications for both family intervention and public policy, given that more families are expected to participate in caregiving in coming decades.

Hepatic mesenchymal hamartoma in a neonate: a case report and review of the literature.

To describe an unusual presentation of mesenchymal hamartoma in a critically ill neonate necessitating a novel therapeutic embolization before definitive resection. An unusual presentation of a large hepatic mass in a newborn complicated by pulmonary hypertension and vascular "steal" with renal insufficiency is presented. The mass was initially successfully embolized, but then revascularized, necessitating resection in an attempt to improve the clinical status of the critically ill neonate. The resected mass was a mesenchymal hamartoma with a necrotic center and extensive arterial collateralization. The patient began improving immediately after resection. Mesenchymal hamartoma may present in the neonate as a diagnostic dilemma. This is the first case report describing persistent pulmonary hypertension and renal compromise from this tumor. Embolization as a therapeutic modality to address this tumor is described. The cause of the persistent and severe pulmonary hypertension remains unclear,but may be related to the tumor.

Expression of the Oct-1 transcription factor and characterization of its interactions with the Bob1 coactivator.

The Oct-1 transcription factor regulates a variety of tissue-specific and general housekeeping genes by recruiting specialized coactivators of transcription. It acts synergistically with the B-cell-specific coactivator Bob1 (OCA-B, OBF-1) to stimulate transcription of immunoglobulin genes. To analyze Oct-1's interactions with Bob1 and other regulatory proteins, we have overexpressed and purified different functional domains of the recombinant proteins. A version of Oct-1 that encompasses the amino-terminal activation region and the POU DNA-binding domain was extensively characterized (OctDeltaC1; comprising residues 1-445). Using an in vitro transcription assay, we demonstrate that this fragment is sufficient and necessary to stimulate transcription from an immunoglobulin promoter with Bob1. It also coactivates from the herpes simplex virus ICPO promoter element in the presence of VP16. Using a range of spectroscopic and biophysical techniques, we demonstrate that the activation domains of Oct-1 and Bob1 have little globular structure and that they do not physically interact. Thus, their functional synergy is likely to arise by the co-recruitment of common factors as part of a larger regulatory assembly. We propose a hypothesis to explain why the activation domains of these and other transcription factors of metazoans have little if any intrinsic structure.

Electron capture dissociation of gaseous multiply charged ions by Fourier-transform ion cyclotron resonance.

Fourier-transform ion cyclotron resonance instrumentation is uniquely applicable to an unusual new ion chemistry, electron capture dissociation (ECD). This causes nonergodic dissociation of far larger molecules (42 kDa) than previously observed (<1 kDa), with the resulting unimolecular ion chemistry also unique because it involves radical site reactions for similarly larger ions. ECD is highly complementary to the well known energetic methods for multiply charged ion dissociation, providing much more extensive protein sequence information, including the direct identification of N- versus C-terminal fragment ions. Because ECD only excites the molecule near the cleavage site, accompanying rearrangements are minimized. Counterintuitively, cleavage of backbone covalent bonds of protein ions is favored over that of noncovalent bonds; larger (>10 kDa) ions give far more extensive ECD if they are first thermally activated. This high specificity for covalent bond cleavage also makes ECD promising for studying the secondary and tertiary structure of gaseous protein ions caused by noncovalent bonding.

The spectrum of postmortem ocular findings in victims of shaken baby syndrome.

BACKGROUND: Ophthalmologists and ocular pathologists are called on to help identify children who have undergone violent shaking. The objective of this study was to describe the spectrum of postmortem ocular findings in victims of shaken baby syndrome and to correlate the ocular findings with the nonocular features found at autopsy. METHODS: The ocular pathology registry at the University of Ottawa Eye Institute was reviewed to identify all victims of fatal shaken baby syndrome whose eyes had been submitted for examination between Apr. 1, 1971, and Dec. 31, 1995. Autopsy reports were accessed from the hospital charts of the identified patients. RESULTS: Six patients, aged 1 to 34 months, were identified. Intraocular findings ranged from a focal globular hemorrhage at the posterior pole to extensive intraocular hemorrhage involving the entire retina with perimacular folds. All the children had evidence of optic nerve sheath hemorrhage. Nonocular findings included intracranial hemorrhage (in all cases), skull fracture (in two), rib fractures (in three) and high spinal cord hemorrhage (in four). The extent of the intraocular hemorrhage was not consistent with the nonocular findings. INTERPRETATION: Abused children may display a range of postmortem ocular findings, with intraocular hemorrhage varying from minimal to severe. These findings may not correlate with the severity of the child's other injuries. The presence of any retinal or optic nerve sheath hemorrhage in an infant, in the absence of an appropriate explanation for these findings, should raise suspicion of child abuse.