Cerulean cataract is an autosomal dominant, early onset, progressive cataract characterized by blue or white opacifications in the nucleus and cortex of the lens. A large four-generation pedigree in ...which cerulean cataract segregates was studied for linkage analysis. A genome wide search was undertaken after the plausible candidate genes were excluded and the cerulean cataract phenotype was mapped to chromosome 17q24. The three markers closest to the disease gene are D17S802 (Z)(theta) = 9.46 at (theta) = 0.085), D17S836 (Z(theta) = 5.26 at (theta) = 0.031) and AFMa238yb5 (Z(theta) = 7.11 at (theta) = 0.032). Multipoint linkage analyses yielded a maximum lod score of Z(theta) = 13.71, placing the cerulean cataract gene between D17S802 and D17S836 at (theta) = 0.048 and (theta) = 0.013, respectively.
Abstract Background The addition of rituximab to chemotherapy has improved the outcome of patients with follicular lymphoma (FL). However, data on grade 3 FL (FL3) and its subtypes are lacking. The ...aims of the study were to determine: 1) the clinical features and outcome of patients with FL3 treated with rituximab and anthracycline-based chemotherapy; and 2) the clinical significance of the three subtypes of FL3. Patients and Methods Eighty-seven FL1/2, 84 FL3 including 46 FL3A, 17 FL3B, and 21 follicular large cleaved cell (FL3C), and 411 diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab and anthracycline-based chemotherapy, and a historical cohort of 167 FL3 patients who received only anthracycline-based chemotherapy (FL3*) are included in this retrospective study. Results The FL3 group had a significantly better overall survival (OS) and event-free survival (EFS) compared to those with FL3* or DLBCL. No significant differences in OS were found among the three subtypes of FL3. However, FL3B had a shorter EFS than FL3A and FL3C. Moreover, FL3B had an outcome similar to DLBCL, whereas FL3A and 3C had significantly better outcomes than DLBCL. Less than 50% of the patients with FL3B and less than 20% of the patients with FL3A+3C have relapsed, and relapses were uncommon after five years. Conclusion The use of rituximab with anthracycline-based chemotherapy has significantly improved the survival of patients with FL3 and should be considered the benchmark by which other therapies for FL3 are evaluated in the future.
Background—The risk of colorectal cancer is higher among relatives of those affected. The neoplastic yield reported from screening such individuals varies enormously between studies and depends on ...the age and strength of the family history of those screened. Aims—To ascertain the neoplastic yield of endoscopic screening of first degree relatives of patients with colorectal cancer by age and familial risk. Subjects—A total of 330 individuals with a family history of colorectal cancer. Method—Endoscopic screening conducted according to a protocol. Results—Adenomas were found in 12%, and adenomas larger than 1 cm in 8%, of “high risk” individuals screened primarily by colonoscopy. Of those with neoplasia, 26% had lesions at or proximal to the splenic flexure. Neoplasia was found in 9.5% of individuals at lower familial risk, screened primarily by 60 cm flexible sigmoidoscopy, 4% of whom had neoplasia larger than 1 cm in size or cancer. Neoplastic yield was greatest in the fourth and fifth decades in those at highest risk, but increased with age in those at lower risk. Conclusions—For individuals with two or more first degree relatives, or relatives who have developed colorectal cancer at a young age, colonoscopy appears to be the only satisfactory method of screening, but 60 cm flexible sigmoidoscopy may be useful in those at lower levels of risk.
Dietary supplementation with folic acid and vitamin B
12 lowers blood homocysteine concentrations by about 25% to 30% in populations without routine folic acid fortification of food and by about 10% ...to 15% in populations with such fortification. In observational studies, 25% lower homocysteine has been associated with about 10% less coronary heart disease (CHD) and about 20% less stroke.
We reviewed the design and statistical power of 12 randomized trials assessing the effects of lowering homocysteine with B-vitamin supplements on risk of cardiovascular disease.
Seven of these trials are being conducted in populations without fortification (5 involving participants with prior CHD and 2 with prior stroke) and 5 in populations with fortification (2 with prior CHD, 2 with renal disease, and 1 with prior stroke). These trials may not involve sufficient number of vascular events or last long enough to have a good chance on their own to detect reliably plausible effects of homocysteine lowering on cardiovascular risk. But, taken together, these 12 trials involve about 52
000 participants: 32
000 with prior vascular disease in unfortified populations and 14
000 with vascular disease and 6000 with renal disease in fortified populations. Hence, a combined analysis of these trials should have adequate power to determine whether lowering homocysteine reduces the risk of cardiovascular events within just a few years.
The strength of association of homocysteine with risk of cardiovascular disease may be weaker than had previously been believed. Extending the duration of treatment in these trials would allow any effects associated with prolonged differences in homocysteine concentrations to emerge. Establishing a prospective meta-analysis of the ongoing trials of homocysteine lowering should ensure that reliable information emerges about the effects of such interventions on cardiovascular disease outcomes.
Today's engineering students recognize the importance of environmental issues, but the traditional engineering curriculum is weak in opportunities for students to experience the link between the ...practice of engineering and the ideals of environmental sustainability. To meet this need, we attempt to offer multi-disciplinary knowledge early in the university course. We suggest a means for educating engineering students to understand environmental problems by viewing them through the eyes of the affected inhabitants. The vehicle for this educational model is Engineers Without Borders. By exposing undergraduate engineering students to real world projects presented by Engineers Without Borders in the first year of their program, the importance of considering the social and environmental issues can be more firmly ingrained in the problem solving process.
The mechanism by which a small but significant proportion of patients with peripheral vascular disease (PVD) rapidly progress to critical ischaemia is unclear. Both experimental and clinical data ...suggest a role for autoantibodies in the pathogenesis of atherosclerotic disease, particularly in the accelerated atherosclerosis seen in patients with systemic lupus erythematosus and the anti-phospholipid syndrome. This review examines the evidence for a role for endothelial cell reactive autoantibodies in PVD and the potential mechanisms by which these autoantibodies could contribute to the acceleration of atherosclerosis in a proportion of patients. The identification of such markers could lead to the identification of patients with PVD who are at risk of developing critical ischaemia and may warrant early and aggressive intervention.
Hedera L. (Araliaceae) is a northern temperate genus of around twelve, largely allopatric, species. No hybrids have been confirmed from the few areas where species distributions naturally intersect. ...The intergeneric hybrid × Fatshedera, introduced in 1910, is believed to be the first known occurrence of hybridisation involving an extant species of Hedera. The existence of a hybrid within Hedera was established by the detection of H. helix × H. hibernica in 2005. Here, aberrant plants recently observed in the UK, USA and Spain, from cultivated and naturalised populations, are shown to be hybrids based on their morphological characters and chromosome counts. Three new infrageneric hybrids in Hedera are described. The names H. × sepulcralis, H. × cazorlensis and H. × nessensis are provided for hybrids between H. hibernica and H. algeriensis, H. helix and H. maroccana, and H. iberica and H. hibernica respectively. The distinguishing features of these plants are discussed and a key allowing identification of the two hybrids known to have arisen in the UK is given. These discoveries reveal the potential for hybridisation within Hedera and geographical separation, therefore, appears to be the main barrier to crossing between species in the wild. As species come increasingly into contact through cultivation and naturalisation, it is predicted that more hybrids will appear. These hybrids highlight a previously unrecognised risk of introgression among these morphologically similar species.
Background: The induction of IgE synthesis in naïve B cells requires two T‐cell‐derived signals: one delivered through CD40 and the other via interleukin‐4 (IL‐4). The natural counterstructure to ...CD40 is the CD40 ligand (CD40L). We have asked about the interplay between CD40L and CD40 mAb that recognize distinct epitopes in delivering signals for regulating IL‐4‐dependent IgE synthesis and the expression of CD23, the low‐affinity IgE receptor, in resting B cells.
Methods: After culture of purified human tonsillar B cells with CD40 agonists and IL‐4, surface CD23 was determined by flow cytometric analysis. CD23 levels in cell lysates and supernatants were quantified by ELISA, as were those of secreted IgE.
Results: With regard to both induction of CD23 and IgE production, soluble CD40L trimer (sCD40LT) showed synergistic interaction with two mAb to CD40 which bind to epitopes located outside the ligand binding site (EA5 and 5C3), but not with a mAb (G28‐5) which effectively competes for CD40L binding to CD40. Each of the two noncompeting mAb to CD40 was able to cooperate strongly with sCD40LT in promoting high‐level induction of CD23 even in the absence of IL‐4, an effect mirrored in the promotion of strong homotypic clustering and high‐rate DNA synthesis. G28‐5, uniquely, induced a down‐regulation in IL‐4‐induced CD23 expression with time, a change that was accompanied by an increase in the amount of soluble CD23 detected. While the two noncompeting mAb consistently synergized with sCD40LT for the promotion of IL‐4‐dependent IgE synthesis, sCD40LT and G28‐5 (which, by itself, was the most potent of the CD40 mAb at inducing IL‐4‐dependent IgE production) exhibited mutual antagonism in this regard, the level of which could be quite profound.
Conclusions: This study demonstrates that appropriate targeting of CD40 can modulate IgE synthesis either positively or negatively.
Members of the Id family of helix-loop-helix proteins function as negative regulators of DNA binding, E protein, helix-loop-helix
transcription factors in the control of cell growth, differentiation, ...and development. By using transient transfection analysis
of COS cells, we show that in the absence of its E protein target, the Id3 protein is localized exclusively to the cytoplasm/perinuclear
region. Co-transfection with E protein (E47) results in nuclear translocation of the Id3 protein, a process requiring both
a functional Id helix-loop-helix dimerization domain and an E protein nuclear localization signal. Id3 that is associated
with E protein displays an extended half-life, while the E protein itself is more rapidly turned over. These observations
demonstrate that E protein, by nuclear chaperoning Id, can regulate the available cellular pool of its own inhibitory partner.
The optimal dose of granulocyte colony-stimulating factor (G-CSF) for mobilization of allogeneic-blood stem cells (AlloBSC) has yet to be determined. As part of a prospective trial, 41 related human ...leukocyte antigen (HLA)-matched donors had blood cells mobilized with G-CSF at 5 micrograms/kg/d by subcutaneous administration. The purpose of this trial was to monitor adverse effects during G-CSF administration and stem-cell collection, to determine the optimal timing for stem-cell collection, and to determine the cellular composition of stem-cell products following G-CSF administration.
The median donor age was 42 years. Apheresis began on day 4 of G-CSF administration. At least three daily 12-L apheresis collections were performed on each donor. A minimum of 1.0 x 10(6) CD34+ cells/kg (recipient weight) and 8.0 x 10(8) mononuclear cells/kg were collected from each donor. All collections were cryopreserved in 5% dimethyl sulfoxide and 6% hydroxyethyl starch.
Toxicities associated with G-CSF administration and the apheresis process included myalgias/arthralgias (83%), headache (44%), fever (27%), and chills (22%). The median baseline platelet count of 242 x 10(4)/ mL decreased to 221, 155, and 119 x 10(6)/mL on days 4, 5, and 6 of G-CSF administration, respectively. Median numbers of CD34+ cells in collections 1, 2, and 3 were 1.99, 2.52, and 3.13 x 10(6)/kg, respectively. The percentage and total number of CD4+, CD8+, and CD56+/CD3- cells remained relatively constant during the three collections. Median total numbers of cells were as follows: CD34+, 7.73 x 10(6)/kg; and lymphocytes, 6.93 x 10(8)/kg.
Relatively low doses of G-CSF can mobilize sufficient numbers of AlloBSC safely and efficiently.
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