Hydrosalpinges adversely affect markers of endometrial receptivity

While in-vitro fertilization (IVF) was initially developed in women with tubal factor infertility, recent clinical studies have suggested that the presence of hydrosalpinges lowers implantation and pregnancy rates. We postulated that these hydrosalpinges cause impaired endometrial receptivity. A total of 103 women with hydrosalpinges were prospectively evaluated, and compared with 55 infertile and 44 fertile controls. All women had endometrial biopsies during the window of implantation, analysed by conventional histological criteria, and also stained for three integrin markers of endometrial receptivity (alpha1beta1, alpha4beta1 and alpha vbeta3). Women with hydrosalpinges (cases) expressed significantly less of the alpha vbeta3 integrin compared with controls. There was no difference in expression of alpha1beta1 or alpha4beta1 among groups. A significantly greater number of cases had out of phase histology and missing alpha vbeta3 (type I defects) and absent integrin expression despite normal histological maturation (type II) defects, compared with controls. Of 20 women with impaired endometrial receptivity who were also biopsied after hydrosalpinx surgery, 70% demonstrated increased alpha vbeta3 expression. Seventy-seven percent of type I and 57% of type II defects were corrected postoperatively. Using markers of endometrial receptivity, this study demonstrates that inflammatory hydrosalpinges have an adverse effect on endometrial receptivity, which in some cases may be overcome by surgical treatment of the hydrosalpinx.      

A method of calculating a lung clinical target volume DVH for IMRT with intrafractional motion

The motion of lung tumors from respiration has been reported in the literature to be as large as 1-2 cm. This motion requires an additional margin between the Clinical Target Volume (CTV) and the Planning Target Volume (PTV). In Intensity Modulated Radiotherapy (IMRT), while such a margin is necessary, the margin may not be sufficient to avoid unintended high and low dose regions to the interior on moving CTV. Gated treatment has been proposed to improve normal tissues sparing as well as to ensure accurate dose coverage of the tumor volume. The following questions have not been addressed in the literature: (a) what is the dose error to a target volume without a gated IMRT treatment? (b) What is an acceptable gating window for such a treatment. In this study, we address these questions by proposing a novel technique for calculating the three-dimensional (3-D) dose error that would result if a lung IMRT plan were delivered without a gated linac beam. The method is also generalized for gated treatment with an arbitrary triggering window. IMRT plans for three patients with lung tumors were studied. The treatment plans were generated with HELIOS for delivery with 6 MV on a CL2100 Varian linear accelerator with a 26 pair MLC. A CTV to PTV margin of 1 cm was used. An IMRT planning system searches for an optimized fluence map phi(x,y) for each port, which is then converted into a dynamic MLC file (DMLC). The DMLC file contains information about MLC subfield shapes and the fractional Monitor Units (MUs) to be delivered for each subfield. With a lung tumor, a CTV that executes a quasiperiodic motion z(t) does not receive phi(x,y), but rather an Effective Incident Fluence EIF(x,y). We numerically evaluate the EIF(x,y) from a given DMLC file by a coordinate transformation to the Target's Eye View (TEV). In the TEV coordinate system, the CTV itself is stationary, and the MLC is seen to execute a motion -z(t) that is superimposed on the DMLC motion. The resulting EIF(x,y) is input back into the dose calculation engine to estimate the 3-D dose to a moving CTV. In this study, we model respiratory motion as a sinusoidal function with an amplitude of 10 mm in the superior-inferior direction, a period of 5 s, and an initial phase of zero.     

bcl-2 transgene expression promotes survival and reduces proliferation of CD3-CD4-CD8- T cell progenitors

Proliferative expansion and apoptotic cell death play prominent roles in T cell development. The molecular control of cell cycle progression and apoptosis appear to be inter-connected since the Bcl-2 protein can inhibit apoptosis and slow cell cycle progression in cortical thymocytes and mature T cells, particularly during the transition from the quiescent state into the cell cycle. Here the impact of bcl-2 transgene expression on CD3-CD4-CD8- T cell progenitors was assessed. Bcl-2 enhanced the survival of these progenitors at all of the four major differentiation stages, CD25- CD44+ (pro-T1), CD25 + CD44+ (pro- T2), CD25 + CD44- (pro-T3) and CD25-CD44- (pro-T4). However, it reduced cell cycling and slowed turnover only in the pro-T4 subset. From an analysis of bcl-2 transgenic mice expressing a TCR transgene or bearing a mutation in the scid or rag-1 gene we conclude that Bcl-2 inhibits proliferation only of T cell progenitors that are activated via the pre- TCR, not those stimulated via c-Kit and the IL-7 receptor.      

Genetic and antigenic analyses of enterovirus 71 isolates in Taiwan during 1998–2005

Enterovirus 71 (EV71) infections can lead to devastating clinical outcomes in children, with an increasing number of severe cases worldwide. The genetic and antigenic variability of EV71 strains isolated in Taiwan in 1998-2005 was evaluated using partial nucleotide sequence analysis of the VP1 gene and the neutralisation assay. Phylogenetic analyses revealed that most EV71 isolates from the 1998 epidemic belonged to sub-genogroup C2, with a minority belonging to sub-genogroup B4. Between 1999 and 2003, isolates belonging to sub-genogroup B4 predominated, followed by a change to sub-genogroup C4 in 2004 and 2005. Antibodies raised in rabbits or collected from infected patients were able to neutralise EV71 virus stocks at high dilutions, regardless of the sub-genogroup of the virus being challenged. The presence of phylogenetically distinct yet antigenically similar populations of EV71 in Taiwan is of concern in the context of herd immunity and vaccine development.     

Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism

Parathyroid hormone secretion is negatively regulated by a 7- transmembrane domain, G-protein coupled Ca(2+)-sensing receptor. We hypothesized that activating mutations in this receptor might cause autosomal dominant hypoparathyroidism (ADHP). Consistent with this hypothesis, we identified, in two families with ADHP, heterozygous missense mutations in the Ca(2+)-sensing receptor gene that cosegregated with the disorder. None of 50 normal controls had either mutation. We also identified a de novo, missense Ca(2+)-sensing receptor mutation in a child with severe sporadic hypoparathyroidism. The amino acid substitution in one ADHP family affected the N-terminal, extracellular domain of the receptor. The other mutations involved the transmembrane region. Unlike patients with acquired hypoparathyroidism, patients with these mutations had hypercalciuria even at low serum calcium concentrations. Their greater hypercalciuria presumably reflected activation of Ca(2+)-sensing receptors in kidney cells, where the receptor negatively regulates calcium reabsorption. This augmented hypercalciuria increases the risk of renal complications and thus has implications for the choice of therapy.      

Symptomatic peripheral arterial disease: the value of a validated questionnaire and a clinical decision rule

BACKGROUND: If a validated questionnaire, when applied to patients reporting with symptoms of intermittent claudication, could adequately discriminate between those with and without peripheral arterial disease, GPs could avoid the diagnostic measurement of the ankle brachial index. AIM: To investigate the Edinburgh Claudication Questionnaire (ECQ) in general practice and to develop a clinical decision rule based on risk factors to enable GPs to easily assess the likelihood of peripheral arterial disease. DESIGN OF STUDY: An observational study. SETTING: General practice in The Netherlands. METHOD: This observational study included patients of > or =55 years visiting their GP for symptoms suggestive of intermittent claudication or with one risk factor. The ECQ and the ankle brachial index were performed. The prevalence of peripheral arterial disease, defined as an ankle brachial index <0.9, was related to risk factors using logistic regression analyses, on which a clinical decision rule was developed and related to the presence of peripheral arterial disease. RESULTS: Of the 4790 included patients visiting their GP with symptoms suggestive of intermittent claudication, 4527 were eligible for analyses. The prevalence of peripheral arterial disease in this group was 48.3%. The sensitivity of the ECQ was only 56.2%. The prevalence of peripheral arterial disease in a clinical decision rule that included age, male sex, smoking, hypertension, hypercholesterolemia, and a positive ECQ, increased from 14% in the lowest to 76% in the highest category. CONCLUSION: This study indicates that the ECQ alone has an inadequate diagnostic value in detecting patients with peripheral arterial disease. The ankle brachial index should be performed to diagnose peripheral arterial disease in patients with complaints suggestive of intermittent claudication, although our clinical decision rule could help to differentiate between extremely high and lower prevalence of peripheral arterial disease.     

Ras mediates translation initiation factor 4E-induced malignant transformation.

Translation initiation factor eIF-4E binds to the eukaryotic mRNA 5' cap structure (m7 GpppN, where N is any nucleotide). eIF-4E is a limiting factor in translation and plays a key role in regulation of translation. We have shown previously that overexpression of eIF-4E in rodent fibroblasts results in tumorigenic transformation. eIF-4E also exhibits mitogenic activity when microinjected into serum-starved NIH-3T3 cells. To understand the mechanisms by which eIF-4E exerts its mitogenic property, we examined the involvement of the Ras signaling pathway in this activity. Here, we report that Ras is activated in eIF-4E-overexpressing cells, as the proportion of GTP-bound Ras is increased. Overexpression of the negative effector of cellular Ras, GTPase activating protein, causes reversion of the transformed phenotype. Furthermore, we show that neutralizing antibodies to Ras, or a dominant-negative mutant of Ras, inhibit the mitogenic activity of eIF-4E. We conclude that eIF-4E exerts its mitogenic and oncogenic activities by the activation of Ras.     

Monoclonal antibodies OKT 11 and OKT 11A have pan-T reactivity and block sheep erythrocyte “receptors”

Monoclonal antibodies OKT11 (γ1) and OKT11A (γ2) are described and appear to have similar binding specificities. They bind, in immunofluorescence, with >95% of infant thymocytes, staining both cortical and medullary cells, 65-80% of blood lymphocytes and selectively stain the T cell-dependent paracortical areas of tonsil. A small proportion (9-12%) of bone marrow lymphocytes stain, but this population excludes the terminal transferase-positive cells. Both the γ1 and γ2 antibodies stain the surface membrane Ig-negative lymphocytes in blood and tonsil and are able to block sheep E rosette formation (to normal or leukemic T cells). In contrast, other monoclonal anti-T reagents tested (OKT1, OKT3, OKT4, OKT6, OKT8, OKT9, OKT10) did not block E rosette formation. E rosette formation and OKT11 binding are coincident on T-ALL cell lines and both are trypsin-sensitive. In a series of 145 leukemias and 26 leukemic cell lines investigated, only leukemias with a T cell phenotype including E rosette positivity were reactive with OKT11 and OKT11A. OKT11A binds to a polypeptide of approximately 50000 molecular weight on thymic lymphocytes. This structure may carry the recognition site for sheep erythrocytes. These antibodies provide additional useful markers for T cell analysis and are of potential therapeutic value.