Exploring the genetic and environmental etiology of high general cognitive ability in fourteen- to thirty-six-month-old twins

Two definitions of normality ("isolated" or "correlated") are considered. The boundaries of "isolated" normality were determined by a statistical procedure, whereas the "correlated" approach was related to a clinical or predictive definition. In the latter case, the biological variations were considered abnormal if they implied a hazard with some significant future ailment as a risk factor. In this pragmatic approach, the upper limit of normal/abnormal variations is the point beyond which medical strategy is related to the most expected benefit when applied to a definite population or to an individual patient. The capacity of a diagnostic test to discriminate between patients with a defined risk and those without risk depends strictly on the value of the parameter chosen. In medical care for the prevention of vascular complications in diabetic patients or with foetal risks in pregnant women, the limits of the so-called normal range of glycaemia and other parameters should be determined according to the objective of the preventive and/or therapeutic measures to be prescribed.     

Myoblast-mediated gene transfer to the joint

Several genetic and acquired pathologic conditions of the musculoskeletal system, such as arthritis and damage to ligament, cartilage, and meniscus, may be amenable to gene therapy. Even though ex vivo gene transfer with synovial cells has been shown to deliver genes encoding for anti-arthritic proteins into the rabbit knee joint, its success has been limited by a transient transgene expression. In this study, data were investigated regarding the use of muscle cells as an alternative gene-delivery vehicle to the joint in newborn rabbit and adult severe combined immunodeficiency mice. We demonstrated that myoblasts were transduced more efficiently than synovial cells with use of the same adenoviral preparation in vitro. After intra-articular injection, the engineered muscle cells adhered to several structures in the joint, including the ligament, capsule, and synovium. In addition, myoblasts fused to form many post-mitotic myotubes and myofibers at different locations of the joint of the newborn rabbit 5 days after the injection. In the knee of the adult mouse, myoblasts fused and expressed the reporter gene for at least 35 days after the injection. The presence of post-mitotic myofibers in the knee joint raises the possibility of long-term expression of the secreted protein. Currently, numerous tissues in the joint (ligament, meniscus, and cartilage) have poor intrinsic healing capacity and frequently need surgical corrections. A stable gene-delivery vehicle to the joint producing proteins that ameliorate these different musculoskeletal conditions may change the clinical implications of these pathologies.     

Tuberculous duodenal obstruction--a case report

Proximal duodenal obstruction due to tuberculosis can masquarade as duodenal ulcer. Although commonest cause of duodenal obstruction is ulcer, other causes must be considered, particularly tuberculosis which is common in tropics.     

Primary structure of an invertebrate dihydrolipoamide dehydrogenase with phylogenetic relationship to vertebrate and bacterial disulfide oxidoreductases

Dihydrolipoamide dehydrogenase (E3) is a flavoprotein component of multi-enzyme complexes catalyzing oxidative decarboxylation of alpha-ketoacids in the Krebs' cycle. We have cloned a 2.4-kb E3 cDNA from an arthropod, Manduca sexta, that codes for 497 amino acids and translates to a 51-kDa protein in vitro. Sequences at and around the dinucleotide binding domains, disulfide active site and the C-terminal interface domain involved in substrate binding are highly conserved in Manduca E3. Phylogenetic analysis of protein sequences from the flavoprotein class of disulfide oxidoreductases family of enzymes suggests that in spite of the homologous nature of E3 and glutathione reductase (goR) in sequence and structure, E3 shares a common ancestor with mercuric reductase (merA), whereas goR is more related to trypanothione reductase (tryR) than to other members. All members, except goRs, seemed to be monophyletic. Plant goRs seemed to have arisen differently and are more closely related to tryRs than to bacterial and vertebrate goRs. Earlier speculation on the nature of origin of E3 in Pseudomonas is not supported by phylogenetic data. A possible structural relationship of Manduca E3 to other pyridine-binding proteins, such as the neurotransmitter transporters and channels, is proposed.     

Mifepristone. Auxiliary therapeutic use in cancer and related disorders

A pilot study was carried out to assess the safety and antigen-presenting properties of allogeneic or autologous dendritic cells (DCs) in six HLA-A2+, HIV-infected patients. Allogeneic DCs obtained from the peripheral blood of HLA-identical, HIV-seronegative siblings were pulsed with recombinant HIV-1 MN gp160 or synthetic peptides corresponding to HLA-A2-restricted cytotoxic epitopes of envelope, Gag, and Pol proteins. The antigen-pulsed cells were infused intravenously six to nine times at monthly intervals and HIV-specific immune responses were monitored. One allogeneic DC recipient with a CD4+ T cell count of 460/mm3 showed increases in envelope-specific CTL- and lymphocyte-proliferative responses, as well as in IFN-gamma and IL-2 production. Another allogeneic DC recipient with a CD4+ T cell count of 434/mm3 also showed an increase in HIV envelope-specific lymphocyte-proliferative responses. A recipient of autologous DCs with a CD4+ T cell count of 730/mm3 showed an increase in peptide-specific lymphocyte-proliferative responses after three infusions. Three other allogeneic DC recipients with CD4+ T cell counts <410/mm3 did not show increases in their HIV-specific immune responses. No clinically significant adverse effects were noted in this study and CD4+ T cell numbers and plasma HIV-1 RNA detected by RT-PCR of all six patients were stable during the study period. Thus, both allogeneic and autologous DC infusions were well tolerated and in patients with normal or near normal CD4+ T cell counts administration of these antigen-pulsed cells enhanced the immune response to HIV. However, since no effect on viral load was observed there was no evidence that this approach provided clinical benefit.     

CVT-313, a specific and potent inhibitor of CDK2 that prevents neointimal proliferation

The activity of cyclin-dependent kinase 2 (CDK2) is essential for progression of cells from G1 to the S phase of the mammalian cell cycle. CVT-313 is a potent CDK2 inhibitor, which was identified from a purine analog library with an IC50 of 0.5 microM in vitro. Inhibition was competitive with respect to ATP (Ki = 95 nM), and selective CVT-313 had no effect on other, nonrelated ATP-dependent serine/threonine kinases. When added to CDK1 or CDK4, a 8.5- and 430-fold higher concentration of CVT-313 was required for half-maximal inhibition of the enzyme activity. In cells exposed to CVT-313, hyperphosphorylation of the retinoblastoma gene product was inhibited, and progression through the cell cycle was arrested at the G1/S boundary. The growth of mouse, rat, and human cells in culture was also inhibited by CVT-313 with the IC50 for growth arrest ranging from 1.25 to 20 microM. To evaluate the effects of CVT-313 in vivo, we tested this agent in a rat carotid artery model of restenosis. A brief intraluminal exposure of CVT-313 to a denuded rat carotid artery resulted in more than 80% inhibition of neointima formation. These observations suggest that CVT-313 is a promising candidate for evaluation in other disease models related to aberrant cell proliferation.     

An evaluation of the potential and limitations of three-dimensional reconstructions from intravascular ultrasound images

Three-dimensional (3D) reconstructions of arteries can be produced using two-dimensional (2D) intravascular ultrasound (IVUS) images. Any artefact that affects 2D images has the potential to limit the quality of a 3D reconstruction. Using a catheter withdrawal technique, a range of test rigs were used to assess: (i) the effect of rotation of the probe orientation; (ii) the ability to reconstruct the true path of a tortuous vessel; (iii) the effect of image distortion on diameter measurements; (iv) the number of images per unit length used to produce a 3D reconstruction; and (v) the quality of the IVUS 3D reconstruction of a stent. These investigations show that 3D IVUS imaging is prone to artefacts. For 3D IVUS images to be used to quantify the vessel path or to make accurate measurements of vessel dimensions, more information about the catheter tip position and orientation is required than is currently available with the pullback technique.     

Gynecologic problems in older women

Regular gynecologic evaluation in older women is an integral part of medical care, just as it is for women of reproductive age. This should be emphasized since older women often neglect early symptoms of gynecologic diseases, some of which are potentially lethal. With this in mind, the health care provider must be cognizant of not only gynecologic problems that affect all women, but also those disease processes which are either specific to or more prevalent in an older population. This article emphasizes these aspects in caring for the older gynecologic patient.