The cholesteryl ester transfer protein (CETP) locus as a candidate gene in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a relatively common disease of the elderly presenting as progressive dilatation of the abdominal aorta. The condition shows a pronounced tendency to cluster in families, indicating a genetic component in the disease aetiology. We have screened the cholesteryl ester transfer protein (CETP) gene, which has been proposed as a candidate gene in AAA, by means of SSCP, DNA sequencing and restriction analysis in a cohort of patients with AAA and a matching control group drawn from the Irish population. The analysis has demonstrated sequence variation at four sites in the CETP gene: an A-T transversion in exon 9 (producing a Lys309-Stop codon substitution), a G-A transition in exon 14 (producing a conservative Va1421-Ile substitution), a C-T transition in intron 12 and a G-A transition in intron 15. None of the last three sites corresponded with sites of functional significance in the protein, suggesting that this reflects neutral polymorphism at the CETP locus. Furthermore, the frequencies of these four polymorphisms in the AAA patient and control groups were not significantly different. These data therefore suggest that CETP may be excluded as a candidate gene in abdominal aortic aneurysm.     

Non homologous end joining-mediated DNA break repair is impaired in B lymphocytes of aging mice

Aging is an irreversible physiological process characterized by increased risk of diseases, reduced effectiveness of vaccines, and decreased immune responses. One of the most prominent paradigms of aging and age related conditions is the progressive accumulation of un-repaired DNA breaks leading to apoptosis and exhaustion of stem cells. Here we hypothesized that B lymphocytes from old mice have reduced DNA repair mechanisms as a contributing factor for DNA break accumulation. We analyzed class switch recombination (CSR) of naïve B lymphocytes from old and adult mice to delineate the DNA double strand repair mechanisms during aging. In vitro CSR assays and DNA break analysis by labeling phosphorylated histone H2AX showed that old mice had significantly reduced DNA repair efficiency following DNA breaks. Functional efficiency analysis of DNA break repairs using plasmid ligation method showed that B lymphocytes from old mice had poor repair efficiency and increased misrepair of linear plasmid. Diminished DNA repair in old age can contribute to reduced immune cell repertoire and impaired immunity; increased occurrence of cancer; and reduced stem cell reserve.     

Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.     

Blood sugar profile in diabetics receiving plain insulin

Blood sugar profile was studied by checking multiple plasma venous samples at 1/2 hr interval after porcine plain insulin. Mean blood sugar was the highest (198.8 +/- 24.6 mg%) at 1 1/2 hrs and the lowest (86.3 +/- 18.4) at 4 1/2 hrs after breakfast. 52% of the patients had hypoglycemias between 4 and 5 hrs. It is recommended that pre-lunch blood sugar be checked in those receiving plain insulin.     

Inducible gene silencing in podocytes: a new tool for studying glomerular function

Glomerular filtration is one of the primary functions of the kidney. Podocytes, a highly specialized cell type found in glomeruli, are believed to play a critical role in that function. Null mutations of genes expressed in podocytes like WT1, nephrin, and NEPH1 result in an embryo and perinatal lethal phenotype and therefore do not allow the functional analysis of these genes in the adult kidney. Here is describes the generation of a model that will allow such studies. We have engineered transgenic mice in which the disruption of targeted genes can be induced in a temporally controlled fashion in podocytes. For this, a transgene encoding the mutated estrogen receptor-Cre recombinase fusion protein was introduced into the mouse genome. Animals were crossed with Z/AP reporter mice to test for efficient and inducible recombination. We found that, after injection of inducer drug tamoxifen, Cre fusion protein translocates to the nuclei of podocytes, where it becomes active and mediates recombination of DNA carrying loxP target sequences. These animals provide for the first time a tool for silencing genes selectively in podocytes of adult animals.     

Comprehensive Musculoskeletal Sonographic Evaluation of the Hand and Wrist

Sonography is widely used for evaluation of hand and wrist lesions. The easy accessibility, cost‐effectiveness, and good diagnostic accuracy of sonography coupled with the numerous benefits of real‐time imaging make it desirable. The aim of this article is to describe the typical sonographic appearances of lesions in the hand and wrist that are encountered frequently in routine clinical practice, such as inflammatory arthropathies, tumors, traumatic injuries, foreign bodies, and nerve entrapment syndromes. Relevant anatomy, scanning methods, and recent developments in musculoskeletal sonography are also discussed.