Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway

Werner Syndrome (WS) is characterized by premature aging, genomic instability, and cancer. The combined impact of WRN helicase deficiency and limiting telomere reserves is central to disease pathogenesis. Here, we report that cells doubly deficient for telomerase and WRN helicase show chromosomal aberrations and elevated recombination rates between telomeres of sister chromatids. Somatic reconstitution of WRN function, but not a WRN helicase-deficient mutant, abolished telomere sister chromatid exchange (T-SCE), indicating that WRN normally represses T-SCEs. Elevated T-SCE was associated with greater immortalization potential and resultant tumors maintained telomeres via the alternative lengthening of telomere (ALT) pathway. We propose that the increased incidence of chromosomal instability and cancer in WS relates in part to aberrant recombinations between sister chromatids at telomeres, which facilitates the activation of ALT and engenders cancer-relevant chromosomal aberrations and tumor formation.     

The beneficial effects of one treatment session and recording of nightmares on chronic nightmare sufferers.

Twenty subjects with chronic nightmares for 17.2 years mean duration were randomly divided into two groups: Rehearsal and Recording. At inception, subjects in both groups were instructed to write down their nightmares for one month. The Recording group received no other intervention. Rehearsal subjects received a single treatment group session teaching an imagery rehearsal technique to reduce nightmare frequency. At inception and three months follow-up, both groups were compared for nightmare frequency and for self-rated distress with scales (Symptom Checklist and Symptom Questionnaire) measuring anxiety, depression, hostility, somatization and total distress. Nightmare frequency decreased significantly in both groups: Rehearsal group-7.2 per month to 2.0 per month (72% reduction) (p < 0.006); Recording group-9.4 per month to 5.0 per month (47% reduction) (p < 0.02). There were no statistically significant differences in the nightmare frequency reductions between groups. All anxiety, depression, somatization, hostility and total distress scores decreased substantially in the Rehearsal group. Most changes were significant. Changes in the Recording group were inconsistent and not significant. Two brief case histories are presented.     

The site of synthesis and functions of acute phase plasma proteins: Close relation-ship with the reticulo-endothelial system

The evidence that the acute phase glycoproteins of plasma are synthesized by the liver parenchymal cells is critically examined, and is found to be inconclusive. Some evidence is cited which favors the reticulo-endothelial system (RES) in general, and Kupffer cells in particular, as the site of synthesis of these proteins: 1. The entire RES contains non-glycogenic periodic acid Schiff-positive substances. 2. The diseases which affect glycoprotein levels are also known to affect the function of the RES. 3. When the animal is subjected to stress, the RES function is initially depressed and then stimulated. A similar biphasic behavior is shown by plasma glycoprotein levels. 4. Adrenal cortico-steriods are the major regulators of the RES function and of the synthesis of acute phase proteins. Moreover, both are stimulated at low concentrations, and depressed at high concentrations of the hormone. Some of the glycoproteins of the acute phase (prothrombin, the third component of complement, haptoglobin, transferrin and ceruloplasmin) have defense-related functions. The others seem to participate in phenomena like detoxification, promotion of phagocytosis, wound healing, prevention of tissue injury by lysosomal enzymes, prevention of trauma and recovery from inflammation. It is proposed that the acute phase proteins, together with antibodies, form major components of the defense system, and the RES attempts to deal with injury by mobilization of increased amounts of these substances.     

Cigarette smoking and lung cancer in 'Hispanic' whites and other whites in New Mexico.

A population-based case-control study of lung cancer was performed in New Mexico to explain the differing patterns of lung cancer occurrence in the state's "Hispanic" Whites and other Whites. From 1980 through 1982, interviews were completed with 521 cases and 769 controls. In the male controls, the prevalence of current and previous cigarette usage was similar in the two ethnic groups, but Hispanics smoked fewer cigarettes daily. In the female controls, a lower percentage of Hispanics had ever smoked and their usual consumption was less than that of other White women. Older Hispanic female smokers had used hand-rolled cigarettes for an average of 8.8 years, whereas other White women of the same age had used this type for less than one-half year. Both stratified and multiple logistic analysis showed comparable risks of lung cancer in Hispanic White and other White smokers. There was no evidence of interaction between ethnicity and cigarette smoking. These analyses imply that the differences in lung cancer incidence between New Mexico's Hispanic Whites and other Whites are largely explained by the patterns of cigarette smoking of these two groups.     

Development and assessment of a verbal response scale for the Patient-Specific Functional Scale (PSFS) in a low-literacy,non-western population

Quality of Life Research - The Patient-Specific Functional Scale (PSFS) is a routinely used measure of physical function with a 0–10 response scale. We aimed to develop verbal response...     

Genetic predisposition and specific chromosomal defects associated with Sinclair swine malignant melanomas

Vesnarinone, (3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1- piperazinyl]-2(1H)-quinolinone), a quinolinone derivative, is a positive inotropic agent. We examined the cytotoxicity either by vesnarinone alone or in combination with doxorubicin (DXR), in vitro. The cytotoxic effect of vesnarinone against HL-60 cells did not increase, even at concentrations as high as (50 mu g/ml). The cytotoxicity of DXR, however, was enhanced after being combined with 30 mu g/ml of vesnarinone. The intracellular level of DXR increased when DXR was administered after incubation with vesnarinone and the efflux of DXR was delayed when the cells were incubated in the presence of vesnarinone after DXR exposure. Flow cytometry showed that the combination of DXR and vesnarinone increased the cell population below the G(0)/G(1) region. Vesnarinone induced DNA ladder formation, but only when these cells were incubated for 72 h, while in addition, when DXR was combined with vesnarinone, the DNA ladder formation was enhanced. Based on the above findings, we thus conclude that the cytotoxicity of DXR was enhanced when combined with vesnarinone.     

Characterization of variants of a human breast-cancer cell-line isolated from metastases in different organs of nude-mice

The MDA-MB-435 human breast cancer cell line metastasizes from tumors growing in the mammary fatpad of nude mice; metastases are found in the lymph nodes and lungs of 75 to 100% of tumor-bearing mice, and at a lower incidence in other organs such as the heart, skeletal muscle, adrenal gland and brain. Variants of this breast cancer cell line were established from metastases in different organs, including the lungs and brain of nude mice; these lines were designated 435-Lung2 and 435-Br1, respectively. Karyotypic analysis of the new variants suggested a clonal origin for the different organ metastases. The lung-derived cells were as metastatic as the original cell line when re-injected in nude mice, yet the cells from the brain metastasis produced few metastases. Analyses of the invasive potential of the cell lines showed that they did not differ in expression of mRNA for 72-kDa type IV-collagenase, or in gelatinase activity (by zymography), or in ability to invade through a Matrigel-coated filter. The poorly metastatic 435-Br1 cells showed reduced binding to cultured monolayers of mouse lung-endothelial cells, compared with the metastatic 435-Lung2 and MDA-MB-435 cells. When the breast cancer cells were artificially arrested in the lungs of nude mice, by injecting Cytodex beads coated with cells, all three cell lines grew equally well, suggesting that the deficiency found in the metastatic potential of the 435-Br1 cells may be associated with interactions with endothelial cells, rather than growth potential in the lungs. Further comparisons of these two metastasis-derived variants of a heterogeneous cell line will lead to greater understanding of the metastatic phenotype of human breast cancer.     

Senile systemic amyloidosis--a case report

An 85 years old female presented with acute pain and weakness in left lower extremity and doppler evidence of femoropopliteal block was made which subsequently proved fatal. Necropsy revealed extensive amyloid deposition in the heart and amyloid angiopathy in rest of the organs.     

Costs of epilepsy in an intermediate care facility for persons with mental retardation

Epilepsy is a significant comorbid condition in institutionalized persons with developmental disabilities and may contribute significant additional costs. This study was conducted to provide an estimate of the costs of epilepsy from the institutional perspective. Costs were measured retrospectively for 50 persons with epilepsy and 50 persons without epilepsy matched by severity of developmental disability. A time and motion study was employed to assign opportunity costs to documented nursing and physician activities. Two separate methods of attribution were used and incremental costs attributable to epilepsy were found to be approximately $825 and $918 per person over a 6-month period. The following categories accounted for costs: personnel (47.0%), drug (39.6%), hospitalization (9.4%), and laboratories/procedures (4.0%). Results are useful for describing the economic burden of epilepsy.     

The Structure of Celiprolol

The crystal structure and nuclear magnetic resonance (NMR) spectra and assignments of celiprolol, N-[3-acetyl-4[3-[N-t-butylamino-2-hydroxypropoxy]phenyl]-N, N-diethylurea, are reported. Celiprolol crystallizes in the monoclinic space group, P2_l/a, with a = 9.081(2), b = 13.800(4), and c = 17.471(5) Å and = 95.04(2)°. Structure was solved by direct methods; structure refinement to R of 0.058. Intermolecular hydrogen-bonding in the crystal is discussed. The ¹H, ¹³C, and two-dimensional (2D) NMR spectra of the hydrochloride have been obtained and definitive signal assignments made.