A Mouse Model of Chronic Pancreatitis Induced by an Alcohol and High Fat Diet.

BACKGROUND/AIMS: Study of acute pancreatitis in chemically-induced rodent models has provided useful data; models of alcoholic chronic pancreatitis have not been available in mice. The aim of the present study was to characterize a mouse model of chronic pancreatitis induced solely with an alcohol and high fat (AHF) diet. METHODS: Mice were fed a liquid high fat diet containing 6% alcohol as well as a high fat supplement (57% total dietary fat) over a period of five months or as control, normal chow ad libitum. Pain related measures utilized as an index of pain included mechanical sensitivity of the hind paws determined using von Frey filaments and a smooth/rough textured plate. A modified hotplate test contributed information about higher order behavioral responses to visceral hypersensitivity. Mice underwent mechanical and thermal testing both with and without pharmacological treatment with a peripherally restricted µ-opioid receptor agonist, loperamide. RESULTS: Mice on the AHF diet exhibited mechanical and heat hypersensitivity as well as fibrotic histology indicative of chronic pancreatitis. Low dose, peripherally restricted opiate loperamide attenuated both mechanical and heat hypersensitivity. CONCLUSION: Mice fed an alcohol and high fat diet develop histology consistent with chronic pancreatitis as well as opioid sensitive mechanical and heat hypersensitivity.

Vagal and sciatic nerve stimulation have complex, time-dependent effects on chemically-induced seizures: a controlled study.

Previous studies of the effects of electrical vagus stimulation on experimental seizures were without suitable controls or statistical validation, and ignored the potential role of vagally-induced hemodynamic depression on seizure expression. This study addresses these limitations. The effects of periodic left vagus nerve stimulation (LVNS) on chemically-induced seizures in rats were compared with control groups receiving no stimulation (NoS), left sciatic nerve stimulation (LSNS) and LVNS after pretreatment with methyl atropine (MA-LVNS). Stimulation followed a 30 s on-120 s off cycle over 130 min. Seizures were scored visually and the temporal variation of their probability P(s) across the stimulation cycle was measured statistically. P(s) was significantly different (P<0.01) for all groups: LSNS had the highest and MA-LVNS the lowest seizure probability; LVNS and NoS had intermediate values. While LVNS blocked seizures, it also precipitated them, explaining why its anti-seizure effect was only slightly greater than NoS. Neither LVNS nor MA-LVNS induced changes in cortical rhythms ('activation') associated with decreased P(s), unlike LSNS which increased cortical rhythm synchrony and with it, P(s). LVNS alone induced marked bradycardia and moderate hypoxemia. In conclusion, cranial and peripheral nerve stimulation have complex, time-varying effects on cerebral excitability: low frequency LSNS facilitated seizures, while LVNS both suppressed and facilitated them. The anti-seizure effect of LVNS was small and may have, in part, been due to a hemodynamically-induced deficit in energy substrates. The effects of MA-LVNS on seizure duration and P(s) raise the possibility that, in the absence of hemodynamic depression, stimulation of this nerve does not have a strong anti-seizure effect.

Stochastic modeling and prediction of experimental seizures in Sprague-Dawley rats.

Most seizure prediction methods are based on nonlinear dynamic techniques, which are highly computationally expensive, thus limiting their clinical usefulness. The authors propose a different approach for prediction that uses a stochastic Markov chain model. Seizure (Ts) and interictal (Ti) durations were measured from 11 rats treated with 3-mercaptopropionic acid. The duration of a seizure Ts was used to predict the time (Ti2) to the next one. Ts and Ti were distributed bimodally into short (S) and long (L), generating four probable transitions: S --> S, S --> L, L --> S, and L --> L. The joint probability density f (Ts, Ti2) was modeled, and was used to predict Ti2 given Ts. An identical model predicted Ts given the duration Ti1 of the preceding interictal interval. The median prediction error was 3.0 +/- 3.5 seconds for Ts (given Ti1) and 6.5 +/- 2.0 seconds for Ti2 (given Ts). In comparison, ranges for observed values were 2.3 seconds < Ts < 120 seconds and 6.6 seconds < Ti < 782 seconds. These results suggest that stochastic models are potentially useful tools for the prediction of seizures. Further investigation of the probable temporal interdependence between the ictal and interictal states may provide valuable insight into the dynamics of the epileptic brain.

Remittances and circulation behavior in the livelihood process: transmigrant families in South Sumatra, Indonesia.

The impact of migrant remittances in Indonesia is examined using data gathered in interviews undertaken in 21 households and with village leaders participating in the transmigration program in Cinta Karya, Sumatra, Indonesia. "Our findings illustrate that remittance behavior is spatially controlled and temporally variable, as families balance their labor and capital resources among farm production, local industry and investments, and the often unpredictable nature of circulation employment and remittances. We emphasize the linked and recursive nature of elements in the livelihood process and the related importance of temporal family dynamics in decision-making strategies."

CABG after successful PTCA: a case-control study.

We sought characteristics predictive of the need for operative revascularization subsequent to a successful coronary angioplasty. Through June 1993, 128 patients who had successful percutaneous transluminal coronary angioplasty (PTCA) between January 1982 and March 1989 required subsequent coronary artery bypass grafting (CABG) at our hospital. These cases were matched with 128 controls who had a successful PTCA but did not require subsequent CABG. Controls were matched to cases by the date of their initial PTCA. Before initial PTCA there were no differences between the cases and controls in terms of age, sex, prior myocardial infarction, ejection fraction, duration of anginal symptoms, hypertension, hyperlipidemia, family history, or obesity (all not significant). A greater number of cases had diabetes (35 versus 18; p = 0.009). Angiography before initial PTCA revealed that cases had a greater mean number of total lesions (4.1 versus 3.3; p = 0.002) and a higher incidence of left anterior descending and circumflex artery stenoses of 70% or greater (98 versus 75 and 57 versus 34, respectively; p = 0.006). The mean number of lesions successfully dilated was greater in cases (2.4 versus 1.7; p = 0.0001). Cases had CABG at a mean interval of 16.7 +/- 23 months. There were 17 late deaths among cases and 9 among the controls at a mean of 38.6 +/- 30 months. The survival probability at 5 years was 94.5% for controls and 87.9% for cases (p = 0.048). Initial revascularization by PTCA is followed by CABG at a brief interval in a subset of patients who have markers of more severe disease than do patients who do not require early CABG.(ABSTRACT TRUNCATED AT 250 WORDS)

The human DNA repair gene, ERCC2 (XPD), corrects ultraviolet hypersensitivity and ultraviolet hypermutability of a shuttle vector replicated in xeroderma pigmentosum group D cells.

To determine the contribution of a human DNA repair gene, ERCC2 (XPD), to mutagenesis in human cells, two ERCC2 (XPD)-transformed xeroderma pigmentosum complementation group D (XPD) cell lines with increased UV survival compared to XP6BE(SV40), the original XPD line, were studied: D6BE-ER2-2 with slightly increased UV survival; and D6BE-ER2-9 with normal UV survival. ERCC2 (XPD) antibody-reactive protein levels were elevated 4.8-fold in D6BE-ER2-2 and 17.6-fold in D6BE-ER2-9 relative to XP6BE(SV40). DNA repair ability was assessed by measuring the ability of the cells to restore expression to UV-treated plasmids. Transfection of pRSVcat exposed to 1000 J/m2 UV resulted in 0.3% chloramphenicol acetyltransferase activity in XP6BE(SV40) cells but 20-80% in D6BE-ER2-2, D6BE-ER2-9, and repair-proficient cells compared to untreated control plasmids. The UV hypersensitivity of the mutagenesis shuttle vector pSP189 in XP6BE(SV40) cells was partially corrected and the UV hypermutability and excess of G:C-->A:T mutations of pSP189 fell to the normal range in D6BE-ER2-2 and D6BE-ER2-9 cells. However, the frequency of plasmids recovered with multiple base substitution mutations was significantly reduced with XP6BE(SV40) cells and remained low in D6BE-ER2-2 and D6BE-ER2-9 cells, when compared with the normal fibroblasts. The human DNA excision repair gene, ERCC2 (XPD), substantially corrected the plasmid UV hypersensitivity and UV hypermutability of xeroderma pigmentosum complementation group D cells; however, the dose response relationship varied for different end points.

Negative superhelicity promotes ATP-dependent binding of yeast RAD3 protein to ultraviolet-damaged DNA.

The RAD3 gene of Saccharomyces cerevisiae is required for excision repair of UV-damaged DNA and is essential for cell viability. Remarkable homology exists between RAD3 and the human excision repair gene XPD, whose mutational inactivation underlies the cancer-prone disorder in xeroderma pigmentosum group D patients. Our previous work demonstrated that RAD3-encoded protein contains a DNA helicase activity. Here, we show that RAD3 binds preferentially to UV-damaged DNA over nondamaged DNA. Removal of pyrimidine dimers from damaged DNA by enzymatic photoreactivation does not affect binding, suggesting an affinity of RAD3 for pyrimidine (6-4) pyrimidone photoproducts. Damage-specific binding by RAD3 is strongly dependent on ATP and on the degree of negative superhelicity in DNA. The requirement of superhelicity in damage binding may target RAD3 to regions of DNA undergoing transcription, resulting in the preferential repair of these regions. The rad3 Arg-48 mutant protein, which lacks the DNA helicase activity, also binds UV-damaged DNA preferentially, indicating that DNA helicase and damage binding are two distinct and separable functional entities in RAD3.

The Saccharomyces cerevisiae DNA repair gene RAD23 encodes a nuclear protein containing a ubiquitin-like domain required for biological function.

In eukaryotes, the posttranslational conjugation of ubiquitin to various cellular proteins marks them for degradation. Interestingly, several proteins have been reported to contain ubiquitin-like (ub-like) domains that are in fact specified by the DNA coding sequences of the proteins. The biological role of the ub-like domain in these proteins is not known; however, it has been proposed that this domain functions as a degradation signal rendering the proteins unstable. Here, we report that the product of the Saccharomyces cerevisiae RAD23 gene, which is involved in excision repair of UV-damaged DNA, bears a ub-like domain at its amino terminus. This finding has presented an opportunity to define the functional significance of this domain. We show that deletion of the ub-like domain impairs the DNA repair function of RAD23 and that this domain can be functionally substituted by the authentic ubiquitin sequence. Surprisingly, RAD23 is highly stable, and the studies reported herein indicate that its ub-like domain does not mediate protein degradation. Thus, in RAD23 at least, the ub-like domain affects protein function in a nonproteolytic manner.

Elderly migration and development in small communities.

"This paper develops a conceptual model of the process of community change [in the United States] in response to elderly inmigration. Analysis of intra-regional variation in elderly migration patterns in Appalachia, and synthesis of an emergent literature on the benefits and costs of attracting elderly migrants, serve as a backdrop for case studies, based on field observations and interviews, of three contrasting Appalachian communities at different stages of development as retirement destinations."

Women, family, and work in Indonesian transmigration.

PIP: The gender contribution to employment may be a critical factor in determining household economic viability. The significance for the resettlement program of the poor and landless from Indonesia's Inner Islands to the Outer Islands is clear. The aim of this paper is to examine the nature and extent of the role of women in off-farm employment (OFE) in a sample of South Sumatra, Indonesia transmigrants during the summer of 1989 at 9 different sites with different agricultural environments, settlement histories, and access to markets. A summary is provided of the literature on women's work and peasant household economies in Indonesia. Spatial and structural characteristics of employment among transmigrant women are described as well as life course influences on men's and women's OFE. A descriptive and explanatory model is presented that characterizes women's work and includes the influences of changing family structure on time allocation. Women's work appears fundamentally different from men's; household domestic work has a degree of flexibility in timing and tasks can be accomplished simultaneously. The hypothesis is that women will try to maximize their levels of flexibility and simultaneity in their income generating efforts. Discussion focuses on several theories of peasant household economies: 1) the Chayanov peasant model which posits that labor allocation for farm production in order to satisfy consumption needs is dependent on household demographic structure and the consumer labor balance; and 2) the New Home Economics theory which emphasizes the single utility function of the household. The villages represent 3 irrigated rice-growing and double cropping areas with established infrastructures and access to markets; 3 area with tidal swamp rice production and few resources; and area with rainfed rice production and limited resources and an area with ample resources; and 2 areas with smallholder rubber production. There were 560 ethnically Javanese households included in the sample, with an average proportion of 10% in each settlement. OFE is either on scheme, which means within the transmigration scheme and involves short distances to work, or off scheme, which entails longer work trips. 61% of the sample were involved in on scheme and 42% were involved in off scheme OFE, of which 10% were heads of households and 4% were spouses.^ieng

The extremely conserved amino terminus of RAD6 ubiquitin-conjugating enzyme is essential for amino-end rule-dependent protein degradation.

The RAD6 gene of Saccharomyces cerevisiae encodes a ubiquitin-conjugating enzyme that is required for DNA repair, damage-induced mutagenesis, and sporulation. In addition, RAD6 mediates the multiubiquitination and degradation of amino-end rule protein substrates. The structure and function of RAD6 have been remarkably conserved during eukaryotic evolution. Here, we examine the role of the extremely conserved amino terminus, which has remained almost invariant among RAD6 homologs from yeast to human. We show that RAD6 is concentrated in the nucleus and that the amino-terminal deletion mutation, rad6 delta 1-9, does not alter the location of the protein. The amino-terminal domain, however, is essential for the multiubiquitination and degradation of amino-end rule substrates. In the rad6 delta 1-9 mutant, beta-galactosidase proteins bearing destabilizing amino-terminal residues become long lived, and purified rad6 delta 1-9 protein is ineffective in ubiquitin-protein ligase (E3)-dependent protein degradation in the proteolytic system derived from rabbit reticulocytes. The amino terminus is required for physical interaction of RAD6 with the yeast UBR1-encoded E3 enzyme, as the rad6 delta 1-9 protein is defective in this respect. The rad6 delta 1-9 mutant is defective in sporulation, shows reduced efficiency of DNA repair, but is proficient in UV mutagenesis. E3-dependent protein degradation by RAD6 could be essential for sporulation and could affect the efficiency of DNA repair.

Photochemotherapy in human heart transplant recipients at high risk for fatal rejection.

Heart transplant recipients in whom high levels of lymphocytotoxic antibodies directed towards a spectrum of histocompatibility antigens develop frequently represent difficult management problems. Recipients of multiple transplants and multiparous females generally form higher levels of panel reactive antibodies, which have been associated with fatal rejection episodes and accelerated graft atherosclerosis. In this study, two multiple transplant patients with preexistent high levels of panel reactive antibodies and two multiparous women who were considered at risk of sensitization were treated with a new form of immunotherapy termed photochemotherapy in addition to conventional immunosuppression. High levels of panel reactive antibodies have been reduced, and patients have suffered few rejection episodes and no infectious complications. This preliminary experience shows that the addition of photochemotherapy to conventional regimens may improve the clinical course of hypersensitized transplant patients without additional immunosuppressive risk.

Off-farm employment in Indonesian transmigration: case studies from south Sumatra.

The authors assess the impact of off-farm employment in the context of Indonesia's transmigration program. "The central objective...is to explore and generalize transmigrant households' employment behavior with respect to off-farm activities.... The specific intent...is to focus upon the individuals participating in off-farm employment: the conditions which lead to the development of their employment behavior as well as the nature of the employment itself." (SUMMARY IN IND)

Ultrasonic angioplasty in totally occluded peripheral arteries. Initial clinical, histological, and angiographic results.

BACKGROUND: Ultrasonic angioplasty was recently shown to ablate thrombi and atherosclerotic plaques in vitro and to recanalize occluded arteries in experimental animal models. The goal of the present study was to examine the clinical feasibility of ultrasonic angioplasty. METHODS AND RESULTS: Intraoperative ultrasonic angioplasty was performed in vivo on totally occluded peripheral arteries (n = 7). The ultrasonic angioplasty device consists of a 1.6-mm diameter flexible wire attached to a piezoelectric crystal generating ultrasound at 20 kHz. The controls, totally occluded human atherosclerotic femoral arterial segments (n = 6), were crossed mechanically with the ultrasound wire ex vivo but without application of ultrasonic energy. Ultrasonic angioplasty achieved successful recanalization without perforation in all vessels. Angiograms of the treated arteries showed an average lumen patency of 82.5%. Histological examination of the recanalized arteries revealed that the recanalization had taken place through intima diffusely involved with complicated plaque. The treated arteries, compared with the controls, had greater area of recanalized lumen (5.9 +/- 1.8 versus 1.7 +/- 0.4 mm2, p less than 0.05) and more flow (49.3 +/- 16.0 versus 11.8 +/- 4.9 ml/min, p less than 0.03). The damage in treated and control arteries was similar. Size-distribution analysis of the plaque debris from the treated arteries showed that 41 +/- 5% of the debris was 0.2-8 microns, 48 +/- 8% was 8-30 microns, and the remainder was 30-100 microns. In the mechanically crossed arteries, there was a shift in the distribution to larger size debris with 47 +/- 1% greater than 100 microns (p less than 0.001). CONCLUSIONS: Ultrasonic angioplasty may be a useful clinical method for recanalization of total occlusions in patients with peripheral vascular disease. Ultrasonic energy appears to cause controlled injury to the atherosclerotic intima by selectively disrupting the ultrasound-sensitive occlusion.

Migration and regional population aging in the Philippines.

There is a growing realization that developing countries will be affected in the future by the problems associated with population aging. Although internal migration could exacerbate the problems of aging at subnational levels, there remains a paucity of research on the role of migration in elderly population change for the developing countries of the world. This study uses 1980 census data for the Philippines to explore the spatial and temporal dynamics of the country's elderly population. Through examination of internal migration patterns among the thirteen regions of the country and population projections, this paper demonstrates the potentially large role that migration plays in determining local patterns of aging.The National Capital Region, which is a primary destination of labor force migrants, exhibits the greatest projected increase in the share of the nation's elderly population, while the centrally located Visayas regions show rapid reductions in the future. The Visayas regions, however, may be expected to have the highest concentrations of elderly in their populations. Such findings suggest that labor force migration patterns, with subsequent aging-in-place, will most strongly influence near future distributions and concentrations of the elderly, and that national planning for the future's elderly population should incorporate regional examinations as a means of appropriately distributing financial and service related support.

Appalachian elderly migration: patterns and implications.

This article seeks to explore the patterns of population aging and elderly migration in Appalachia, with a focus on two distinct and different subregions: eastern Kentucky and western North Carolina. Although the framework of the study is demographic, the foundation is more related to overarching concerns of the implications of migration, particularly with respect to local economies and services, and the potential use of elderly migration as a development strategy.