Vegetable protein intake is associated with lower gallbladder disease risk: Findings from the Women's Health Initiative prospective cohort.

OBJECTIVE: This study aimed to measure associations between gallbladder disease and protein intake patterns, separated by quantity and type (vegetable vs. animal), among postmenopausal women. METHODS: Analyses were based on 130,859 postmenopausal women enrolled from 1993 to 1998 at 40 U.S. clinical centers in the Women's Health Initiative clinical trials and observational study. Women were excluded if they reported a history of gallbladder disease prior to baseline. Cox proportional hazards regression models, adjusted for gallbladder disease risk factors, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between energy-adjusted protein intake and gallbladder disease. RESULTS: In this study sample, 8.1% of postmenopausal women self-reported incident gallbladder disease. In multivariate analysis, women in the highest quintile of energy-adjusted vegetable protein intake (>24.0g/d) had a lower risk of gallbladder disease (HR, 0.87; 95% CI, 0.81-0.93) as compared to women in the lowest quintile (<16.3g/d) (Ptrend<0.001). Total protein intake was modestly protective against gallbladder disease (Ptrend<0.021). Animal protein intake was not associated with gallbladder disease risk. The protective effect of vegetable protein held stable only for women without history of diabetes (HR, 0.86; 95% CI, 0.80-0.92) and without recent weight loss (HR, 0.88; 95% CI, 0.80-0.97). CONCLUSIONS: Vegetable protein intake is inversely associated with gallbladder disease risk in our sample of postmenopausal women. In addition to weight management, healthcare providers could emphasize vegetable protein as an additional dietary modality to promote lower risk for gallbladder disease.

Concomitant cholecystectomy should be routinely performed with laparoscopic Roux-en-Y gastric bypass.

INTRODUCTION: As the popularity of a laparoscopic Roux-en-Y Gastric Bypass (RYGB) surpassed that of an open approach, practice of concomitant cholecystectomy declined. Low rates of gallbladder disease following RYGB and high complication rates of concomitant cholecystectomy have been published, but these population-based studies have lacked long-term outcomes and survival data. STUDY DESIGN: The California Office of Statewide Health Planning and Development longitudinal database was queried for patients who underwent RYGB with or without cholecystectomy between 1995 and 2009. Additionally, patients who underwent cholecystectomy after RYGB were compared to all cholecystectomy patients. Primary outcome was survival; secondary long-term outcomes included cholangitis, common duct stones, dumping syndrome, metabolic derangements, ventral hernia, any hernia, marginal ulcers, and reoperation. Cox proportional hazard analysis was performed to determine adjusted survival and outcomes. RESULTS: Of 134,584 RYGB patients, 21,022 underwent concomitant cholecystectomy. Concomitant cholecystectomy improved both survival (HR[95 % CI] 0.51[.48-.54]) and long-term outcomes (HR 0.84[.77-.91]). Incidence of gallbladder disease following RYGB was 6.8 and 15.2 % at 1 and 5 years. In subsequent analysis of 829,333 cholecystectomy patients, 7,099 underwent prior RYGB with higher risk of conversion to open (HR 1.58[1.41-1.78]), post-operative complication (HR 1.47[1.36-1.6]) and death (HR 1.32[1.17-1.5]). CONCLUSIONS: Concomitant cholecystectomy is safe for RYGB patients. Given high rates of gallbladder disease and increased risk when cholecystectomy is performed following RYGB, cholecystectomy should be considered at the time of RYGB.

Menopausal hormone therapy for the primary prevention of chronic conditions: U.S. Preventive Services Task Force recommendation statement.

DESCRIPTION: Update of the 2005 U.S. Preventive Services Task Force (USPSTF) recommendation statement on hormone therapy for the prevention of chronic conditions in postmenopausal women. METHODS: The USPSTF commissioned a review of the literature to update evidence about the benefits and harms of using menopausal hormone therapy to prevent chronic conditions, as well as whether the benefits and harms of hormone therapy differ by population subgroups defined by age; the presence of comorbid medical conditions; and the type, dose, and method of hormonal delivery. POPULATION: This recommendation applies to postmenopausal women who are considering hormone therapy for the primary prevention of chronic medical conditions. It does not apply to women who are considering hormone therapy for the management of menopausal symptoms, such as hot flashes or vaginal dryness. It also does not apply to women younger than 50 years who have had surgical menopause. RECOMMENDATION: The USPSTF recommends against the use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women. (Grade D recommendation).The USPSTF recommends against the use of estrogen for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy. (Grade D recommendation).

Effect of preserving the hepatic vagal nerve during laparoscopic Nissen fundoplication on postoperative biliary functions.

BACKGROUND: Cutting the hepatic branch of the anterior vagus nerve (HB-AVn) technically facilitates the laparoscopic Nissen fundoplication. The aim of this study was to investigate the effects of preserving or sacrificing this branch on postoperative gallbladder functions. METHODS: The patients (n = 40) were prospectively randomized into two groups. The HB-AVn was preserved during the dissection of the lesser omentum in the first group. The nerve was cut in the second group. Postoperative fasting gallbladder volumes were calculated by ultrasonography. Postoperative gallbladder ejection fraction (GEF) and gallbladder emptying time (GET) were determined by calculating intestinal transit time scintigraphically. RESULTS: Fasting gallbladder volumes and GEF values were not different between the groups. On the other hand, in patients with HB-AVn preserved, GET measurements were found to be significantly shorter than those with HB-AVn sacrificed. CONCLUSIONS: Sacrificing the hepatic branch causes prolongation in the GET. This change in the motor functions of the gallbladder does not cause any symptomatic effect during the early postoperative period. However, the delay in the GET may increase the risk of gallbladder stone formation in the long term.

Menopausal hormone therapy for the primary prevention of chronic conditions: a systematic review to update the U.S. Preventive Services Task Force recommendations.

BACKGROUND: Menopausal hormone therapy to prevent chronic conditions is currently not recommended because of its adverse effects. PURPOSE: To update evidence about the effectiveness of hormone therapy in reducing risk for chronic conditions and adverse effects, and to examine whether outcomes vary among women in different subgroups. DATA SOURCES: MEDLINE (January 2002 to November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the 3rd quarter of 2011), Scopus, and reference lists. STUDY SELECTION: Randomized, placebo-controlled trials of menopausal hormone therapy published in English since 2002 that assessed primary prevention of chronic conditions. DATA EXTRACTION: Investigators extracted data on participants, study design, analysis, follow-up, and results; 2 investigators independently rated study quality by using established criteria. DATA SYNTHESIS: 9 fair-quality trials met the inclusion criteria. The Women's Health Initiative reported most of the results, had 11 years of follow-up, and had data most applicable to postmenopausal women in the United States. It showed that estrogen plus progestin therapy reduced fractures (46 fewer per 10 000 woman-years) and increased invasive breast cancer (8 more per 10 000 woman-years), stroke (9 more per 10 000 woman-years), deep venous thrombosis (12 more per 10 000 woman-years), pulmonary embolism (9 more per 10 000 woman-years), lung cancer death (5 more per 10 000 woman-years), gallbladder disease (20 more per 10 000 woman-years), dementia (22 more per 10 000 woman-years), and urinary incontinence (872 more per 10 000 woman-years). Estrogen-only therapy reduced fractures (56 fewer per 10 000 woman-years), invasive breast cancer (8 fewer per 10 000 woman-years), and death (2 fewer per 10 000 woman-years) and increased stroke (11 more per 10 000 woman-years), deep venous thrombosis (7 more per 10 000 woman-years), gallbladder disease (33 more per 10 000 woman-years), and urinary incontinence (1271 more per 10 000 woman-years). Outcomes did not consistently differ by age or comorbid conditions. LIMITATION: Limitations of the trials included low adherence, high attrition, inadequate power to detect risks for some outcomes, and evaluation of few regimens. CONCLUSION: Estrogen plus progestin and estrogen alone decreased risk for fractures but increased risk for stroke, thromboembolic events, gallbladder disease, and urinary incontinence. Estrogen plus progestin increased risk for breast cancer and probable dementia, whereas estrogen alone decreased risk for breast cancer. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Complications of endoscopic ultrasonography.

Since its development in the 1980s, endoscopic ultrasonography (EUS) has undergone a great deal of technological modifications. EUS has become an important tool in the evaluation of patients with various clinical disorders and is increasingly being utilized in many centers. EUS has been evolving over the years; EUS-guided fine needle aspiration (FNA) for cytological and/or histological diagnosis has become standard practice and a wide array of interventional and therapeutic procedures are performed under EUS guidance for diseases which otherwise would have needed surgery, with its associated morbidities. EUS shares the risks and complications of other endoscopic procedures. This article addresses the specific adverse effects and risks associated with EUS, EUS-FNA and interventional EUS, namely perforation, bleeding, pancreatitis and infection. Measures to help minimizing these risks will also be discussed.

Systematic review of management of gallbladder disease in patients undergoing minimally invasive bariatric surgery.

The introduction and subsequent widespread adaptation of minimally invasive approaches for bariatric surgery have not only changed the outcomes of bariatric surgery but also called into question the management of co-morbid surgical conditions, in particular gallbladder disease. The American Society for Metabolic and Bariatric Surgery Foregut Committee performed a systematic review of the published literature from 1995-2018 on management of gallbladder disease in patients undergoing bariatric surgery. The papers reviewed generated the following results. (1) Routine prophylactic cholecystectomy at the time of bariatric surgery is not recommended. (2) In symptomatic patients who are undergoing bariatric surgery, concomitant cholecystectomy is acceptable and safe. (3) Ursodeoxycholic acid may be considered for gallstone formation prophylaxis during the period of rapid weight loss. (4) Routine preoperative screening and postoperative surveillance ultrasound is not recommended in asymptomatic patients. In the era of minimally invasive surgery, the management of gallbladder disease in patients undergoing bariatric surgery continues to evolve.

A Whole-Food-Based Health Product (A-F Betafood®) Improves Gallbladder Function in Humans at Risk of Gallbladder Insufficiency: A Randomized, Placebo-Controlled Clinical Trial.

A-F Betafood® is a whole food-based health product. The product contains phytonutrients and bioactives with antioxidant properties that may support gallbladder and liver function. Herein, we investigated the efficacy of A-F Betafood® on gallbladder and liver function. In this randomized, placebo-controlled, parallel study fifty overweight but otherwise healthy adults received A-F Betafood® or placebo for 12 weeks. Gallbladder function as assessed by gallbladder volume, ejection fraction (GBEF), ejection rate, wall thickness and liver function determined via aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase, and high-sensitivity c-reactive protein analysis at baseline and week 12 were the primary outcomes. Total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglycerides, and oxidative stress markers including oxidized low-density lipoprotein, tumor necrosis factor-α, adiponectin and malonyldialdehyde (MDA) were assessed as secondary outcomes. A-F Betafood®-supplementation significantly reduced gallbladder wall thickness (p = 0.049) by 9% compared to placebo from baseline to week 12. The A-F Betafood® group alone had significant improvements in gallbladder volume (32%; p = 0.044) and GBEF (19%; p = 0.047) at week 12. There were no changes in liver function, oxidative stress markers or blood lipid concentrations, though MDA concentrations decreased in both groups. Our findings demonstrate A-F Betafood®-supplementation significantly improves measures of gallbladder function and support healthy gallbladder function in the individuals with gall bladder condition.

Separate and joint effects of alcohol and smoking on the risks of cirrhosis and gallbladder disease in middle-aged women.

The separate and joint effects of alcohol and smoking on incidences of liver cirrhosis and gallbladder disease were examined in a prospective study of 1,290,413 United Kingdom women (mean age, 56 years) recruited during 1996-2001. After a mean follow-up of 6.1 years (1996-2005), incidence rates of cirrhosis and gallbladder disease were 1.3 per 1,000 persons (n = 2,105) and 15 per 1,000 persons (n = 23,989), respectively, over 5 years. Cirrhosis risk increased with increasing alcohol consumption, while the risk of gallbladder disease decreased (P(trend) < 0.0001 for each). Comparing women who drank > or =15 units/week with those who drank 1-2 units/week, the relative risk was 4.32 (95% confidence interval (CI): 3.71, 5.03)) for cirrhosis and 0.59 (95% CI: 0.55, 0.64) for gallbladder disease. Increasing numbers of cigarettes smoked daily increased the risk of both conditions (P(trend) < 0.0001 for each). Comparing current smokers of > or =20 cigarettes/day with never smokers, the relative risk was 3.76 (95% CI: 3.25, 4.34) for cirrhosis and 1.29 (95% CI: 1.22, 1.37) for gallbladder disease. Effects of alcohol and smoking were more than multiplicative for cirrhosis (P(interaction) = 0.02) but not for gallbladder disease (P(interaction) = 0.4). Findings indicate that alcohol and smoking affect the risks of the 2 conditions in different ways. For cirrhosis, alcohol and smoking separately increase risk, and their joint effects are particularly hazardous. For gallbladder disease, alcohol reduces risk and smoking results in a small risk increase.

[Gallbladder complications after bariatric surgery]. / Complications vésiculaires après chirurgie bariatrique.

With the increased incidence of obesity in the developed countries, and the failure of medical treatments, bariatric surgery has increased rapidly. Although laparoscopic gastroplasty is the most popular bariatric intervention in France, the gold standard tends to be the laparoscopic gastric bypass. The severe weight loss caused by this type of procedure induces specific middle or long term complications such as biliary lithiasis. In this literature we describe different physiopathological mechanisms of lithiasis after gastric bypass by coeliosurgery or gastroplasty, their diagnosis, and preventive treatment to avoid these complications.

Transhepatic biliary catheterization before graft implant in living donor liver transplantation.

AIM: Despite the evolution in surgical technique, the biliary anastomosis remains the technical Achilles' heel of liver transplantation, especially in living donor liver transplantation. Interventional radiology or endoscopic procedures constitute the most common options to treat complications from the biliary anastomosis. We report a novel technique to prevent biliary complications following the transplant. METHODS: During the donor procedure a wire guide was introduced in the severed duct, left or right, in retrograde fashion. The liver surface was then perforated and the wire guide exposed. A 4F catheter was then attached to the wire guide and pulled into the bile duct passing through the end-to-end duct-to-duct anastomosis or hepaticojejunostomy. RESULTS: This technique was performed in six living donor grafts: one right lobe, two left lobes, and three left lateral segments. All patients had no complications from the stent placement, biliary strictures, or leaks. One developed a hepatic artery thrombosis on the posttransplant day 14 with no major biliary complications.

Serum ascorbic acid and gallbladder disease prevalence among US adults: the Third National Health and Nutrition Examination Survey (NHANES III).

BACKGROUND: Ascorbic acid-deficient guinea pigs frequently develop gallstones, and ascorbic acid status may also affect the risk of gallbladder disease in humans. To examine the relationship of ascorbic acid, an antioxidant nutrient involved in cholesterol catabolism, to gallbladder disease, we analyzed data collected from a probability sample of US adults. METHODS: Analyses of data from 7042 women and 6088 men enrolled in the Third National Health and Nutrition Examination Survey, 1988-1994, were performed. Multiple logistic regression models stratified by sex were examined, controlling for the effects of age, race, diet, body mass index, and other potential confounders. RESULTS: A total of 761 women (11%) and 235 men (4%) reported a history of clinical gallbladder disease (symptomatic gallstones or cholecystectomy). Of the 9650 participants without a history of clinical gallbladder disease or abdominal pain consistent with gallbladder disease, and with valid abdominal ultrasonography, 408 (8%) of 4863 women and 274 (6%) of 4787 men had asymptomatic gallstones. Serum ascorbic acid level was inversely related to prevalence of clinical and asymptomatic gallbladder disease among women, but not among men. Among women, each SD (27 micromol/L) increase in serum ascorbic acid level was independently associated with a 13% lower prevalence of clinical gallbladder disease (P = .006) and asymptomatic gallstones (P = .048). CONCLUSION: Ascorbic acid, which affects the catabolism of cholesterol to bile acids and, in turn, the development of gallbladder disease in experimental animals, may affect the risk of gallbladder disease among women.

Alcohol consumption in relation to risk of cholecystectomy in women.

BACKGROUND: Alcohol consumption has been linked to a lower risk of gallstone disease. However, the magnitude of the association is uncertain, and little is known about the relation of alcohol consumption patterns and individual types of alcoholic beverages to gallstone disease risk. OBJECTIVE: We prospectively examined the association between alcohol intake and cholecystectomy, a surrogate for symptomatic gallstone disease, in a large cohort of women. DESIGN: Women from the Nurses' Health Study who had no history of gallstone disease in 1980 (n = 80,898) were followed for 20 y. Alcohol consumption, which was measured every 2-4 y by food-frequency questionnaires, was used to predict subsequent cholecystectomy through multivariate analysis. RESULTS: We ascertained 7831 cases of cholecystectomy. Relative to subjects who had no alcohol intake, subjects who had alcohol intakes of 0.1-4.9, 5.0-14.9, 15.0-29.9, 30.0-49.9, and >/=50.0 g/d had multivariate relative risks of cholecystectomy of 0.95, 0.86, 0.80, 0.67, and 0.62 (95% CI: 0.49, 0.79), respectively. Relative to subjects who never consumed alcohol, subjects who consumed alcohol 1-2, 3-4, 5-6, and 7 d/wk had multivariate relative risks of cholecystectomy of 0.94, 0.88, 0.87, and 0.73 (0.63, 0.84), respectively. All alcoholic beverage types were inversely associated with cholecystectomy risk, independent of consumption patterns (for quantity of alcohol consumed, P = 0.04, 0.001, and 0.003 for wine, beer, and liquor, respectively; for frequency of alcohol consumption, P = 0.01, 0.07, and <0.0001 for wine, beer, and liquor, respectively). CONCLUSIONS: The intake of all alcoholic beverage types is inversely associated with the risk of cholecystectomy. Recommendations regarding the benefit of consuming moderate quantities of alcohol should be weighed against the potential health hazards.

Prophylactic cholecystectomy with gastric bypass operation: incidence of gallbladder disease.

BACKGROUND: Morbid obesity is one of the major risk factors for gallbladder disease, and this risk is even greater following rapid weight loss. Because of this, prophylactic cholecystectomy has been offered to our patients undergoing the transected silastic ring vertical Roux-en-Y gastric bypass (TSRVRYGBP). A study was undertaken to determine the incidence of pathologic gallbladders in patients undergoing this prophylactic cholecystectomy. METHOD: The records of all patients who underwent TSRVRYGBP from June 1999 through December 2000 were reviewed. Pathologic findings of the gallbladder were documented as cholelithiasis, cholecystitis, cholesterolosis, polyps or normal. RESULTS: 761 patients underwent the operation. 178 patients (23%) had cholecystectomy before the surgery. 154 (20%) had gallstones documented by ultrasound and had cholecystectomy at the time of the surgery. 324 of the 429 patients with negative preoperative findings by ultrasound had pathologic evidence of gallbladder disease. CONCLUSION: Because of the high incidence of gallbladder disease even with negative preoperative findings in morbidly obese patients and the lack of significant morbidity with cholecystectomy in experienced hands, routine cholecystectomy at the time of the weight loss operation is justified.

A review of long-term studies evaluating the efficacy of weight loss in ameliorating disorders associated with obesity.

Obesity leads to and exacerbates many serious disorders, including hypertension, dyslipidemia, cardiovascular disease, non-insulin-dependent diabetes mellitus, gallbladder disease, respiratory dysfunction, gout, and osteoarthritis. Many short-term studies have shown that weight loss can ameliorate or, in some cases, reverse such disorders. Fewer long-term studies-defined as those whose combined acute intervention and follow-up phases extend for at least 1 year-of the therapeutic benefits of weight loss on specific disorders have been undertaken. Those long-term studies that have been performed tend to confirm the results of briefer studies. Even when weight loss has been comparatively modest or some degree of weight regain has occurred, weight loss is generally associated with a decrease in risk factors and the alleviation of clinical symptoms.

Obesity and cholecystectomy among women: implications for prevention.

Almost all studies of the association of body mass with the risk of gallbladder disease have found that risk increases with obesity. Some studies report a nonlinear relationship of body mass to gallbladder disease risk, and some report that the association of excess body mass with increased risk of gallbladder disease is confined to younger women. We examined the association of body mass with the risk of cholecystectomy based on data from 14 years of follow-up of 16,638 women. The cholecystectomy rate was much greater in the highest quintile of Quetelet's body mass index than in other quintiles. The striking association of high rates of cholecystectomy with the highest quintile of Quetelet's body mass index was observed in each age group studied. The low incidence of cholecystectomy in young, thin women made the relative risk of cholecystectomy in women in the fifth quintile of body mass highest in women under 25 years of age. The observation that cholecystectomy rates are not linearly associated with obesity suggests that women in the highest quintiles of body mass could be considered a reasonable group in which strategies for prevention of gallbladder disease might be tested.

PIP: The Walnut Creek Contraceptive Drug Study which began in 1968 and ended in 1972, monitored 16,638 women as part of a multiphasic health checkup and collected information on oral contraceptive (OC) use; smoking, alcohol use; other habits, and family and medical histories. The number of women years was determined in each age and weight category. The rates of gallbladder disease were similarly calculated. The Cox proportional hazards model was utilized as implemented in the multivariate life table analyses. In addition, Quetelet's body mass index as a measure of obesity was applied. 16,240 women had an intact gallbladder; of these 432 were hospitalized with diagnosis of gallbladder disease. The diagnosis was confirmed in 423 women: 98% had cholelithiasis accompanied by pathologic evidence of cholecystitis. The gallbladder disease rate increased with age, with body mass index, and it was dramatically higher in women in the highest quintile of Quetelet's body mass index than in other quintiles at all ages. A nonlinear association of cholecystectomy with obesity persisted. At least 500,000 cholecystectomies are carried out in the US annually, and the risk is much higher in women in the uppermost quintile, thus it is reasonable to suggest that preventive efforts should focus on this group.

Do biliary endoprostheses decrease biliary complications after liver transplantation?

AIM: Most technical complications after orthotopic liver transplantation (OLT) are related to the biliary tree. This report reviews the role of routine intraoperative placement of stents to reduce biliary complications. METHODS: We retrospectively analyzed 396 consecutive OLTs. We reviewed rates of biliary complications after hepaticojejunostomy (HJA) as well as following choledochocholedochostomy (CCA) groups: "experimental" group (routine intraoperative biliary stenting, last 10 months), "recent" control group (nonstented, previous 10 months), "historical" control group (prior to that period of time). RESULTS: All groups were matched for donor/recipient characteristics and for graft cold/warm ischemia time. The overall prevalence of biliary complications was 30.7% after CCA versus 35% after HJA. In the experimental group 21 patients had a 4.8% biliary complication rate compared to the recent control and historical groups, where biliary complication rates were 30% and 32.6%, respectively (P <.05). CONCLUSIONS: The intraoperative use of biliary stents is feasible and appears to decrease the rate of biliary complications. These results support the need for a prospective randomized trial.

The effects of enteral stimulation on gallbladder bile during total parenteral nutrition in the neonatal piglet.

The neonatal piglet is a satisfactory model for the human neonate requiring total parenteral nutrition (TPN). Bile status and subsequent liver and gallbladder dysfunction have long been documented as serious complications of long-term TPN. The purpose of this study was to determine whether small amounts of enteral formula during TPN will maintain normal bile appearance and composition. Thirty-one Hanford miniswine, 3 to 6 days old underwent surgery for the placement of central venous catheters. Two days postoperatively, the animals were separated into three groups, according to dietary regimens. Group 1 (n = 10), the control group, received pig formula (SPF-lac) orally (200 cal/kg/d); group 2 (n = 11), was maintained on TPN (180 cal/kg/d) with an enteral supplement of SPF-lac (20 cal/kg/d); group 3 (n = 10), was maintained on TPN only (200 cal/kg/d). The TPN formula consisted of 35 g/kg/d of glucose, 10 g/kg/d of protein, and 3 g/kg/d of lipid. The animals were maintained on these diets for 6 weeks. At necropsy, gallbladder with bile was weighed and bile volume and appearance was recorded. Chemical analyses was performed on 26 bile samples. Gallbladder weight was significantly decreased in groups 2 and 3 compared with group 1 (P less than .0003, P less than .033, respectively, using Students t test with Bonferoni adjustment). Volume was significantly decreased only in group 2 (P less than .003). Group differentiation in relation to bile appearance was determined by the presence or absence of either bile sludge or crystals.(ABSTRACT TRUNCATED AT 250 WORDS)