Whole-exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: Outcomes from a cohort of 50 families.

The inherited peripheral neuropathies (IPNs) are characterized by marked clinical and genetic heterogeneity and include relatively frequent presentations such as Charcot-Marie-Tooth disease and hereditary motor neuropathy, as well as more rare conditions where peripheral neuropathy is associated with additional features. There are over 250 genes known to cause IPN-related disorders but it is estimated that in approximately 50% of affected individuals a molecular diagnosis is not achieved. In this study, we examine the diagnostic utility of whole-exome sequencing (WES) in a cohort of 50 families with 1 or more affected individuals with a molecularly undiagnosed IPN with or without additional features. Pathogenic or likely pathogenic variants in genes known to cause IPN were identified in 24% (12/50) of the families. A further 22% (11/50) of families carried sequence variants in IPN genes in which the significance remains unclear. An additional 12% (6/50) of families had variants in novel IPN candidate genes, 3 of which have been published thus far as novel discoveries (KIF1A, TBCK, and MCM3AP). This study highlights the use of WES in the molecular diagnostic approach of highly heterogeneous disorders, such as IPNs, places it in context of other published neuropathy cohorts, while further highlighting associated benefits for discovery.

Communication satisfaction of professional nurses working in public hospitals.

AIM: This study aimed to establish and describe the level of communication satisfaction that professional nurses experience in selected public hospitals in the City of Johannesburg, South Africa. BACKGROUND: The success of any organisation depends on the effectiveness of its communication systems and the interaction between staff members. METHOD: Data were collected by means of questionnaires, based on the Communication Satisfaction Questionnaire (CSQ), from a sample of 265 professional nurses from different categories, chosen using a disproportionate random stratified sampling method. RESULTS: The results indicated poor personal feedback between nurse managers (operational managers) and professional nurses, as well as dissatisfaction among nurse managers and professional nurses with regard to informal communication channels. A lack of information pertaining to policies, change, financial standing and achievements of hospitals was identified. CONCLUSION: Nurse managers should play a leadership role in bringing staff of different departments together by creating interactive communication forums for the sharing of ideas. IMPLICATIONS FOR NURSING MANAGEMENT: The results emphasise the need for nurse managers to improve communication satisfaction at all levels of the hospital services in order to enhance staff satisfaction and create a positive working environment for staff members.

Relationship between fractional pancreatic beta cell area and fasting plasma glucose concentration in monkeys.

AIMS/HYPOTHESIS: We sought to establish the relationship between fasting plasma glucose concentrations and pancreatic fractional beta cell area in adult cynomolgus monkeys (Macaca fascicularis). METHODS: Fasting plasma glucose and pancreatic fractional beta cell area were measured in 18 control and 17 streptozotocin-treated adult primates (17.0 +/- 1.2 vs 15.4 +/- 1.2 years old). RESULTS: Fasting plasma glucose was increased (12.0 +/- 2.0 vs 3.4 +/- 0.1 mmol/l, p < 0.01) and fractional beta cell area was decreased (0.62 +/- 0.13% vs 2.49 +/- 0.35%, p < 0.01) in streptozotocin-treated monkeys. The relationship between fasting plasma glucose and pancreatic fractional beta cell area was described by a wide range of beta cell areas in controls. In streptozotocin-treated monkeys there was an inflection of fasting blood glucose at approximately 50% of the mean beta cell area in controls with a steep increase in blood glucose for each further decrement in beta cell area. CONCLUSIONS/INTERPRETATION: In adult non-human primates a decrement in fractional beta cell area of approximately 50% or more leads to loss of glycaemic control.

Clinicopathologic characterization of naturally occurring diabetes mellitus in vervet monkeys.

Diabetes mellitus (DM) is a group of chronic metabolic diseases characterized by persistent fasting hyperglycemia, and it can be of either polygenic or monogenic origin. Animal models have played an important role in elucidating the pathophysiology of the polygenic Type 1 and type 2 DM forms; however, useful animal models of the monogenic forms do not exist. The authors describe 4 cases of naturally occurring DM in vervet monkeys (Chlorocebus aethiops sabaeus), 1 of which has clinicopathologic findings consistent with type 2 DM, including persistent hyperglycemia, hypertriglyceridemia, islet amyloidosis, and reduced islet insulin immunostaining. In contrast, the 3 remaining animals have clinicopathologic similarities to a monogenic form of the disease, including a lack of islet amyloidosis and hypertriglyceridemia, as well as normal islet insulin immunostaining. In addition, pedigree analysis conducted on one of these animals is consistent with either an autosomal dominant or mitochondrial inheritance pattern, which supports a monogenic form of DM. The authors thus hypothesize that a naturally occurring monogenic form of diabetes may occur in vervet monkeys, making them a potential animal model for future studies.

The DEAH-box splicing factor Prp16 unwinds RNA duplexes in vitro.

BACKGROUND: During pre-mRNA splicing, dynamic rearrangement of RNA secondary structure within the spliceosome is crucial for intron recognition and formation of the catalytic core. Splicing factors belonging to the DExD/DExH-box family of RNA-dependent ATPases are thought to have a central role in directing these rearrangements by unwinding RNA helices. Proof of this hypothesis has, however, been conspicuously lacking. RESULTS: Prp16 is a DEAH-box protein that functions in the second step of splicing in vitro. Using various RNA duplexes as substrate, we have shown that Prp16 has an ATP-dependent RNA unwinding activity. This activity is independent of sequence in either the single-stranded or duplexed regions of the RNA substrate. A mutation (prp16-1) near the ATP-binding motif of Prp16 inhibits both the RNA-dependent ATPase activity and the ATP-dependent RNA unwinding activity. CONCLUSIONS: Our findings provide strong biochemical evidence that Prp16 can disrupt a duplexed RNA structure on the spliceosome. Because the purified protein lacks sequence specificity in unwinding RNA duplexes, targeting of the unwinding activity of Prp16 in the spliceosome is likely to be determined by other interacting protein factors. The demonstration of unwinding activity will also help our understanding of how the fidelity of branchpoint recognition is controlled by Prp16.

A hydroxyl radical-like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease.

Recent evidence argues strongly that the marked increase in risk for atherosclerotic heart disease seen in diabetics cannot be explained by a generalized increase in oxidative stress. Here, we used streptozotocin to induce hyperglycemia in cynomolgus monkeys for 6 months and tested whether high glucose levels promote localized oxidative damage to artery wall proteins. We focused on three potential agents of oxidative damage: hydroxyl radical, tyrosyl radical, and reactive nitrogen species. To determine which pathways operate in vivo, we quantified four stable end products of these reactants -- ortho-tyrosine, meta-tyrosine, o,o'-dityrosine, and 3-nitrotyrosine -- in aortic proteins. Levels of ortho-tyrosine, meta-tyrosine, and o,o'-dityrosine, but not of 3-nitrotyrosine, were significantly higher in aortic tissue of hyperglycemic animals. Of the oxidative agents we tested, only hydroxyl radical mimicked this pattern of oxidized amino acids. Moreover, tissue levels of ortho-tyrosine and meta-tyrosine correlated strongly with serum levels of glycated hemoglobin, a measure of glycemic control. We conclude that short-term hyperglycemia in primates promotes oxidation of artery wall proteins by a species that resembles hydroxyl radical. Our observations suggest that glycoxidation reactions in the arterial microenvironment contribute to early diabetic vascular disease, raising the possibility that antioxidant therapies might interrupt this process.

Estrogen and progesterone replacement therapy reduces low density lipoprotein accumulation in the coronary arteries of surgically postmenopausal cynomolgus monkeys.

The effect of estrogen and progesterone replacement therapy on the initiating events in atherogenesis was studied in surgically postmenopausal cynomolgus monkeys. Monkeys were ovariectomized and divided randomly into two groups, one receiving 17 beta-estradiol and cyclic progesterone treatment (n = 9) and ovariectomized controls receiving no hormone replacement therapy (n = 8). The monkeys were fed a moderately atherogenic diet for 18 wk to accelerate the early pathogenic processes but not to be of sufficient duration to produce grossly visible atherosclerotic lesions. Sex hormone replacement therapy decreased the accumulation of LDL and products of LDL degradation in the coronary arteries by greater than 70% while having no significant effect on plasma lipid, lipoprotein, or apoprotein concentrations. Arterial intimal lesions were small with no difference between groups. The reduction in arterial LDL metabolism occurred very early in the pathogenesis of atherosclerosis and was independent of indices of endothelial cell injury, such as enhanced endothelial cell turnover or leukocyte adhesion to the endothelium. Results of this study suggest that one mechanism by which sex hormone treatment inhibits the initiation of atherosclerosis is a direct effect at the level of the arterial wall by suppressing the uptake and/or degradation of LDL.

[Fistula between the urinary bladder and large bowel due to sigmoid tuberculosis]. / Fistulisation vésicale d'une tuberculose sigmoïdienne.

A sigmoid tuberculosis is very rare. We report a case of sigmoid pseudotumoral tuberculosis with a fistulization into the urinary bladder in a 10-year-old girl. The diagnosis of tuberculosis was made by histopathological examination of the surgical specimen after segmental colectomy. Surgery completed by antitubercular chemotherapy gave a good result.

Elongation factor-1 alpha is a selective regulator of growth factor withdrawal and ER stress-induced apoptosis.

To identify genes that contribute to apoptotic resistance, IL-3 dependent hematopoietic cells were transfected with a cDNA expression library and subjected to growth factor withdrawal. Transfected cells were enriched for survivors over two successive rounds of IL-3 withdrawal and reconstitution, resulting in the identification of a full-length elongation factor 1 alpha (EF-1alpha) cDNA. Ectopic EF-1alpha expression conferred protection from growth factor withdrawal and agents that induce endoplasmic reticulum stress, but not from nuclear damage or death receptor signaling. Overexpression of EF-1alpha did not lead to growth factor independent cell proliferation or global alterations in protein levels or rates of synthesis. These findings suggest that overexpression of EF-1alpha results in selective resistance to apoptosis induced by growth factor withdrawal and ER stress.

Prospective study of fluorodeoxyglucose-positron emission tomography imaging of lymph node basins in melanoma patients undergoing sentinel node biopsy.

PURPOSE: To prospectively compare positron emission tomography (PET) imaging of regional lymph node basins to sentinel node biopsy (SNB) in patients with American Joint Committee on Cancer (AJCC) stage I, II, and III melanoma localized to the skin. METHODS: Patients with cutaneous melanoma with Breslow's depth greater than 1 mm (AJCC T2-4N0M0) or localized regional cutaneous recurrence (TxN2bM0) underwent whole-body imaging of glucose metabolism with fluorodeoxyglucose (FDG) PET followed by SNB. PET scans were interpreted in a blinded fashion and compared with histologic analyses of SNB specimens and clinical follow-up examination. Nodal tumor volumes were estimated. RESULTS: Eighty-nine lymph node basins were evaluated by FDG-PET and SNB in 70 assessable patients. Eighteen patients (25.7%) had lymph node metastases at the time of FDG-PET imaging: 17 proved by SNB (24.3%) and one by follow-up examination (1.4%). Median tumor volume in positive sentinel node basins was 4.3 mm3 (range, 0.07 to 523 mm3). Sensitivity of SNB for detection of occult regional lymph node metastases was 94.4%, specificity was 100%, positive predictive value (PPV) was 100%, and negative predictive value (NPV) was 98.6%. Sensitivity of FDG-PET was 16.7%, specificity was 95.8%, PPV was 50%, and NPV was 81.9%. At a median follow-up duration of 16.6 months, seven patients (10%) developed recurrent disease. PET predicted one recurrence (14.3%) in a node basin missed by SNB. CONCLUSION: FDG-PET is an insensitive indicator of occult regional lymph node metastases in patients with melanoma because of the minute tumor volumes in this population. FDG-PET does not have a primary role for staging regional nodes in patients with clinically localized melanoma.

A comparison of tibolone and conjugated equine estrogens effects on coronary artery atherosclerosis and bone density of postmenopausal monkeys.

This study compared the effects of tibolone, a tissue-specific compound for the treatment of climacteric symptoms and the prevention of osteoporosis, with those of conjugated equine estrogens (CEE) with and without medroxyprogesterone (MPA) on bone mineral density and coronary atherosclerosis (CAA) of postmenopausal cynomolgus monkeys. The groups were tibolone [two doses were used, 0.05 mg/kg (LoTib) and 0.2 mg/kg (HiTib)], CEE (0.042 mg/kg), CEE (0.042 mg/kg) plus MPA (0.167 mg/kg given continuously), and a control group given no treatment for 2 yr. Compared with no treatment, bone mineral density was higher by 6.3% (P = 0.0004) in the LoTib group and by 9.5% (P = 0.02) in the HiTib group compared with 4.3% (P = 0.12) for CEE and 4.5% (P = 0.10) for CEE+MPA. Plasma high density lipoprotein cholesterol was reduced by 49% with HiTib and by 34% with LoTib. There were no differences in CAA between control and HiTib (P = 0.60) or LoTib (P = 0.58). CEE and CEE+MPA both reduced CAA by about 62% (CEE vs. control, P = 0.02; CEE+MPA vs. control, P = 0.01). Despite adverse effects of tibolone on plasma lipoprotein concentrations, there was no increase in CAA, suggesting that tibolone is a cardiovascular-safe treatment for climacteric symptoms and the prevention of osteoporosis.

Insulin sensitivity and cardiovascular risk factors in ovariectomized monkeys with estradiol alone or combined with nomegestrol acetate.

We have previously shown that medroxyprogesterone acetate (MPA), either alone or combined with conjugated equine estrogens (CEE), significantly decreased insulin sensitivity (SI), compared with both untreated controls and those treated with CEE alone. The purpose of this study was to determine the effects of estradiol (E2), with and without nomegestrol acetate (NA; a potent progestin that lacks androgenic activity), on SI and arterial antioxidant activity, as determined by F2-isoprostanes. Thirty-six adult female cynomolgus monkeys (Macaca fascicularis) were ovariectomized and fed a moderately atherogenic diet, with one of the following three treatments added to the diet, for 12 weeks: 1) no treatment (control); 2) E2; or 3) continuous combined E2 + NA (E2+NA). SI and glucose effectiveness were assessed by the frequently sampled i.v. glucose tolerance test using a third-phase insulin infusion after 10 weeks of treatment. Cholesterol content and F2-isoprostanes were measured in the thoracic aorta after 12 weeks of treatment. E2 treatment resulted in a significantly greater SI, compared with control or E2+NA-treated monkeys (10.03 +/- 0.91 vs. 6.35 and 6.49 x 10(-4) min(-1) microU(-1) mL; P < 0.05). In contrast to our studies of CEE and MPA, E2+NA treatment, though reducing the SI below that of the E2 group, did not reduce the SI below that of control monkeys. As expected, the short period of treatment resulted in no significant differences in aortic cholesterol content. There was no treatment effect on total F2-isoprostanes (representing F2-isoprostane formation caused primarily by autooxidation), suggesting minimal antioxidant activity. However, there was a treatment difference in the prostaglandin F2alpha (PGF2alpha) isomer (a prostaglandin (PG) isomer formed by both autooxidation of arachidonate and cyclooxygenase activity). PGF2alpha concentrations were 32% lower with E2 treatment, compared with controls, and 36% lower, compared with E2+NA treatment (0.48 +/- 0.08 vs. 0.71 +/- 0.12 and 0.75 +/- 0.06; P < 0.05), suggesting differences in PG synthesis between hormone treatments. In conclusion, NA, a progestin without androgenic activity, may still affect some cardiovascular risk factors differently than estrogen-only therapy. However, it seems to be less detrimental than MPA.

Effects of hormone replacement modalities on low density lipoprotein composition and distribution in ovariectomized cynomolgus monkeys.

This study was designed to determine the effect of several hormone replacement therapies on LDL size, density, heterogeneity, and composition in surgically postmenopausal cynomolgus monkeys fed an atherogenic diet. Groups (n = 5 each) of ovariectomized cynomolgus monkeys were untreated (control), or treated with conjugated equine estrogens, medroxyprogesterone acetate (progesterone), combined estrogen-progesterone, or tamoxifen for 9 weeks. There were no differences among treatment groups in total plasma, LDL, or HDL cholesterol or triglyceride concentrations. Plasma LDL were isolated by ultracentrifugation and size exclusion chromatography and subfractionated by density gradient centrifugation for subsequent chemical analysis. Estrogen treatment was associated with significantly smaller (measured as LDL molecular weight, 3.9 +/- 0.2 g/mu mol) and denser plasma LDL (1.034 g/ml peak density) compared with control (4.5 +/- 0.1 g/mu mol; 1.030 g/ml peak density) or progesterone-treated animals (4.6 +/- 0.2; 1.029 g/ml peak density). LDL from the estrogen group were relatively enriched in protein and triglyceride and poor in cholesteryl ester and apolipoprotein F (apoE) compared to the control group. Triglyceride enrichment with estrogen treatment occurred predominantly in the lighter, larger LDL subfractions (d = 1.015-1.025 g/ml), which were reduced in concentration (26 +/- 10 mg cholesterol/dl) compared to control (61 +/- 19 mg/dl) or progesterone treated animals (67 +/- 16 mg/dl). Combined estrogen-progesterone or tamoxifen treatment resulted in changes in LDL that followed the same trend as those observed with estrogen treatment. We conclude that short-term estrogen treatment of ovariectomized cynomolgus monkeys results in changes in plasma LDL size, density, and composition while having no apparent effect on overall plasma lipid concentrations.

A study of caloric restriction and cardiovascular aging in cynomolgus monkeys (Macaca fascicularis): a potential model for aging research.

Caloric restriction has been demonstrated to retard aging processes and extend maximal life span in rodents, and is currently being evaluated in several nonhuman primate trials. We initiated a study in 32 adult cynomolgus monkeys to evaluate the effect of caloric restriction on parameters contributing to atherosclerosis extent. Following pretrial determinations, at which time a baseline measure of ad libitum (ad lib) dietary intake was assessed, animals were randomized to an ad lib fed group (control) or a caloric restriction group (30% reduction from baseline intake). The animals are being evaluated for glycated proteins, insulin, glucose, insulin sensitivity measures, and specific measures of body fat composition by CT scans (e.g., intra-abdominal fat) over specified intervals. The results from the first year of observation demonstrate a significant diet effect on body weight, and specifically intra-abdominal fat. Further, insulin sensitivity has been significantly increased after 1 year of caloric restriction compared to the ad lib fed group. These studies indicate that caloric restriction has a marked effect on a pathologic fat depot, and this change is associated significantly with an improvement in peripheral tissue insulin sensitivity.

Chronic hyperglycemia increases arterial low-density lipoprotein metabolism and atherosclerosis in cynomolgus monkeys.

Diabetes mellitus confers a threefold to fivefold increased risk of mortality from vascular disease. The primary cause of this increased incidence of vascular disease is atherosclerosis, but the mechanisms accounting for the increase are unclear. Chronic hyperglycemia is a common feature of all forms of diabetes mellitus and may contribute greatly to the increased incidence of atherosclerosis, via promotion of both lipoprotein and tissue glycation, which may have atherogenic effects. The present study investigated the effect of chronic hyperglycemia on measures of low-density lipoprotein (LDL) metabolism and atherosclerosis in streptozotocin-induced diabetic (STZ-DM) and control cynomolgus monkeys after 6 months of study. Consistent with a chronic hyperglycemic state, diabetic monkeys had significant increases in glycated hemoglobin (GHb) and glycated plasma LDL concentrations, but had minimal changes in total plasma cholesterol (TPC) or triglyceride (TG) concentrations during the study. Forty-eight hours before necropsy, control and in vitro-glycated LDL were differentially radiolabeled and coinjected into diabetic and control monkeys. There was a significant increase in arterial LDL accumulation in femoral arteries from diabetic monkeys compared with controls, with similar trends in other arterial sites. The effect of LDL glycation on arterial LDL accumulation was minimal in both groups. Arterial segments from diabetic monkeys also had greater amounts of arterial cholesterol content compared with controls. Histomorphometric analyses showed that diabetic monkeys had significantly greater intimal areas in the femoral artery and abdominal aorta compared with controls. Diabetic monkeys also had reduced arterial remodeling, or compensation, in the femoral artery and abdominal aorta. However, there was no difference in advanced glycation end products (AGE) in arterial collagen between groups. In conclusion, experimentally induced diabetes mellitus increases arterial LDL accumulation and atherosclerosis extent in cynomolgus monkeys before changes in AGE formation. The increased atherogenesis may be due to changes in lipoproteins or direct effects of hyperglycemia on the artery wall.

Sex steroids increase cholesterol 7alpha-hydroxylase mRNA in nonhuman primates.

One mechanism that may account for our prior observation that oral contraceptives decrease the hepatic cholesterol concentration independently of the low-density lipoprotein (LDL) receptor in sexually intact nonhuman primates is that sex hormones increase biliary cholesterol secretion by increasing hepatic mRNA abundance for cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in the conversion of cholesterol into bile acids. To examine the independent effect of estrogen, progestin, and combined estrogen and progestin on the hepatic cholesterol concentration and cholesterol 7alpha-hydroxylase mRNA abundance, 34 ovariectomized adult female cynomolgus monkeys were fed a moderately atherogenic diet for 12 weeks with either oral conjugated equine estrogen ([CEE] n = 8), medroxyprogesterone acetate ([MPA] n = 9), or combined CEE + MPA (n = 9) and compared with a control group (n = 8) that did not receive exogenous sex hormones. After 12 weeks, hepatic cholesterol was significantly lower in CEE-treated (6.2 +/- 1.2 mg/g liver) and CEE + MPA-treated (6.4 +/- 0.9 mg/g liver) animals compared with the control (12.6 +/- 1.9 mg/g liver) and MPA-treated (14.6 +/- 1.6 mg/g liver) groups. Hepatic cholesterol 7alpha-hydroxylase mRNA abundance was significantly increased in CEE-treated (0.553 +/- 0.08 pg/microg RNA), MPA-treated (0.734 +/- 0.12 pg/microg RNA), and CEE + MPA-treated (0.487 +/- 0.07 pg/microg RNA) animals compared with the controls (0.318 +/- 0.03 pg/microg RNA). There was no significant difference in the plasma LDL cholesterol concentration and hepatic LDL receptor mRNA abundance between the groups. These data support but do not prove the hypothesis that low-dose oral estrogen induces an increase in cholesterol 7alpha-hydroxylase mRNA abundance, which is correlated with biliary cholesterol secretion and may result in depletion of hepatic cholesterol.

Soy protein reduces the arterial low-density lipoprotein (LDL) concentration and delivery of LDL cholesterol to the arteries of diabetic and nondiabetic male cynomolgus monkeys.

We have previously shown that soy protein consumption improves lipoprotein concentrations and reduces the progression of atherosclerosis in cynomolgus monkeys. The mechanism for these beneficial effects is unclear. The purpose of this study was to determine potential mechanisms for the atheroprotective effects of soy and to determine if these effects extend to diabetic monkeys. We designed an experiment with a 2 x 2 factorial design in which adult male monkeys (N = 23) were fed an atherogenic diet with a protein source of either soy isolate or casein and lactalbumin, and the monkeys were either control or streptozotocin-induced diabetic. Diabetics had significantly increased fasting glucose and glycated hemoglobin (GHb) levels; this relationship was not affected by the type of dietary protein. Diabetics also had increased total (TC) and low-density lipoprotein cholesterol (LDLC) concentrations. However, soy consumption significantly reduced TC and LDLC concentrations in both control and diabetic monkeys. Plasma and arterial LDL metabolism was determined by injecting 125I-LDL at 48 hours and 131I-tyramine cellobiose LDL at 1 hour prior to necropsy. This allowed a determination of the arterial LDL concentration, permeability, and arterial LDL delivery. An increase in the whole-body plasma LDL fractional catabolic rate (FCR) was found with soy. Soy significantly reduced the arterial LDL concentration across all arterial sites by an average of 50%. Soy also significantly reduced the delivery of LDLC to all arterial sites by an average of 40%. While this was primarily due to the lower plasma LDLC concentration, LDL permeability in the carotid bifurcation and internal carotid arteries was also reduced. There was no additional effect of diabetes. These beneficial effects on plasma and arterial LDL metabolism would be expected to reduce atherosclerosis and were found in both control and diabetic monkeys.

The effects of hormone replacement therapy on carbohydrate metabolism and cardiovascular risk factors in surgically postmenopausal cynomolgus monkeys.

Controversy exists regarding the effects of estrogen and estrogen/progestin replacement therapies on glucose tolerance and insulin resistance. Also unknown are whether changes in glucose tolerance and insulin resistance with hormone therapy affect arterial glycation and atherosclerosis. We studied ovariectomized female monkeys fed a lipid-lowering diet and given either no hormone replacement therapy (n = 25) or conjugated equine estrogens (CEE) alone (n = 22) or combined with medroxyprogesterone acetate ([MPA] n = 21) for 30 months. Monkeys receiving combined hormone replacement had significantly higher fasting glucose and insulin levels and higher insulin responses to a glucose challenge compared with controls or those given estrogen alone. Monkeys given estrogen-only therapy had lower body weights, lower measures of abdominal adiposity, and decreased serum androgen concentrations. However, due to the effective dietary lipid decrease, there was no additional effect of hormone treatment on atherosclerosis. Also, there was no correlation between either arterial glycation or insulin levels and atherosclerosis extent. Thus, although there were adverse effects of combined hormone replacement therapy on carbohydrate metabolism, we were unable to determine whether these effects altered the extent of atherosclerosis.

Dietary soy protein and estrogen replacement therapy improve cardiovascular risk factors and decrease aortic cholesteryl ester content in ovariectomized cynomolgus monkeys.

Estrogen replacement therapy (ERT) decreases the progression of coronary artery atherosclerosis in monkeys. Dietary soy protein also retards the progression of atherosclerosis relative to animal proteins such as casein. Soy protein contains weakly estrogenic compounds called isoflavones or phytoestrogens that may be responsible for the cardioprotective effects. This study was designed as a 2 x 2 factorial to determine the magnitude of soy protein's effects on cardiovascular risk factors relative to casein and lactalbumin, with or without estradiol treatment. Ovariectomized female monkeys were randomized to four treatment groups based on past dietary cholesterol consumption, their origin, and past reproductive history, and studied for 7 months. The animals were divided into (1) a group fed casein and lactalbumin as the protein source (n = 14), (2) a group fed casein and lactalbumin as the protein source plus 17 beta-estradiol (E2) (n = 13), (3) a group fed soybean protein isolate as the protein source (n = 11), and (4) a group fed soybean protein isolate as the protein source plus E2 (n = 10). Soy protein compared with casein consumption resulted in a significant improvement in plasma lipid and lipoprotein concentrations, a significant improvement in insulin sensitivity and glucose effectiveness as determined by minimal-model analyses, and a decrease in arterial lipid peroxidation. E2-treated monkeys had a significant reduction in fasting insulin levels and insulin to glucose ratios, total body weight, and amounts of abdominal fat, and had smaller low-density lipoprotein (LDL) particles. In addition, E2 treatment resulted in a significant reduction (P = .001) in aortic cholesteryl ester content. A similar trend (P = .14) was found for soy protein compared with casein. There also was a significant interaction (P = .02) with soy and E2, such that animals consuming soy protein +E2 had the least arterial cholesteryl ester content. These results suggest that both ERT and dietary soybean protein have beneficial effects on cardiovascular risk factors. Interestingly, the two treatments affected different risk factors and together resulted in the greatest reduction in arterial cholesterol content. Further studies are needed to determine the active component of the soy protein and to assess its long-term effects on the cardiovascular system and other organ systems (such as the bones and reproductive system).

Influence of caloric restriction on the development of atherosclerosis in nonhuman primates: progress to date.

Caloric restriction (CR) has been observed to retard aging processes and extend the maximum life span in rodents. In an effort to evaluate the effect of this nutritional intervention on physiologic variables in higher species, several nonhuman primate trials are ongoing. In particular, a study evaluating the independent effect of CR on the extent of atherosclerosis was initiated in 1993 in 32 adult cynomolgus monkeys. Therefore, the trial was designed to achieve identical cholesterol intake after animals were randomized to a control group or a calorie-restricted group (30% reduction from baseline caloric intake). The animals were routinely evaluated for glycated proteins, plasma insulin and glucose levels, insulin sensitivity, and specific measures for abdominal fat distribution by CT scans over a 4-year interval. The results from 4 years of intervention demonstrate that CR improves cardiovascular risk factors (such as visceral fat accumulation) and improves insulin sensitivity. In contrast to other primate studies with normolipidemic animals, CR had no independent effects on plasma lipid levels and composition in the presence of equivalent amounts of dietary cholesterol intake. Preliminary analysis of atherosclerotic lesion extent in the abdominal aorta has failed to demonstrate differences between control animals and CR animals. Follow-up studies are being conducted to determine the effect of CR on atherosclerosis extent in coronary and carotid arteries.