Supplementing Exposure to Hypoxia with a Copper Depleted Diet Does Not Exacerbate Right Ventricular Remodeling in Mice

Background

Pulmonary hypertension and subsequent right ventricular (RV) failure are associated with high morbidity and mortality. Prognosis is determined by occurrence of RV failure. Currently, adequate treatment for RV failure is lacking. Further research into the molecular basis for the development of RV failure as well as the development of better murine models of RV failure are therefore imperative. We hypothesize that adding a low-copper diet to chronic hypoxia in mice reinforces their individual effect and that the combination of mild pulmonary vascular remodeling and capillary rarefaction, induces RV failure.

Methods

Six week old mice were subjected to normoxia (N; 21% O₂) or hypoxia (H; 10% O₂) during a period of 8 weeks and received either a normal diet (Cu+) or a copper depleted diet (Cu-). Cardiac function was assessed by echocardiography and MRI analysis.

Results and Conclusion

Here, we characterized a mouse model of chronic hypoxia combined with a copper depleted diet and demonstrate that eight weeks of chronic hypoxia (10%) is sufficient to induce RV hypertrophy and subsequent RV failure. Addition of a low copper diet to hypoxia did not have any further deleterious effects on right ventricular remodeling.     

ANTICOAGULANT THERAPY IN HEART DISEASE—A Summary of the Literature

Considerable experience by many independent workers with the use of anticoagulants in the treatment of certain types of heart disease has shown that such therapy reduces significantly the incidence of thromboembolic complications and, largely through this effect, the morbidity and mortality rate from heart disease of these types.This is certainly established in acute coronary occlusion with myocardial infarction and in those instances of rheumatic heart disease with auricular fibrillation in which repeated embolic phenomena have occurred. The case for the administration of the anticoagulants in congestive heart failure is less secure, although there is no doubt that the number of thromboembolic complications is reduced by use of them.The administration of the anticoagulants requires considerably more exacting attention than does the administration of the majority of therapeutic agents in use commonly today. Hence, it is suggested that the use of anticoagulants in heart disease be restricted to those instances in which the indications are clear and facilities are compatible with the efficient and safe use of the drug, whether Dicumarol or heparin.     

CORRECTABLE CARDIAC FAILURE

The concept of reversible cardiac failure has hitherto been applicable mostly to rare instances of acute afflictions of the myocardium wherein cardiac compensation returns with the healing of the process. Recent strides in cardiac surgery have brought into focus a wide variety of conditions where operative removal of the cause of heart failure can successfully restore compensation.The concept of increased work of the heart—cardiac overload—is presented and classified with special reference to those forms where surgical removal of the cause of the overload is possible.Now, since surgical treatment of a patient in functional class IV need no longer entail risk of prohibitive mortality, a careful search is indicated in patients in a state of chronic cardiac failure, particularly in the younger age group, for a correctable factor or factors.     

Diabetic Ketoacidosis During the Influenza Epidemic

During eight weeks of a recent influenza epidemic 29 patients with ketoacidosis were admitted to the General Hospital, Birmingham. This was an exceptionally large number of cases. Of these, 14 had complained of a cough, nine had clinical evidence of respiratory infection, and four extensive bronchopneumonia. Hypokalaemia was present on admission in several instances and caused respiratory failure and death in three patients. Since the dangers of initial hypokalaemia are increased during the treatment of ketoacidosis, especially when sodium bicarbonate is used, serum potassium levels must be estimated initially and, if necessary, potassium chloride given intravenously at more frequent intervals than usual.     

The effect of a lathyritic diet on the sensitivity of tendon to strain rate

While the tensile failure properties of rat-tail tendon depend on strain rate, the sensitivity to strain rate decreases with age, especially during sexual maturation. The object of this study was to determine the effect of an experimental model of chronic lathyrism on age-dependent changes in the sensitivity of developing tendon strength to strain rate. Tensile failure experiments were conducted at high and low strain rate on tendons excised from test and control animals aged 1 to 6 mo. The tensile "yield" response of tendon was significantly affected by the diet resulting in a reduced tensile strength and failure strain. While the sensitivity of tendon failure to strain rate was slightly elevated by the experimental diet, age-dependent changes compared with controls. Since the diet supplement is thought to inhibit covalent crosslinking of collagen in the developing tendon, other factors are likely responsible for decrease in the sensitivity of tendon strength to strain rate during maturation.     

Deaths During Skin and Scuba Diving in California in 1970

An investigation of 30 recorded deaths in sport diving in California in 1970 gave evidence of equipment failure in two, a failure of the victims'' judgment or training in 13, and a failure of rescue attempts in four instances. In three histories no cause could be found. Factors associated with the deaths are reported. In the same period there were recorded in the state 171 drownings in home pools out of a total of 712 drownings in water sports.     

Recombinant bovine somatotropin: association with reproductive performance in dairy cows

A clinical trial was performed to determine the effect of bST on reproductive performance in dairy cows on 4 Michigan dairy farms when bST was used according to labeled directions. Holstein cows (n = 555) at 4 Michigan dairy farms were randomly assigned to receive bovine somatotropin (bST) or to serve as untreated controls. Bovine somatotropin (500 mg, s.c.) was administered every 14 d beginning at 63 to 69 d of lactation and continuing until approximately 21 d prior to the end of lactation or until the producer removed the animal from the herd. A total of 229 (42.57%) animals consisting of 112 (48.91%) controls and 117 (51.09%) bST-treated cows were not diagnosed pregnant and were considered as having reproductive failure by 150 d of lactation and 92 (17.10%) of the animals consisting of 45 (48.91%) controls and 47 (51.09%) bST-treated cows had reproductive failure at the end of their lactation. No significant difference in the incidence of reproductive failure existed between the study treatment groups during either time frame. Cows with cystic ovarian disease had more instances of reproductive failure at 150 d of lactation than cows without this disease. Cows with dystocia, twin births, metritis, displaced abomasum and cystic ovarian disease had more instances of reproductive failure by the end of lactation than cows without these diseases. The bST-treated cows developed more nonspecific off feed conditions during the study lactation and had more twin births at the calving following bST administration compared to control cows. No differences were found between the study treatment groups in calculations of reproductive parameters. Logistic regression analysis found no significant effect of bST on reproductive failure; the odds ratios for the bST treatment effect on reproductive failure at 150 d of lactation and reproductive failure at the end of lactation were 0.95 (95% CI 0.67 to 1.36) and 0.95 (95% CI 0.59 to 1.54), respectively. Overall, bST was not found to have a significant impact on reproductive performance in the herds studied.     

Tricuspid Valve Replacement in Rheumatic Heart Disease

The diagnosis of tricuspid valve disease is often difficult; the best treatment is not yet established. Twenty patients had tricuspid valve replacements at St. Thomas''s Hospital as part of multiple valve replacement procedures. The hospital mortality was 25%, most deaths being due to a low cardiac output causing hepatorenal failure. Preoperative cardiac cachexia had a fatal outcome in all cases. Except in two instances, surviving patients returned to a satisfactory level of activity.     

Treatment of Shock Caused by Bacterial Infections

Bacteremia caused by Gram-negative enteric organisms accounts for the majority of instances of shock complicating bacterial infection. Control of the infection and maintenance of normal blood volume constitute the primary considerations in immediate treatment. The use of three or four doses of corticosteroid agent over a period of 24 hours is regarded as advantageous for routine treatment. Conservative and selective use of isoproterenol and phentolamine are justified for management of patients who do not respond to the administration of bactericidal drugs and volume repletion. Levarterenol and metaraminol are rarely indicated. Intravascular coagulation complicated by bleeding diathesis may serve as an indication for anticoagulation.With more effective management of the hemodynamic defects, patients are now more likely to survive the shock state only to develop a fatal form of pulmonary failure which is yet poorly understood. Close attention to respiratory management is therefore advised.     

Atrial natriuretic peptides in man

Research on the physiological role of atrial peptides in man is limited, and the potential for these peptides, or more stable analogues, in therapeutics is uncertain. It is clear, however, that plasma levels of immunoreactive atrial natriuretic peptide (IR-ANP) are increased in volunteers taking a high sodium diet, and are elevated in patients with heart failure, chronic renal failure, and primary aldosteronism. There is suggestive evidence that IR-ANP levels are increased also in essential hypertension, although overlap with normotensives is considerable. Injection or infusion of atrial peptides into man results in a diuresis, an increased output of urine electrolytes, a fall in blood pressure and a rise in heart rate, suppression of aldosterone and sometimes of renin also, and stimulation of norepinephrine. In essential hypertensives, urinary effects may be greater than in normotensives. Heart failure patients show a rise in cardiac output and falls in both systemic and pulmonary arterial pressure. Over the next few years and especially if specific antagonists can be developed, the physiologic and pathophysiologic roles of atrial peptides in normal man and in clinical disorders should be clarified. It is possible that stable analogues of atrial peptides will find a place in the treatment of cardiac failure, renal failure, and perhaps hypertension.     

High Fat High Cholesterol Diet (Western Diet) Aggravates Atherosclerosis,Hyperglycemia and Renal Failure in Nephrectomized LDL Receptor Knockout Mice: Role of Intestine Derived Lipopolysaccharide

A high fat meal, frequently known as western diet (WD), exacerbates atherosclerosis and diabetes. Both these diseases are frequently associated with renal failure. Recent studies have shown that lipopolysaccharide (LPS) leaks into the circulation from the intestine in the setting of renal failure and after WD. However, it is not clear how renal function and associated disorders are affected by LPS. This study demonstrates that circulatory LPS exacerbates renal insufficiency, atherosclerosis and glucose intolerance. Renal insufficiency was induced by 2/3 nephrectomy in LDL receptor knockout mice. Nx animals were given normal diet (Nx) or WD (Nx+WD). The controls were sham operated animals on normal diet (control) and WD (WD). To verify if LPS plays a role in exaggerating renal insufficiency, polymyxin (PM), a known LPS antagonist, and curcumin (CU), a compound known to ameliorate chronic kidney disease (CKD), was given to Nx animals on western diet (Nx+WD+PM and Nx+WD+CU, respectively). Compared to control, all other groups displayed increased circulatory LPS. The Nx+WD cohort had the highest levels of LPS. Nx group had significant renal insufficiency and glucose intolerance but not atherosclerosis. WD had intense atherosclerosis and glucose intolerance but it did not show signs of renal insufficiency. Compared to other groups, Nx+WD had significantly higher cytokine expression, macrophage infiltration in the kidney, renal insufficiency, glucose intolerance and atherosclerosis. PM treatment blunted the expression of cytokines, deterioration of renal function and associated disorders, albeit not to the levels of Nx, and was significantly inferior to CU. PM is a non-absorbable antibiotic with LPS binding properties, hence its beneficial effect can only be due to its effect within the GI tract. We conclude that LPS may not cause renal insufficiency but can exaggerate kidney failure and associated disorders following renal insufficiency.     

Ovarian effects of a high lactose diet in the female rat

Young women with galactosemia experience ovarian failure at a very early age raising concern about the ovarian toxicity of galactose. While galactose may be present in the diet as a monosaccharide, it is predominantly derived from cleavage of the disaccharide lactose within the intestine. Our previous studies in animals have shown that high galactose diets inhibit ovarian follicular development and long-term exposure to high lactose diets retards growth of rats. The objective of the present study was to determine whether galactose exposure in the form of dietary lactose mimics the effects found previously with diets rich in galactose. Sixty female Long-Evans rats (25-day-old) were randomly assigned to two groups and fed a control diet (41.9% glucose in AIN93G [American Institute of Nutrition], CON) before lactose treatment. Unilateral ovariectomy (uOVX) was performed on half of the rats in each group to determine baseline ovarian follicle numbers. The study diet was a high lactose diet (HLD) containing 41.9% lactose in AIN93G. Study diet exposure started 1 month after uOVX (3 months old) and continued for 7 months in the treatment group. The control group remained on the 41.9% glucose diet throughout. Vaginal cytology, ovarian morphometric analyses, and serum concentrations of estradiol and progesterone were examined. Long-term exposure to the HLD decreased the body weights of animals and progesterone concentrations in the serum but produced no harmful effects on ovarian morphology or function. Beginning at 5 months of age (two months of lactose treatment) increasing numbers of females began to cycle irregularly but there was no difference between the glucose and lactose diet groups. These negative findings imply that administration of galactose in the form of lactose seems to be much less toxic than when galactose is fed to animals. From a human health perspective, these results are somewhat reassuring, since in general, women eat lactose-containing foods rather than foods that contain large amounts of free galactose.     

Selective effect of low protein diets in chronic renal diseases.

It has recently been established that the rate of progression of chronic renal failure in man can be slowed by restricting dietary protein. Consequently, the short term and long term effects of a low protein diet on the course of different chronic nephropathies were studied in an attempt to delineate the factors that determine the response to such a diet. When a low protein diet was given for six months renal function improved significantly in nine patients with chronic tubulointerstitial nephritis (p less than 0.025); the diet had a marginally beneficial effect in 12 patients with chronic glomerulonephritis (p less than 0.05) and no effect in nine with hypertensive nephrosclerosis. The heterogeneous functional response in the patients with chronic glomerulonephritis correlated closely with the effect of the diet on these patients'' proteinuria (r = 0.76, p less than 0.01). In a short term study (four weeks) of 12 patients with chronic renal failure changes in renal plasma flow were proportional to dietary protein intake. Renal vascular resistance fell during a high protein diet and increased when dietary protein was restricted. The changes in renal plasma flow during the low protein diet correlated well with the patients'' long term functional response to the diet (r = 0.76, p less than 0.01). It is concluded that the response to a low protein diet in chronic renal failure is determined, firstly, by the nature of the underlying nephropathy, with maximal benefit being observed in non-glomerular disorders; secondly, by the effect of the diet on the proteinuria in chronic glomerulonephritis; and, thirdly, by the haemodynamic response to the diet, with patients with a reactive renal vascular bed improving with a low protein diet.     

SPSRG: a prediction approach for correlated failures in distributed computing systems

Failure instances in distributed computing systems (DCSs) have exhibited temporal and spatial correlations, where a single failure instance can trigger a set of failure instances simultaneously or successively within a short time interval. In this work, we propose a correlated failure prediction approach (CFPA) to predict correlated failures of computing elements in DCSs. The approach models correlated-failure patterns using the concept of probabilistic shared risk groups and makes a prediction for correlated failures by exploiting an association rule mining approach in a parallel way. We conduct extensive experiments to evaluate the feasibility and effectiveness of CFPA using both failure traces from Los Alamos National Lab and simulated datasets. The experimental results show that the proposed approach outperforms other approaches in both the failure prediction performance and the execution time, and can potentially provide better prediction performance in a larger system.     

Effects of a new amino acid supplement on blood AA pools in patients with chronic renal failure

Summary We designed a new formula for AA supplement in order to correct blood pools of AA in chronic renal failure (CRF). This supplement was given to 5 patients with CRF and its effectiveness was tested during long term (12–24 weeks) administration. The patients had previously been on a diet providing 0.6 g of protein and 34–36 kcal/kg/day. The diet was then modified to one providing the same caloric content but only 0.3 g/kg high biological value protein per day with the addition of the AA supplement (0.3 g/kg). The new diet corrected most of the abnormalities in blood AA pools. After 1 month of treatment Val, Leu, Thr, Ser and Tyr levels rose and became normal throughout the study. Ratios Tyr/Phe, Ser/Gly and Val/Gly also improved. During the treatment no side effect or toxicity was observed, and serum albumin, transferrin and nutritional anthropometric parameters persisted to be normal. It is concluded that this specially designed AA supplement added to a hypoproteic diet is an acceptable regimen which can quite completely correct the imbalance in blood AA pools in CRF.     

Interdisciplinary Study of Diazepam Sedation for Outpatient Dentistry

Patients unable to submit themselves to routine dental treatment under local anaesthesia were studied during treatment under diazepam sedation accompanied by local anaesthesia, and compared with a matched control group for psychiatric assessment. Physiological responses, operating conditions, amnesia, pain threshold, and recovery were all assessed by various tests.Some of the patients had an anxiety neurosis, and several had been referred because of previous failure to complete dental treatment. Satisfactory conditions were obtained in all but two instances, and no adverse physiological responses occurred with diazepam in an intravenous dose of 0·2 mg./kg. Patients were clinically safe to leave accompanied by a responsible adult within one hour of administration of the drug. Some patients showed an improvement in attitude towards dentistry following treatment.     

Fruit Peels: Food Waste as a Valuable Source of Bioactive Natural Products for Drug Discovery

Fruits along with vegetables are crucial for a balanced diet. These not only have delicious flavors but are also reported to decrease the risk of contracting various chronic diseases. Fruit by-products are produced in huge quantity during industrial processing and constitute a serious issue because they may pose a harmful risk to the environment. The proposal of employing fruit by-products, particularly fruit peels, has gradually attained popularity because scientists found that in many instances peels displayed better biological and pharmacological applications than other sections of the fruit. The aim of this review is to highlight the importance of fruit peel extracts and natural products obtained in food industries along with their other potential biological applications.     

The artificial kidney and related procedures; a report on clinical experience

The Skeggs-Leonards artificial kidney and related methods were applied by the author in about thirty instances in patients with various kinds of renal disease. The treatment brought about clinical improvement of varying degree and appeared to be life-saving in four of five patients with acute renal failure. Treatment with the artificial kidney is indicated for patients with acute renal failure who develop clinical signs of uremia. The artificial kidney should be applied before the patient's condition has become irreversible. Removal of edema fluid is possible with modern artificial kidney equipment and appears to extend the therapeutic possibilities of the procedure. The artificial kidney may be of help in barbiturate and other intoxications. It affords temporary palliation in certain patients with chronic uremia; it may be used to overcome acute exacerbations of chronic renal disease; it may make it possible to operate on uremic patients who otherwise could not withstand operation.     

Maximum likelihood estimation for interval-censored data using a Weibull-based accelerated failure time model.

The accelerated failure time regression model is most commonly used with right-censored survival data. This report studies the use of a Weibull-based accelerated failure time regression model when left- and interval-censored data are also observed. Two alternative methods of analysis are considered. First, the maximum likelihood estimates (MLEs) for the observed censoring pattern are computed. These are compared with estimates where midpoints are substituted for left- and interval-censored data (midpoint estimator, or MDE). Simulation studies indicate that for relatively large samples there are many instances when the MLE is superior to the MDE. For samples where the hazard rate is flat or nearly so, or where the percentage of interval-censored data is small, the MDE is adequate. An example using Framingham Heart Study data is discussed.     

Experimental protein malnutrition during gestation and breeding performance of squirrel monkeys,Saimiri sciureus

The report summarizes our four year experience with the breeding of squirrel monkeys, a New World species used widely in experimental research. Breeding squirrel monkeys in captivity has hitherto been considered capricious, with success in most instances not exceeding 50%. By a combination of hand picking the animals, housing in a harem-type situation with one male to several females, and sound nutrition, a success rate of 85–91% live births to number of pregnancies has been achieved. The rate of stillbirths and abortions in the group maintained on a well-balanced diet did not exceed 10% of the total pregnancies. This compares favorably with any successful breeding program with Old World monkeys, whose reproductive physiology is relatively well understood. It is clear from our studies that adequate quantities of proteins are essential for optimum reproduction. Among the pregnant animals maintained on a diet containing about 50% of their normal requirements of protein (8% calories from a protein source), the incidence of abortions increases significantly. In this group, the rate of abortions to total pregnancies ranges from 40.5 to 61.5%. The females maintained on a protein deficient diet during pregnancy are so protein hungry that an extruded fetus is a welcome food and no time is lost in devouring all of the placenta and the fetus. This type of cannibalism has never been observed among the mothers maintained on a high protein regimen.