Impact of Dynamical Collapse Models on Inflationary Cosmology.

Inflation solves several cosmological problems at the classical and quantum level, with a strong agreement between the theoretical predictions of well-motivated inflationary models and observations. In this Letter, we study the corrections induced by dynamical collapse models, which phenomenologically solve the quantum measurement problem, to the power spectrum of the comoving curvature perturbation during inflation and the radiation-dominated era. We find that the corrections are strongly negligible for the reference values of the collapse parameters.

Bivalves rapidly repair shells damaged by fatigue and bolster strength.

Hard external armors have to defend against a lifetime of threats yet are traditionally understood by their ability to withstand a single attack. Survival of bivalve mollusks thus can depend on the ability to repair shell damage between encounters. We studied the capacity for repair in the intertidal mussel Mytilus californianus by compressing live mussels for 15 cycles at ∼79% of their predicted strength (critically fracturing 46% of shells), then allowing the survivors 0, 1, 2 or 4 weeks to repair. Immediately after fatigue loading, mussel shells were 20% weaker than control shells that had not experienced repetitive loading. However, mussels restored full shell strength within 1 week, and after 4 weeks shells that had experienced greater fatiguing forces were stronger than those repetitively loaded at lower forces. Microscopy supported the hypothesis that crack propagation is a mechanism of fatigue-caused weakening. However, the mechanism of repair was only partially explained, as epifluorescence microscopy of calcein staining for shell deposition showed that only half of the mussels that experienced repetitive loading had initiated direct repair via shell growth around fractures. Our findings document repair weeks to months faster than demonstrated in other mollusks. This rapid repair may be important for the mussels' success contending with predatory and environmental threats in the harsh environment of wave-swept rocky coasts, allowing them to address non-critical but weakening damage and to initiate plastic changes to shell strength. We highlight the significant insight gained by studying biological armors not as static structures but, instead, as dynamic systems that accumulate, repair and respond to damage.

Position statement: asthma in Latin America. IS short-acting beta-2 agonist helping or compromising asthma management?

In Latin-America, with 603 million inhabitants, the average prevalence of asthma is estimated at 17%, but with wide fluctuations, ranging from 5% in some cities (Mexico) to 30% in Costa Rica. The risk of severe exacerbations seems to be higher in Latin America compared with other regions. A majority of patients uses daily quick-relief medication, with the belief that it is the most important treatment because of its rapid onset of action; without treating the underlying inflammation. Overuse of short-acting beta2 agonists (SABAs) is associated with increased risk of asthma deaths in a dose-response manner. Beta2 agonists increase the severity of asthma through enhanced bronchial hyperresponsiveness and reduced lung function. Also, it has been shown that overreliance on SABA delays recognition of a potentially life-threatening asthma attack. We believe that overreliance on SABA in asthma is also an important public health issue. The fact that SABA use in GINA is not supported by a randomized trial but by an anonymous paper; makes us guess that we use SABA just because we are used to do so. In 2019 GINA strategy introduces one of the most important changes in the management of Asthma in the past 30 years, highlighting anti-inflammatory reliever therapy. A combination of low dose ICS/fast action bronchodilator will not only treat symptoms, but more importantly the underlying inflammation, protecting patients from preventable asthma attacks. After 50 years of a SABA centric approach in asthma management, it is time to leave behind a treatment based just on the bronchodilation and tackle the inflammation.

Triggering immunological memory against the tapeworm Hymenolepis diminuta to protect against colitis.

Infection with parasitic helminths can ameliorate the severity of concomitant inflammatory disease. To use the tapeworm, Hymenolepis diminuta, and to extend this concept by assessing whether triggering a memory response against the worm inhibits dinitrobenzene sulphonic acid (DNBS)-induced colitis in Balb/c mice. Initial studies revealed that oral infection with 1, 3 or 5 H. diminuta cysticercoids 8 days before intrarectal administration of DNBS (3 mg) resulted in less severe inflammation and that infected mice displayed an increased propensity for T helper-2 immunity. A 1 mg dose of a PBS-soluble extract of the worm (HdAg) delivered intraperitoneally concomitant with DNBS was anticolitic as determined by macroscopic and histological disease scores 72 hour post-DNBS. Mice infected 28 days previously had a memory response as determined by HdAg-evoked increases in interleukin (IL)-4 and IL-10 from in vitro stimulated splenocytes and serum anti-H. diminuta IgG. Moreover, mice infected with 5 H. diminuta 28 days previously were protected from DNBS-induced colitis by secondary infection or 100 µg HdAg (ip.) at the time of DNBS treatment. An additional approach to managing inflammatory disease could be infection with H. diminuta followed by eliciting antiworm recall responses.

Cholecystoduodenal fistula, an infrequent complication of cholelithiasis: Our experience in its surgical management. / Fístula colecistoduodenal, complicación infrecuente de litiasis vesicular: nuestra experiencia en su manejo quirúrgico.

INTRODUCTION: Bilioenteric fistulas are the abnormal communication between the bile duct system and the gastrointestinal tract that occurs spontaneously and is a rare complication of an untreated gallstone in the majority of cases. These fistulas can cause diverse clinical consequences and in some cases be life-threatening to the patient. AIM: To identify the incidence of bilioenteric fistula in patients with gallstones, its clinical presentation, diagnosis through imaging study, surgical management, postoperative complications, and follow-up. MATERIALS AND METHODS: A retrospective study was conducted to search for bilioenteric fistula in patients that underwent cholecystectomy at our hospital center due to cholelithiasis, cholecystitis, or cholangitis, within a 3-year time frame. RESULTS: Four patients, 2 men and 2 women, were identified with cholecystoduodenal fistula. Their mean age was 81.5 years. Two of the patients presented with acute cholangitis and 2 presented with bowel obstruction due to gallstone ileus. All the patients underwent surgical treatment and the diagnostic and therapeutic management of each of them was analyzed. CONCLUSIONS: The incidence of cholecystoduodenal fistula was similar to that reported in the medical literature. It is a rare complication of gallstones and its diagnosis is difficult due to its nonspecific symptomatology. It should be contemplated in elderly patients that have a contracted gallbladder with numerous adhesions.

Group 1 LEA proteins, an ancestral plant protein group, are also present in other eukaryotes, and in the archeae and bacteria domains.

Water is an essential element for living organisms, such that various responses have evolved to withstand water deficit in all living species. The study of these responses in plants has had particular relevance given the negative impact of water scarcity on agriculture. Among the molecules highly associated with plant responses to water limitation are the so-called late embryogenesis abundant (LEA) proteins. These proteins are ubiquitous in the plant kingdom and accumulate during the late phase of embryogenesis and in vegetative tissues in response to water deficit. To know about the evolution of these proteins, we have studied the distribution of group 1 LEA proteins, a set that has also been found beyond the plant kingdom, in Bacillus subtilis and Artemia franciscana. Here, we report the presence of group 1 LEA proteins in green algae (Chlorophyita and Streptophyta), suggesting that these group of proteins emerged before plant land colonization. By sequence analysis of public genomic databases, we also show that 34 prokaryote genomes encode group 1 LEA-like proteins; two of them belong to Archaea domain and 32 to bacterial phyla. Most of these microbes live in soil-associated habitats suggesting horizontal transfer from plants to bacteria; however, our phylogenetic analysis points to convergent evolution. Furthermore, we present data showing that bacterial group 1 LEA proteins are able to prevent enzyme inactivation upon freeze-thaw treatments in vitro, suggesting that they have analogous functions to plant LEA proteins. Overall, data in this work indicate that LEA1 proteins' properties might be relevant to cope with water deficit in different organisms.

New evidence of a dihydropyridine-activated cationic channel in the MDCK cell line.

Newborn rat distal cells express an apical Ca2+ channel activated by dihydropyridine drugs. Similarly, in Madin-Darby canine kidney (MDCK) cells, nifedipine increased Ca2+i in a concentration-dependent manner (IC50=4 µM) in fura-2-loaded cells. Response to nifedipine was abolished by EGTA, suggesting that it depends on extracellular calcium. Ca2+ channel antagonist isradipine and agonist BayK8644 increased Ca2+i indicating that this effect is related to the dihydropyridine group. Diltiazem (20 µM) and gadolinium (200 µM) decreased the nifedipine effect (62 and 43%, respectively). Lanthanum (100 µM) did not change the response. Valinomycin clamping of the membrane potential did not modify nifedipine-induced increment, indicating that it was unrelated to potassium fluxes. We performed whole cell clamp experiments in MDCK cells maintained at -50 mV with perfusion solution containing 10 mM CaCl2. Nifedipine (20 µM) induced an increase in current (1.2±0.3 nA), which was partially inhibited by Gd3+. No significant current was induced by nifedipine in the presence of 0.5 mM EGTA. To determine the effects of nifedipine on the membrane potential, we performed oxonol fluorescence experiments. The addition of nifedipine or Bay K8644 induced depolarization, highly dependent on external sodium. Nifedipine (20 µM) induced depolarization of 6.9±0.8 mV (n=21). EC50 to nifedipine was in the 10 µM range. We conclude that MDCK cells exhibit a dihydropyridine-activated cationic channel.

Effects of aflatoxin chronic intoxication in renal function of laying hens.

Aflatoxins (AF) have a high impact in both human and animal health, causing significant economic losses in the poultry industry, especially by diminution of avian growth, feed efficiency, and product quality. Aflatoxins affect the whole organism, particularly liver and kidney. The objective of this study was to evaluate renal function alterations in laying hens during chronic AF ingestion. Randomly, 84 Leghorn Hy-Line laying hens (13 wk old) were assigned into 4 experimental groups (n = 21): 0.0, 0.5, 1.0, and 1.5 mg of AF/kg of feed. The AF (B(1), B(2), G(1), and G(2)) was obtained from 2 toxicogenic local strains of Aspergillus flavus grown in corn grains; the grain was sterilized, ground, and added to basal diets to achieve the selected AF concentrations. Hens ingested, during 17 and 42 wk, feed contaminated with AF. Data were analyzed in a 4 x 2 factorial arrangement. Hens were anesthetized, ureteral urine samples were collected, and arterial blood samples were taken. The renal functional tests were evaluated by spectrophotometric and flame photometric methods, including a) Na, K, Ca, and phosphate fractional excretions; b) renal hemodynamic studies, glomerular filtration rate and renal plasma flow by inulin and p-aminohippurate clearances, respectively; and c) identification of macroscopic and histopathologic lesions. The hens intoxicated at all levels of AF showed significant (P < 0.05) increases in Ca, Na, and phosphate fraction excretions. Sodium and phosphates were excreted in a pattern of response time-dose. However, glomerular filtration rate exhibited a significant reduction (P < 0.05). The K fractional excretion and renal plasma flow remained unchanged. These results suggest that AF chronic ingestion affects renal functions of laying hens and induces Ca(++), (-3)PO(4), and Na(+) losses, which are of great concern to the poultry industry.

Kupffer Cells Undergo Fundamental Changes during the Development of Experimental NASH and Are Critical in Initiating Liver Damage and Inflammation.

Non-alcoholic fatty liver disease has become the leading liver disease in North America and is associated with the progressive inflammatory liver disease non-alcoholic steatohepatitis (NASH). Considerable effort has been made to understand the role of resident and recruited macrophage populations in NASH however numerous questions remain. Our goal was to characterize the dynamic changes in liver macrophages during the initiation of NASH in a murine model. Using the methionine-choline deficient diet we found that liver-resident macrophages, Kupffer cells were lost early in disease onset followed by a robust infiltration of Ly-6C+ monocyte-derived macrophages that retained a dynamic phenotype. Genetic profiling revealed distinct patterns of inflammatory gene expression between macrophage subsets. Only early depletion of liver macrophages using liposomal clodronate prevented the development of NASH in mice suggesting that Kupffer cells are critical for the orchestration of inflammation during experimental NASH. Increased understanding of these dynamics may allow us to target potentially harmful populations whilst promoting anti-inflammatory or restorative populations to ultimately guide the development of effective treatment strategies.

Cell-Wall Proteins Induced by Water Deficit in Bean (Phaseolus vulgaris L.) Seedlings.

In the last few years, much attention has been given to the role of proteins that accumulate during water deficit. In this work, we analyzed the electrophoretic patterns of basic protein extracts, enriched for a number of cell-wall proteins, from bean (Phaseolus vulgaris L.) seedlings and 21-d-old plants subjected to water deficit. Three major basic proteins accumulated in bean seedlings exposed to low water potentials, with apparent molecular masses of 36, 33, and 22 kD, which we refer to as p36, p33, and p22, respectively. Leaves and roots of 21-d-old plants grown under low-water-availability conditions accumulated only p36 and p33 proteins. In 21-d-old plants subjected to a fast rate of water loss, both p33 and p36 accumulated to approximately the same levels, whereas if the plants were subjected to a gradual loss of water, p33 accumulated to higher levels. Both p36 and p33 were glycosylated and were found in the cell-wall fraction. In contrast, p22 was not glycosylated and was found in the soluble fraction. The accumulation of these proteins was also induced by abscisic acid (0.1-1.0 mM) treatment but not by wounding or by jasmonate treatment.

The ATP levels in kidneys and blood are mainly decreased by acute ingestion of tullidora (Karwinskia humboldtiana).

Our previous acute toxicity studies with Karwinskia humboldtiana (Kh) in rats showed renal hemodynamic changes with a marked increase in the fractional excretion of sodium and morphological damage. To analyse the effects of Kh or 'tullidora' on energetic metabolism, a single dose of an oral preparation from the seed fruits was given to Wistar rats (1.25 g/kg). In tullidora-treated rats there was 8% mortality. ATP concentrations in renal tissue decreased significantly (control: 53.85+/-3.34, tullidora 38.28+/-5.31 micromol/g fresh tissue, P<0.05). Total blood (54.8+/-0.96, tullidora: 40.2+/-1.55 micromol/dL, P<0.01) and haemoglobin-ATP concentrations (3.69+/-0.12, tullidora: 2.56+/-0.11 micromol/g, P<0.01) were also significantly diminished. Moreover, the total protein in renal cortex from tullidora-treated rats decreased as compared to control group (control: 71.43+/-2.88, tullidora: 55.20+/-4.06 mg/g fresh tissue, P<0.05). In contrast, Na+-K+-ATPase activity in tullidora-treated animals was not different from control rats. These findings might partially explain the acute effects and mortality observed in the Kh treated rats.

Influence of sex differences on the renal secretion of organic anions.

The kidney's responsiveness to male sexual hormones has been often neglected. Renal secretion of organic anions is higher in male than in female individuals; as a consequence, most of the xenobiotics that are excreted from the organism through this pathway are eliminated more rapidly by males than by female animals. To gain further insight into this issue, we studied in vitro and in vivo characteristics of the transport of p-aminohippurate (PAH), a suitable marker for this system, in male and female rats, under different hormonal conditions. Kinetics of PAH showed a shorter elimination half-time in male than in female rats (t(1/2el): male = 16.2 +/- 2.1 min, female = 25.7 +/- 4.5 min, P < 0.05). Castration of male rats increased t(1/2el) to a value similar to that of female rats (t(1/2el): orchiectomized rat = 28.1 +/- 7.1 min). Testosterone treatment of female rats increased the elimination rate to a value similar to that of male rats. In vitro PAH uptake by renal cortical slices from intact male rats was higher than that by slices from orchiectomized rats. Kinetic analyses of PAH uptake suggest that the difference was caused by a lower number of transporting molecules in orchiectomized than in intact animals, whereas the transporting capacity for each carrier was similar in male and in orchiectomized rats. Our results suggest that testosterone increases the number of functional carriers for PAH in the kidney.

Inhibitory effect of the antioxidant ethoxyquin on electron transport in the mitochondrial respiratory chain.

Ethoxyquin (6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline, EQ) is an antioxidant used as a preservative in animal and human foods. In a previous work, we demonstrated that EQ induces an inhibition of renal secretory mechanisms that are dependent on metabolic energy; EQ inhibits renal ATPases. In the present study, we analyzed the effects of EQ on the metabolic pathways of renal and hepatic rat cells, as well as on mitochondrial and submitochondrial particles isolated from bovine heart and kidney. EQ induced a mild inhibition of oxygen uptake when it was added to whole homogenates of rat renal cortex in the presence of glucose. In contrast, a strong concentration-dependent inhibition was produced when EQ was added to preparations of intact liver mitochondria or to submitochondrial particles isolated from renal cortex. In the presence of NADH, 90% inhibition was attained at a final concentration of 1 mM EQ. The direct inhibitory effect of EQ on NADH dehydrogenase was a most relevant finding, since no inhibitor for the partial reaction of NADH-ferricyanide on this complex has been reported previously.

Plasma membrane lipids modulate the response to water deprivation in rat kidney.

The lipid composition of biological membranes determines many of the cellular responses to stimuli such as hormones and drugs. It is known that the neonate has differences in renal function compared to the adult individual, which determine the characteristics of pharmacokinetics and pharmacodynamics at this age. We studied the lipid composition of renal plasma membranes, the renal response to water deprivation, and the activity of plasma membrane gamma-glutamyl transpeptidase (GGTP) in newborn, 21-d-old, and adult rat. It was found that the cholesterol/phospholipid (CH/PL) ratio of newborn membranes was significantly higher than that of membranes from 21-d-old and adult rats, which were similar. These findings paralleled low ability to concentrate urine in the newborn and higher sensitivity of the neonatal kidney to water deprivation. Kidney membranes from 21-d-old and adult rats showed similar lipid composition, and the response to water deprivation was also similar. The changes observed in GGTP activity at different ages varied with the cholesterol content of kidney plasma membranes. These findings suggest participation of the lipid composition of kidney membranes in modulation of the renal response to water deprivation.

Pancreatic lipid peroxidation in alloxan-induced diabetes mellitus.

The time-course of pancreatic lipid peroxidation and reduced glutathione, and blood glucose were studied in adult male CD-1 mice after each of three sequential injections of alloxan, administered at intervals of 48 h. Twenty four hours after alloxan administration an increment of blood glucose and pancreatic lipoperoxidation was observed. Lipoperoxidation partially recovered, while blood glucose was increased after the third administration to a value of 150 mg/100 ml. Pancreas reduced glutathione content remained without any significant change throughout the experiment. These results suggest that the establishment of alloxan-induced diabetes is preceded by an increment in pancreatic lipid peroxidation that could be associated with permanent damage to pancreatic tissue.

Model of intestinal amebiasis: structural and functional lesions to the rabbit colon mucosa by Entamoeba histolytica lysates.

Although the events occurring during the initial interaction of E. histolytica trophozoites with the mucosa of the large intestine probably determine the invasion by the parasites, an appropriate experimental model does not exist. To develop such a model we used full-thickness rabbit colon preparations (0.28 cm2) mounted in Ussing-type chambers. Untreated preparations had electrophysiological properties (potential difference, short-circuit current and electrical resistance) similar in magnitude and duration to those reported for stripped colonic mucosa. Exposure to E. histolytica trophozoite lysates for up to 80 min produced dose-dependent lesions in the colon, consisting of: (a) increased decay rates for potential difference, short-circuit current and transmural resistance, and (b) mucosal lesions involving vacuolation at the bases and shortening of epithelial cells, loss of intercellular junctions, destruction of microvilli, and necrosis of interglandular epithelial zones. The specificity and speed of the electrophysiologic effects and their correlation with the microscopic lesions suggest that this new model will help to understand the initial pathogenic events of intestinal amebiasis.

Participation of the kidney in the kinetics of arginine vasopressin in the water-loaded rat.

The kidney is a target organ for antidiuretic hormone (ADH) and it is also the main organ involved in the clearance of this hormone. There is controversy on the mechanisms involved in the renal handling of ADH, mainly in regard to whether it is secreted or reabsorbed. Kinetic and renal clearance studies of ADH were performed in water-loaded rats and were compared with inulin (glomerular filtration marker) and tetraethylammonium (TEA, marker of organic cation secretion). The kinetics of the three molecules fitted a bicompartmental model. Distribution constants of [125I]-ADH were twofold higher than those of inulin. Elimination constant was higher for inulin than for ADH (0.049 +/- 0.001 vs. 0.020 +/- 0.003 min-1, respectively), suggesting reabsorption of the hormone. The ratios of Clearance ADH/Clearanceinulin and ClearanceTEA/Clearanceinulin were 0.14 and 4.86, respectively. In summary, data from kinetic studies and from renal clearances suggested that ADH is reabsorbed.

Inhibition of the renal uptake of p-aminohippurate and tetraethylammonium by the antioxidant ethoxyquin in the rat.

Ethoxyquin (6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinolein, EQ) is an antioxidant used in animal foodstuffs and to prevent superficial scalding in some fruits. In renal cortical slices prepared from male rats that had consumed a diet containing EQ, EQ inhibited the specific uptake of 14C-labelled p-aminohippurate ([14C]PAH) and tetraethylammonium ([14C]TEA), markers of organic anion and cation tubular secretion, respectively. The specific uptake of [14C]TEA was five-fold more sensitive to EQ than [14C]PAH uptake (IC50 0.33 and 1.51 mM, respectively). EQ (1 mM) decreased Na+/K(+)-ATPase activity from 1.58 to 1.0 mumol inorganic phosphate/mg protein/min in renal microsomes. The activity of this enzyme provides the energy for the function of both secretory systems. These results suggest that the mechanisms by which EQ inhibits both anion and cation tubular secretion involves a decrease in the Na+/K(+)-ATPase activity. This effect leads to interference with the energy supply required for these tubular secretory mechanisms. Our results indicate that the exposure of animals or humans to high concentrations of ethoxyquin should be avoided.

Renal handling of indomethacin and its relationship with the secretory pathway of prostaglandins.

The uptake of prostaglandin E2, one of the main renal prostaglandins and of p-aminohippurate, an indicator of the anion organic transport, by slices of kidney cortex from adult female rats was studied in the presence and in the absence of indomethacin. The drug's inhibitory effect on the uptake of prostaglandin E2 was observed both after in vivo administration as well as when it was present in the bathing media. The effect was more pronounced when the drug was given in vivo and in addition, was present in the bath. [14C] PAH uptake was inhibited by indomethacin in a dose-related pattern and the kinetic analysis of this effect is indicative of a competitive inhibition. As expected, uptake of PAH by medullary slices was not affected by the presence of either indomethacin of PGE2. Indomethacin was more potent in inhibiting PGE2 uptake than PAH uptake.

Prevention of alloxan-induced diabetes mellitus in the rat by silymarin.

Silymarin is a free-radical scavenger and a membrane stabilizer which prevents lipoperoxidation and its associated cell damage in some experimental models. It has been proposed that lipid peroxidation caused by free radicals may be involved in alloxan-induced diabetes mellitus. Alloxan elicits pancreatic lipid peroxidation which precedes the appearance of hyperglycemia in mice. We studied the effects of silymarin on rat pancreas, the effect of this flavonoid on pancreatic, hepatic and blood glutathione (GSH) together with the pancreatic malondialdehyde concentrations in response to alloxan. On its own, silymarin increases pancreatic and blood GSH without changes in either hepatic GSH or in blood glucose. Silymarin prevents the increase in lipid peroxidation produced by alloxan. It also blunts the sustained increment in plasma glucose induced by alloxan. We suggest that silymarin has a protective effect on the pancreatic damage in experimental diabetes mellitus. This may be related to its antioxidative properties and to the increase in concentrations of plasma and pancreatic glutathione.