Nonequilibrium Steady States in Fluid Transport through Mesopores: Dynamic Mean Field Theory and Nonequilibrium Molecular Dynamics.

We present a dynamic mean field theory (DMFT) and nonequilibrium dual control volume grand canonical molecular dynamics (GCMD) simulation study of steady-state fluid transport in slit-shaped mesopores under an applied chemical potential gradient. The main focus is on states where the bulk conditions on one side of the pore would lead to a capillary condensed state in the pore at equilibrium while those on the other side would lead to a vapor state in the pore. This choice of conditions is motivated by certain separation applications in which condensable vapors permeate through mesoporous membranes. Under these circumstances, we have found partially filled states with a liquid-like state at the high chemical potential end of the pore and a vapor-like state at the low chemical potential end. This phenomenon is accompanied by hysteresis. The existence of partially filled states has been hypothesized in previous work but the present paper reveals them as an emergent feature of the systems. We find that predictions of DMFT are in good qualitative agreement with the overall GCMD results. However, the GCMD results demonstrate that the transport is faster through the partially filled pore than through the unfilled pore, a feature not captured by DMFT.

A comparison of dynamic mean field theory and grand canonical molecular dynamics for the dynamics of pore filling and capillary condensation of fluids in mesopores.

We use results from grand canonical molecular dynamics (GCMD) to test the predictions from dynamic mean field theory (DMFT) for the pore filling and capillary condensation mechanisms of a fluid confined in slit shaped mesopores. The theory predicts that capillary condensation occurs by a nucleation process in which a liquid bridge forms between the two walls, and the pore is filled via the growth of this bridge. For longer pores, multiple bridging is seen. These mechanisms are confirmed by the molecular dynamics simulations. The primary difference between the theory and simulations lies in the role of fluctuations. DMFT predicts a single nucleation time and location, while in GCMD (and in nature) a distribution of nucleation times and locations is seen.

Efficacy and safety of colesevelam in combination with pioglitazone in patients with type 2 diabetes mellitus.

Colesevelam improves glycemic control in patients with type 2 diabetes when added to existing metformin-, sulfonylurea-, or insulin-based regimens. We evaluated colesevelam's effects in subjects on stable pioglitazone-based therapy. This 24-week multicenter, double-blind, randomized, placebo-controlled study enrolled adults with type 2 diabetes who had suboptimal glycemic control [HbA1c ≥ 58 mmol/mol (7.5%) and ≤ 80 mmol/mol (9.5%)] on pioglitazone (30 or 45 mg) with or without 1-2 other oral antidiabetes medications. Subjects were randomized to colesevelam 3.8 g/day (n = 280) or placebo (n = 282) added to existing pioglitazone-based therapy. Primary efficacy variable was mean change in HbA1c from baseline to Week 24. Secondary variables included safety and tolerability, fasting plasma glucose changes, glycemic responses, and lipid profile. Tertiary variables included lipid particle profile changes by nuclear magnetic resonance. Colesevelam decreased HbA1c [least-squares mean treatment difference, - 3.5 mmol/mol (- 0.32%); p < 0.001] and fasting plasma glucose (- 14.7 mg/dl; p<0.001) vs. placebo at Week 24. More subjects receiving colesevelam vs. placebo achieved HbA1c reduction ≥ 7.7 mmol/mol (0.7%) (40% vs. 25%; p<0.001) or HbA1c < 53 mmol/mol (7.0%) (21% vs. 13%; p = 0.012). Colesevelam also decreased total cholesterol (mean treatment difference, - 6.5%), LDL-cholesterol (- 16.4%), non-HDL-cholesterol (- 9.8%), apolipoprotein B (- 8.8%), and total LDL particle concentration, and increased apolipoprotein A1 (+3.4%) and triglycerides (median treatment difference, + 11.3%) vs. placebo (all p < 0.001). There were no serious drug-related adverse events, and the majority of adverse events were mild or moderate. In subjects with type 2 diabetes inadequately controlled with pioglitazone-based therapy, add-on colesevelam therapy improved glycemic control and lipid parameters and was well tolerated. ClinicalTrials.gov identifier: NCT00789750.

The glucose and lipid effects of colesevelam as monotherapy in drug-naïve type 2 diabetes.

Colesevelam has shown efficacy in adults with type 2 diabetes mellitus (T2DM) in combination with metformin-, sulfonylurea-, or insulin-based therapy, lowering hemoglobin A1c (HbA1c) and low-density lipoprotein cholesterol levels. A study was conducted to evaluate colesevelam as monotherapy in drug-naïve patients with T2DM. In this randomized, double-blind, placebo-controlled, parallel-group study, adults with T2DM who had inadequate glycemic control (HbA1c ≥7.5% and ≤9.5%) with diet and exercise alone were randomized to receive colesevelam 3.75 g/day (n=176) or placebo (n=181) for 24 weeks. The primary efficacy variable was HbA1c at week 24. Colesevelam as compared to placebo showed significant reductions from baseline in HbA1c (-2.92 mmol/mol [0.3%]; p=0.01) and fasting plasma glucose (-10.3 mg/dl; p=0.04) at week 24 with last observation carried forward. Colesevelam also significantly reduced low-density lipoprotein cholesterol (-11.2%; p<0.0001), total cholesterol (-5.1%; p=0.0005), non-high-density lipoprotein cholesterol (-7.4%; p=0.0001), and apolipoprotein B (-6.5%; p=0.0001) and increased apolipoprotein A-I (+ 2.4%; p=0.04), and triglycerides (+ 9.7%; p=0.03). Colesevelam monotherapy resulted in statistically significant improvements in glycemic and most lipid parameters in subjects with type 2 diabetes, with no new or unexpected safety and tolerability issues. Modest reductions in HbA1c and low-density lipoprotein cholesterol levels with colesevelam further support its use in combination with other antidiabetes agents when treatment targets for these parameters are close but are not quite achieved.ClinicalTrials.gov identifier: NCT00789737.

Passive sampler housing and sorbent type determine aquatic micropollutant adsorption and subsequent bioassay responses.

The combination of integrative passive sampling and bioassays is a promising approach for monitoring the toxicity of polar organic contaminants in aquatic environments. However, the design of integrative passive samplers can affect the accumulation of compounds and therewith the bioassay responses. The present study aimed to determine the effects of sampler housing and sorbent type on the number of chemical features accumulated in polar passive samplers and the subsequent bioassay responses to extracts of these samplers. To this end, four integrative passive sampler configurations, resulting from the combination of polar organic chemical integrative sampler (POCIS) and Speedisk housings with hydrophilic-lipophilic balance and hydrophilic divinylbenzene sorbents, were simultaneously exposed at reference and contaminated surface water locations. The passive sampler extracts were subjected to chemical non-target screening and a battery of five bioassays. Extracts from POCIS contained a higher number of chemical features and caused higher bioassay responses in 91% of cases, while the two sorbents accumulated similar numbers of features and caused equally frequent but different bioassay responses. Hence, the passive sampler design critically affected the number of accumulated polar organic contaminants as well as their toxicity, highlighting the importance of passive sampler design for effect-based water quality assessment.

Soil self-cleaning capacity: Removal of organic compounds during sub-surface irrigation with sewage effluent.

Globally, the reuse of treated sewage effluent for irrigation purposes is increasingly encouraged as a practical solution against the mismatch between the demand for and availability of freshwater resources. The reuse of sewage effluent for sub-surface irrigation (SSI) in agriculture serves the dual purpose of supplying water to crops and diminishing emissions of contaminants of emerging concern (CoECs) into surface water. To investigate such reuse, in a real scale cropland with SSI using sewage effluent, from September 2017 to March 2019 including the extremely dry year 2018, residues were followed of 133 CoECs as related to their physicochemical properties and quantified by liquid chromatography coupled to high-resolution mass spectrometry. Of the 133 target CoECs, 89 were retrieved in the field, most non-detect CoECs have low persistency. During the growing season with sub-surface irrigation, CoECs spread to the shallow groundwater and rhizosphere. Significantly lower concentrations are found between infiltration pipes as compared to directly next to the pipes in shallow groundwater for all persistency-mobility classes. CoECs belonging to the class pm (low persistency and low mobility) or class PM (high persistency and high mobility) class show no change amongst their removal in the rhizosphere and groundwater in a dry versus normal year. CoECs belonging to the class pM (low persistency and high mobility) show high seasonal dynamics in the rhizosphere and shallow groundwater, indicating that these CoECs break down. CoECs of the class Pm (high persistency and low mobility) only significantly build up in the rhizosphere next to infiltration pipes. Climatic conditions with dry summers and precipitation surplus and drainage in winter strongly affect the fate of CoECs. During the dry summer of 2018 infiltrated effluent is hardly diluted, resulting in significantly higher concentrations for the CoECs belonging to the classes pM and Pm. After the extremely dry year of 2018, cumulative concentrations are still significantly higher, while after a normal year during winter precipitation surplus removes CoECs. For all persistency-mobility classes in the shallow groundwater between the pipes, we find significant removal efficiencies. For the rhizosphere between the pipes, we find the same except for Pm. Next to the pipes however we find no significant removal for all classes in both the rhizosphere and shallow groundwater and even significant accumulation for Pm. For this group of persistent moderately hydrophobic CoECs risk characterization ratio's were calculated for the period of time with the highest normalized concentration. None of the single-chemical RCRs are above one and the ΣRCR is also far below one, implying sufficiently safe ambient exposures. Overall the deeper groundwater (7.0-11.8 m below soil surface) has the lowest response to the sub-surface irrigation for all persistency-mobility. When adopting a SSI STP effluent reuse system care must be taken to monitor the CoECs that are (moderately) hydrophobic as these can build up in the SSI system. For the deeper groundwater and for the discharge to the surface water, we find significant removal for the pM and the PM class but not for other classes. In conclusion, relatively high removal efficiencies are shown benefiting the surface waters that would otherwise receive the STP effluent directly.

Long-term Safety and Tolerability of Colesevelam HCl in Subjects with Type 2 Diabetes.

The bile acid sequestrant, colesevelam hydrochloride, is approved for glycemic control in adults with type 2 diabetes. In three double-masked, placebo-controlled studies, colesevelam hydrochloride 3.75 g/day demonstrated its glycemic-lowering properties when added to existing metformin-, insulin-, or sulfonylurea-based therapy in adults with inadequately controlled type 2 diabetes. This was a 52-week open-label extension study conducted at 63 sites in the United States and one site in Mexico to further evaluate the safety and tolerability of colesevelam hydrochloride in subjects with type 2 diabetes. All subjects who completed the three double-masked, placebo-controlled studies were eligible to enroll in this open-label extension. In total, 509 subjects enrolled and received open-label colesevelam hydrochloride 3.75 g/day for 52 weeks. Safety and tolerability of colesevelam hydrochloride was evaluated by the incidence and severity of adverse events. In total, 360 subjects (70.7%) completed the extension. Of the safety population, 361 subjects (70.9%) experienced an adverse event, most (88.1%) being mild or moderate in severity. Fifty-six adverse events (11.0%) were drug-related; the most frequent drug-related adverse events were constipation and dyspepsia. Thirty-five subjects (6.9%) discontinued due to an adverse event. Fifty-four subjects (10.6%) experienced a serious adverse event; only one was considered drug-related (diverticulitis). Seventeen subjects (3.3%) experienced hypoglycemia; most episodes were mild or moderate in severity. Glycemic improvements with colesevelam hydrochloride were seen without change in weight over 52 weeks (0.2 kg mean reduction from baseline). Colesevelam hydrochloride was safe and well-tolerated as long-term therapy for patients with type 2 diabetes.

Aluminum intoxication in a child: treatment with intraperitoneal desferrioxamine.

We report the successful chelation of aluminum and the clinical resolution of severe aluminum intoxication in an infant receiving chronic peritoneal dialysis through the use of intraperitoneal desferrioxamine. Following the introduction of desferrioxamine, urine and dialysate fluid aluminum levels exceeded those noted without the chelating agent, thus demonstrating enhanced removal of aluminum. As a result of therapy, plasma and bone aluminum levels decreased markedly, and previously noted histomorphometric abnormalities on bone biopsy resolved. Clinically, the aluminum-associated osteomalacia and microcytic hypochromic anemia completely reversed. Moderate developmental delay has also improved slightly but persists. Our experience suggests that intraperitoneal chelation therapy with desferrioxamine may be helpful to reverse aluminum intoxication in children with chronic renal failure. However, limited exposure to aluminum should remain a primary goal.

Muscle spindles in the paraspinal musculature of patients with adolescent idiopathic scoliosis.

Electromyographic studies have determined that muscle imbalance and asymmetry of stretch receptors in the paraspinal muscle of patients with idiopathic scoliosis may have a large role to play in the development and production of the deformity. This project consisted of a detailed histologic and histochemical analysis of the distribution of muscle spindles in paraspinal musculature of patients suffering from idiopathic scoliosis, using the reduced form of nicotinamide-adenine dinucleotide (NADH), adenosine triphosphatase (ATPase), and Tri-chrome stain techniques. Muscle biopsy samples were taken at operation for spinal instrumentation from each of 13 patients (mean age: 16.2 years; 3 males, 10 females) with all but one female exhibiting right thoracic curves. The samples were collected from two specific sites (superficial and deep) on both sides of the vertebral column at the level of the apex of the primary curve and two vertebral levels above and below the apex. From the results there appear to be few muscle spindles in the scoliotic muscle of this region. All of the patients from whom muscle samples were taken possessed at least one sample with a muscle spindle. However, each patient had very few samples which contained a minimum of one muscle spindle (mean: 20.3%; SD: 12.6). It is clear that further examination is necessary, particularly in the area of comparison with 'normal' standards when these standards become available.

Paraspinal muscle imbalance in adolescent idiopathic scoliosis.

Twelve muscle biopsy samples were taken at operation for spinal instrumentation from each of seven patients suffering from idiopathic scoliosis (one male and six female patients; mean age 14.3 years). The samples were collected from two specific sites (superficial and deep) on both sides on the vertebral column at the level of the apex of the primary curve and two vertebral levels above and below the apex. The results of this study support and extend the findings of other workers. Not only was a significantly larger percentage of Type I fibers found in multifidus muscle at the apex on the curve on the convex side as other workers have found but also in the superficial muscles above and below the apex of the curve on the convex side. These results present a complex picture of muscle fiber characteristics associated with idiopathic scoliosis.

The histochemical composition of human vertebral muscle.

This paper describes the ranges of variation of characteristics present in human vertebral muscle. The samples used are from subjects who had a relatively brief history of spinal dysfunction. The samples have been taken in a precise manner and from a specific vertebral level with both sides of the vertebral column being studied including both superficial and deep muscles. These values for typical muscle for the ages investigated now can be used in studies involving abnormal vertebral muscle.

Abnormal proximal tubule apical membrane protein composition in X-linked hypophosphatemic mice.

The hypophosphatemic (Hyp) mouse is characterized by an isolated X-linked defect in proximal tubular phosphate (Pi) reabsorption associated with a decreased maximum velocity (Vmax) and a normal affinity (Km). To directly investigate the underlying cellular defect proximal tubular brush-border membranes (BBM) from normal control (Con) and Hyp male littermates were examined for differences in cholesterol content, total and individual phospholipid composition, phospholipid incorporation rates, membrane fluidity, and by two-dimensional sodium dodecyl sulfate (SDS)-polyacrylamide protein electrophoresis. The cholesterol content, total and individual phospholipid profiles, phospholipid incorporation rates, and membrane fluidity of Con and Hyp BBM samples were comparable. However, the two-dimensional gel electrophoreses of Con and Hyp BBM proteins, run simultaneously under identical conditions, revealed a protein with an apparent abnormal isoelectric migration pattern in Hyp BBM samples. This protein had an apparent molecular weight 56,000 and an apparent pI of 7.2 and was consistently evident on Hyp gels (n = 3) but not on Con gels (n = 3). The appearance of this protein band was associated with a diminution in staining of a control protein of comparable apparent molecular weight but markedly lower apparent pI.

Body mass and sex as determining factors in the development of fever in rats.

1. We have investigated the effect of a single I.P. injection (20 microgram/kg) of bacterial endotoxin on rectal temperature in rats of both sexes and from a wide range of body mass. 2. In male rats, endotoxin produced a monophasic or a biphasic rise in temperature, or a monophasic fall. 3. The extent of the rise in rectal temperature in male rats is related to body mass. There is a statistically significant correlation between body mass and the mean change in temperature measured over 100 min after injection of endotoxin. 4. In the female rats, endotoxin produced a monophasic fall in rectal temperature. The extent of the fall was not significantly correlated with body mass. 5. We suggest that the effect of endotoxin in male rats is determined by the physical relationship between body mass and surface area, because larger animals developed greater fevers. 6. The difference between the effect of endotoxin in male and female rats may have a physiological explanation and may involve differences in susceptibility to cutaneous vasodilation occurring immediately after injection of endotoxin.

Contrasting roles of 5-hydroxytryptamine and noradrenaline in fever in rats.

1. We have investigated the effects of endogenous monoamine depletion on the development of fever in rats. 2. Fever was produced in rats by a single intraperitoneal injection of Salmonella typhosa endotoxin or leucocyte pyrogen manufactured from ox blood. 3. Depletion of brain 5-hydroxytryptamine (5-HT) by pretreatment with p-chlorophenylalanine prevented the rise in rectal temperature produced both by bacterial endotoxin and by leucocyte pyrogen. 4. On the other hand depletion of noradrenaline (NA) by 6-hydroxydopamine pretreatment resulted in a potentiation of the fever produced by bacterial endotoxin. 5. These results suggest that 5-HT is involved in mechanisms responsible for the rise in temperature during fever and that NA is involved in mechanisms which serve to attenuate the rise.

The skin of primates. XLII. The skin of the silvered sakiwinki (Pithecia monachus).

The following characteristics indicate that the skin of the silvered sakiwinki (Pithecia monachus, E. Geoffroy, 1812) is not only basically similar to other primitive cebids, but also remarkably close to that of callithricids: a thin epidermis with diminished monoamine oxidase activity; a poorly-developed dermis, paucity of elastic fibers, and scant adnexal blood supply; hair follicles arranged in linear perfect sets; grouped hairs present on the cheek; an absence of glycogen and phosphorylase in most sebaceous glands; apocrine glands present throughout most haired body regions, but totally absent from the dorsum; and poorly-differentiated eccrine glands, confined to volar friction surfaces, which are characterized by unusual glycolytic properties. Other noteworthy cutaneous traits include: concomitant epidermal and dermal pigmentation in the face and scalp; Merkel-like disks in the friction surfaces; moderately well-developed Haarscheibe, associated with large, dorsal guard hairs; small, discrete sebaceous glands throughout the dorsum; a 1:1 ratio of apocrine glands to hair follicles in the facial, gular and anogenital areas; and numerous cholinesterase-reactive nerves around eccrine but not apocrine secretory coils. Although previous comparative studies on the skin of New World monkeys suggest that the systematic designation of two familial taxa is warranted, information regarding five of the fifteen genera which comprise the families Callithricidae and Cebidae is totally lacking. Given that three of these genera (Leontopithecus, Chiropotes and Brachyteles) can no longer be obtained from animal dealers because of exportation laws, the authors were fortunate to acquire representatives of the remaining two genera: Callicebus (titi monkeys) and Pithecia (sakiwinkis). Besides defining cutaneous characteristics common to specific taxa, two earlier works by Hanson and Montagna ('62) and Perkins et al, ('68) also suggested that members of the cebid subfamilies Aotinae and Pitheciinae possess cutaneous traits that bridge an interesting gap with the callithricids. Therefore, the acquisition of these two additional aotine and pithecine genera provided the opportunity to test this hypothesis. The following, therefore, is not just another detailed manuscript regarding the skin of primates. Rather, it is an effort to define the integumental characteristics of the last obtainable New World monkey genera, and to assess those cutaneous signatures which are interfamilially common to both the callithricids and more primitive cebids. Primary emphasis is placed on the genus Pithecia; pertinent findings concerning Callicebus will be incorporated into the forthcoming and final summarization of the phylogenetic significance of the skin of New World monkeys (Perkins, '75).