THE INHERITANCE OF THE PROTEIN AND NUCLEIC ACID CHARACTERISTICS OF T2 AND T6 BACTERIOPHAGE

A study of the immunological properties of phage strains derived from T2 x T6 crosses revealed that the majority of the progeny differ serologically from the parental viruses. Some hybrids were found to contain head membranes having the serological specificity of both T2 and T6 phages, while others contained tail sheaths of the former and the tail fibers of the latter. Since the immunological properties of all hybrids were heritable, it has been concluded that the serological specificity of the head proteins of T2 and T6 is controlled by at least two genetic determinants, and that the specificities of the fiber and sheath proteins may be governed by single genes. Furthermore it was found that nucleic acids of hybrids had similar proportions of unsubstituted, mono- and diglucosylated hydroxymethylcytosine nucleotides to the nucleic acid of either T2 or T6 phage. Since the parental and hybrid viruses having chemically similar nucleic acids contained in some instances serologically different proteins, it has also been concluded that the extent of glucosylation of the hydroxymethylcytosine component of viral nucleic acids and the immunological properties of viral proteins are independently heritable traits of T2 and T6 bacteriophages.     

A study of the antigenicity of T3 and T4 coli-dysentery bacteriophages during the vegetative stage of development

The development of viral neutralizing antibodies in animals injected with T₃ or T₄ phage is considerably inhibited by the presence of bacterial antigens. A new procedure has been described to liberate phage from infected E. coli B bacteria by inducing lysis with penicillin. By immunological means it has been shown that T₄-infected cultures of E. coli B, in which phage development has been inhibited with proflavine, contain the viral neutralizing antigen after lysis. In contrast, it has not been possible to demonstrate by immunological means the appearance of viral neutralizing antigen in E. coli B infected with T₃ prior to the appearance of intracellular phage.     

Type 1 T helper and type 2 T helper cells: Functions,regulation and role in protection and disease

Summary Two very distinct cytokine secretion patterns have been defined amoung murine CD4⁺ T cells. Type 1 helper (T_H1), but not type 2 helper (T_H2), cells produce interleukin (IL)-2, gamma-interferon (IFN-γ) and tumour necrosis factor-β, whereas T_H2, but not T_H1, cells express IL-4, IL-5, IL-6 and IL-10. The different cytokine patterns lead to different functions of the two types of T cell. In general, T_H2 cells are excellent helpers for B-cell antibody secretion, particularly IgE responses. On the other hand T_H1 cells induce delayed-type hypersensitivity reactions. There is general agreement that the different functional subsets of T_H cells arise post-thymically from a common pool of precursors and as a consequence of activation of antigen. However, the factors affecting differentiation of T_H precursors into the T_H1 or T_H2 subsets are still unclear. Mutual cross-regulation between T_H1 (via IFN-γ) and T_H2 (via IL-10) has also been reported. Recently, human T cell clones similar to murine T_H1 and T_H2 cells have been demonstrated. Most allergen- or helminthic antigen-specific CD4⁺ human T cell clones have a T_H2 phenotype, whereas the majority of T-cell clones specific for mycobacterial antigens or antigens responsible for type IV hypersensitivity exhibit a T_H1 phenotype. Human T_H2 clones provide B-cell help for IgE synthesis, whereas most T_H1 clones are cytolytic for antigen-presenting cells, including B lymphocytes. It is highly probable that the selective or preferential activation of CD4⁺ T-cell subsets secreting defined patterns of cytokines is of major importance in determining the class of immune effector function, thus influencing both protection and immunopathology.     

Dietary Modification of Thyroxine Deiodination in Rat Liver is Not Mediated by Hepatic Sulfhydryls

The enzymatic deiodination of thyroxine (T₄) is thiol dependent. Fasting (72 h) depresses hepatic T₄ deiodination and lowers the hepatic content of nonprotein sulfhydryls (NP-SH) and reduced glutathione (GSH). It has been proposed that the fasting effect may be mediated through these alterations in hepatic sulfhydryls. To test the importance of tissue (hepatic) thiol content in the modification of T₄ deiodination consequent to dietary manipulation, we examined the sequential deiodination of T₄ to 3,5,3′-triiodothyronine (T₃) (5′-deiodination) and 3,3′,5-triiodothyronine (reverse T₃, rT₃) (5-deiodination) in liver homogenates without added thiol from groups of rats fed Purina lab chow (P) (a protein-rich diet), glucose alone (G), or glucose plus cysteine (G_c) for 72 h or fasted (F) for the same period. The initial rate of each reaction was compared to the tissue concentrations of NP-SH and GSH.     

Studies on bacteriophage. II. Inhibition of lysis of Escherichia coli B by the somatic antigen of Phase II Shigella sonnei

By serological means it has been shown that E. coli B contains an antigen closely related to the protein-lipocarbohydrate complex of Phase II Sh. sonnei. Lysis of E. coli B by three of the T viruses, T₃, T₄, and T₇, can be inhibited by the Phase II dysentery antigen. It has been suggested that the receptor of E. coli B with which these viruses combine is this newly described antigenic component. Two variants of the virus T₃ have also been described, in stocks which have been treated with the Phase II antigen. One of these variants infects both Phase II Sh. sonnei and E. coli B, and the other infects only the latter microorganism; neither of the two variants is inhibited by concentrations of the Phase II antigen of 1 mg. per cc. The distinctive properties of the variants are not hereditary.     

The effect of antipyrine, phenobarbitol and rifampicin on thyroid hormone metabolism in man

Abstract. The effect of three different liver microsomal enzyme inducing drugs on thyroid hormone metabolism was investigated. Seven volunteers were randomly allocated in a crossover design to either antipyrine (1200 mg), phenobarbital (100 mg) or rifampicin (1200 mg) daily for 14 days. Before and after each treatment the following parameters of enzyme induction were measured: antipyrine clearance, y-glutamyltranspepti-dase, d-glucaric acid and 6-β-hydroxycortisol urinary excretion. In addition, thyroxine-binding globulin (TBG), T₃-resin uptake (RT₃U), thyroxine (T₄), free thyroxine (FT₄), triiodothyronine (T₃), reverse T₃ (rT₃), and thyroid stimulating hormone (TSH) were estimated. Following antipyrine and phenobarbital antipyrine clearance increased by about 45%, while with rifampicin an increase of 125% was observed. The indices of thyroid function did not change following phenobarbital and antipyrine, but after rifampicin T₄, FT₄ and rT₃ decreased by about 14%, and T₃ increased by 25%. In addition, the impact of rifampicin on the clearance of injected ¹²⁵I-T₄ was investigated in six additional volunteers by blocking thyroid iodine uptake. The ¹²⁵I-T₄ halflife decreased from 155 to 106 h and its clearance increased from 35 to 50 ml/h, while a fall in T₄, FT₄ and rT₃ by about 40% and no rise but a decrease in T₃by 25% occurred. Therefore an increased clearance of T₄ and rT₃ but not of T₃ seems likely following rifampicin, which might be due to enhanced hepatic metabolism and biliary excretion.     

THE NUCLEIC ACID AND CARBOHYDRATE OF INFLUENZA VIRUS

Both ribonucleic and desoxyribonucleic acids have been obtained from purified particles of PR8 influenza virus. These particles were also found by extraction with formamide to contain carbohydrate in addition to that of the nucleic acids. Carbohydrate-rich fractions, essentially devoid of nucleic acid, were obtained not only from the particles representing PR8 virus but from those of Lee influenza virus as well. The carbohydrate in each case appeared to be a polysaccharide composed of mannose, galactose, and glucosamine units.     

Effect of Oral Sebacic Acid on Postprandial Glycemia, Insulinemia, and Glucose Rate of Appearance in Type 2 Diabetes

OBJECTIVE

Dicarboxylic acids are natural products with the potential of being an alternate dietary source of energy. We aimed to evaluate the effect of sebacic acid (a 10-carbon dicarboxylic acid; C10) ingestion on postprandial glycemia and glucose rate of appearance (R_a) in healthy and type 2 diabetic subjects. Furthermore, the effect of C10 on insulin-mediated glucose uptake and on GLUT4 expression was assessed in L6 muscle cells in vitro.

RESEARCH DESIGN AND METHODS

Subjects ingested a mixed meal (50% carbohydrates, 15% proteins, and 35% lipids) containing 0 g (control) or 10 g C10 in addition to the meal or 23 g C10 as a substitute of fats.

RESULTS

In type 2 diabetic subjects, the incremental glucose area under the curve (AUC) decreased by 42% (P < 0.05) and 70% (P < 0.05) in the 10 g C10 and 23 g C10 groups, respectively. At the largest amounts used, C10 reduced the glucose AUC in healthy volunteers also. When fats were substituted with 23 g C10, AUC of R_a was significantly reduced on the order of 18% (P < 0.05) in both healthy and diabetic subjects. The insulin-dependent glucose uptake by L6 cells was increased in the presence of C10 (38.7 ± 10.3 vs. 11.4 ± 5.4%; P = 0.026). This increase was associated with a 1.7-fold raise of GLUT4.

CONCLUSIONS

Sebacic acid significantly reduced hyperglycemia after a meal in type 2 diabetic subjects. This beneficial effect was associated with a reduction in glucose R_a, probably due to lowered hepatic glucose output and increased peripheral glucose disposal.The World Health Report launched in 2002 by the World Health Organization advised that more than 1 billion adults worldwide are overweight and at least 300 million are clinically obese. Type 2 diabetes can be considered a threatening obesity-related disease because hyperglycemia causes relevant complications such as micro- and macroangiopathy. Patients with type 2 diabetes exhibit increased hepatic glucose output, which is identified as the main cause of fasting hyperglycemia and is associated with impaired plasma glucose clearance (1) and reduced hepatic synthesis of glycogen of ∼25–45% compared with that in nondiabetic subjects (2). Increased hepatic gluconeogenesis has been considered to be responsible for elevated hepatic glucose output in type 2 diabetes (3). When glycogen is available in adequate amounts, there is an autolimitation of hepatic glucose production. In diabetes, a breakdown of this autoregulation may occur if glycogenolysis is limited by glycogen depletion (4).Jenkins et al. (5) have shown that spreading the nutrient load over a longer period of time by increased meal frequency, the so-called nibbling diet, is beneficial in terms of reduction of circulating levels of glucose, insulin, and free fatty acids in type 2 diabetes. Thus, the availability of snacks poor in fat and that do not induce hyperglycemia and/or overstimulate insulin secretion would be a good tool in the diet of insulin-resistant, type 2 diabetic subjects.Dicarboxylic acids are naturally occurring substances produced by both higher plants and animals via ω-oxidation of fatty acids (6,7). In plants, long-chain dicarboxylic acids are components of natural protective polymers, cutin and suberin, which support biopolyesters involved in waterproofing the leaves and fruits, regulating the flow of nutrients among various plant cells and organs, and minimizing the deleterious impact of pathogens (7). In animals and humans, medium chain dicarboxylic acids, which include prevalently sebacic (C10) and dodecanedioic (C12) acids, derive from the β-oxidation of longer chain dicarboxylic acids (8). Long-chain dicarboxylic acids, in turn, are formed from the correspondent fatty acids by ω-oxidation in the microsomal membranes (9) or are taken in with a diet rich in vegetables (7).We have shown previously that medium-chain dicarboxylic acids represent a suitable alternate energy substrate to glucose in clinical conditions with marked insulin resistance and/or impaired aerobic glycolysis (10). Interestingly, in type 2 diabetes, medium-chain dicarboxylic acids are rapidly oxidized, do not stimulate insulin secretion, and reduce muscle fatigue (11). Nevertheless, the effect of C10 or C12, not as a substitute but in addition to available carbohydrates, on glucose homeostasis has never been studied.On this basis, our aim was to investigate the effect of oral administration of C10 on postprandial glycemia, insulinemia, and glucose rate of appearance (R_a) in type 2 diabetic subjects compared with that in healthy volunteers. To further elucidate the mechanism of action of sebacic acid in diabetes, insulin-mediated glucose uptake and GLUT4 protein expression were assessed in L6 cells in vitro.     

ANTIGENICITY OF POLYPEPTIDES (POLY ALPHA AMINO ACIDS) : XV. STUDIES ON THE IMMUNOGENICITY OF SYNTHETIC POLYPEPTIDES IN MICE

The response of mice to synthetic linear polypeptides of known composition but random sequence has been studied. Neither Swiss mice nor a number of inbred strains could respond to copolymers of only 2 amino acids (G₆₀L₄₀, G₆₀A₄₀, G₉₀T₁₀). Upon introduction of as little as 4 mole per cent of a third amino acid, good immune responses were obtained, regardless of the nature of the third amino acid. The level of the immune response to a series of glu-lys-ala polymers increased with increasing alanine content of the polymer.     

CERTAIN INTERFACIAL TENSION RELATIONS AND THE BEHAVIOR OF BACTERIA IN FILMS

To account for the behavior of a solid particle in the interface between two fluids it is necessary to consider, as indicated by Clark Maxwell, three surface tensions: T_so, the tension in the interface between the solid particle and the organic phase; T_sw, the tension in the interface between solid particle and aqueous phase; and T_ow, the organic phase-water interfacial tension. If T_so > T_sw + T_ow, (2), the stronger solid-organic phase tension should pull the line of intersection of the three phases around the periphery of the solid particle until the particle is completely enveloped in the water phase. If T_sw > T_ow + T_ow (3), the solid-water tension should pull the line of meeting of the phases about the particle until it is enveloped in the organic phase. If See PDF for Equation the particle should be stable in the interface, only leaving it when mechanical work overcomes the equilibrium due to the balance of interfacial tensions. The ordinary bacteria used have been stable in the interfaces between water or aqueous solutions and all organic liquids tested; i.e., condition (4) obtains. In preparations in which T_ow is large, stability has been found by experiment to be greater than when T_ow is small, as follows from condition (4). The force, dependent upon condition (4), which holds bacteria in the liquid-liquid interface, and the force, dependent upon unequal distribution of tension in the liquid-liquid interface, which causes bacteria to glide along the interface, prove to be of the same order of magnitude as the force due to bacterial flagella. Interfacial tensions or its own motility may dominate the movement of the bacterium, according to circumstances. When bacteria thresh their way out of the interface, escape is into the aqueous phase. Acid-fast bacteria possess very low or, in some cases, no stability in the interface, passing easily or even spontaneously into the organic phase. Good evidence has been advanced by other workers to indicate that the surfaces of ordinary bacteria contain many polar radicals; on the other hand, the acid-fast microorganisms are coated with predominantly non-polar substances. It follows from known principles, therefore, that T_sw should be greater than T_sw with ordinary bacteria, and T_sw should be greater than T_so with acid-fast bacteria. Consideration of relations (2) and (3) above will show that these conditions should result in the differences in behavior of acid-fast and ordinary bacteria actually found by experiment. The theoretical and experimental data here developed contradict the theoretical formulations of the surface tension factor in phagocytosis advanced by Rhumbler and by Tait and substantiate those of Fenn.     

Combined measurement of perfusion,venous oxygen saturation,and skeletal muscle T2* during reactive hyperemia in the leg

Background

The function of the peripheral microvascular may be interrogated by measuring perfusion, tissue oxygen concentration, or venous oxygen saturation (SvO₂) recovery dynamics following induced ischemia. The purpose of this work is to develop and evaluate a magnetic resonance (MR) technique for simultaneous measurement of perfusion, SvO₂, and skeletal muscle T₂*.

Methods

Perfusion, Intravascular Venous Oxygen saturation, and T₂* (PIVOT) is comprised of interleaved pulsed arterial spin labeling (PASL) and multi-echo gradient-recalled echo (GRE) sequences. During the PASL post-labeling delay, images are acquired with a multi-echo GRE to quantify SvO₂ and T₂* at a downstream slice location. Thus time-courses of perfusion, SvO₂, and T₂* are quantified simultaneously within a single scan. The new sequence was compared to separately measured PASL or multi-echo GRE data during reactive hyperemia in five young healthy subjects. To explore the impairment present in peripheral artery disease patients, five patients were evaluated with PIVOT.

Results

Comparison of PIVOT-derived data to the standard techniques shows that there was no significant bias in any of the time-course-derived metrics. Preliminary data show that PAD patients exhibited alterations in perfusion, SvO₂, and T₂* time-courses compared to young healthy subjects.

Conclusion

Simultaneous quantification of perfusion, SvO₂, and T₂* is possible with PIVOT. Kinetics of perfusion, SvO₂, and T₂* during reactive hyperemia may help to provide insight into the function of the peripheral microvasculature in patients with PAD.     

The role of glucose,long-chain triglycerides and amino acids for promotion of amino acid balance across peripheral tissues in man

The role of amino acids, glucose and lipids in improving amino acid balance in peripheral tissues was evaluated. Primed constant infusion of L -[ring-²H₅]phenylalanine in combination with flux measurements of glucose, free fatty acids (FFA) and amino acids across arm and leg tissues were applied in male volunteers after an overnight fast with subsequent primed constant infusions of amino acids (0·2 g N kg^?1 body weight day^?1), long-chain triglycerides (0·98–1·079 g kg^?1 day^?1) and glucose (3·13–3·62 g kg^?1 day^?1). Amino acids and phenylalanine tracer infusion continued for 6 h; the lipid infusion was provided during 2–6 h from the start, and glucose infusion was provided between 4 and 6 h. Flux measurements were performed at steady state before the next infusion started. Arterial concentrations of infused substrates increased during provision, but remained constant thereafter. Plasma insulin increased when glucose was provided, whereas insulin-like growth factor (IGF) I was unchanged during all infusions. Blood flow was unchanged in arm tissue during all infusions, while leg blood flow increased during fat and glucose infusion. FFA and glucose balance were unchanged during amino acid infusion but improved during lipid and glucose infusions. Amino acid balance was negative across arm and leg tissues in the fasted state, but reached balance during amino acid infusion. This effect was equally dependent on protein synthesis and protein degradation without any contribution from lipids and glucose. 3-Methylhistidine release from tissues was not influenced by any substrate. Our results suggest that extracellular amino acid concentrations determine amino acid balance across peripheral tissues independently of non-protein calories, insulin and IGF-I.     

Identification of locations susceptible to osteoarthritis in patients with anterior cruciate ligament reconstruction: Combining knee joint computational modelling with follow-up T1ρ and T2 imaging

BackgroundFinite element modelling can be used to evaluate altered loading conditions and failure locations in knee joint tissues. One limitation of this modelling approach has been experimental comparison. The aims of this proof-of-concept study were: 1) identify areas susceptible to osteoarthritis progression in anterior cruciate ligament reconstructed patients using finite element modelling; 2) compare the identified areas against changes in T₂ and T_1ρ values between 1-year and 3-year follow-up timepoints.MethodsTwo patient-specific finite element models of knee joints with anterior cruciate ligament reconstruction were created. The knee geometry was based on clinical magnetic resonance imaging and joint loading was obtained via motion capture. We evaluated biomechanical parameters linked with cartilage degeneration and compared the identified risk areas against T₂ and T_1ρ maps.FindingsThe risk areas identified by the finite element models matched the follow-up magnetic resonance imaging findings. For Patient 1, excessive values of maximum principal stresses and shear strains were observed in the posterior side of the lateral tibial and femoral cartilage. For Patient 2, high values of maximum principal stresses and shear strains of cartilage were observed in the posterior side of the medial joint compartment. For both patients, increased T₂ and T_1ρ values between the follow-up times were observed in the same areas.InterpretationFinite element models with patient-specific geometries and motions and relatively simple material models of tissues were able to identify areas susceptible to post-traumatic knee osteoarthritis. We suggest that the methodology presented here may be applied in large cohort studies.     

DNA vaccines: development, standardization and regulation

Nucleic acid vaccines contain nonvectored nucleic acids intended to be used as prophylactic vaccines in humans or animals. In addition to the Guidelines Assuring the Quality of DNA Vaccines published by the WHO, further standards for the manufacture and preclinical testing are being developed. Theoretical risks have been taken into account and assessed before human use has been considered. Legal requirements for clinical trials and licensing of nucleic vaccines are in place in Germany and other European member states which allow further testing and development of proprietary medicinal products based on nucleic acids and intended for prophylactic vaccination.     

Chemocatalytic value addition of glucose without carbon–carbon bond cleavage/formation reactions: an overview

As the monomeric unit of the abundant biopolymer cellulose, glucose is considered a sustainable feedstock for producing carbon-based transportation fuels, chemicals, and polymers. The chemocatalytic value addition of glucose can be broadly classified into those involving C–C bond cleavage/formation reactions and those without. The C₆ products obtained from glucose are particularly satisfying because their syntheses enjoy a 100% carbon economy. Although multiple derivatives of glucose retaining all six carbon atoms in their moiety are well-documented, they are somewhat dispersed in the literature and never delineated coherently from the perspective of their carbon skeleton. The glucose-derived chemical intermediates discussed in this review include polyols like sorbitol and sorbitan, diols like isosorbide, furanic compounds like 5-(hydroxymethyl)furfural, and carboxylic acids like gluconic acid. Recent advances in producing the intermediates mentioned above from glucose following chemocatalytic routes have been elaborated, and their derivative chemistry highlighted. This review aims to comprehensively understand the prospects and challenges associated with the catalytic synthesis of C₆ molecules from glucose.

Recent advances on the production and applications of major C₆ products from glucose have been reported in this review. The preparation and derivative chemistry of sorbitol, sorbitan, 5-(hydroxymethyl)furfural, and isosorbide have been elaborated.     

磁共振T1 加权像在急性闭塞性脑血管病诊断中的价值

目的 评价磁共振Ｔ１加权像在急性闭塞性脑血管病诊断中的价值。方法 急性闭塞性脑务管病１５例,其中急性脑皮层动脉闭塞９例,急性脑静脉窦闭塞６例。结果 ９例急性脑皮层动脉闭塞,Ｔ１加权像上ＭＲ信号强度正常,但可见梗死区脑肿胀征象;Ｔ２加权像时,病变区信号强度无异常发现。６例急性脑静脉窦闭塞中,横窦和乙状窦闭塞４例,上矢状窦后１／３处闭塞２例。Ｔ１加权像见闭塞的静脉窦血管流空影消失,静脉窦呈稍高信号强度     

Iron phosphide nanoparticles as a pH-responsive T1 contrast agent for magnetic resonance tumor imaging

In this work, the potential of FeP nanoparticles as a pH-responsive T₁ contrast agent was investigated. The FeP nanoparticles have good biocompatibility and can significantly amplify T₁ magnetic resonance signals in response to the acidic microenvironment of solid tumors, holding great promise in serving as an acid-activatable T₁ contrast agent for tumor imaging.

In this work, the potential of FeP nanoparticles as a pH-responsive T₁ contrast agent was investigated.

Magnetic resonance imaging (MRI) is currently one of the most powerful medical imaging techniques due to its noninvasive character, deep tissue penetration, and ability to provide images with excellent anatomical details.^1–3 MRI contrast agents are a group of contrast media that can improve the accuracy and specificity of MRI.^4–6 In general, MRI contrast agents can be divided into T₁ positive contrast agents and T₂ negative contrast agents according to the relaxation processes. T₁ contrast agents shorten the longitudinal relaxation time of water protons, resulting in a brighter signal, while T₂ contrast agents reduce the transverse relaxation time, leading to a darker signal.^7,8 Nanomaterials containing paramagnetic metal ions (e.g., Gd³⁺, Mn²⁺, and Fe³⁺) have been widely used as T₁ MRI contrast agents.^9–14 On the other hand, magnetic nanoparticles with high saturation magnetization are the most commonly used as T₂ contrast agents because they can generate a local magnetic field in the presence of the external magnetic field to accelerate the dephasing of surrounding water protons.^15–17The exploitation of highly specific and sensitive imaging contrast agents is of great importance for precise disease diagnosis.¹⁸ Activatable imaging contrast agents that can respond to biological stimulis (e.g., pH, redox potential, and enzyme) to produce contrast signals, have emerged as the next generation of molecular imaging probes.^19–22 They can minimize the signal from nontarget background, therefore greatly improve the target-to-background ratio. Conventional T₁ contrast agents such as Gd₂O₃ nanoparticles and MnO nanoparticles have been demonstrated that can afford effective T₁ shortening effect to improve the visibility. However, these contrast agents continuously emit signals are “always on”, which fail to response to pathological parameters and hence lack in specificity and sensitivity. Activatable MRI contrast agents that only generate signals in response to a certain stimuli (e.g., physiological difference in pH in tumor microenvironment) thus are highly desirable, because they not only greatly enhance the specificity and sensitivity of disease diagnosis, but also potentially allow MRI to monitor biological processes.^23–25 Herein, we report a novel pH-activatable T₁ contrast agent based on FeP nanoparticles. We found that the as-synthesized FeP nanoparticles can respond to the acidic microenvironment of solid tumor to produce significant T₁ contrast enhancement by releasing paramagnetic Fe ions. Furthermore, both in vitro and in vivo investigations indicate that the FeP nanoparticles have good biocompatibility that show no obvious cytotoxicity and harmful effects. Therefore, the FeP nanoparticles can potentially serve as an acid-responsive T₁ MRI contrast agent for tumor imaging.     

Synthesis,characterization, and properties of a novel aromatic ester-based polybenzoxazine

Polybenzoxazines with molecular design flexibility have excellent properties by using suitable raw materials. A new benzoxazine monomer terephthalic acid bis-[2-(6-methyl-4H-benzo[e][1,3]oxazin-3-yl)]ethyl ester (TMBE) with bis-ester groups has been synthesized from the simple esterification reaction of terephthaloyl chloride and 2-(6-methyl-4H-benzo[e][1,3]oxazin-3-yl)-ethanol (MB-OH). The chemical structure of TMBE was characterized by Fourier transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance spectroscopy (¹H-NMR, ¹³C-NMR). Polymerization behavior of TMBE was studied by differential scanning calorimetry (DSC) and FT-IR after each cure stage. The cross-linked polybenzoxazine (PTMBE) gave a transparent film through the thermal casting method. The dynamic mechanical analysis of PTMBE showed that the T_g was 110 °C. Thermogravimetric analysis reveals better thermal stability as evidenced by the 5% and 10% weight-loss temperatures (T_d5 and T_d10) of PTMBE, which were 263 and 289 °C, respectively, with a char yield of 27% at 800 °C. The tensile test of the film revealed that the elongation at break was up to 14.2%.

A novel benzoxazine monomer contain ester group was obtained by an indirect molecular design method. Its polymer showed excellent flexibility.     

Characterization of Renal Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and Subjects With Type 2 Diabetes

OBJECTIVE

To examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [T_mG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique.

RESEARCH DESIGN AND METHODS

Subjects with type 2 diabetes (n = 12) and matched healthy subjects (n = 12) underwent pancreatic/SHC (plasma glucose range 5.5–30.5 mmol/L) at baseline and after 7 days of dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves.

RESULTS

At baseline, type 2 diabetic subjects had elevated T_mG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the T_mG and splay in both groups. However, the most significant effect of dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects.

CONCLUSIONS

The SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the T_mG and threshold at which glucose is excreted in the urine.The current study was undertaken to examine the mechanism (decreased maximum renal glucose reabsorptive capacity [T_mG], increased splay, and reduced threshold) through which sodium-glucose transporter 2 (SGLT2) inhibition induces glucosuria in diabetic and nondiabetic subjects. In humans, the kidney filters ∼162 g of glucose per day (glomerular filtration rate [GFR] = 180 L/day × fasting plasma glucose [FPG] = ∼5 mmol/L [90 mg/dL]), and virtually all the filtered glucose is reabsorbed (1). The high-capacity, low-affinity SGLT2 in the proximal tubule reabsorbs ∼80–90% of filtered glucose (2,3). T_mG varies among individuals and averages ∼375 mg/min (2–4). Because the filtered glucose load does not exceed T_mG in nondiabetic individuals, all filtered glucose is reabsorbed and returned to the circulation. If the filtered glucose load exceeds the T_mG, all glucose in excess of the T_mG is excreted. The plasma glucose concentration at which the filtered glucose load reaches 375 mg/min is ∼10 mmol/L (180 mg/dL) (2–4). Above the T_mG, the glucose excretion rate increases linearly and parallels the increase in filtered glucose load. Glucose reabsorption and excretion curves display a nonlinear transition as T_mG is approached. This rounding of the curves is termed splay (Fig. 1). The plasma glucose concentration at which glucose first appears in the urine is termed threshold and corresponds to the beginning of the splay.Open in a separate windowFigure 1Relationship between the rate of urinary glucose reabsorption/renal glucose filtration and the plasma glucose concentration during SHC in type 2 diabetic and healthy subjects at baseline and after 7 days of dapagliflozin treatment. Thin line, rate of glucose filtration; ○, observed rate of reabsorption; thick line, predicted rate of reabsorption; dashed line, geometric mean of T_mG.In patients with poorly controlled type 1 or 2 diabetes, T_mG is increased (5,6). Similar observations have been made in diabetic animal models (7,8). At the molecular level, increased T_mG may be explained by increased SGLT2 mRNA and protein in the proximal tubule (9–11).SGLT2 inhibitors have been developed for the treatment of type 2 diabetes (4,12–14) and have proven to be efficacious in reducing glycated hemoglobin (HbA_1c) (12–16). Because their mechanism of action is independent of severity of insulin resistance and β-cell failure, they can be used at any stage of type 2 diabetes (14,16,17). Clinical trials with SGLT2 inhibitors have demonstrated that treatment in healthy subjects results in continuously excreted glucose in the absence of hyperglycemia (18,19), suggesting that factors other than a reduction in T_mG must account for the drug’s glucosuric effect. Because no previous study to our knowledge has comprehensively characterized the changes in renal glucose handling through which SGLT2 inhibitors augment renal glucose excretion in humans, the current study was undertaken to examine the mechanisms through which dapagliflozin produces its glucosuric effect in individuals with type 2 diabetes and those with normal glucose tolerance.