Ambient heat and diabetes hospitalizations: Does the timing of heat exposure matter?

BACKGROUND: Although ambient heat exposure is linked with diabetes mortality, the impacts of heat exposure on diabetes-related hospitalizations remain controversial. Previous research did not examine the timing of heat-diabetes associations and relation with comorbidities/risk factors. OBJECTIVE: We examined the association between heat exposure and diabetes-related hospitalizations in the transitional and summer months and identified populations vulnerable to heat. METHODS: We conducted a time-stratified case-crossover study. Data on diabetes hospital admissions (primary diagnosis of type 1 and type 2 diabetes, 2013-2020) were collected by the New York State (NYS) Department of Health under the state legislative mandate. We treated temperature and air pollutants as continuous variables and defined the heat exposure as per interquartile range (IQR, a measure between the 25th and 75th percentiles) increase of daily mean temperature. Conditional logistic regressions were performed to quantify the heat-diabetes associations after controlling for air pollutants and time variant variables. Multiplicative-scale interactions between heat and demographics/comorbidities/risk factors on diabetes hospitalizations were investigated. RESULTS: Each IQR increase in temperature was associated with significantly increased risks for diabetes admissions that occurred immediately and lasted for an entire week during multi-day lags in the transitional month of May (ranges of excess risk: 3.1 %-4.8 %) but not in the summer (June-August) (ranges of excess risk: -0.3 %-1.3 %). The significant increases in the excess risk of diabetes were also found among diabetes patients with complications of neuronopathy (excess risk: 27.7 %) and hypoglycemia (excess risk: 19.1 %). Furthermore, the modification effects on the heat-diabetes association were significantly stronger in females, Medicaid enrollees, non-compliant patients, and individuals with comorbidities of atherosclerotic heart disease and old myocardial infarction. CONCLUSIONS: Ambient heat exposure significantly increased the burden of hospital admissions for diabetes in transitional rather than summer months indicating the importance of exposure timing. Vulnerability to heat varied by demographics and heart comorbidity.

Genome sequence of a tigecycline-resistant Acinetobacter seifertii recovered in human bloodstream infection in China.

OBJECTIVES: The phylogenetic characteristics of Acinetobacter seifertii clinical strain are not well-studied. Here, we reported one tigecycline-resistant ST1612Pasteur A. seifertii isolated from bloodstream infections (BSI) in China. METHODS: Antimicrobial susceptibility tests were conducted via broth microdilution. Whole-genome sequencing (WGS) was performed and annotation was conducted using rapid annotations subsystems technology (RAST) server. Multilocus sequence typing (MLST), capsular polysaccharide (KL), and lipoolygosaccharide (OCL) were analysed using PubMLST and Kaptive. Resistance genes, virulence factors, and comparative genomics analysis were performed. Cloning, mutations of efflux pump-related genes, and expression level were further investigated. RESULTS: The draft genome sequence of A. seifertii ASTCM strain is made up of 109 contigs with a total length of 4,074,640 bp. Based on the RAST results, 3923 genes that belonged to 310 subsystems were annotated. Acinetobacter seifertii ASTCM was ST1612Pasteur with KL26 and OCL4, respectively. It was resistant to gentamicin and tigecycline. ASTCM harboured tet(39), sul2, and msr(E)-mph(E), and one amino acid mutation in Tet(39) (T175A) was further identified. Nevertheless, the signal mutation failed to contribute to susceptibility change of tigecycline. Of note, several amino acid substitutions were identified in AdeRS, AdeN, AdeL, and Trm, which could lead to overexpression of adeB, adeG, and adeJ efflux pump genes and further possibly lead to tigecycline resistance. Phylogenetic analysis showed that a huge diversity was observed among A. seifertii strains based on 27-52,193 SNPs difference. CONCLUSION: In summary, we reported a tigecycline-resistant ST1612Pasteur A. seifertii in China. Early detection is recommended to prevent their further spread in clinical settings.

Association between extreme ambient heat exposure and diabetes-related hospital admissions and emergency department visits: A systematic review.

Background and objectives: Diabetes is an increasing public health concern worldwide. The impact of extreme heat exposure on diabetes healthcare utilization such as diabetes-related hospital admissions and emergency department (ED) visits was understudied although extreme temperature exposure was linked with diabetes mortality. In addition, very few systematic reviews have been conducted in this field. This review aims to systematically evaluate the currently available evidence on the association between extreme ambient heat exposure and hospital admissions/ED visits for diabetes and the vulnerable population to heat extremes. Methods: A systematic literature review was conducted by using the keywords/terms "ambient temperature or heatwave or heat wave or extreme temperature or high temperature effect " and "diabetes morbidity or diabetes hospital admissions or diabetes emergency room visits " for available publications until August 2022. The heat exposure was categorized into four groups using difference definitions. The outcomes were diabetes-related hospital admissions/ED visits. A meta-analysis was performed to estimate the pooled effects of relative risk (RR)/odds ratio (OR) and 95% confidence intervals (CI) for each of the associations of interest. Results: Eighteen articles were selected from forty full-text, English written papers based on the inclusion and exclusion criteria. The overall pooled effect of excessive heat on diabetes, across all groups, was 1.045 (95% CI 1.024-1.066). The pooled effects for each exposure group were significant/borderline significant. Additionally, the pooled effect of the RR/OR was 1.100 (95% CI: 1.067-1.135) among adults aged 65 years or older. The most controlled confounders were air pollutants. The commonly listed limitation in those studies was misclassification of exposure. Conclusions: The body of evidence supports that ambient extreme heat exposure is associated with diabetes-related hospital admissions/ED visits. Additionally, adults 65 years of age or older with diabetes are vulnerable to heat extremes. Future studies should consider controlling for various biases and confounders.

Indole Inhibitors of MMP-13 for Arthritic Disorders.

Here, we described the design, by fragment merging and multiparameter optimization, of selective MMP-13 inhibitors that display an appropriate balance of potency and physicochemical properties to qualify as tool compounds suitable for in vivo testing. Optimization of potency was guided by structure-based insights, specifically to replace an ester moiety and introduce polar directional hydrogen bonding interactions in the core of the molecule. By introducing polar enthalpic interactions in this series of inhibitors, the overall beneficial physicochemical properties were maintained. These physicochemical properties translated to excellent drug-like properties beyond potency. In a murine model of rheumatoid arthritis, treatment of mice with selective inhibitors of MMP-13 resulted in a statistically significant reduction in the mean arthritic score vs control when dosed over a 14 day period.

Carbamoyl Anion Addition to Azirines.

The addition of carbamoyl anions to azirines affords synthetically useful 2-aziridinyl amide building blocks. The reaction scope was explored with respect to both formamide and azirine, and the addition was found to be highly diastereoselective. A one-pot conversion of a ketoxime to an aziridinyl amide was demonstrated. The method was employed to incorporate an aziridine residue into a dipeptide segment.

Computationally Assisted Mechanistic Investigation and Development of Pd-Catalyzed Asymmetric Suzuki-Miyaura and Negishi Cross-Coupling Reactions for Tetra-ortho-Substituted Biaryl Synthesis.

Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra-ortho-substituted biaryls leads to chiral atropisomeric products that introduces the opportunity to use catalyst-control to develop asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were identified for the Suzuki-Miyaura and Negishi cross-coupling reactions, respectively. Unique ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational study on these Suzuki-Miyaura and Negishi cross-coupling reactions enabled an understanding in the differences between the enantiodiscriminating events between these two cross-coupling reactions. These results support that enantioselectivity in the Negishi reaction results from the reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to the overall enantioselection with transmetalation and reductive elimination providing the most contribution to the observed selectivities.

Diastereoselective Synthesis of α-Quaternary Aziridine-2-carboxylates via Aza-Corey-Chaykovsky Aziridination of N-tert-Butanesulfinyl Ketimino Esters.

A general, scalable, and highly diastereoselective aziridination of N-tert-butanesulfinyl ketimino esters is described. The methodology has been utilized to provide straightforward access to previously unobtainable, biologically relevant α-quaternary amino esters and derivatives starting from readily available precursors.

A physical/psychological and biological stress combine to enhance endoplasmic reticulum stress.

The generation of an immune response against infectious and other foreign agents is substantially modified by allostatic load, which is increased with chemical, physical and/or psychological stressors. The physical/psychological stress from cold-restraint (CR) inhibits host defense against Listeria monocytogenes (LM), due to early effects of the catecholamine norepinephrine (NE) from sympathetic nerves on ß1-adrenoceptors (ß1AR) of immune cells. Although CR activates innate immunity within 2h, host defenses against bacterial growth are suppressed 2-3 days after infection (Cao and Lawrence 2002). CR enhances inducible nitric oxide synthase (iNOS) expression and NO production. The early innate activation leads to cellular reduction-oxidation (redox) changes of immune cells. Lymphocytes from CR-treated mice express fewer surface thiols. Splenic and hepatic immune cells also have fewer proteins with free thiols after CR and/or LM, and macrophages have less glutathione after the in vivo CR exposure or exposure to NE in vitro. The early induction of CR-induced oxidative stress elevates endoplasmic reticulum (ER) stress, which could interfere with keeping phagocytized LM within the phagosome or re-encapsuling LM by autophagy once they escape from the phagosome. ER stress-related proteins, such as glucose-regulated protein 78 (GRP78), have elevated expression with CR and LM. The results indicate that CR enhances the unfolded protein response (UPR), which interferes with host defenses against LM. Thus, it is postulated that increased stress, as exists with living conditions at low socioeconomic conditions, can lower host defenses against pathogens because of oxidative and ER stress processes.

Silica nanoparticles induce oxidative stress and inflammation of human peripheral blood mononuclear cells.

In the present study, the effects of 10- or 100-nm silica oxide (SiO2) NPs on human peripheral blood mononuclear cells (PBMC) were examined. Cytotoxic effects and oxidative stress effects, including glutathione (GSH) depletion, the formation of protein radical species, and pro-inflammatory cytokine responses, were measured. PBMC exposed to 10-nm NP concentrations from 50 to 4,000 ppm showed concentration-response increases in cell death; whereas, for 100-nm NPs, PBMC viability was not lost at <500 ppm. Interestingly, 10-nm NPs were more cytotoxic and induced more oxidative stress than 100-nm NPs. Immunoelectron micrographs show the cellular distribution of GSH and NPs. As expected based on the viability data, the 10-nm NPs disturbed cell morphology to a greater extent than did the 100-nm NPs. Antibody to the radical scavenger, 5,5-dimethyl-1-pyrroline N-oxide (DMPO), was used for Western blot analysis of proteins with radicals; more DMPO proteins were found after exposure to 10-nm NPs than 100-nm NPs. Examination of cytokines (TNF-α, IL-1ra, IL-6, IL-8, IL-1ß, and IFN-γ) indicated that different ratios of cytokines were expressed and released after exposure to 10- and 100-nm NPs. IL-1ß production was enhanced by 10- and 100-nm NPs;, the cytotoxicity of the NPs was associated with an increase in the IL-1ß/IL-6 ratio and 100-nm NPs at concentrations that did not induce loss of cell viability enhanced IL-1ß and IL-6 to an extent similar to phytohemagglutinin (PHA), a T cell mitogen. In conclusion, our results indicate that SiO2 NPs trigger a cytokine inflammatory response and induce oxidative stress in vitro, and NPs of the same chemistry, but of different sizes, demonstrate differences in their intracellular distribution and immunomodulatory properties, especially with regard to IL-1ß and IL-6 expression.

The maternal autoimmune environment affects the social behavior of offspring.

Autism spectrum disorders (ASD) are neurodevelopmental disorders with unknown etiology. BTBR-T(+)tf/J (BTBR) mice, a mouse strain with behaviors that resemble autism and with elevated levels of anti-brain antibodies (Abs), have enhanced activation of peripheral B cells and CD4(+) T cells and an expanded percentage of CD4(+) T cells expressing Vß6 chains. The CD4(+)CD25(+)Vß6(+) and Vß6-splenic cells of BTBR mice have elevated levels of IL-4, IFN-γ and IL-17, but there appears to be no preferential CD4(+) T subset skewing/polarization. The high level of IgG production by BTBR B cells was dependent on T cells from BTBR mice. The CD4(+) T cells of BTBR mice, especially those expressing Vß6 become spontaneously activated and expanded in an autoimmune-like manner, which occurred in both BTBR and B6 hosts that received an equal number of BTBR and B6 bone marrow cells. BTBR mice also have an elevated percentage of peripheral blood neutrophils, which may represent their elevated inflammatory state. B6 offspring derived from B6 dams that were gestationally injected with purified IgG from sera of BTBR mice, but not IgG of B6 mice, developed significantly impaired social behavior. Additionally, B6 offspring that developed in BTBR dams had impaired social behavior, while BTBR offspring that developed in B6 dams had improved social behavior. All of the immunological and behavioral parameters of BTBR mice were compared with those of B6 mice, which have relatively normal behaviors. The results indicate maternal Abs and possibly other maternal influences affect the social behavior of offspring.

Stress-induced effects, which inhibit host defenses, alter leukocyte trafficking.

Acute cold restraint stress (ACRS) has been reported to suppress host defenses against Listeria monocytogenes, and this suppression was mediated by beta1-adrenoceptors (ß1-ARs). Although ACRS appears to inhibit mainly early innate immune defenses, interference with leukocyte chemotaxis and the involvement of ß1-AR (or ß2-AR) signaling had not been assessed. Thus, the link between sympathetic nerve stimulation, release of neurotransmitters, and changes in blood leukocyte profiles, including oxidative changes, following ACRS was evaluated. The numbers of leukocyte subsets in the blood were differentially affected by ß1-ARs and ß2-ARs following ACRS; CD3(+) (CD4 and CD8) T-cells were shown to be decreased following ACRS, and the T cell lymphopenia was mediated mainly through a ß2-AR mechanism, while the decrease in CD19(+) B-cells was influenced through both ß1- and ß2-ARs, as assessed by pharmacological and genetic manipulations. In contrast to the ACRS-induced loss of circulating lymphocytes, the number of circulating neutrophils was increased (i.e., neutrophilia), and this neutrophilia was mediated through ß1-ARs. The increase in circulating neutrophils was not due to an increase in serum chemokines promoting neutrophil emigration from the bone marrow; rather it was due to neutrophil release from the bone marrow through activation of a ß1-AR pathway. There was no loss of glutathione in any of the leukocyte subsets suggesting that there was minimal oxidative stress; however, there was early production of nitric oxide and generation of some protein radicals. Premature egress of neutrophils from bone marrow is suggested to be due to norepinephrine induction of nitric oxide, which affects the early release of neutrophils from bone marrow and lessens host defenses.

Exploration of cathepsin S inhibitors characterized by a triazole P1-P2 amide replacement.

This paper details exploration of a class of triazole-based cathepsin S inhibitors originally reported by Ellman and co-workers. SAR studies involving modifications across the whole inhibitor provide a perspective on the strengths and weaknesses of this class of inhibitors. In addition, we put the unique characteristics of this class of compounds into perspective with other classes of cathepsin S inhibitors.

Immunomodulatory Effects of Danshen (Salvia miltiorrhiza) in BALB/c Mice.

Danshen, the root and rhizome of Salvia miltiorrhiza Bge, a Traditional Chinese Medicine, especially for cardiovascular and cerebrovascular diseases, has unique immunomodulatory effects. Danshen is capable of anti-inflammation and antiallergy, which are immunosuppressive activities, whereas it is also able to promote immunity against cancer, viruses, and bacteria. Most previous reports were performed with use of a purified compound or compounds of Danshen. Since there are more than twenty active compounds in Danshen, it is very difficult to predict that one compound will act the same way when it is combined with other compounds. In order to overcome this limitation, we used the crude form of Danshen to study its immunomodulatory effects in a mouse model. The mice were fed daily diet supplements of Danshen for three months and then tested for their immunity, including leukocyte subsets in peripheral blood, humoral and cell-mediated immune responses, and host defenses against a Listeria monocytogenes (LM) infection. Different doses of Danshen caused different immunomodulatory effects. Danshen at 0.5% decreased serum IgE production in BALB/c mice; 1% Danshen promoted cell-mediated immunity; Danshen at 0.5 and 1% inhibited the production of oxygen free radicals in liver and spleen and NO production in liver; 2% Danshen enhanced the host resistance against LM with increased numbers of peripheral monocytes and natural killer (NK) cells and decreased production of IL-1 ß and NO.

Aberrant immune responses in a mouse with behavioral disorders.

BTBR T+tf/J (BTBR) mice have recently been reported to have behaviors that resemble those of autistic individuals, in that this strain has impairments in social interactions and a restricted repetitive and stereotyped pattern of behaviors. Since immune responses, including autoimmune responses, are known to affect behavior, and individuals with autism have aberrant immune activities, we evaluated the immune system of BTBR mice, and compared their immunity and degree of neuroinflammation with that of C57BL/6 (B6) mice, a highly social control strain, and with F1 offspring. Mice were assessed at postnatal day (pnd) 21 and after behavioral analysis at pnd70. BTBR mice had significantly higher amounts of serum IgG and IgE, of IgG anti-brain antibodies (Abs), and of IgG and IgE deposited in the brain, elevated expression of cytokines, especially IL-33 IL-18, and IL-1ß in the brain, and an increased proportion of MHC class II-expressing microglia compared to B6 mice. The F1 mice had intermediate levels of Abs and cytokines as well as social activity. The high Ab levels of BTBR mice are in agreement with their increased numbers of CD40(hi)/I-A(hi) B cells and IgG-secreting B cells. Upon immunization with KLH, the BTBR mice produced 2-3 times more anti-KLH Abs than B6 mice. In contrast to humoral immunity, BTBR mice are significantly more susceptible to listeriosis than B6 or BALB/c mice. The Th2-like immune profile of the BTBR mice and their constitutive neuroinflammation suggests that an autoimmune profile is implicated in their aberrant behaviors, as has been suggested for some humans with autism.

Induction of autoimmunity to brain antigens by developmental mercury exposure.

A.SW mice, which are known to be prone to mercury (Hg)-induced immune nephritis, were assessed for their ability to develop autoimmunity to brain antigens after developmental exposure to Hg. Maternal drinking water containing subclinical doses of 1.25µM methyl Hg (MeHg) or 50µM Hg chloride (HgCl(2)) were used to evaluate developmental (exposure from gestational day 8 to postnatal day 21) induction of immune responses to brain antigens. Only HgCl(2) induced autoantibody production; the HgCl(2)-exposed offspring showed an increased number of CD4(+) splenic T cells expressing CD25 and V(ß) 8.3 chains, and the brain-reactive immunoglobulin G (IgG) antibodies were predominantly against nuclear proteins (30 and 34 kD). The antibodies were deposited in all brain regions. Although male and female A.SW mice exposed to HgCl(2) showed deposition of IgG in multiple brain regions, inflammation responses were observed only in the cerebellum (CB) of female A.SW mice; these responses were associated with increased levels of exploratory behavior. The developmental exposure to MeHg also induced inflammation in the CB and increased exploratory behavior of the female A.SW mice, but the change did not correlate with increased IgG in the brain. Interestingly, the non-Hg-exposed female A.SW mice habituated (adapted to the information and/or stimuli of a new environment) more than the male A.SW mice during exploratory behavior assessment, and the Hg exposure eliminated the habituation (i.e., no changes in behavior with subsequent trials), making the female behaviors more like those of the male A.SW mice. Additionally, gender differences in A.SW brain cytokine expressions prior to Hg exposure were eliminated by the Hg exposure.

SAR studies of non-zinc-chelating MMP-13 inhibitors: improving selectivity and metabolic stability.

SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1' pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound.

Dendritic cells in immunotoxicity testing.

Dendritic cells (DCs) are now recognized to play the key role in the development of adaptive immunity by promoting activation of naïve T cells. Herein, we describe the methodologies to investigate how DCs can be modified by an environmental toxicant and subsequently influence immunity. The prototypic toxicant used as an example for altering DC development and functional influences on T cell development is lead (Pb). It has been reported that the environmental exposure to Pb enhances IgE production in children, which leads to an increase in the incidence of asthma. This effect has been suggested to be due to the preferential enhancement of helper T cell type 2 (Th2) cell responses by Pb. The predominant promotion of Th2 cell development is posited to be due to the altered characteristics of the bone marrow (BM)-DCs from Pb-treated mice (Pb-DCs) when compared to those of the BM-DCs that develop from progenitors in the absence of Pb. The Pb-DCs have a different immunophenotype as well as different cytokine expression after activation. In vitro and in vivo studies confirm that Pb-DCs have the ability to promote antigen-specific T cells to Th2 cells, favoring type-2-related humoral (HI) and cell mediated (CMI) immunity, which may be extracellular signal-regulated kinase (Erk)/mitogen-activated protein (MAP) kinase pathway dependent.

Improving potency and selectivity of a new class of non-Zn-chelating MMP-13 inhibitors.

Discovery and optimization of potency and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of protein co-crystal structural information is reported. This inhibitor was observed to have a binding mode distinct from previously published MMP-13 inhibitors. Potency and selectivity were improved by extending the hit structure out from the active site into the S1' pocket.

Synthesis and SAR studies of indole-based MK2 inhibitors.

Chemistry has been developed to specifically functionalize two structurally similar classes of indole-based MK2 inhibitors at positions prompted by a combination of X-ray crystallographic and computer assisted drug design. A gain in molecular potency was obtained by introducing aminomethyl groups to the lactam rings of 6-arylcarbamoyl-tetrahydro-beta-carbolinone and 6-arylcarbamoyl-dihydropyrazino[1,2-a]indolone MK2 inhibitors. In addition, improvements in molecular potency were achieved by expansion of the lactam from a 6- to 7-membered ring leading to 7-arylcarbamoyl-tetrahydro-[1,4]diazepino[1,2-a]indolones.

Discovery and optimization of p38 inhibitors via computer-assisted drug design.

Integration of computational methods, X-ray crystallography, and structure-activity relationships will be disclosed, which lead to a new class of p38 inhibitors that bind to p38 MAP kinase in a Phe out conformation.