bluuebunny/crossref_metadata_2025 huggingface dataset:
Sugammadex: A Novel Agent for the Reversal of Neuromuscular Blockade
Authors: Nicholson Wayne T. , Sprung Juraj , Jankowski Christopher J.
Published: July 2007

To achieve spontaneous ventilation after completion of surgery, the nondepolarizing effects on skeletal muscle relaxation are often reversed by administration of an acetylcholinesterase inhibitor. However, these agents increase acetylcholine at both the neuromuscular junction and the muscarinic receptors. Therefore, coadministration of an anticholinergic agent is required to prevent parasympathetic adverse effects. In addition, a relative pharmacologic ceiling effect is seen with inhibition of acetylcholinesterase, necessitating some recovery of neuromuscular function before an acetylcholinesterase inhibitor is administered. Sugammadex is a new modified γ‐cyclodextrin compound under clinical investigation in the United States. It does not interact with cholinergic mechanisms to elicit reversal. Instead, it is a selective relaxant binding agent and acts by forming a 1:1 complex with steroidal nondepolarizing neuromuscular blockers in the plasma, lowering the effective concentration available at the receptor. Due to its selectivity, sugammadex does not inhibit the effects of nondepolarizing agents of the benzylisoquinolinium class. In contrast to acetylcholinesterase inhibition, sugammadex is effective even when administered during profound blockade, and it does not require coadministration of an anticholinergic agent. It provides a novel mechanism of action for reversal of the neuromuscular block induced by nondepolarizing aminosteroidal agents.
Linezolid‐Associated Peripheral and Optic Neuropathy, Lactic Acidosis, and Serotonin Syndrome
Authors: Narita Masashi , Tsuji Brian T. , Yu Victor L.
Published: July 2007

Linezolid is an oxazolidinone antibacterial agent indicated for serious gram‐positive infections. Only minor adverse effects were seen in phase III trials. However, more serious adverse effects were reported after commercial release, including cases of lactic acidosis, peripheral and optic neuropathy, and serotonin syndrome. Peripheral and optic neuropathy was usually seen after several months of linezolid therapy (median 5 mo), lactic acidosis after several weeks (median 6 wks), and serotonin syndrome after several days (median 4 days). Death occurred in two of seven reported cases of lactic acidosis, and three of 15 reported cases of serotonin syndrome. Improvement or complete recovery occurred in all cases of optic neuropathy, whereas complete recovery failed to occur in any patient with peripheral neuropathy. Linezolid should be discontinued immediately in patients experiencing these adverse effects. Patients receiving linezolid for more than 28 days should be monitored for signs of peripheral and optic neuropathy.
Rapid Development of Acinetobacter baumannii Resistance to Tigecycline
Authors: Reid Gail E. , Grim Shellee A. , Aldeza Christine A. , Janda William M. , Clark Nina M.
Published: July 2007

A 53‐year‐old woman experienced a multidrug‐resistant (MDR) Acinetobacter baumannii urinary tract infection 5 months after undergoing kidney and liver transplantation. The tigecycline minimum inhibitory concentration (MIC) for her A. baumannii isolate was 1.5 μg/ml; the patient received 2 weeks of therapy with intravenous tigecycline as a 100‐mg loading dose followed by 50 mg every 12 hours, with no lapses in treatment and with resolution of the infection. Three weeks later, MDR A. baumannii was isolated from her sputum in the setting of clinical evidence of pneumonia, and tigecycline was restarted; the tigecycline MIC for the A. baumannii isolate was 2 μg/ml. At approximately the same time, the patient was found to have a paraspinal abscess and spinal osteomyelitis. Cultures of the abscess fluid grew A. baumannii with a tigecycline MIC of 24 μg/ml. A follow‐up sputum culture again yielded A. baumannii, but with a tigecycline MIC of 24 μg/ml. Urine culture at that time also grew A. baumannii with a tigecycline MIC of 24 μg/ml. Clinicians should be aware that tigecycline MICs for A. baumannii isolates may increase during therapy with tigecycline after only brief exposure to the drug. Patients receiving tigecycline for Acinetobacter should be monitored for the development of clinical resistance, and isolates should be monitored for evidence of microbiologic resistance.
Acute Seizures in a Patient Receiving Divalproex Sodium After Starting Ertapenem Therapy
Authors: Lunde Jesse L. , Nelson Robert E. , Storandt Harrison F.
Published: July 2007

Divalproex sodium is an anticonvulsant widely prescribed to treat several types of seizure disorders, including tonic‐clonic and simple or complex partial seizures. We describe a 41‐year‐old man who experienced recurring tonic‐clonic seizures after a drug interaction between divalproex sodium and ertapenem, a carbapenem antibiotic. The patient's valproic acid serum concentration was 130 μg/ml approximately 3 months before he started ertapenem 2000 mg/day (20.6 mg/kg/day). On day 7 of ertapenem therapy, the patient was brought to the emergency department with tonic‐clonic seizures; his valproic acid serum concentration was 70 μg/ml. His divalproex sodium dosage was increased, and he was released from the emergency department only to return 4 days later with recurring seizures. This time his valproic acid serum concentration was 10.7 μg/ml. Ertapenem was discontinued, and his divalproex sodium dosage was increased further. The patient's valproic acid level rapidly returned to a therapeutic level 2 days after ertapenem discontinuation, and he had no further seizures. Using the Naranjo adverse drug reaction probability scale to determine the probability of the drug interaction, we found that the likelihood of the interaction was probable (score of 7). Similar interactions have been reported between other carbapenem antibiotics and valproic acid. Clinicians should be aware of this potential interaction between divalproex sodium and ertapenem; concurrent administration of these two drugs should be approached with caution. In patients prescribed this combination, the valproic acid serum concentration should be carefully monitored to prevent recurring seizures.
Specification of a Dopaminergic Phenotype from Adult Human Mesenchymal Stem Cells
Authors: Trzaska Katarzyna A. , Kuzhikandathil Eldo V. , Rameshwar Pranela
Published: July 2007

Dopamine (DA) neurons derived from stem cells are a valuable source for cell replacement therapy in Parkinson disease, to study the molecular mechanisms of DA neuron development, and for screening pharmaceutical compounds that target DA disorders. Compared with other stem cells, MSCs derived from the adult human bone marrow (BM) have significant advantages and greater potential for immediate clinical application. We report the identification of in vitro conditions for inducing adult human MSCs into DA cells. Using a cocktail that includes sonic hedgehog and fibroblast growth factors, human BM-derived MSCs were induced in vitro to become DA cells in 12 days. Based on tyrosine hydroxylase (TH) expression, the efficiency of induction was determined to be ∼67%. The cells develop a neuronal morphology expressing the neuronal markers NeuN and β III tubulin, but not glial markers, glial fibrillary acidic protein and Olig2. As the cells acquire a postmitotic neuronal fate, they downregulate cell cycle activator proteins cyclin B, cyclin-dependent kinase 2, and proliferating cell nuclear antigen. Molecular characterization revealed the expression of DA-specific genes such as TH, Pitx3, Nurr1, DA transporter, and vesicular monoamine transporter 2. The induced MSCs also synthesize and secrete DA in a depolarization-independent manner. The latter observation is consistent with the low expression of voltage gated Na+ and Ca2+ channels in the induced MSCs and suggests that the cells are at an immature stage of development likely representing DA neuronal progenitors. Taken together, the results demonstrate the ability of adult human BM-derived MSCs to form DA cells in vitro.

Disclosure of potential conflicts of interest is found at the end of this article.
Concise Review: The Potential of Stem Cells for Auditory Neuron Generation and Replacement
Authors: Coleman Bryony , de Silva Michelle G. , Shepherd Robert K.
Published: July 2007

Sensory hair cells in the mammalian cochlea are sensitive to many insults including loud noise, ototoxic drugs, and ageing. Damage to these hair cells results in deafness and sets in place a number of irreversible changes that eventually result in the progressive degeneration of auditory neurons, the target cells of the cochlear implant. Techniques designed to preserve the density and integrity of auditory neurons in the deafened cochlea are envisaged to provide improved outcomes for cochlear implant recipients. This review examines the potential of embryonic stem cells to generate new neurons for the deafened mammalian cochlea, including the directed differentiation of stem cells toward a sensory neural lineage and the engraftment of exogenous stem cells into the deafened auditory system. Although still in its infancy the aim of this therapy is to restore a critical number of auditory neurons, thereby improving the benefits derived from a cochlear implant.

Disclosure of potential conflicts of interest is found at the end of this article.
TRUNK REITERATION PROMOTES EPIPHYTES AND WATER STORAGE IN AN OLD‐GROWTH REDWOOD FOREST CANOPY
Authors: Sillett Stephen C. , Pelt Robert Van
Published: July 2007

Sequoia sempervirens(redwood) is a long‐lived, shade‐tolerant tree capable of regeneration without disturbances and thus often present in all sizes within a single forest. In order to evaluate functional linkages among structures, plant distribution, and biodiversity in the canopy, we quantified all vascular plants from ground level to the treetops in an old‐growth redwood forest (Prairie Creek Redwoods State Park, California, USA). This involved mapping terrestrial and epiphytic trees, shrubs, and ferns as well as climbing 27 trees up to 101 m tall within a 1‐ha plot. We monitored canopy microclimates using sensor arrays that collected hourly data for up to 30 months. The plot held 4283 Mg/ha of aboveground dry mass in living plants, 95.4% of which was contributed by redwood. A high degree of structural complexity and individuality was evident in the crowns of the 14 largest trees in the form of reiterated trunks arising from main trunks, other trunks, and limbs. Thirteen species of vascular plants occurred as epiphytes in the plot, and all but one of these were restricted to the 14 largest trees. The evergreen shrubVaccinium ovatumhad the highest biomass of any epiphyte (212 kg/ha) followed by the evergreen fernPolypodium scouleri(196 kg/ha). The spatial aggregation of reiterated trunks was highly coincident with epiphyte masses, explaining 92% of the variation in fern and 75% of the variation in woody plant distribution along the vertical gradient. In addition to epiphyte biomass, there were 2366 kg/ha of soil in the canopy. Soils in crotches held 2–4 times as much water as soils on branches or limbs, and deeper layers held more water than shallower layers. During two years of monitoring, the volume of water stored in dead wood and soils in the canopy fluctuated between 24.7 m3and 53.4 m3/ha. The vast majority of the plot's structure and arboreal habitats was held in the crowns of the 14 largest trees. Reiterated trunks and limbs on a small number of trees have important ecological functions in old‐growth redwood forests, and it may be feasible to accelerate the development of structural complexity and biodiversity in maturing redwood stands.
A GAP ANALYSIS AND COMPREHENSIVE CONSERVATION STRATEGY FOR RIVERINE ECOSYSTEMS OF MISSOURI
Authors: Sowa Scott P. , Annis Gust , Morey Michael E. , Diamond David D.
Published: July 2007

North America harbors an astounding proportion of the world's freshwater species, but it is facing a freshwater biodiversity crisis. A first step to slowing the loss of biodiversity involves identifying gaps in existing efforts to conserve biodiversity and prioritizing opportunities to fill these gaps. In this monograph we detail two separate, but complementary, conservation planning efforts—a Gap Analysis (GAP) and a State Wildlife Action Plan (WAP)—for Missouri that address this first step. The goal of the Missouri Aquatic GAP Project was to identify riverine ecosystems, habitats, and species not adequately represented (i.e., gaps) within existing conservation lands. The goal of the freshwater component of the Missouri Wildlife Action Plan was to identify and map a set of conservation‐opportunity areas (COAs) that holistically represent all riverine ecosystems, habitats, and species in Missouri. Since conservation planning is a geographical exercise, both efforts utilized geographic information systems (GIS). Four principal GIS data sets were used in each planning effort: (1) a hierarchical riverine ecosystem classification, (2) predicted species distributions, (3) public ownership/stewardship, and (4) a human‐threat index. Results of the gap analyses are not encouraging. Forty five, mostly rare, threatened, or endangered, species are not represented in lands set aside for conserving biodiversity. Results also illustrate the fragmented nature of conservation lands, which are mainly situated in the uplands and fail to provide connectivity among riverine habitats. Furthermore, many conservation lands are severely threatened by an array of human disturbances. In contrast, results of the WAP provide hope that relatively intact riverine ecosystems still exist. A total of 158 COAs, representing ∼6% of the total kilometers of stream in Missouri, were selected for the WAP. This illustrates that a wide spectrum of biodiversity can be represented within a small portion of the total resource base, but the area of conservation concern is often much larger. Identifying priority riverscapes for conservation is an important first step toward effective biodiversity conservation. Yet, achieving the ultimate goal of conserving biodiversity will require vigilance on the part of all responsible parties, with particular attention to addressing and coordinating the many remaining logistical tasks.
The SUMO Conjugating Enzyme Ubc9 is a Regulator of GLUT4 Turnover and Targeting to the Insulin-Responsive Storage Compartment in 3T3-L1 Adipocytes
Authors: Liu Li-Bin , Omata Waka , Kojima Itaru , Shibata Hiroshi
Published: July 2007

The small ubiquitin-related modifier (SUMO) conjugating enzyme Ubc9 has been shown to upregulate GLUT4 in L6 myoblast cells, although the mechanism of action has remained undefined. Here we investigated the physiological significance of Ubc9 in GLUT4 turnover and subcellular targeting by adenovirus vector–mediated overexpression and by small interfering RNA (siRNA)-mediated gene silencing of Ubc9 in 3T3-L1 adipocytes. Overexpression of Ubc9 resulted in an inhibition of GLUT4 degradation and promoted its targeting to the unique insulin-responsive GLUT4 storage compartment (GSC), leading to an increase in GLUT4 amount and insulin-responsive glucose transport in 3T3-L1 adipocytes. Overexpression of Ubc9 also antagonized GLUT4 downregulation and its selective loss in GSC induced by long-term insulin stimulation. By contrast, siRNA-mediated depletion of Ubc9 accelerated GLUT4 degradation and decreased the amount of the transporter, concurrent with its selective loss in GSC, which resulted in attenuated insulin-responsive glucose transport. Intriguingly, overexpression of the catalytically inactive mutant Ubc9-C93A produced effects indistinguishable from those with wild-type Ubc9, suggesting that Ubc9 regulates GLUT4 turnover and targeting to GSC by a mechanism independent of its catalytic activity. Thus, Ubc9 is a pivotal regulator of the insulin sensitivity of glucose transport in adipocytes.
Impaired Fat Oxidation After a Single High-Fat Meal in Insulin-Sensitive Nondiabetic Individuals With a Family History of Type 2 Diabetes
Authors: Heilbronn Leonie K. , Gregersen Søren , Shirkhedkar Deepali , Hu Dachun , Campbell Lesley V.
Published: July 2007

Individuals with insulin resistance and type 2 diabetes have an impaired ability to switch appropriately between carbohydrate and fatty acid oxidation. However, whether this is a cause or consequence of insulin resistance is unclear, and the mechanism(s) involved in this response is not completely elucidated. Whole-body fat oxidation and transcriptional regulation of genes involved in lipid metabolism in skeletal muscle were measured after a prolonged fast and after consumption of either high-fat (76%) or high-carbohydrate (76%) meals in individuals with no family history of type 2 diabetes (control, n = 8) and in age- and fatness-matched individuals with a strong family history of type 2 diabetes (n = 9). Vastus lateralis muscle biopsies were performed before and 3 h after each meal. Insulin sensitivity and fasting measures of fat oxidation were not different between groups. However, subjects with a family history of type 2 diabetes had an impaired ability to increase fatty acid oxidation in response to the high-fat meal (P < 0.05). This was related to impaired activation of genes involved in lipid metabolism, including those for peroxisome proliferator–activated receptor coactivator-1α (PGC1α) and fatty acid translocase (FAT)/CD36 (P < 0.05). Of interest, adiponectin receptor-1 expression decreased 23% after the high-fat meal in both groups, but it was not changed after the high-carbohydrate meal. In conclusion, an impaired ability to increase fatty acid oxidation precedes the development of insulin resistance in genetically susceptible individuals. PGC1α and FAT/CD36 are likely candidates in mediating this response.
Nkx2.2 Regulates β-Cell Function in the Mature Islet
Authors: Doyle Michelle J. , Sussel Lori
Published: July 2007

Nkx2.2 is a homeodomain transcription factor that is critical for pancreatic endocrine cell specification and differentiation in the developing mouse embryo. The purpose of this study was to determine whether Nkx2.2 is also required for the maintenance and function of the mature β-cell in the postnatal islet. We have demonstrated previously that a repressor derivative of Nkx2.2 can functionally substitute for endogenous Nkx2.2 to fully restore α- and immature β-cells in the embryonic islet; however, Nkx2.2 activator functions appear to be required to form a functional β-cell. In this study, we have created transgenic mouse lines to express the Nkx2.2-repressor derivative in the mature β-cell in the presence of endogenous Nkx2.2. The transgenic mice were assessed for β-cell function, overall islet structure, and expression of β-cell–specific markers. Using this transgenic approach, we have determined that the Nkx2.2-repressor derivative disrupts endogenous Nkx2.2 expression in adult mice and causes downregulation of the mature β-cell factors, MafA and Glut2. Consistently, the Nkx2.2-repressor mice display reduced insulin gene expression and pancreatic insulin content and impaired insulin secretion. At weaning, the male Nkx2.2-repressor mice are overtly diabetic and all Nkx2.2-repressor transgenic mice exhibit glucose intolerance. Furthermore, the loss of β-cell function in the Nkx2.2-repressor transgenic mice is associated with disrupted islet architecture. These studies indicate a previously undiscovered role for Nkx2.2 in the maintenance of mature β-cell function and the formation of normal islet structure.
The Actions of a Novel Potent Islet β-Cell–Specific ATP-Sensitive K+ Channel Opener Can Be Modulated by Syntaxin-1A Acting on Sulfonylurea Receptor 1
Authors: Ng Betty , Kang Youhou , Elias Chadwick L. , He Yan , Xie Huanli , Hansen John B. , Wahl Philip , Gaisano Herbert Y.
Published: July 2007

Islet β-cell–specific ATP-sensitive K+ (KATP) channel openers thiadiazine dioxides induce islet rest to improve insulin secretion, but their molecular basis of action remains unclear. We reported that syntaxin-1A binds nucleotide binding folds of sulfonylurea receptor 1 (SUR1) in β-cells to inhibit KATP channels. As a strategy to elucidate the molecular mechanism of action of these KATP channel openers, we explored the possibility that 6-chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NNC55-0462) might influence syntaxin-1A–SUR1 interactions or vice versa. Whole-cell and inside-out patch-clamp electrophysiology was used to examine the effects of glutathione S-transferase (GST)-syntaxin-1A dialysis or green fluorescence protein/syntaxin-1A cotransfection on NNC55-0462 actions. In vitro pull-down binding studies were used to examine NNC55-0462 influence on syntaxin-1A–SUR1 interactions. Dialysis of GST–syntaxin-1A into the cell cytoplasm reduced both potency and efficacy of extracellularly perfused NNC55-0462 in a HEK cell line stably expressing Kir6.2/SUR1 (BA8 cells) and in rat islet β-cells. Moreover, inside-out membrane patches excised from BA8 cells showed that both GST–syntaxin-1A and its H3 domain inhibited KATP channels previously activated by NNC55-0462. This action on KATP channels is isoform-specific to syntaxin-1A because syntaxin-2 was without effect. Furthermore, the parent compound diazoxide showed similar sensitivity to GST–syntaxin-1A inhibition. NNC55-0462, however, did not influence syntaxin-1A–SUR1 binding interaction. Our results demonstrated that syntaxin-1A interactions with SUR1 at its cytoplasmic domains can modulate the actions of the KATP channel openers NNC55-0462 and diazoxide on KATP channels. The reduced levels of islet syntaxin-1A in diabetes would thus be expected to exert a positive influence on the therapeutic effects of this class of KATP channel openers.
Deletion of STAT-1 Pancreatic Islets Protects Against Streptozotocin-Induced Diabetes and Early Graft Failure but Not Against Late Rejection
Authors: Callewaert Hanne I. , Gysemans Conny A. , Ladrière Laurence , D'Hertog Wannes , Hagenbrock Julianna , Overbergh Lutgart , Eizirik Decio L. , Mathieu Chantal
Published: July 2007

OBJECTIVE—Exposure of β-cells to inflammatory cytokines leads to apoptotic cell death through the activation of gene networks under the control of specific transcription factors, such as interferon-γ–induced signal transducer and activator of transcription (STAT)-1. We previously demonstrated that β-cells lacking STAT-1 are resistant to cytokine-induced cell death in vitro. The aim of this study was to investigate the effect of STAT-1 elimination on immune-mediated β-cell destruction in vivo.

RESEARCH DESIGN AND METHODS—Multiple low-dose streptozotocin (STZ) was given to C57BL/6 mice after syngeneic STAT-1−/− or wild-type islet transplantation. STAT-1−/− and wild-type islets were also transplanted in alloxan-diabetic BALB/c and spontaneously diabetic nonobese diabetic (NOD) mice. Additionally, mice were treated with interleukin (IL)-1 blockade (IL-1 receptor antagonist [IL-1ra]) and low-dose T-cell suppression (cyclosporine A [CsA]).

RESULTS—When exposed to multiple low-dose STZ in an immune-competent host, STAT-1−/− islets were more resistant to destruction than wild-type islets (28 vs. 100% diabetes incidence, P ≤ 0.05). STAT-1 deletion also protected allogeneic islet grafts against primary nonfunction in autoimmune NOD mice (0 vs. 17% using wild-type islets). However, no difference in survival time was observed. Additionally, treating recipients with IL-1ra and CsA prolonged graft survival in chemically diabetic BALB/c mice, whereas no difference was seen between STAT-1−/− and C57BL/6 grafts.

CONCLUSIONS—These data indicate that STAT-1 is a key player in immune-mediated early β-cell dysfunction and death. When considering the many effector mechanisms contributing to β-cell death following islet transplantation, multiple combined interventions will be needed for prolongation of β-cell survival in the autoimmune context of type 1 diabetes.
Excess Lipid Availability Increases Mitochondrial Fatty Acid Oxidative Capacity in Muscle
Authors: Turner Nigel , Bruce Clinton R. , Beale Susan M. , Hoehn Kyle L. , So Trina , Rolph Michael S. , Cooney Gregory J.
Published: July 2007

A reduced capacity for mitochondrial fatty acid oxidation in skeletal muscle has been proposed as a major factor leading to the accumulation of intramuscular lipids and their subsequent deleterious effects on insulin action. Here, we examine markers of mitochondrial fatty acid oxidative capacity in rodent models of insulin resistance associated with an oversupply of lipids. C57BL/6J mice were fed a high-fat diet for either 5 or 20 weeks. Several markers of muscle mitochondrial fatty acid oxidative capacity were measured, including 14C-palmitate oxidation, palmitoyl-CoA oxidation in isolated mitochondria, oxidative enzyme activity (citrate synthase, β-hydroxyacyl CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, and carnitine palmitoyl-transferase 1), and expression of proteins involved in mitochondrial metabolism. Enzyme activity and mitochondrial protein expression were also examined in muscle from other rodent models of insulin resistance. Compared with standard diet–fed controls, muscle from fat-fed mice displayed elevated palmitate oxidation rate (5 weeks +23%, P < 0.05, and 20 weeks +29%, P < 0.05) and increased palmitoyl-CoA oxidation in isolated mitochondria (20 weeks +49%, P < 0.01). Furthermore, oxidative enzyme activity and protein expression of peroxisome proliferator–activated receptor γ coactivator (PGC)-1α, uncoupling protein (UCP) 3, and mitochondrial respiratory chain subunits were significantly elevated in fat-fed animals. A similar pattern was present in muscle of fat-fed rats, obese Zucker rats, and db/db mice, with increases observed for oxidative enzyme activity and expression of PGC-1α, UCP3, and subunits of the mitochondrial respiratory chain. These findings suggest that high lipid availability does not lead to intramuscular lipid accumulation and insulin resistance in rodents by decreasing muscle mitochondrial fatty acid oxidative capacity.
Adipose Tissue Inflammation and Increased Ceramide Content Characterize Subjects With High Liver Fat Content Independent of Obesity
Authors: Kolak Maria , Westerbacka Jukka , Velagapudi Vidya R. , Wågsäter Dick , Yetukuri Laxman , Makkonen Janne , Rissanen Aila , Häkkinen Anna-Maija , Lindell Monica , Bergholm Robert , Hamsten Anders , Eriksson Per , Fisher Rachel M. , Orešic̆ Matej , Yki-Järvinen Hannele
Published: July 2007

OBJECTIVE— We sought to determine whether adipose tissue is inflamed in individuals with increased liver fat (LFAT) independently of obesity.

RESEARCH DESIGN AND METHODS— A total of 20 nondiabetic, healthy, obese women were divided into normal and high LFAT groups based on their median LFAT level (2.3 ± 0.3 vs. 14.4 ± 2.9%). Surgical subcutaneous adipose tissue biopsies were studied using quantitative PCR, immunohistochemistry, and a lipidomics approach to search for putative mediators of insulin resistance and inflammation. The groups were matched for age and BMI. The high LFAT group had increased insulin (P = 0.0025) and lower HDL cholesterol (P = 0.02) concentrations.

RESULTS— Expression levels of the macrophage marker CD68, the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1α, and plasminogen activator inhibitor-1 were significantly increased, and those of peroxisome proliferator–activated receptor-γ and adiponectin decreased in the high LFAT group. CD68 expression correlated with the number of macrophages and crown-like structures (multiple macrophages fused around dead adipocytes). Concentrations of 154 lipid species in adipose tissue revealed several differences between the groups, with the most striking being increased concentrations of triacylglycerols, particularly long chain, and ceramides, specifically Cer(d18:1/24:1) (P = 0.01), in the high LFAT group. Expression of sphingomyelinases SMPD1 and SMPD3 were also significantly increased in the high compared with normal LFAT group.

CONCLUSIONS— Adipose tissue is infiltrated with macrophages, and its content of long-chain triacylglycerols and ceramides is increased in subjects with increased LFAT compared with equally obese subjects with normal LFAT content. Ceramides or their metabolites could contribute to adverse effects of long-chain fatty acids on insulin resistance and inflammation.
Adiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice
Authors: Lin Hua V. , Kim Ja-Young , Pocai Alessandro , Rossetti Luciano , Shapiro Lawrence , Scherer Philipp E. , Accili Domenico
Published: July 2007

OBJECTIVE— Adiponectin increases insulin sensitivity and contributes to insulin's indirect effects on hepatic glucose production.

RESEARCH DESIGN AND METHODS— To examine adiponectin's contribution to insulin action, we analyzed adiponectin levels and activation of AMP-activated protein kinase (AMPK) in insulin receptor transgenic/knockout mice (L1), a genetic model of resistance to insulin's indirect effects on hepatic glucose production.

RESULTS— In euglycemic, insulin-resistant L1 mice, we detected hyperadiponectinemia with normal levels of adiponectin receptor-1 and -2. Moreover, adiponectin administration is unable to lower glucose levels or induce activation of AMPK, consistent with a state of adiponectin resistance. In a subset of hyperglycemic L1 mice, we observed decreased mRNA expression of AdipoR2 in liver and muscle, as well as decreased peroxisome proliferator–activated receptor (PPAR)α target gene expression in liver, raising the possibility that deterioration of adiponectin/AdipoR2 signaling via PPARα activation contributes to the progression from compensated insulin resistance to diabetes. In contrast, we failed to detect changes in other markers of the systemic or local inflammatory response.

CONCLUSIONS— These data provide evidence for a mechanism of adiponectin resistance and corroborate the notion that adiponectin potentiates hepatic insulin sensitivity.
Effects of Physical Activity and Weight Loss on Skeletal Muscle Mitochondria and Relationship With Glucose Control in Type 2 Diabetes
Authors: Toledo Frederico G.S. , Menshikova Elizabeta V. , Ritov Vladimir B. , Azuma Koichiro , Radikova Zofia , DeLany James , Kelley David E.
Published: July 2007

OBJECTIVE— Reduced mitochondrial capacity in skeletal muscle occurs in type 2 diabetic patients and in those at increased risk for this disorder, but the extent to which mitochondrial dysfunction in type 2 diabetic patients is remediable by physical activity and weight loss intervention is uncertain. We sought to address whether an intervention of daily moderate-intensity exercise combined with moderate weight loss can increase skeletal muscle mitochondrial content in type 2 diabetic patients and to address the relationship with amelioration of insulin resistance and hyperglycemia.

RESEARCH DESIGN AND METHODS— Muscle biopsies were obtained before and after a 4-month intervention to assess mitochondrial morphology, mitochondrial DNA content, and mitochondrial enzyme activities. Glucose control, body composition, aerobic fitness, and insulin sensitivity were measured.

RESULTS— In response to a weight loss of 7.1 ± 0.8% and a 12 ± 1.6% improvement in Vo2max (P < 0.05), insulin sensitivity improved by 59 ± 21% (P < 0.05). There were significant increases in skeletal muscle mitochondrial density (by 67 ± 17%, P < 0.01), cardiolipin content (55 ± 17%, P < 0.01), and mitochondrial oxidation enzymes. Energy expenditure during physical activity correlated with the degree of improvement in insulin sensitivity (r = 0.84, P < 0.01), and, in turn, improvement in mitochondrial content was a strong correlate of intervention-induced improvement in A1C and fasting plasma glucose.

CONCLUSIONS— Intensive short-term lifestyle modifications can restore mitochondrial content and functional capacity in skeletal muscle in type 2 diabetic patients. The improvement in the oxidative capacity of skeletal muscle may be a key component mediating salutary effects of lifestyle interventions on hyperglycemia and insulin resistance.
Skeletal Muscle Adaptation to Exercise Training
Authors: Röckl Katja S.C. , Hirshman Michael F. , Brandauer Josef , Fujii Nobuharu , Witters Lee A. , Goodyear Laurie J.
Published: July 2007

Regular endurance exercise has profound benefits on overall health, including the prevention of obesity, cardiovascular disease, and diabetes. The objective of this study was to determine whether AMP-activated protein kinase (AMPK) mediates commonly observed adaptive responses to exercise training in skeletal muscle. Six weeks of voluntary wheel running induced a significant (P < 0.05) fiber type IIb to IIa/x shift in triceps muscle of wild-type mice. Despite similar wheel running capacities, this training-induced shift was reduced by ∼40% in transgenic mice expressing a muscle-specific AMPKα2 inactive subunit. Sedentary mice carrying an AMPK-activating mutation (γ1TG) showed a 2.6-fold increase in type IIa/x fibers but no further increase with training. To determine whether AMPK is involved in concomitant metabolic adaptations to training, we measured markers of mitochondria (citrate synthase and succinate dehydrogenase) and glucose uptake capacity (GLUT4 and hexokinase II). Mitochondrial markers increased similarly in wild-type and AMPKα2-inactive mice. Sedentary γ1TG mice showed a ∼25% increase in citrate synthase activity but no further increase with training. GLUT4 protein expression was not different in either line of transgenic mice compared with wild-type mice and tended to increase with training, although this increase was not statistically significant. Training induced a ∼65% increase in hexokinase II protein in wild-type mice but not in AMPKα2-inactive mice. Hexokinase II was significantly elevated in sedentary γ1TG mice, without an additional increase with training. AMPK is not necessary for exercise training-induced increases in mitochondrial markers, but it is essential for fiber type IIb to IIa/x transformation and increases in hexokinase II protein.
Soluble Insulin Receptor Ectodomain Is Elevated in the Plasma of Patients With Diabetes
Authors:   The Soluble Insulin Receptor Study Group
Published: July 2007

OBJECTIVE—Insulin binds to the α-subunit of the insulin receptor (IRα) and subsequently exerts its effects in the cells. The soluble ectodomains of several receptors have been found to circulate in the plasma. Therefore, we hypothesized that soluble human insulin receptor (hIR) ectodomain (α-subunit and a part of β-subunit) may exist in the plasma of diabetic patients.

RESEARCH DESIGN AND METHODS—We identified soluble hIR ectodomain in human plasma by a two-step purification followed by immunoblotting and gel-filtration chromatography. Furthermore, we established an hIRα-specific enzyme-linked immunosorbent assay and measured the plasma IRα levels in patients with diabetes. We also investigated this phenomenon in streptozotocin-induced diabetic hIR transgenic mice.

RESULTS—Soluble hIRα, but not intact hIRβ or whole hIR, exists in human plasma. The plasma IRα levels were significantly higher in type 1 (2.00 ± 0.60 ng/ml; n = 53) and type 2 (2.26 ± 0.80; n = 473) diabetic patients than in control subjects (1.59 ± 0.40 ng/ml; n = 123 (P < 0.001 vs. control). Plasma IRα level was positively correlated with blood glucose level, and 10–20% of the insulin in plasma bound to hIRα. In the in vivo experiments using diabetic hIR transgenic mice, hyperglycemia was confirmed to increase the plasma hIRα level and the half-life estimated to be ∼6 h.

CONCLUSIONS—We propose that the increased soluble IR ectodomain level appears to be a more rapid glycemic marker than A1C or glycoalbumin.
Miniaturized Oligonucleotide Arrays
Authors: Sotto Albert , Richard Jean-Louis , Jourdan Nathalie , Combescure Christophe , Bouziges Nicole , Lavigne Jean-Philippe ,   on behalf of the Nîmes University Hospital Working Group on the Diabetic Foot (GP30)
Published: July 2007

OBJECTIVE—We sought to evaluate the use of oligonucleotide arrays to discriminate colonization from infection due to Staphylococcus aureus in diabetic foot ulcers.

RESEARCH DESIGN AND METHODS—We included diabetic patients hospitalized in a diabetic foot department for an episode of foot ulcer. Only patients who had no antibiotic treatment during the previous 6 months were included. At admission, ulcers were classified on clinical examination, according to the Infectious Diseases Society of America system. Seventy-two patients with a culture positive only for S. aureus as the sole pathogen were included. In individuals with a grade 1 ulcer, a second wound bacterial specimen was obtained 1 month later. Using oligonucleotide arrays, S. aureus resistance and virulence genes were compared between grade 1 and grades 2–4 ulcers.

RESULTS—S. aureus was initially isolated from 22 grade 1 and 50 grade 2–4 ulcers: 35 were methicillin resistant and 37 methicillin sensitive. In 20 grade 1 ulcers (92%), no virulence genes were identified, whereas these genes were present in all but 1 grade 2–4 ulcers. During follow-up, the two grade 1 ulcers that were infected with strains carrying virulence genes rapidly deteriored; the array technology showed unchanged genotype profiles. On the contrary, two grade 1 ulcers healed: the genotype profiles were different from those at inclusion but without appearance of virulence genes.

CONCLUSIONS—The DNA array appears as a promising technique and is easy to perform. Our observational study suggests that it might help distinguish colonized grade 1 from infected grade 2 wounds, predict ulcer outcome, and contribute to a more adequate use of antibiotics.
Diffusional decomposition of supersaturated solid solutions at grain boundaries
Authors: Slezov Vitaly , Boyko Yuri , Weissmüller Jörg
Published: July 2007

A kinetic theory of nucleation and growth of single atom phase precipitates in a supersaturated solid solution at grain boundaries is developed. In the present theory, particular attention is devoted to the analysis of two stages of the overall transformation process: (1) – a stage of quasi-steady-state nucleation and (2) – a transient stage of coarsening. As a result of this analysis, the quasi-steady-state nucleation rate, the number of new phase particles formed via nucleation and diffusional growth, and the time-evolution of the size distribution of the precipitates are established. Moreover, estimates are given for the duration of the different stages of the decomposition process.
Calorimetric study and thermodynamic assessment of the SrO–Ga2O3 system
Authors: Zinkevich Matvei
Published: July 2007

Enthalpies of formations of Sr4Ga2O7, SrGa2O4, and SrGa12O19 are measured for the first time using high-temperature oxide-melt drop-solution calorimetry. A self-consistent thermodynamic dataset for the SrO – Ga2O3 system is derived by means of the CALPHAD method based on these data, literature phase diagram information, and recent structural studies. In total seven compounds, Sr4Ga2O7, Sr10Ga6O19, Sr3Ga2O6, Sr3Ga4O9, SrGa2O4, SrGa4O7, and SrGa12O19 are included. Their enthalpy of formation as well as the enthalpy of mixing of the liquid is strongly exothermic. The systematic variation of thermodynamic properties with composition is discussed in terms of the structural relationships between strontium gallates and the possible formation of associates in the liquid phase.
Participation in Virtual Prehabilitation and Outcomes Following Thoracic Cancer Surgery
Authors: Mao Jun J. , Molena Daniela , Desai Krupali , Baser Raymond E. , Seluzicki Christina , Rocco Gaetano , Jones David
Published: March 2024

This cohort study evaluates the association of a virtual synchronized prehabilitation program with perioperative outcomes among patients undergoing thoracic cancer surgery.
Encapsulated Mesenchymal Stromal Cells as Cyclic Providers of Immunomodulatory Secretomes: A Living on‐Demand Delivery System
Authors: Sousa Ana Rita , Gonçalves Diana C. , Neves Beatriz Guapo , Santos‐Coquillat Ana , Oliveira Mariana B. , Mano João F.
Published: March 2024

The stimulation of mesenchymal stromal cells (MSCs) with inflammatory molecules is often used to boost their therapeutic effect. Prolonged exposure to inflammatory molecules has been explored to improve their action because MSCs therapies seem to be improved transiently with such stimuli. However, the possibility of cyclically stimulating MSCs to recover their optimized therapeutic potential is still to be elucidated, although the efficacy of cell‐based therapies may be dependent on the ability to readapt to the relapse pathological conditions. Here, the response of MSCs, encapsulated in alginate hydrogels and cultured for 22 d, is explored using three different regimes: single, continuous, and intermittent stimulation with IFNγ. Exposure to IFNγ leads to a decrease in the secretion of IL‐10, which is cyclically countered by IFNγ weaning. Conditioned media collected at different stages of pulsatile stimulation show an immunomodulatory potential toward macrophages, which directly correlates with IL‐10 concentration in media. To understand whether the correlation between cyclic stimulation of MSCs and other biological actions can be observed, the effect on endothelial cells is studied, showcasing an overall modest influence on tube formation. Overall, the results describe the response of encapsulated MSCs to unusual pulsatile simulation regimens, exploring encapsulated MSCs as a living on‐demand release system of tailored secretomes with recoverable immunomodulatory action.
Leukemia cutis revealing relapse of a chronic myeloid leukemia: A case report
Authors: Chérif Amine , Chérif Mohammad Yassine , Trépant Anne‐Laure , Meert Anne‐Pascale , Ilzkovitz Maxime
Published: March 2024

Key Clinical Message

Clinical presentation of leukemia cutis (LC) is polymorphic and can reveal a malignant hemopathy. More commonly described in cases of acute myeloid leukemia (AML), LC can also occur in case of chronic myeloid leukemia (CML).

Leukemia cutis is a rare form of extramedullary feature of malignant hemopathy, seldom associated with CML. Its clinical presentation is pleiotropic and differential diagnosis is broad. It relies on clinical and typical histological and biomolecular concordance. Once confirmed, treatment is based on that of the primary condition. We present a case of a leukemia cutis revealing a relapse of a CML successfully treated by tyrosine kinase inhibitor.
Epidermoid cyst of the craniovertebral junction—A case report
Authors: Kien Duong Trung , Hung Nguyen Manh , Duc Nguyen Viet , Tuan Duong Dinh , Quang Luong Minh , Van Duong Pham , Hoang Tran Viet , Anh Vu Ngoc
Published: March 2024

Key clinical message

An epidermoid cyst is a benign tumor in many locations. The symptoms of an epidermoid cyst depend on its location. The brain or spine MRI can confirm the lesion. Removing total decompression is the first choice in treatment with a symptomatic cyst.
Lessons learned from eDNA adoption in the management of bigheaded carps in Chicago IL USA Area Waterways
Authors: Lodge David M.
Published: March 2024

The Chicago Area Waterway System (CAWS) connects the Great Lakes watershed with the Mississippi watershed via canals that withdraw water from Lake Michigan. From 2009 through 2011, collaborators and I provided research, development, and application of eDNA to invasive species management in the CAWS in cooperation with the US Army Corps of Engineers (USACE). The research team's approach was a high‐stakes test of a novel combination of proven technologies (field sampling techniques and laboratory genetics). In the first application of eDNA to a large scale, urgent management goal, we quickly discovered eDNA of two species of bigheaded carps in parts of the waterway where traditional tools had not captured fish. The central research question was whether the sensitivity (probability of detecting a fish when it was present) of eDNA was higher than that of traditional fish sampling tools (e.g., nets, electrofishing). The effort was part of what became a very large, complex, on‐going initiative to reduce access by invasive species to Lake Michigan. This immediately garnered much attention, initiating a dialog about the reliability of eDNA, public discussion about the benefits and costs of the CAWS, and skepticism from industries that use the CAWS. Government agencies formed the Asian Carp Rapid Response Workgroup, which eventually became the Invasive Carp Regional Coordinating Committee (ICRCC). The ICRCC continues its coordinating role on the use of eDNA and other management responses in the CAWS. With the benefit of hindsight, I draw several lessons from the experience that may help in other settings where eDNA is now being deployed with increasing confidence and acceptance; evaluate the on‐going CAWS surveillance and management effort; and recommend strengthening the current approach by broadening and deepening participation in a collaborative governance approach. Stronger public‐private partnerships would accelerate research, development, commercialization, and application of eDNA analysis to the benefit of society.
Recent Advances in Biomass Waste Derived Carbon Materials for Supercapacitors: A Review
Authors: Chen Yarong , Wang Xingyan , Wang Xianyou
Published: March 2024

As the core component of supercapacitors (SCs), the electrode material plays a decisive role in performance. Among electrode materials, carbon materials are the most widely used due to high porosity and specific surface area (SSA, 1000–3000 m2 g−1). Biomass carbon stands out in carbon materials because of its wide source, low cost, and less pollution. This work reviews the recent advances on carbon materials derived from biomass waste for SCs and explores the effects of different biomass sources including plant, animal, and aquatic organism waste on the performance of biomass waste‐derived carbon materials (BWDCs). Because of its high conductivity (1.25 × 103 ≈ 3 × 105 S m−1), power density (>10 kW kg−1), and extended cycle life (>10 000 cycles), BWDCs are advancing quickly in energy storage. It also discusses different methods and optimization pathways of BWDCs thoroughly. Finally, the challenges and future prospects for BWDCs are summarized. Overall, this critical will help researchers to gain a better understanding of source selection, structural classification, and research strategies for BWDCs, thereby promoting the application of BWDCs in electrochemistry and resource utilization.
Enhancing euthanasia protocols: a compassionate approach in equine and large animal practice
Authors: Richards Iain
Published: March 2024

Euthanasia revolves around essential principles of compassion towards owners and gentleness towards patients which apply to all species, regardless of circumstances. That we can ensure a ‘good’ death (in sometimes trying circumstances) is something that we, as a profession, excel at; however, farm and equine work, because of the size of animals involved and the relatively remote conditions of work, do bring additional challenges. This article is based on a presentation given for many years at the Society of Practising Veterinary Surgeons final‐year seminar and is aimed especially at new or recent graduates. It is more an approach than an absolute instruction manual.