Tissue Glucose Concentrations Research Articles

Transient Changes in Cerebral Tissue Oxygen, Glucose, and Temperature by Microstrokes: A Computational Study.

This study focuses on evaluating the disruptions in key physiological parameters during microstroke events to assess their severity. A mathematical model was developed to simulate the changes in cerebral tissue pO2, glucose concentration, and temperature due to blood flow interruptions. The model considers variations in baseline cerebral blood flow (CBF), capillary density, and blood oxygen/glucose levels, as well as ambient temperature changes. Simulations indicate that complete blood flow obstruction still allows for limited glucose availability, supporting nonoxidative metabolism and potentially exacerbating lactate buildup and acidosis. Partial obstructions decrease tissue pO2, with minimal impact on glucose level, which can remain almost unchanged or even slightly increase. Reduced CBF, capillary density, or blood oxygen due to aging or disease enhances hypoxia risk at lower obstruction levels, with capillary density having a significant effect on stroke severity by influencing both pO2 and glucose levels. Conditions could lead to co-occurrence of hypoxia/hypoglycemia or hypoxia/hyperglycemia, each worsening outcomes. Temperature effects were minimal in deep brain regions but varied near the skull by 0.2-0.8°C depending on ambient temperature. The model provides insights into the conditions driving severe stroke outcomes based on estimated levels of hypoxia, hypoglycemia, hyperglycemia, and temperature changes.

Triple threat: how diabetes results in worsened bacterial infections.

Diabetes mellitus, characterized by impaired insulin signaling, is associated with increased incidence and severity of infections. Various diabetes-related complications contribute to exacerbated bacterial infections, including hyperglycemia, innate immune cell dysfunction, and infection with antibiotic-resistant bacterial strains. One defining symptom of diabetes is hyperglycemia, resulting in elevated blood and tissue glucose concentrations. Glucose is the preferred carbon source of several bacterial pathogens, and hyperglycemia escalates bacterial growth and virulence. Hyperglycemia promotes specific mechanisms of bacterial virulence known to contribute to infection chronicity, including tissue adherence and biofilm formation. Foot infections are a significant source of morbidity in individuals with diabetes and consist of biofilm-associated polymicrobial communities. Bacteria perform complex interspecies behaviors conducive to their growth and virulence within biofilms, including metabolic cross-feeding and altered phenotypes more tolerant to antibiotic therapeutics. Moreover, the metabolic dysfunction caused by diabetes compromises immune cell function, resulting in immune suppression. Impaired insulin signaling induces aberrations in phagocytic cells, which are crucial mediators for controlling and resolving bacterial infections. These aberrancies encompass altered cytokine profiles, the migratory and chemotactic mechanisms of neutrophils, and the metabolic reprogramming required for the oxidative burst and subsequent generation of bactericidal free radicals. Furthermore, the immune suppression caused by diabetes and the polymicrobial nature of the diabetic infection microenvironment may promote the emergence of novel strains of multidrug-resistant bacterial pathogens. This review focuses on the "triple threat" linked to worsened bacterial infections in individuals with diabetes: (i) altered nutritional availability in diabetic tissues, (ii) diabetes-associated immune suppression, and (iii) antibiotic treatment failure.

Enhanced ileum function in weaned piglets via Laminaria digitata and alginate lyase dietary inclusion: A combined proteomics and metabolomics analysis

Laminaria digitata, a brown seaweed with prebiotic properties, can potentially enhance the resilience of weaned piglets to nutritional distress. However, their cell wall polysaccharides elude digestion by monogastric animals' endogenous enzymes. In vitro studies suggest alginate lyase's ability to degrade such polysaccharides. This study aimed to assess the impact of a 10% dietary inclusion of L. digitata and alginate lyase supplementation on the ileum proteome and metabolome, adopting a hypothesis-generating approach. Findings indicated that control piglets escalated glucose usage as an enteric energy source, as evidenced by the increased abundance of PKLR and PCK2 proteins and decreased tissue glucose concentration. Additionally, the inclusion of seaweed fostered a rise in proteins linked to enhanced enterocyte structural integrity (ACTBL2, CRMP1, FLII, EML2 and MYLK), elevated peptidase activity (NAALADL1 and CAPNS1), and heightened anti-inflammatory activity (C3), underscoring improved intestinal function. In addition, seaweed-fed piglets showed a reduced abundance of proteins related to apoptosis (ERN2) and proteolysis (DPP4). Alginate lyase supplementation appeared to amplify the initial effects of seaweed-only feeding, by boosting the number of differential proteins within the same pathways. This amplification is potentially due to increased intracellular nutrient availability, making a compelling case for further exploration of this dietary approach. SignificancePig production used to rely heavily on antibiotics and zinc oxide to deal with post-weaning stress in a cost-effective way. Their negative repercussions on public health and the environment have motivated heavy restrictions, and a consequent search for alternative feed ingredients/supplements. One of such alternatives is Laminaria digitata, a brown seaweed whose prebiotic components that can help weaned piglets deal with nutritional stress, by improving their gut health and immune status. However, their recalcitrant cell walls have antinutritional properties, for which alginate lyase supplementation is a possible solution. By evaluating ileal metabolism as influenced by dietary seaweed and enzyme supplementation, we aim at discovering how the weaned piglet adapts to them and what are their effects on this important segment of the digestive system.

133-LB: Proof-of-Concept Study Results with a New Osmotic-Pressure–Based Continuous Glucose Sensor

Background: The Sencell sensor (Lifecare AS, Bergen, Norway) uses glucose induced changes in an osmotic pressure chamber for continuous measurement of glucose concentrations in the subcutaneous tissue. A close to linear correlation between the raw sensor signal and the glucose concentration and a very long duration of use (of up to 6-12 months or longer) are theoretically to be expected. The final device is planned to have the size of a grain of rice and to be implanted employing wireless energy and data transfer. Method: For a first clinical proof of concept study in humans, a wired version of the core sensing technology was embedded into a 4 mm needle and inserted into the abdominal subcutaneous tissue of healthy volunteers. The study was conducted to collect first human proof-of-concept performance data for algorithm development during meal experiments and for further device optimization. The raw data was analyzed after one-point calibration and minor trend correction in comparison to the Statstrip blood glucose meter and the Freestyle Libre 2 glucose sensor. Results: Seven participants (5 female, 2 male, age: 49±11 years) delivered a total of 105 direct comparator data-points (vs. Statstrip blood glucose meter) during repeated meal experiments with observation periods between 2 h and up to 72 days. The osmotic-pressure sensor followed glucose changes similar to the FreeStyle Libre device and reached an MARD of 9.8% in comparison to StatStrip (87 % and 13 % of the datapoints were lying in zones A and B of the consensus error grid, respectively). Conclusions: In this first human proof-of-concept study, the osmotic-pressure based continuous glucose sensor was shown to track s.c. glucose concentrations in a comparable manner as the Libre 2 needle sensor. The clinical performance characteristics of the first wired prototypes provide an encouraging perspective for the upcoming next development steps. Disclosure A. Pfützner: Consultant; Novo Nordisk A/S, Research Support; LifeScan Diabetes Institute, Speaker's Bureau; AstraZeneca, Stock/Shareholder; Lifecare A/S, Diakard. M. Hanna: None. N. Thomé: None. H. Jensch: None. Funding Lifecare AS (LIFC-SEN-001)

Calving prediction with continuous measurement of subcutaneous tissue glucose concentration in pregnant cows.

To reduce losses of dams and calves due to unfortunate events, such as dystocia and freezing to death, identifying the onset of calving and providing necessary assistance are crucial. Prepartum increase in blood glucose concentration is a known indicator to detect labor in pregnant cows. However, some issues, including the need for frequent blood sampling and stress on cows, must be resolved before establishing a method for anticipating calving using changes in blood glucose concentrations. Herein, instead of measuring the blood glucose concentrations, subcutaneous tissue glucose concentration (tGLU) was measured in peripartum primiparous (n=6) and multiparous (n=8) cows at 15min intervals using a wearable sensor. A transient increase in tGLU was observed in the peripartum period, with peak individual concentrations occurring between 2.8h before and 3.5h after calving. tGLU in primiparous cows was significantly higher than that in multiparous cows. To account for individual variations in basal tGLU, the maximum relative increase in the 3-h moving average of tGLU (Max MA) was used to predict calving. Cutoff points for Max MA were established by parity, with receiver operating characteristic analysis predicting calving within 24, 18, 12, and 6h. Except for one multiparous cow that showed an increase in tGLU just before calving, all cows reached at least two cutoff points and calving was predicted successfully. The time interval between reaching the tGLU cutoff points that predicted calving within 12h and actual calving was 12.3±5.6h. In conclusion, this study demonstrated the potential role of tGLU as a predictive indicator of calving in cows. Advancements in machine learning-based prediction algorithms and bovine-optimized sensors will help in increasing the accuracy of calving prediction using tGLU.

Special Circumstances of Persons with Dementia and Agitation in Hospice Care.

AbstractBackgroundApproximately 45% of patients with dementia will experience agitation in the last stages of disease. Furthermore, approximately 35% of patients in the late stages of their lives will present agitation despite being treated with lorazepam, morphine, and atypical antipsychotics. Since agitation is particularly prevalent in hospice care, we estimate that at least 45% of the subjects with dementia in hospice care, or approximately 80,000 individuals a year, will die suffering from symptoms of agitation.MethodsDifferences between agitation in dementia at different stages of the disease were evaluated.ResultsAgitation in patients with dementia in the moderate stages of the disease requires the correction of the medical condition that could contribute to the presence of agitation. In hospice care eligible patients with agitation and dementia, these conditions are often untreatable and/or side effects associated with treatment could be more deleterious than the presence of agitation. In the treatment of hospice care eligible patients with agitation and dementia, the main concern is to control symptoms and improve patient’s comfort level while preserving alertness and controlling pain and other symptoms frequently present in terminal patients, including nausea and dyspnea, rather than to uncover and treat the potential underlying cause(s) of the syndrome. In addition, several distinct physiological processes develop both in the CNS and in the periphery during the last few weeks of an individual’s life, including changes in tissue concentrations of glucose, lactate, pyruvate, ATP, ADP, AMP, and phosphocreatine (reflecting brain energy metabolism changes observed during the process of dying and after cardiopulmonary resuscitation).ConclusionSymptoms of agitation in moderate demented patients appear to be biologically and symptomatically different than symptoms of agitation in hospice care eligible patients with dementia. Therefore, the hospice care eligible patients with agitation and dementia need to be better studied and treatments tailored to these specific conditions should be developed.

Feasibility of Interstitial Fluid Ketone Monitoring with Microneedles.

Diabetic ketoacidosis (DKA) is one of the most dangerous and costly complications of diabetes, accounting for approximately 50% of deaths in diabetic individuals under 24 years. This results in over 130,000 hospital admissions yearly and costs the USA over USD 2.4 billion annually. Earlier diagnosis, treatment, and management of DKA are of critical importance to achieving better patient outcomes and preventing prolonged hospital admissions. Diabetic patients undergoing stress from illness or injury may not recognize early ketosis and often present advanced ketoacidosis, requiring intensive care admission. We have recently developed a microneedle-based technology to extract dermal interstitial fluid (ISF) from both animals and humans, which could enable wearable sensors to rapidly detect ketosis. Metabolite concentrations in ISF may differ in urine and blood and could likely represent local metabolic conditions in the surrounding tissue. Development of a wearable ketone detector will require an understanding of ketone concentrations and kinetics in ISF. Here, we report data that is first of its kind, with regard to the ketone concentrations present in the dermal ISF of rats, their correlation to blood, and the possible impact on the development of a wearable ISF “early warning system” to prevent morbidity from DKA. We extracted ISF, using minimally invasive microneedle arrays, from control Sprague Dawley rats and 17 h fasted rats. ISF and blood ketone levels were measured using a common glucose/ketone meter and strips. Local tissue concentrations of glucose were similar to those of blood, with an average blood to ISF glucose ratio of 0.99 ± 0.15 mg/dL. ISF ketones (0.4 ± 0.3 mM) were significantly higher (p = 4.2 × 10−9), compared with blood ketones (0.0 ± 0.0 mM). Although the fasted animals had slightly higher ISF ketones (1.3 ± 1.1 mM) compared with blood ketones (1.0 ± 1.0 mM), the difference was not significant (p = 0.3). This suggests ISF could possibly be useful as a surrogate for blood when determining ketone levels within a clinical setting.

Improved Accuracy of Tissue Glucose Measurement Using Low Magnification Optical Coherence Tomography

Optical coherence tomography (OCT) has a comparatively high spatial resolution among tomographic bioimaging techniques and is less affected by changes in physiological conditions such as temperature, blood pressure, and osmolytes in the tissue. OCT detects changes in the refractive index of tissues, which is a function of the tissue glucose concentration (TGC). OCT signal intensity generally decreases with tissue depth, and its slope is expected to show a negative correlation with TGC in the interstitial fluid, reflecting blood glucose concentration (BGC). The currently applied OCT system for measuring TGC does not satisfy the accuracy for clinical demand, mainly because of the temporal and spatial variations of living tissues. In this paper, we propose a low magnification OCT (LM-OCT) for noninvasive monitoring of TGC by reducing the spatial resolution and show that LM-OCT significantly improves the accuracy of glucose measurement. The continuous development of LM-OCT in this direction is expected to offer a reliable and noninvasive tool for the clinical monitoring of TGC.

Modeling continuous glucose monitoring with fractional differential equations subject to shocks

Continuous Glucose Monitoring (CGM) produces long time-series of noisy observations of a single variable (tissue glucose concentration), whose evolution may be explained by a dynamical model. In order to represent the unknown mixture of possible control mechanisms of different orders affecting the measured variable, a fractional differential approach seems justified. In any case, variations in food intake and/or physical activity ought to be taken into account if a plausible interpretation of the dynamics is to be obtained. In the present work, the mathematical construction and the numerical implementation of a Fractional Differential Equations (FDE) initial value problem are systematically reviewed, with the intent of offering the reader a concise and mathematically rigorous description of this approach. An FDE model for CGM is formulated: the model includes compartments for stomach and intestinal glucose contents and for blood and tissue (subcutaneous) glucose concentrations, as well as the shock effects of food ingestion and of increased glucose consumption due to physical activity. The model parameters, including the (non-integer) order of differentiation, are estimated from CGM observations on six Type 1 diabetic patients. The best-fit fractional orders for the six subjects range from 1.59 to 2.13. For comparison, best fits have also been computed for all subjects using an average fractional order of 1.9 and integer orders of 1 and 2.The results indicate that in the case of CGM the fractional differential model, which should be physiologically more appropriate, in fact fits the data much better than the first-order model and also better than the 2nd-order model.

Noninvasive Monitoring of Glucose Using Near-Infrared Reflection Spectroscopy of Skin-Constraints and Effective Novel Strategy in Multivariate Calibration.

For many years, successful noninvasive blood glucose monitoring assays have been announced, among which near-infrared (NIR) spectroscopy of skin is a promising analytical method. Owing to the tiny absorption bands of the glucose buried among a dominating variable spectral background, multivariate calibration is required to achieve applicability for blood glucose self-monitoring. The most useful spectral range with important analyte fingerprint signatures is the NIR spectral interval containing combination and overtone vibration band regions. A strategy called science-based calibration (SBC) has been developed that relies on a priori information of the glucose signal (“response spectrum”) and the spectral noise, i.e., estimates of the variance of a sample population with negligible glucose dynamics. For the SBC method using transcutaneous reflection skin spectra, the response spectrum requires scaling due to the wavelength-dependent photon penetration depth, as obtained by Monte Carlo simulations of photon migration based on estimates of optical tissue constants. Results for tissue glucose concentrations are presented using lip NIR-spectra of a type-1 diabetic subject recorded under modified oral glucose tolerance test (OGTT) conditions. The results from the SBC method are extremely promising, as statistical calibrations show limitations under the conditions of ill-posed equation systems as experienced for tissue measurements. The temporal profile differences between the glucose concentration in blood and skin tissue were discussed in detail but needed to be further evaluated.

VLSI design of intelligent, Self-monitored and managed, Strip-free, Non-invasive device for Diabetes mellitus patients to improve Glycemic control using IoT

To overcome the problems of existing invasive blood glucose monitoring, like pain while pricking, uncomfortable test strips, possibilities of infections, a real-time display and 24 hours non-invasive intelligent blood glucose level monitoring system is proposed. The proposed architecture acquires data with high speed and accuracy regarding levels of blood and tissue glucose concentration in the peripheral or central blood resulting in improved glycemic control. Furthermore, the substantial random noise is filtered before the results are displayed in the real–time display monitor. The device will provide accurate readings and generate alert signals using IoT so that untoward events can be prevented due to extreme fluctuations in the blood glucose levels. The system consists of a pulsed laser diode, a photoelectric transducer, low noise amplifier, high-speed analog to digital converter (ADC), and field programmable gate array (FPGA) and the LCD. The signal to noise ratio and sampling speed are maximized. The proposed system is realized using FPGA and produces maximum efficiency and high throughput with low energy consumption.

The Relationship of Fasting Free Fatty Acids, Adipose Tissue, Insulin Resistance, and Fasting Glucose Concentrations with Subsequent ß-Cell Function in Nondiabetic Subjects

Elevations in both plasma free fatty acids (FFA) and glucose concentrations during fasting are associated with impaired β-cell function and predict progression from prediabetes to diabetes. Their interaction and subsequent effect on β-cell function as quantified by Disposition Index (DI) is unknown. We therefore measured total, saturated, mono-unsaturated and poly-unsaturated FFA concentrations using LC/MS in 120 nondiabetic subjects (across a range of fasting glucose < 6.9 mmol/l) who underwent a 2 hour oral glucose tolerance test (OGTT). Insulin secretion and action were quantified using the oral minimal model. The adipose tissue insulin resistance index (Adipo-IR) was calculated for each subject. Subjects were categorized by normal (NFG) or impaired (IFG) fasting glucose and by 2-hour glucose into normal (NGT) or impaired (IGT) glucose tolerance. Fasting total FFA were increased (p < 0.01) in IFG/IGT (835 ± 47 μmol/L) and in NFG/IGT (835 ± 30 μmol/L) but, intriguingly, not in IFG/NGT (593 ± 26 μmol/L) when compared to NFG/NGT (652 ± 29 μmol/L). These differences were no longer apparent within 60 minutes of OGTT and all groups suppressed FFA to the same nadir (166 ± 12 vs. 191 ± 18 vs. 184 ± 12 vs. 174 ± 17μmol/L, p = 0.59). On the other hand, an inverse relationship (p < 0.01) of fasting FFA (r = -0.33) and of Adipo-IR (r = -0.28) was observed with insulin action (Si). Fasting FFA did not correlate with β-cell responsivity (ϕ, r = 0.04). However, higher Adipo-IR was associated with higher values of ϕ (r = 0.36, p < 0.01). Fasting glucose concentrations did not alter these relationships; specifically no interaction of glucose with FFA during the fasting state to influence DI was evident. It remains to be ascertained whether the elevation in FFA reflects defects in production or in uptake, and whether the effect of changes in fasting glucose concentrations on DI is modulated by fasting FFA concentrations. Disclosure M.D. Hurtado: None. J. Adams: None. M.C. Laurenti: Other Relationship; Self; GlySens Incorporated. C. Dalla Man: None. C. Cobelli: Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Novo Nordisk Inc.. R.A. Rizza: None. M.D. Jensen: Other Relationship; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. A. Vella: Research Support; Self; Novo Nordisk Inc., XOMA Corporation. Advisory Panel; Self; VTV Therapeutics, Bayer AG.

Evidence for brain glucose dysregulation in Alzheimer's disease

IntroductionIt is unclear whether abnormalities in brain glucose homeostasis are associated with Alzheimer's disease (AD) pathogenesis. MethodsWithin the autopsy cohort of the Baltimore Longitudinal Study of Aging, we measured brain glucose concentration and assessed the ratios of the glycolytic amino acids, serine, glycine, and alanine to glucose. We also quantified protein levels of the neuronal (GLUT3) and astrocytic (GLUT1) glucose transporters. Finally, we assessed the relationships between plasma glucose measured before death and brain tissue glucose. ResultsHigher brain tissue glucose concentration, reduced glycolytic flux, and lower GLUT3 are related to severity of AD pathology and the expression of AD symptoms. Longitudinal increases in fasting plasma glucose levels are associated with higher brain tissue glucose concentrations. DiscussionImpaired glucose metabolism due to reduced glycolytic flux may be intrinsic to AD pathogenesis. Abnormalities in brain glucose homeostasis may begin several years before the onset of clinical symptoms.

Behavioural, physiological and biochemical responses to aquatic hypoxia in the freshwater crayfish, Paranephrops zealandicus

Hypoxia resulting from aquatic eutrophication threatens the population health of the New Zealand freshwater crayfish (koura), Paranephrops zealandicus. An integrated study, combining behavioural, physiological and biochemical approaches, was therefore conducted to characterise the tolerance of this species to hypoxia. When provided with a choice between water flows of high or low dissolved oxygen in short-term laboratory assays, crayfish did not preferentially inhabit waters of higher PO2. However, when an aerial refuge was provided and dissolved oxygen was progressively decreased, crayfish emersed at a PO2 of 0.56±0.03kPa, suggesting a relatively high tolerance to hypoxia. Closed-box respirometry delineated a Pcrit, the point at which crayfish transition from oxyregulating to oxyconforming, of 6.0kPa. Simultaneous measurement of heart rate showed no changes across the PO2 range. In response to 6-h exposures to fixed dissolved oxygen levels (normoxia, 19.3kPa; moderate hypoxia, 3.5kPa; and severe hypoxia, 1.7kPa), P. zealandicus showed a haemolymph PO2 that declined with the magnitude of hypoxia, and while plasma pH declined in severe hypoxia, there were no changes in plasma PCO2. Plasma glucose concentrations fell, and plasma lactate increased in both hypoxic groups. There were no changes in tissue glucose or lactate concentrations. These data indicate that P. zealandicus is relatively tolerant of hypoxia, and possesses biochemical and physiological mechanisms that facilitate survival during short-term exposures to acute hypoxia. If hypoxia is severe and/or prolonged, then this species is capable of escaping to aerial refugia.

Abscisic acid improves tomato fruit quality by increasing soluble sugar concentrations

ABSTRACTAbscisic acid (ABA) is crucial in fruit maturation and senescence and is considered as the other ripening control factor other than ethylene. Important components in ripening fruit are soluble sugars, which make the fruit sweeter and carotenoids, important flavor compounds in ripened fruit. The purpose of this study was to examine the effects of foliar ABA and calcium (Ca) fertilizer treatments (individually and in combination) on determinate beef-steak greenhouse tomato (Solanum lycopersicum) leaf chlorophylls and carotenoids, fruit carotenoids, and soluble sugar concentrations. Foliar spray treatment of 500 mg L−1 ABA increased zeaxanthin (ZEA) and β-carotene (BC) in tomato leaf tissue. Increases in Ca fertilizer treatments significantly decreased tomato leaf violaxanthin (VIO), but no effect on other carotenoids. The application of 500 mg L−1 ABA foliar spray significantly increased glucose and fructose concentrations in tomato fruit tissue. Foliar application of ABA treatments can increase overall chlorophyll, carotenoid content, and fruit quality.

Microdialysis as a Part of Invasive Cerebral Monitoring During Porcine Septic Shock.

Metabolic changes in critically ill patients with endotoxin-induced septic shock are measured primarily by techniques that afford organ-specific metabolic monitoring based on interstitial fluid samples. The present study was designed to evaluate the role of cerebral microdialysis (MD) as a part of invasive neuromonitoring during endotoxemia in a porcine model. Continuous endotoxin infusion was administered to 7 female pigs and, in addition to hemodynamic monitoring and blood chemistry, interstitial lactate, pyruvate, glucose and glycerol concentrations in muscle, liver, and cerebral tissue were measured via in vivo MD for an observation period of 180 minutes. The cerebral concentrations of lactate and glycerol showed no significant increases, whereas the hepatic and muscular levels rose dramatically under endotoxemia. However, the lactate/pyruvate ratio and especially the lactate/glucose ratio showed a profound and significant increase in brain tissue as well. Cerebral perfusion pressure decreased from 77 to 50 mm Hg without reaching pathologic values. Although our results confirm the special protection of the brain during endotoxemia compared with other organs, early metabolic changes become evident by increasing lactate/pyruvate ratio and lactate/glucose ratio. MD appears to be a suitable additional technique in invasive neuromonitoring for obtaining early information about metabolic deterioration in the brain during septic shock.

Microdialysis to Optimize Cord Perfusion and Drug Delivery in Spinal Cord Injury.

There is lack of monitoring from the injury site to guide management of patients with acute traumatic spinal cord injury. Here, we describe a bedside microdialysis monitoring technique for optimizing spinal cord perfusion and drug delivery at the injury site. Fourteen patients were recruited within 72 hours of severe spinal cord injury. We inserted intradurally at the injury site a pressure probe, to monitor continuously spinal cord perfusion pressure, and a microdialysis catheter, to monitor hourly glycerol, glutamate, glucose, lactate, and pyruvate. The pressure probe and microdialysis catheter were placed on the surface of the injured cord. Microdialysis monitoring did not cause serious complications. Spinal cord perfusion pressure 90 to 100mm Hg and tissue glucose >4.5mM minimized metabolic derangement at the injury site. Increasing spinal cord perfusion pressure by ∼10mm Hg increased the entry of intravenously administered dexamethasone at the injury site 3-fold. This study determined the optimum spinal cord perfusion pressure and optimum tissue glucose concentration at the injury site. We also identified spinal cord perfusion pressure as a key determinant of drug entry into the injured spinal cord. Our findings challenge current guidelines, which recommend maintaining mean arterial pressure at 85 to 90mm Hg for a week after spinal cord injury. We propose that future drug trials for spinal cord injury include pressure and microdialysis monitoring to optimize spinal cord perfusion and maximize drug delivery at the injury site. Ann Neurol 2016;80:522-531.

Cryoprotectant Production in Freeze-Tolerant Wood Frogs Is Augmented by Multiple Freeze-Thaw Cycles.

Ice nucleation across the skin of wood frogs (Lithobates sylvaticus) rapidly induces endogenous production of glucose, a cryoprotectant necessary for freeze tolerance. In laboratory studies of freeze tolerance, wood frogs are cooled slowly, often at -0.05°C h(-1), to facilitate high cryoprotectant production and survival. Under natural conditions in Alaska, however, wood frogs accumulate maximal tissue glucose concentrations while cooling at much faster rates, -0.35° to -1.6°C h(-1), and in addition undergo multiple successive freeze-thaw cycles before remaining frozen for the winter. We examined whether simulating these ecologically relevant cooling rates and repeated freeze-thaw events in captive wood frogs results in the high glucose concentrations found in naturally frozen wood frogs. We found that over successive freezing and thawing events, glucose concentrations increased stepwise in all measured tissues. Short thawing periods did not result in a statistically significant decline of glucose concentrations. Wood frogs that experienced three freeze-thaw events had fresh weight glucose concentrations that approached values found in tissues of wood frogs frozen in natural conditions. Laboratory wood frogs survive frozen for 2 mo, while wood frogs frozen under natural conditions survive frozen for up to 7 mo at temperatures below -18°C. We hypothesize that repeated freeze-thaw cycles with rapid cooling and warming rates allow for greater survival in Alaskan wood frogs through enhanced cryoprotectant production.

Neurometabolic coupling between neural activity, glucose, and lactate in activated visual cortex.

Neural activity is closely coupled with energy metabolism but details of the association remain to be identified. One basic area involves the relationships between neural activity and the main supportive substrates of glucose and lactate. This is of fundamental significance for the interpretation of non-invasive neural imaging. Here, we use microelectrodes with high spatial and temporal resolution to determine simultaneous co-localized changes in glucose, lactate, and neural activity during visual activation of the cerebral cortex in the cat. Tissue glucose and lactate concentration levels are measured with electrochemical microelectrodes while neural spiking activity and local field potentials are sampled by a microelectrode. These measurements are performed simultaneously while neurons are activated by visual stimuli of different contrast levels, orientations, and sizes. We find immediate decreases in tissue glucose concentration and simultaneous increases in lactate during neural activation. Both glucose and lactate signals return to their baseline levels instantly as neurons cease firing. No sustained changes or initial dips in glucose or lactate signals are elicited by visual stimulation. However, co-localized measurements of cerebral blood flow and neural activity demonstrate a clear delay in the cerebral blood flow signal such that it does not correlate temporally with the neural response. These results provide direct real-time evidence regarding the coupling between co-localized energy metabolism and neural activity during physiological stimulation. They are also relevant to a current question regarding the role of lactate in energy metabolism in the brain during neural activation. Dynamic changes in energy metabolites can be measured directly with high spatial and temporal resolution by use of enzyme-based microelectrodes. Here, to examine neuro-metabolic coupling during brain activation, we use combined microelectrodes to simultaneously measure extracellular glucose, lactate, and neural responses in the primary visual cortex to visual stimulation. We demonstrate rapid decreases in glucose and increases in lactate during neural activation. Changes in glucose and lactate signals are transient and closely coupled with neuronal firing.

Reply by the Authors

As pointed out by Dr. Turunc, emphysematous pyelonephritis (EPN) is a life-threatening condition characterized by the presence of gas in renal parenchyma, collecting systems, and/or adjacent tissues. A timely diagnosis and adequate identification of prognostic factors are crucial to decision-making process and selection of optimal treatment. Unfortunately, in our opinion, radiographic appearance is not as accurate as needed to determine the prognosis of a patient with EPN. Recently, our group published a multicenter series of 62 patients with EPN. 1 Olvera-Posada D. Armengod-Fischer G. Vazquez-Lavista L. et al. Emphysematous pyelonephritis: multicenter clinical and therapeutic experience in Mexico. Urology. 2014; 83: 1280-1284 Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Surprisingly, we found that there was no difference in mortality rates when comparing Huang's classification 2 Huang J.J. Tseng C.C. Emphysematous pyelonephritis: clinicoradiological classification, management, prognosis, and pathogenesis. Arch Intern Med. 2000; 160: 797-805 Crossref PubMed Scopus (508) Google Scholar categories (P = .55). Instead, a thorough clinical workup supported by radiographic evaluation is recommended. Previously, we have demonstrated that impaired consciousness, multiple organ failure, hyperglycemia, and elevated leukocyte count are independent predictors of poor outcome. 3 Olvera-Posada D. Garcia-Mora A. Culebro-Garcia C. et al. Prognostic factors in emphysematous pyelonephritis. Actas Urol Esp. 2013; 37: 228-232 Crossref PubMed Scopus (12) Google Scholar Moreover, in our opinion, initial approach and treatment guided by strict criteria such as Surviving Sepsis Campaign recommendations 4 Dellinger R.P. Levy M.M. Carlet J.M. et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock. Crit Care Med. 2008; 36: 296-327 Crossref PubMed Scopus (3942) Google Scholar is more reliable than radiologic criteria alone. The Management of Emphysematous Pyelonephritis and Importance of Minimally Invasive TreatmentUrologyVol. 84Issue 4PreviewEmphysematous pyelonephritis (EPN) is one of the most common clinical form of emphysematous infections of upper urinary tract.1 EPN is an acute, severe, necrotizing infection of the renal parenchyma and perirenal tissue, which causes gas within the renal parenchyma, collecting system, or perinephric tissue.2 It usually affects one kidney and occurs mostly in diabetic patients.1,3 The combination of the presence of gas-producing microorganisms, a high tissue glucose concentration, and impaired tissue perfusion favors the development of the emphysematous infections of the urinary tract. Full-Text PDF