Evaluation of coagulation profile in dogs with ACTH-dependent hyperadrenocorticism compared to healthy dogs by rotational thromboelastometry (ROTEM).

Despite their low morbidity, thromboembolic events in hyperadrenocorticism are associated with high mortality. Identifying the main hemostatic abnormalities will improve the prophylactic approach of these canine patients. The aim of this study was to evaluate hemostatic alterations related with ACTH-dependent HAC and its association with hypercoagulable state. For this purpose, 25 dogs diagnosed with ACTH-dependent HAC were compared with 28 healthy dogs as a control group. The hemostatic variables included platelet count, antithrombin, fibrinogen, D-dimer, PT, aPTT, rotational thromboelastometry (ROTEM) and platelet aggregation. Results showed a hypercoagulable state in 32% (8/25) dogs by ROTEM, which had at least 2 of the next features: decreased coagulation time (CT) or clot formation time (CFT) on INTEM (5/25) or EXTEM (4/25); increased maximum clot firmness (MCF) on INTEM (9/25), EXTEM (6/25) and FIBTEM (9/25). These same variables had a significant difference (P≤ 0.05) compared with the control group, as well as the parameters of α-angle and CT. Median fibrinogen levels (310 vs.178 mg/dL), mean platelet aggregation (11.1 vs. 7.9 Ohms), median platelet count (360 vs. 225 ×103/µL) and mean antithrombin activity (140 vs. 119%) were increased in ACTH-dependent HAC dogs compared to control group. PT (7.1 vs. 8.0 seconds) and aPTT (11.6 vs. 15.2 seconds) were also shortened in ACTH-dependent HAC dogs. Our findings confirm the presence of a hypercoagulable tendency in dogs with HAC. Although multifactorial, fibrinogen concentration and MCF FIBTEM showed the relevance of this protein for hypercoagulability in HAC.

Cadaveric study of the ultrasound-guided erector spinae plane block over the transverse process of the twelfth thoracic vertebra in dogs: Transversal vs longitudinal approach.

This study describes a transversal (TV) ultrasound-guided erector spinae plane (ESP) block technique over the transverse process of T12. And evaluates the distribution of the dye and affected nerves branches compared to a longitudinal (LNG) approach over the transverse process of T12 in canine cadavers. Secondly, it also compares de anatomy and dimensions of the transverse processes of T12 with T9 and T5. For this double-masked, cadaveric experimental study, 12 adult Beagle cadavers were injected with 0.6 mL/kg of dye/contrast. Spread was evaluated by computed tomography (CT) and dissection. Mean bodyweight was 9.76 (±0.59) kg. The TV and LNG approaches stained a median (range) of four (2-6) and three (1-6) medial branches of the dorsal rami of the spinal nerves, three (2-6) and three (2-5) lateral branches, and one (0-3) and one (0-4) ventral branches, respectively. Dye was detected in the epidural space in 55.6% and 66.7% of cases for the TV and LNG approaches, respectively (P=0.63). And in the ventral paravertebral compartment in 22.2% and lymphatics in 88.8% in both approaches. There were no statistical differences for the spread. The dorsolateral edge of the transverse process (TP) was not visible with CT at T12. The mean (±SD) length of the TP was significantly shorter at T12 [3.34 (±0.22)] mm, compared to T9 [6.08 (±0.47)] mm and T5 [5.93 (±0.62)] mm (P <0.001). This study showed similar distribution whether using a TV or LNG approach and differences in the anatomy and length of the T12 TP.

The clinical management of children with achondroplasia in Italy: results of clinician and parent/caregiver surveys.

PURPOSE: This study aimed to assess the real-world management of achondroplasia in Italy. METHODS: Two online surveys addressed to (1) parents/caregivers of individuals with achondroplasia and (2) Italian clinicians managing individuals with achondroplasia were conducted to assess real-world perspectives on achondroplasia management. Both surveys collected data on either patient or clinician demographics, details on diagnoses and referrals, disease complications, and views/experiences with limb lengthening surgery. RESULTS: In total, 42 parents/caregivers and 19 clinicians (from 18 hospitals) completed the surveys. According to parents/caregivers, achondroplasia diagnosis was most commonly made in the third trimester of gestation (55% of respondents), with a genetic test performed to confirm the diagnosis in all but one case. In contrast, the clinicians indicated that, while achondroplasia was typically suspected during the prenatal period (78%), diagnosis was more frequently confirmed postnatally (72%). Parents/caregivers reported that the greatest impact of achondroplasia-related complications occurred in their children between the ages of 2-5 years. The most significant complications were otitis, sleep apnoea, stenosis of the foramen magnum or pressure on the spinal cord, and hearing difficulties. Lengthening surgery had been presented as a treatment option to 92% of responding parents/caregivers, with 76% of clinicians viewing surgery favourably. Typically, clinicians' reasons for suggesting limb lengthening surgery were to improve patient quality of life, increase patient autonomy and self-acceptance, improve trunk-limb disproportion, short stature and walking, and ensure that all possible treatment options had been presented to the parents/caregivers. CONCLUSION: This survey provides insight into the real-world management of individuals with achondroplasia in Italy.

The diagnosis of hypophosphatasia in children as a multidisciplinary effort: an expert opinion.

Hypophosphatasia (HPP) is a rare genetic disorder in which pathogenic variants of the ALPL gene lead to a marked decrease of tissue non-specific alkaline phosphatase (TNSALP) activity. Although HPP is a systemic disorder, its clinical manifestations are more evident on bones, teeth, muscle and central nervous system. The clinical spectrum ranges from severe forms with extreme skeletal deformities, respiratory impairment, seizures, to very mild forms with onset in late adulthood and few clinical signs. The diagnosis can be suspected by measurement of TNSALP activity, but the insufficient awareness among health professionals and the lack of official guidelines are responsible for delayed diagnosis in children with HPP. The purpose of the current document is to provide an expert opinion directed at optimizing the diagnostic pathway of pediatric HPP. From April to December 2022, a multidisciplinary working group of 6 experts including two pediatric endocrinologists, a pediatric neurologist, a pediatric odontologist, a clinical geneticist, and a molecular biologist gathered in a series of periodic meetings to discuss the main issues related to the diagnosis of HPP in children and formalize an Expert Opinion statement. The experts agreed on a diagnostic trail that begins with the recognition of specific clinical signs, leading to biochemical analyses of TNSALP activity and vitamin B6 serum concentration. Very important are the neurological and dental manifestation of the disease that should be thoroughly investigated. The evaluation of TNSALP activity must consider sex and age variability and low activity must be persistent. Repeated blood measurements are thus necessary. The molecular analysis is then mandatory to confirm the diagnosis and for genetic counseling.

Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance.

Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity decrease in AT, and PEPD is released into the systemic circulation, which promotes fibrosis and AT IR. Loss of the enzymatic function of PEPD by genetic ablation or pharmacological inhibition causes AT fibrosis in mice. In addition to its intracellular enzymatic role, secreted extracellular PEPD protein enhances macrophage and adipocyte fibro-inflammatory responses via EGFR signalling, thereby promoting AT fibrosis and IR. We further show that decreased prolidase activity is coupled with increased systemic levels of PEPD that act as a pathogenic trigger of AT fibrosis and IR. Thus, PEPD produced by macrophages might serve as a biomarker of AT fibro-inflammation and could represent a therapeutic target for AT fibrosis and obesity-associated IR and type 2 diabetes.

Extracellular vesicles released by steatotic hepatocytes alter adipocyte metabolism.

The composition of extracellular vesicles (EVs) is altered in many pathological conditions, and their molecular content provides essential information on features of parent cells and mechanisms of crosstalk between cells and organs. Metabolic Syndrome (MetS) is a cluster of clinical manifestations including obesity, insulin resistance, dyslipidemia and hypertension that increases the risk of cardiovascular disease and type 2 diabetes mellitus. Here, we investigated the crosstalk between liver and adipocytes by characterizing EVs secreted by primary hepatocytes isolated from Zucker rat model, and studied the effect they have on 3T3-L1 adipocytes. We found that steatotic hepatocytes secrete EVs with significantly reduced exosomal markers in comparison with their lean counterpart. Moreover, proteomic analysis revealed that those EVs reflect the metabolic state of the parent cell in that the majority of proteins upregulated relate to fat metabolism, fatty acid synthesis, glycolysis, and pentose phosphate pathway. In addition, hepatocytes-secreted EVs influenced lipolysis and insulin sensitivity in recipient 3T3-L1 adipocytes. Untargeted metabolomic analysis detected alterations in different adipocyte metabolic pathways in cells treated with hepatic EVs. In summary, our work showed that steatosis has a significant impact in the amount and composition of EVs secreted by hepatocytes. Moreover, our data point to the involvement of hepatic-EVs in the development of pathologies associated with MetS.

Comparative study of a novel portable indirect calorimeter to a reference breath-by-breath instrument and its use in telemedicine settings.

BACKGROUND & AIMS: Resting Energy Expenditure (REE) quantitatively describes the calories used to support body function (e.g. breathing, blood circulation, etc.) at resting condition. Assessment of the REE is essential for successful weight management and the understanding of metabolic health. REE is typically determined via indirect calorimetry. Current biomedical indirect calorimetry technologies, utilizing assessment of oxygen consumption (VO2) and carbon dioxide production (VCO2) rates (which are typically in the form factor of a metabolic cart) are bulky and require on-site calibration and/or trained professionals to operate. We introduce a novel wearable medical device with FDA clearance to determine REE accurately, portable, and user-friendly format, which can be used both by health professionals in a clinical environment and by the patient at home. Previously, we have reported the validation of Breezing Med (also named as Breezing Pro™) through Douglas Bag Method, a gold standard for gas exchange measurement, and excellent agreement has been found between the two methods for the determination of REE, VO2, and VCO2 rates (Mora et al., 2020). Now we present the validation of Breezing Med against Medical Graphics (MGC) CPX Ultima™, a FDA 510 k cleared metabolic cart, which principle is based on breath-by-breath analysis. In addition, we present Breezing Med as a tool for daily measurement of metabolic rate by the lay person at home. METHODS: A) The validation study was executed via parallel measurement of 20 healthy participants under resting conditions using both the Breezing Med and the MGC Ultima CPX™ (10 min test). B) Breezing Med measurements were carried out by six subjects at home during stay-at-home order due to COVID-19 for 30 days. RESULTS: A) The resulting measurements from both devices was compared with correlation slope's and R-squared coefficients close to 1. B) Results were recorded and analyzed for variability. The pilot study demonstrated the advantage of Breezing Med device to be easy-to-use at home by lay people, which make the valuable device for telemedicine applications related to weight management from home. CONCLUSIONS: This result shows that the MGC Ultima CPX™ and Breezing Med are substantially equivalent for REE measurement; and an advantage of this device for metabolic assessment under the current COVID-19 pandemic situation, for people with impaired physical mobility, and for those who lives in rural areas or face impediments that limit physical access to care.

Development of a new aerosol barrier mask for mitigation of spread of SARS-CoV-2 and other infectious pathogens.

The COVID-19 pandemic has caused huge impact on public health and significantly changed our lifestyle. This is due to the fast airborne oro-nasal transmission of SARS-CoV-2 from the infected individuals. The generation of liquid aerosolized particles occurs when the COVID-19 patients speak, sing, cough, sneeze, or simply breathe. We have developed a novel aerosol barrier mask (ABM) to mitigate the spread of SARS-CoV-2 and other infectious pathogens. This Aerosol Barrier Mask is designed for preventing SARS-CoV-2 transmission while transporting patients within hospital facilities. This mask can constrain aerosol and droplet particles and trap them in a biofilter, while the patient is normally breathing and administrated with medical oxygen. The system can be characterized as an oxygen delivery and mitigation mask which has no unfiltered exhaled air dispersion. The mask helps to prevent the spread of SARS-CoV-2, and potentially other infectious respiratory pathogens and protects everyone in general, especially healthcare professionals.

Monte Carlo study of patient and medical staff radiation exposures during interventional cardiology.

The aim of this study is to assess the radiation exposure of the patient and the medical staff during interventional cardiology procedures. Realistic exposure scenarios were developed using the adult reference anthropomorphic phantoms adopted by the International Commission on Radiological Protection (ICRP110Male and ICRP110Female), and the radiation transport code Geant4 (version 10.3). The calculated equivalent and effective doses were normalised by the simulated Kerma-Area Product (KAP), resulting in two conversion coefficients HT/KAP and E/KAP. To properly evaluate the risk of exposure, several dose-dependent parameters have been investigated, namely: radiological parameters (tube kilovoltage peak (kVp), type of projection, field size (FOV)), and operator positions. Four projections (AP,PA,LAO25° and RAO25°) were simulated for three X-ray energy spectra (80,100 and 120 kVp) with four different values of FOV (15×15 cm2,20×20 cm2,25×25 cm2 and 30×30 cm2). The results showed that the conversion coefficients values increase with increasing tube voltage as well as the FOV size. Recommended projection during the interventional cardiology procedures, whenever possible, should be the PA projection rather than AP projection. The most critical projection for the patient and the main operator is the RAO25° projection and the LAO25° projection respectively. The comparison of our results with the literature data showed good agreement allowing their use in the dosimetric characterization of interventional cardiology procedures.

Electron-Nuclear Dynamics Accompanying Proton-Coupled Electron Transfer.

Although photoinduced proton-coupled electron transfer (PCET) plays an essential role in photosynthesis, a full understanding of the mechanism is still lacking due to the complex nonequilibrium dynamics arising from the strongly coupled electronic and nuclear degrees of freedom. Here we report the photoinduced PCET dynamics of a biomimetic model system investigated by means of transient IR and two-dimensional electronic-vibrational (2DEV) spectroscopies, IR spectroelectrochemistry (IRSEC), and calculations utilizing long-range-corrected hybrid density functionals. This collective experimental and theoretical effort provides a nuanced picture of the complicated dynamics and synergistic motions involved in photoinduced PCET. In particular, the evolution of the 2DEV line shape, which is highly sensitive to the mixing of vibronic states, is interpreted by accurate computational modeling of the charge separated state and is shown to represent a gradual change in electron density distribution associated with a dihedral twist that occurs on a 120 fs time scale.

Development of a new Aerosol Barrier Mask for mitigation of spread of SARS-CoV-2 and other infectious pathogens.

The COVID-19 pandemic has caused huge impact on public health and significantly changed our lifestyle. This is due to the fast airborne oro-nasal transmission of SARS-CoV-2 from the infected individuals. The generation of liquid aerosolized particles occurs when the COVID-19 patients speak, sing, cough, sneeze, or simply breathe. We have developed a novel aerosol barrier mask (ABM) to mitigate the spread of SARS-CoV-2 and other infectious pathogens. This Aerosol Barrier Mask is designed for preventing SARS-CoV-2 transmission while transporting patients within hospital facilities. This mask can constrain aerosol and droplet particles and trap them in a biofilter, while the patient is normally breathing and administrated with medical oxygen. The system can be characterized as an oxygen delivery and mitigation mask which has no unfiltered exhaled air dispersion. The mask helps to prevent the spread of SARS-CoV-2, and potentially other infectious respiratory pathogens and protects everyone in general, especially healthcare professionals.

An Unobstructive Sensing Method for Indoor Air Quality Optimization and Metabolic Assessment within Vehicles.

This work investigates the use of an intelligent and unobstructive sensing technique for maintaining vehicle cabin's indoor air quality while simultaneously assessing the driver metabolic rate. CO2 accumulation patterns are of great interest because CO2 can have negative cognitive effects at higher concentrations and also since CO2 accumulation rate can potentially be used to determine a person's metabolic rate. The management of the vehicle's ventilation system was controlled by periodically alternating the air recirculation mode within the cabin, which was actuated based on the CO2 levels inside the vehicle's cabin. The CO2 accumulation periods were used to assess the driver's metabolic rate, using a model that considered the vehicle's air exchange rate. In the process of the method optimization, it was found that the vehicle's air exchange rate (λ [h-1]) depends on the vehicle speeds, following the relationship: λ = 0.060 × (speed) - 0.88 when driving faster than 17 MPH. An accuracy level of 95% was found between the new method to assess the driver's metabolic rate (1620 ± 140 kcal/day) and the reference method of indirect calorimetry (1550 ± 150 kcal/day) for a total of N = 16 metabolic assessments at various vehicle speeds. The new sensing method represents a novel approach for unobstructive assessment of driver metabolic rate while maintaining indoor air quality within the vehicle cabin.

Mechanistic aspects in the photodynamic inactivation of Candida albicans sensitized by a dimethylaminopropoxy porphyrin and its equivalent with cationic intrinsic charges.

Photocytotoxic effect induced by 5,10,15,20-tetrakis[4-(3-N,N-dimethylaminopropoxy)phenyl]porphyrin (TAPP) and 5,10,15,20-tetrakis[4-(3-N,N,N-trimethylaminepropoxy)phenyl]porphyrin (TAPP+4) was examined in Candida albicans to obtain information on the mechanism of photodynamic action and cell damage. For this purpose, the photokilling of the yeast was investigated under anoxic conditions and cell suspensions in D2O. Moreover, photoinactivation of C. albicans was evaluated in presence of reactive oxygen species scavengers, such as sodium azide and d-mannitol. The results indicated that singlet molecular oxygen was the main reactive species involved in cell damage. On the other hand, the binding and distribution of these porphyrins in the cells was observed by fluorescence microscopy. Morphological damage was studied by transmission electron microscopy (TEM), indicating modifications in the cell envelopment. Furthermore, deformed cells were observed after photoinactivation of C. albicans by toluidine blue staining. In addition, modifications in the cell envelope due to the photodynamic activity was found by scanning electron microscopy (SEM). Similar photodamage was observed with both porphyrin, which mainly produced alterations in the cell barriers that lead to the photoinactivation of C. albicans.

SALIVARY CORTISOL LEVELS AND RESPONSE TO THE REMISSION INDUCTION TREATMENT IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA.

Cancer in children, and mainly the acute lymphoblastic leukemia (ALL), is considered as one of the leading public health problems in Mexico. Glucocorticoids used to treat ALL may cause suppression of the hypothalamic-pituitary-adrenal axis. The aim of the present study was to determine whether cortisol levels in saliva of the patients with ALL are related to the response to the remission induction therapy. The authors have conducted a clinical, prospective and comparative study. The Mann-Whitney U test was used to compare the variables values by gender or type of evolution. According to the patients' evolution, ROC curves were made for salivary cortisol levels and uric acid. An absolute value of 1000 blasts in peripheral blood count after a week of prednisone regimen was defined as a satisfactory response to the treatment. Review of the data has shown that area under the salivary cortisol levels' curve (AUC) was greater than that under the uric acid levels', as a predictor of a poor response to the remission induction. There were no statistically significant gender-associated differences in any variables except in erythrocytes. High levels of cortisol in saliva at the time of diagnosis of ALL seem to be of bad prognosis of the response to the remission induction therapy.

Proton-coupled electron transfer across benzimidazole bridges in bioinspired proton wires.

Designing molecular platforms for controlling proton and electron movement in artificial photosynthetic systems is crucial to efficient catalysis and solar energy conversion. The transfer of both protons and electrons during a reaction is known as proton-coupled electron transfer (PCET) and is used by nature in myriad ways to provide low overpotential pathways for redox reactions and redox leveling, as well as to generate bioenergetic proton currents. Herein, we describe theoretical and electrochemical studies of a series of bioinspired benzimidazole-phenol (BIP) derivatives and a series of dibenzimidazole-phenol (BI2P) analogs with each series bearing the same set of terminal proton-accepting (TPA) groups. The set of TPAs spans more than 6 pK a units. These compounds have been designed to explore the role of the bridging benzimidazole(s) in a one-electron oxidation process coupled to intramolecular proton translocation across either two (the BIP series) or three (the BI2P series) acid/base sites. These molecular constructs feature an electrochemically active phenol connected to the TPA group through a benzimidazole-based bridge, which together with the phenol and TPA group form a covalent framework supporting a Grotthuss-type hydrogen-bonded network. Infrared spectroelectrochemistry demonstrates that upon oxidation of the phenol, protons translocate across this well-defined hydrogen-bonded network to a TPA group. The experimental data show the benzimidazole bridges are non-innocent participants in the PCET process in that the addition of each benzimidazole unit lowers the redox potential of the phenoxyl radical/phenol couple by 60 mV, regardless of the nature of the TPA group. Using a series of hypothetical thermodynamic steps, density functional theory calculations correctly predicted the dependence of the redox potential of the phenoxyl radical/phenol couple on the nature of the final protonated species and provided insight into the thermodynamic role of dibenzimidazole units in the PCET process. This information is crucial for developing molecular "dry proton wires" with these moieties, which can transfer protons via a Grotthuss-type mechanism over long distances without the intervention of water molecules.

"Block-and-replace" treatment in Graves' disease: experience in a cohort of pediatric patients.

PURPOSE: The "block-and-replace" (BR) method involves the use of a high dose of antithyroid drugs (ATD) with levothyroxine (L-T4). Its use in the management of Graves' disease (GD) is still debated mainly because the frequency of side effects of ATD is dose dependent. We retrospectively studied the effect of medium dose of ATD with L-T4 versus monotherapy with ATD in pediatric patients with unstable GD. METHODS: 28 pediatric patients with GD with unstable response to ATD were treated with L-T4 and medium dose of ATD. We compared the rate of euthyroidism, hypothyroidism and hyperthyroidism episodes observed during treatment with methimazole alone with those observed during the BR approach. We evaluated the occurrence of side effects and the rate of remission in patients treated with ATD + L-T4 therapy and the efficacy of combination therapy to postpone a definitive treatment (radioiodine and thyroidectomy). RESULTS: Patients showed a better control of thyroid function during the BR therapy, presenting fewer episodes of hyperthyroidism and hypothyroidism. No serious side effects during the BR approach were observed. Only one patient went into remission with the ATD + L-T4 therapy. Fifteen patients required a definitive therapy (4 radioiodine, 11 thyroidectomy). The use of BR method has delayed radioiodine treatment for 4.9 years and surgery for 2.9 years. CONCLUSIONS: The BR method does not increase the remission rates. It may be useful to combine L-T4 with a medium dose of methimazole when GD is difficult to manage with methimazole alone. It may represent a therapeutic option to postpone definitive treatments to a suitable age.

FGF23-related hypophosphatemia in patients with low bone mineral density and fragility fractures: challenges in diagnosis and management.

PURPOSE: Hypophosphatemia (HP) can be observed in patients evaluated for skeletal fragility. We investigated prevalence of HP among outpatients referred for low bone density or fragility fractures, HP-associated clinical and biochemical features and outcomes of recommended diagnostic algorithm in our cohort. METHODS: Chronic HP (phosphate ≤ 2.7 mg/dL over 6 months or longer) was retrospectively investigated among 2319 patients. In renal wasting-related HP, intact FGF23 was assessed; non-suppressed FGF23 prompted the performance of 68Ga-DOTATOC PET/CT in the suspicion of tumor-induced steomalacia (TIO). RESULTS: Renal wasting-related HP (median 2.2, range 1.6-2.6 mg/dL) was observed in 19 patients (0.82%). FGF23 levels were suppressed in two patients diagnosed with renal tubular disease, increased in one and within normal range in most patients. X-linked hypophosphatemic rickets was diagnosed in one woman. In the remaining 16 patients, highly prevalent fragility fractures (50%) and severely reduced bone mineral density were detected, though diagnostic criteria for osteomalacia were not fulfilled. 68Ga-PET was performed in nine patients and was positive in four. While intact FGF23 levels alone failed to differentiate PET's outcomes (positive: FGF23 median 70.5 pg/mL; negative: 52 pg/mL, P = 0.462), the coexistence of multiple biochemical and radiologic alterations performed better in prediction of PET's positivity. CONCLUSION: Mild, apparently unexplained HP is observed in 0.82% of patients with low bone density or fragility fractures. In asymptomatic patients with isolated mild hypophosphatemia, the probability of finding an underlying tumor disease is very low, and utility of extensive and expensive diagnostic workup should be carefully considered in this setting.

Proton-Coupled Electron Transfer Drives Long-Range Proton Translocation in Bioinspired Systems.

Proton-coupled electron transfer (PCET) combines the movement of fundamental charged species to form an essential link between electron- and proton-transport reactions in bioenergetics and catalysis in general. The length scale over which proton transport may occur within PCET processes and the thermodynamic consequences of the resulting proton chemical potential to the oxidation reaction driving these PCET processes have not been generally established. Here we report the design of bioinspired molecules that employ oxidation-reduction processes to move reversibly two, three, and four protons via a Grotthuss-type mechanism along hydrogen-bonded networks up to ∼16 Šin length. These molecules are composed of benzimidazole moieties linking a phenol to the final proton acceptor, a cyclohexylimine. Following electrochemical oxidation of the phenol, the appearance of an infrared band at 1660 cm-1 signals proton arrival at the terminal basic site. Switching the electrode potential to reducing conditions reverses the proton translocation and resets the structure to the initial species. In addition to mimicking the first step of the iconic PCET process used by the Tyrz-His190 redox relay in photosystem II to oxidize water, this work specifically addresses theoretically and experimentally the length scale over which PCET processes may occur. The thermodynamic findings from these redox-driven, bioinspired "proton wires" have implications for understanding and rationally designing pumps for the generation of proton-motive force in artificial and reengineered photosynthesis, as well as for management of proton activity around catalytic sites, including those for water oxidation and oxygen reduction.

Pregabalin for the treatment of syringomyelia-associated neuropathic pain in dogs: A randomised, placebo-controlled, double-masked clinical trial.

Pregabalin is the first-line treatment for neuropathic pain (NeP) in humans. Dogs with Chiari-like malformation and syringomyelia (CM/SM) associated with NeP could benefit from pregabalin. The aim of this study was to evaluate the efficacy of pregabalin for NeP in dogs with CM/SM. Eight dogs with symptomatic CM/SM were included in a double-masked, randomised, crossover placebo-controlled clinical trial. All dogs received anti-inflammatory drugs as base-line treatment during placebo or pregabalin phase of 14±4 days each. Analgesic efficacy was assessed with a daily numerical rating scale (NRS) recorded by dog owners (0-10, 10=worst pain) and quantitative sensory testing at baseline, placebo and pregabalin phases. Blood samples were collected to report pregabalin exposure and to assess renal function. Daily NRS scores recorded by dog owners in the pregabalin group were lower than in the placebo group (P=0.006). Mechanical thresholds were higher with pregabalin compared to baseline or placebo (P=0.037, P<0.001). Cold latency at 15°C was prolonged on the neck and humeri with pregabalin compared to baseline (P<0.001 for both) or placebo (P=0.02, P=0.0001). Cold latency at 0°C was longer on pregabalin compared to baseline and placebo (P=0.001, P=0.004). There was no pregabalin accumulation between first and last dose. This study demonstrates the efficacy of pregabalin for the treatment of NeP due to CM/SM on daily pain scores recorded by dog owners. Pregabalin significantly reduced mechanical hyperalgesia, cold hyperalgesia (0°C) and allodynia (15°C) compared to placebo. Pregabalin was non-cumulative and well tolerated with occasional mild sedation.