Regulation of glucose and insulin release following acute and repeated treatment with the synthetic galanin analog NAX-5055

The neuropeptide galanin is widely expressed in both the central and peripheral nervous systems. However there is limited understanding of how individual galanin receptor (GalR1, 2, and 3) subtypes mediate the physiological activity of galanin in vivo. To address this issue we utilized NAX-5055, a systemically available, metabolically stable galanin analog. NAX-5055 displays a preference for GalR1 receptors and possesses potent anticonvulsant activity in vivo, suggesting that NAX-5055 engages central galanin receptors. To determine if NAX-5055 also modulates the activity of peripheral galanin receptors, we evaluated the effect of NAX-5055 on blood glucose and insulin levels in mice. Acute and repeated (once daily for four days) systemic administration of NAX-5055 (4 mg/kg) significantly increased blood glucose levels compared to vehicle treated mice. However, a hyperglycemic response was not observed following systemic administration of NAX-805-1, a scrambled analog of NAX-5055, with critical receptor binding residues, Trp² and Tyr⁹, reversed. These results suggest that chemical modifications independent of the galanin backbone of NAX-5055 are not responsible for the hyperglycemic response. The effect of NAX-5055 on glucose homeostasis was further evaluated with a glucose tolerance test (GTT). Mice administered either acute or repeated (once daily for four days) injections of NAX-5055 (4 mg/kg) displayed impaired glucose handling and reduced insulin response to an acute glucose (1g/kg) challenge. Here we have shown that systemic administration of a centrally active GalR1-preferring galanin analog produces acute hyperglycemia and an inhibition of insulin release in vivo and that these effects are not attenuated with repeated administration. NAX-5055 thus provides a new pharmacological tool to further the understanding of function of both central and peripheral GalR1 receptors in vivo.     

Free Water Loss–induced Heterogeneous Residual Strain and Reduced Fatigue Resistance in Root Dentin: A 3-dimensional Digital Image Correlation Analysis

IntroductionThis study evaluated free water loss–induced residual strain with and without axial compressive loading and assessed the mechanical effect of cyclic loading in fully hydrated and partially dehydrated root dentin.MethodsRoot dentin sections prepared from freshly extracted human premolars were used. Customized 3-dimensional digital image correlation was used to qualitatively and quantitatively analyze the residual strain induced by 2 hours of free water loss in different regions of root dentin. Residual strain in partially dehydrated root dentin during axial compressive loading was also analyzed using 3-dimensional digital image correlation. The effect of cyclic loading on load to fracture in fully hydrated and partially dehydrated dentin and their fractography were analyzed using micro–computed tomographic imaging.ResultsFree water loss resulted in a heterogeneous distribution of residual strain and an overall formation of residual compressive strain with areas of tensile strain localized to the root canal and outer dentin. More residual compressive strain was observed in the apical dentin compared with the cervical dentin (P < .05), and more residual shear strain was observed in outer dentin compared with inner dentin (P < .05). Axial loading resulted in an increase in the load-induced compressive strain in the direction perpendicular to dentinal tubules (P < .05). Fully hydrated roots displayed a higher mean (P < .05) and median (P < .05) number of cycles to fracture with microcracks characteristic of toughness.ConclusionsAfter free water loss, root dentin displayed an increased formation of heterogenous residual strain, which resulted in increased axial compressive load-induced strain and a decreased resistance to fatigue failure. The effect of free water loss in the loss of mechanical integrity of root-filled teeth needs further investigation.     

Cefoperazone-sulbactam and risk of coagulation disorders or bleeding: a retrospective cohort study

ABSTRACT

Objectives: Limited evidence has suggested that cefoperazone-sulbactam causes coagulation disorders and bleeding.

Methods: The authors conducted a retrospective study to compare patients receiving cefoperazone-sulbactam versus those treated with cefoperazone-tazobactam or ceftazidime. Propensity-score matching was used to explore whether treatment with cefoperazone-sulbactam increased the risk of prothrombin time (PT) prolongation, coagulation disorders, and bleeding, or decreased platelets (PLT).

Results: The cohort included 23,242 patients. Among patients receiving cefoperazone-sulbactam, the risk of PT prolongation, coagulation disorders, decreased PLT, and bleeding was 5.3%, 9.2%, 15.7%, and 4.2%, respectively. Propensity-score matching analyses suggested that cefoperazone-sulbactam increased the risk of PT prolongation (aOR 2.26, 95% CI 1.61–3.18), coagulation disorders (aOR 1.81, 95% CI 1.43–2.30), and decreased PLT (aOR 1.46, 95% CI 1.25–1.72), but not increase bleeding (aOR 1.05, 95% CI 0.79–1.40) compared with ceftazidime. Patients receiving cefoperazone-sulbactam had higher risk of PT prolongation (aOR 1.53, 95% CI 1.11–2.10), coagulation disorders (aOR 1.53, 95% CI 1.21–1.95), but not decreased PLT (aOR 0.93, 95% CI 0.81–1.07) or bleeding (aOR 1.11, 95% CI 0.87–1.42), compared with those receiving cefoperazone-tazobactam.

Conclusion: Cefoperazone-sulbactam may be associated with a higher risk of PT prolongation and coagulation disorders compared with cefoperazone-tazobactam and ceftazidime.     

Variations in insulin requirements can be an early indicator of sepsis in burn patients

IntroductionA >25% increase in daily insulin dosing is suggestive of possible sepsis in burn patients, however, no conclusive evidence is available regarding the time point at which insulin dosing begins to increase. The purpose of this study is to determine the exact time point at which the insulin requirement increases among non-diabetic burn patients with sepsis.MethodsA retrospective chart review in non-diabetic burn patients with ≥20% total body surface area burned (TBSA) during 2010–2018 who received a blood culture for suspected sepsis. Absolute insulin dosing at intervals (0, 24, 48, 72, and 96 h prior to blood culture) were Box–Cox transformed and compared vs.?96 h reference using mixed-effects models accounting for within-patient dependencies.ResultsFifty-eight patients (84% males, age 44 ± 17 years, TBSA% 49 ± 17.5) were included. When cube root of daily insulin dosing was regressed on each time point in a mixed-effects model, statistically significant increase in insulin dosing compared to baseline was observed for ?48 (p = 0.018), ?24 (p = 0.011), and 0 h (p = 0.008).ConclusionDaily insulin dosing increases 48 h prior to development of other clinical signs of sepsis and can be used as a sensitive early marker.     

Posterior Tibial Tendinopathy and Osteopenia as Primary Symptoms of Celiac Disease: A Case Report

This case report describes posterior tibial tendon (PTT) tendinopathy, valgus deformity with tenosynovitis, and osteopenia at the medial malleolus as the primary symptoms of a young patient with celiac disease (CD) without gastrointestinal symptoms. CD is an autoimmune condition that is a chronic inflammatory disorder of the small intestine triggered by ingestion of gluten in individuals with a particular genetic background. Without typical gastrointestinal symptoms, CD patients are often misdiagnosed or undiagnosed. The patient was diagnosed with CD by duodenal biopsy. He underwent a surgical procedure, including medial displacement calcaneal osteotomy, tenosynovectomy of the PTT and flexor digitorum longus (FDL), FDL transfer to the navicular for a pes planovalgus deformity, and drilling of the medial malleolus for a stress reaction. The mechanism of the PTT tear and associated heel valgus deformity was assumed to be related to the fact that his heel alignment on the affected side changed gradually from normal to valgus and pes planus owing to CD and mechanical stress, because his normal-side heel alignment was neutral before surgery and at final follow-up. His operated ankle was pain-free, with full range of motion, 1.5 years after surgery. The patient was able to restart running and exercise gradually. Foot and ankle specialists should consider the possibility of CD in patients presenting with a PTT tear without injury or trauma and osteopenia with no obvious reason.     

Vasoactive Intestinal Peptide Immunoregulatory Role at the Periapex: Associative and Mechanistic Evidences from Human and Experimental Periapical Lesions

IntroductionThe balance between the host proinflammatory immune response and the counteracting anti-inflammatory and reparative responses supposedly determine the outcome of periapical lesions. In this scenario, the vasoactive intestinal peptide (VIP) may exert a protective role because of its prominent immunoregulatory capacity. In this study, we investigated (in a cause-and-effect manner) the potential involvement of VIP in the development of human and experimental periapical lesions.MethodsPeriapical granulomas (n = 124) and control samples (n = 48) were comparatively assessed for VIP and multiple immunologic/activity marker expression through real-time polymerase chain reaction. Experimental periapical lesions (C57Bl/6 wild-type mice) were evaluated regarding endogenous VIP expression correlation with lesion development and the effect of recombinant VIP therapy in lesion outcome. CCR4KO and IL4KO strains and anti-glucocorticoid-induced TNFR-related protein inhibition were used to test the involvement of Treg and Th2 cells in VIP-mediated effects.ResultsVIP expression was more prevalent in periapical granulomas than in controls, presenting a positive association with immunoregulatory factors and an inverse association/correlation with proinflammatory mediators and the receptor activator of nuclear factor kappa B ligand/osteoprotegerin ratio. Endogenous VIP expression up-regulation was temporally associated with lesion immunoregulation and a decline of bone loss. VIP therapy in mice prompted the arrest of lesion development, being associated with an anti-inflammatory and proreparative response that limits the proinflammatory, Th1, Th17, and osteoclastogenic response in the periapex. The VIP protective effect was dependent of Treg migration and activity and independent of interleukin 4.ConclusionsOur results show that VIP overexpression in human and experimental periapical lesions is associated with lesion inactivity and that VIP therapy results in the attenuation of experimental lesion progression associated with the immunosuppressive response involving Treg cells.     

Yield of ASPECTS and Collateral CTA Selection for Mechanical Thrombectomy within 6–24 hours from Symptom Onset in a Hub and Spoke System

BackgroundRecent extended window trials support the benefit of mechanical thrombectomy in anterior circulation large vessel occlusions with clinical-radiographic dissociation. Using trial imaging criteria, 6% were found eligible for MT in the EW in a hub-and-spoke system. We examined the eligibility and outcomes in consecutive extended window-mechanical thrombectomy patients using more pragmatic selection criteria.MethodsWe retrospectively analyzed single-institution data of anterior circulation large vessel occlusions patients presenting between 6–24 h who underwent mechanical thrombectomy based on a priori determined criteria including non-contrast CT head ASPECTS ≥ 6 and/or CTA collateral scores ASITN/SIR 2-4. Primary outcomes consisted of post-mechanical thrombectomy TICI 2b-3 and 3-month modified Rankin scores; safety outcomes consisted of in-hospital mortality and symptomatic intracerebral hemorrhage.Results767 consecutive acute ischemic strokes patients presented within the 6-24 hour window, and of these 48 (6%) anterior circulation large vessel occlusions patients underwent mechanical thrombectomy. In this cohort the mean age was 63±17 years, 56% were male, the median NIHSS was 16 [IQR 10–19], the median ASPECTS was 9 (IQR 8-10), and 79% (n=38) had good CTA collaterals. Occlusions were primarily M1 MCA (46%), with 29% tandem occlusions. Successful recanalization (mTICI 2b or 3) was achieved in 73% (n=35), while 6% (n=3) of patients developed symptomatic intracerebral hemorrhage. In-hospital mortality was 25% (n=12) while 40% (n=19) achieved 3-month modified Rankin Scores 0–2.ConclusionsOur data suggest the use of pragmatic imaging approach of ASPECTS ≥6 with CTA collateral grade in extended time window which is already established in most hospitals.