What do we really know about vital pulp therapy?

DESIGN: Retrospective cohort study using STROBE cohort reporting guidelines. COHORT SELECTION: Patients from Mehr Dental Clinic in Tehran, Iran, who received different types of vital pulp therapy (VPT) by a single endodontist, due to carious pulpal exposure, between April 2011 and October 2022. These were: Full Pulpotomy (FP), Miniature Pulpotomy (MP) and Direct Pulp Capping (DPC). Data were accessed via the dental clinic's electronic database. Patients were deemed eligible if they had pulpal exposure due to caries, but not trauma. Pre-operative, immediate post-operative and at least one follow-up radiograph at a minimum 3-month interval were required. Demographic, diagnostic, and procedural data as well as informed consent were also required. Teeth with probing depths greater than 4 mm or pulpal necrosis were excluded. DATA ANALYSIS: Patient, tooth and treatment factors were statistically analysed for an outcome of success or failure using a Cox proportional hazards model. Kaplan/Meier curves were used to establish the mean survival times. The Log-rank test was used to compare survival across the three treatment groups. The Omnibus test of model and the -2 log likelihood ratio (-2LL) were used to assess sensitivity and model fitness. Statistical analyses were determined using the IBM SPSS Statistics for Windows Version 21.0, with P value set at <0.05. RESULTS: 1257 VPTs from 1149 patients had complete data and were used in the analysis. 802 cases were excluded due to no follow up radiograph. The VPT cases were divided into FP (n = 272), MP (n = 217) and DPC (n = 768). The average follow up was 42.21 months, with an overall 116-month survival rate of 99.1% and success rate of 91.6%. FP had a mean survival time of 99.43 months; for MP it was 104.26 months; for DPC it was 102.27 months. There were no significant differences between these groups (P = 0.363). There were statistically significant correlations between symptomatic Irreversible Periodontitis (IP), radiographic signs of Apical Periodontitis (AP), restoration type, restoration surfaces and the outcome of VPT. CONCLUSIONS: This is one of the largest cohort studies of its kind, with over 1250 cases of various VPT techniques in 10 years. There was deviation from gold standard practice, with lack of rubber dam. A lack of haemostasis after 2 min could be construed as bacterially infected pulpal tissue and require further resection of pulp. Yet, these approaches still resulted in successful outcomes. Another interesting finding was that symptomatic IP with associated AP was treated with VPT, with a 78% success rate. Considering this study and other emerging evidence in the literature, application of VPT as an alternative to conventional Root Canal Treatment could be adopted in general practice, depending on the skills and knowledge of the practitioner and patient preferences.

Artificial intelligence and dental panoramic radiographs: where are we now?

DATA SOURCES: Bielefeld Academic Search Engine (BASE), Google Scholar Association for Computing Machinery: Guide to Computing Literature (ACM) and National Library of Medicine: PubMed databases were searched for systematic reviews. STUDY SELECTION: This study addressed a structured PICO question (Population, Intervention, Comparison, Outcome). Population was panoramic radiographs in human subjects. Intervention was use of artificial intelligence (AI) diagnostics, compared to human-only diagnosis. Quantitative or qualitative AI efficiency was the outcome. Systematic reviews were considered if they stated 'systematic review' in their title or abstract, were published in English and were not bound by a certain time frame. No supplemental primary studies were included. Screening and removal of duplicates were performed using the Rayyan tool. DATA EXTRACTION AND SYNTHESIS: Data were extracted from each systematic review by two authors, with a third author having the deciding vote in cases of inconsistency. Cohen's Kappa co-efficient was used to measure reliability between authors, resulting in almost perfect agreement. The risk of bias was accounted for using the ROBIS method which resulted in one paper being rejected, so only 11 included in results. Data were then grouped into seven domains which were detected by AI: teeth identification and numbering, detection of periapical lesions, periodontal bone loss, osteoporosis, maxillary sinusitis, dental caries, and other tasks. The effectiveness of the AI systems was assessed by various outcome metrics - accuracy, sensitivity, specificity, and precision being the most common variables. RESULTS: Results of this overview show a significant increase in accuracy of AI in analysing OPTs between 1988-2023. Latest AI models are most accurate in teeth identification and numbering (93.67%) whilst caries detection and osteoporosis showed 91.5% and 89.29% accuracy, respectively. Accurate results were also observed for the detection of maxillary sinusitis and periodontal bone loss. However, given the heterogeneity of source studies used in these systematic reviews, results should be interpreted with caution. CONCLUSIONS: With improving AI technology, its use in dental radiology can be increasingly effective in supporting dentists in the detection of different pathologies. This overview has shown that systematic reviews of AI can quickly become outdated and that results of any systematic review should be treated with caution as this field advances. As such, regular updating and ongoing research is required.

5α-Tetrahydrocorticosterone: A topical anti-inflammatory glucocorticoid with an improved therapeutic index in a murine model of dermatitis.

BACKGROUND AND PURPOSE: Glucocorticoids are powerful anti-inflammatory drugs, but are associated with many side-effects. Topical application in atopic dermatitis leads to skin thinning, metabolic changes, and adrenal suppression. 5α-Tetrahydrocorticosterone (5αTHB) is a potential selective anti-inflammatory with reduced metabolic effects. Here, the efficacy and side-effect profile of 5αTHB were compared with hydrocortisone in preclinical models of irritant dermatitis. EXPERIMENTAL APPROACH: Acute irritant dermatitis was invoked in ear skin of male C57BL/6 mice with a single topical application of croton oil. Inflammation was assessed as oedema via ear weight following treatment with 5αTHB and hydrocortisone. Side-effects of 5αTHB and hydrocortisone were assessed following chronic topical steroid treatment (28 days) to non-irritated skin. Skin thinning was quantified longitudinally by caliper measurements and summarily by qPCR for transcripts for genes involved in extracellular matrix homeostasis; systemic effects of topical steroid administration also were assessed. Clearance of 5αTHB and hydrocortisone were measured following intravenous and oral administration. KEY RESULTS: 5αTHB suppressed ear swelling in mice, with ED50 similar to hydrocortisone (23 µg vs. 13 µg). Chronic application of 5αTHB did not cause skin thinning, adrenal atrophy, weight loss, thymic involution, or raised insulin levels, all of which were observed with topical hydrocortisone. Transcripts for genes involved in collagen synthesis and stability were adversely affected by all doses of hydrocortisone, but only by the highest dose of 5αTHB (8× ED50 ). 5αTHB was rapidly cleared from the systemic circulation. CONCLUSIONS AND IMPLICATIONS: Topical 5αTHB has potential to treat inflammatory skin conditions, particularly in areas of delicate skin.

Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis.

Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that the KMO product 3-hydroxykynurenine primes innate immune signaling to exacerbate systemic inflammation during experimental AP. We find a tissue-specific role for KMO, where mice lacking Kmo solely in hepatocytes have elevated plasma 3-hydroxykynurenine levels that prime inflammatory gene transcription. 3-Hydroxykynurenine synergizes with interleukin-1ß to cause cellular apoptosis. Critically, mice with elevated 3-hydroxykynurenine succumb fatally earlier and more readily to experimental AP. Therapeutically, blockade with the highly selective KMO inhibitor GSK898 rescues the phenotype, reducing 3-hydroxykynurenine and protecting against critical illness and death. Together, our findings establish KMO and 3-hydroxykynurenine as regulators of inflammation and the innate immune response to sterile inflammation. During critical illness, excess morbidity and death from multiple organ failure can be rescued by systemic KMO blockade.

Memory deficits in a juvenile rat model of type 1 diabetes are due to excess 11ß-HSD1 activity, which is upregulated by high glucose concentrations rather than insulin deficiency.

AIMS/HYPOTHESIS: Children with diabetes may display cognitive alterations although vascular disorders have not yet appeared. Variations in glucose levels together with relative insulin deficiency in treated type 1 diabetes have been reported to impact brain function indirectly through dysregulation of the hypothalamus-pituitary-adrenal axis. We have recently shown that enhancement of glucocorticoid levels in children with type 1 diabetes is dependent not only on glucocorticoid secretion but also on glucocorticoid tissue concentrations, which is linked to 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity. Hypothalamus-pituitary-adrenal axis dysfunction and memory alteration were further dissected in a juvenile rat model of diabetes showing that excess 11ß-HSD1 activity within the hippocampus is associated with hippocampal-dependent memory deficits. Here, to investigate the causal relationships between diabetes, 11ß-HSD1 activity and hippocampus-dependent memory deficits, we evaluated the beneficial effect of 11ß-HSD1 inhibition on hippocampal-related memory in juvenile diabetic rats. We also examined whether diabetes-associated enhancement of hippocampal 11ß-HSD1 activity is due to an increase in brain glucose concentrations and/or a decrease in insulin signalling. METHODS: Diabetes was induced in juvenile rats by daily i.p. injection of streptozotocin for 2 consecutive days. Inhibition of 11ß-HSD1 was obtained by administrating the compound UE2316 twice daily by gavage for 3 weeks, after which hippocampal-dependent object location memory was assessed. Hippocampal 11ß-HSD1 activity was estimated by the ratio of corticosterone/dehydrocorticosterone measured by LC/MS. Regulation of 11ß-HSD1 activity in response to changes in glucose or insulin levels was determined ex vivo on acute brain hippocampal slices. The insulin regulation of 11ß-HSD1 was further examined in vivo using virally mediated knockdown of insulin receptor expression specifically in the hippocampus. RESULTS: Our data show that inhibiting 11ß-HSD1 activity prevents hippocampal-related memory deficits in diabetic juvenile rats. A significant increase (53.0±9.9%) in hippocampal 11ß-HSD1 activity was found in hippocampal slices incubated in high glucose conditions (13.9 mmol/l) vs normal glucose conditions (2.8 mmol/l) without insulin. However, 11ß-HSD1 activity was not affected by variations in insulin concentration either in the hippocampal slices or after a decrease in hippocampal insulin receptor expression. CONCLUSIONS/INTERPRETATION: Together, these data demonstrate that an increase in 11ß-HSD1 activity contributes to memory deficits observed in juvenile diabetic rats and that an excess of hippocampal 11ß-HSD1 activity stems from high glucose levels rather than insulin deficiency. 11ß-HSD1 might be a therapeutic target for treating cognitive impairments associated with diabetes.

11ß-HSD1 inhibition does not affect murine tumour angiogenesis but may exert a selective effect on tumour growth by modulating inflammation and fibrosis.

Glucocorticoids inhibit angiogenesis by activating the glucocorticoid receptor. Inhibition of the glucocorticoid-activating enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) reduces tissue-specific glucocorticoid action and promotes angiogenesis in murine models of myocardial infarction. Angiogenesis is important in the growth of some solid tumours. This study used murine models of squamous cell carcinoma (SCC) and pancreatic ductal adenocarcinoma (PDAC) to test the hypothesis that 11ß-HSD1 inhibition promotes angiogenesis and subsequent tumour growth. SCC or PDAC cells were injected into female FVB/N or C57BL6/J mice fed either standard diet, or diet containing the 11ß-HSD1 inhibitor UE2316. SCC tumours grew more rapidly in UE2316-treated mice, reaching a larger (P<0.01) final volume (0.158 ± 0.037 cm3) than in control mice (0.051 ± 0.007 cm3). However, PDAC tumour growth was unaffected. Immunofluorescent analysis of SCC tumours did not show differences in vessel density (CD31/alpha-smooth muscle actin) or cell proliferation (Ki67) after 11ß-HSD1 inhibition, and immunohistochemistry of SCC tumours did not show changes in inflammatory cell (CD3- or F4/80-positive) infiltration. In culture, the growth/viability (assessed by live cell imaging) of SCC cells was not affected by UE2316 or corticosterone. Second Harmonic Generation microscopy showed that UE2316 reduced Type I collagen (P<0.001), whilst RNA-sequencing revealed that multiple factors involved in the innate immune/inflammatory response were reduced in UE2316-treated SCC tumours. 11ß-HSD1 inhibition increases SCC tumour growth, likely via suppression of inflammatory/immune cell signalling and extracellular matrix deposition, but does not promote tumour angiogenesis or growth of all solid tumours.

Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice.

The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.

Temperature-Dependent Stimulated Emission Cross-Section in Nd3+:YLF Crystal.

Spectroscopic properties of neodymium-doped yttrium lithium fluoride were measured at different temperatures from 35 K to 350 K in specimens with 1 at% Nd3+ concentration. The absorption spectrum was measured at room temperature from 400 to 900 nm. The decay dynamics of the 4F3/2 multiplet was investigated by measuring the fluorescence lifetime as a function of the sample temperature, and the radiative decay time was derived by extrapolation to 0 K. The stimulated-emission cross-sections of the transitions from the 4F3/2 to the 4I9/2, 4I11/2, and 4I13/2 levels were obtained from the fluorescence spectrum measured at different temperatures, using the Aull-Jenssen technique. The results show consistency with most results previously published at room temperature, extending them over a broader range of temperatures. A semi-empirical formula for the magnitude of the stimulated-emission cross-section as a function of temperature in the 250 K to 350 K temperature range, is presented for the most intense transitions to the 4I11/2 and 4I13/2 levels.

Hybrid guided space-time optical modes in unpatterned films.

Light is confined transversely and delivered axially in a waveguide. However, waveguides are lossy static structures whose modal characteristics are fundamentally determined by their boundary conditions. Here we show that unpatterned planar waveguides can provide low-loss two-dimensional waveguiding by using space-time wave packets, which are unique one-dimensional propagation-invariant pulsed optical beams. We observe hybrid guided space-time modes that are index-guided in one transverse dimension and localized along the unbounded dimension. We confirm that these fields enable overriding the boundary conditions by varying post-fabrication the group index of the fundamental mode in a 2-µm-thick, 25-mm-long silica film, achieved by modifying the field's spatio-temporal structure. Tunability of the group index over an unprecedented range from 1.26 to 1.77 is verified while maintaining a spectrally flat zero-dispersion profile. Our work paves the way to utilizing space-time wave packets in on-chip platforms, and enable phase-matching strategies that circumvent restrictions due to intrinsic material properties.

A Novel Robotic Endoscopic Device Used for Operative Hysteroscopy.

To trial the use of a novel endoscopic robot that functions using concentric tube robots, enabling 2-handed surgery in small spaces, in a bioengineering laboratory. This was a feasibility study of the endoscopic robot for hysteroscopic applications, including removal of a simulated endometrial polyp. The endoscopic robot was successfully used to resect a simulated endometrial polyp from a porcine uterine tissue model in a fluid environment. The potential advantages of this platform to the surgeon may include improved exposure, finer dissection capability, and use of a 2-handed surgical technique. Further study regarding the safe, efficient, and cost-effective use of the endoscopic robot in gynecology is needed.

Three-photon absorption spectra of zinc blende semiconductors: theory and experiment: erratum.

We provide a correction to the spectral dependence of the three-photon absorption in zinc-blende semiconductors using Kane's 4-band model in Opt. Lett.33, 2626 (2008).OPLEDP0146-959210.1364/OL.33.002626.

The effects of mild closed head injuries on tauopathy and cognitive deficits in rodents: Primary results in wild type and rTg4510 mice, and a systematic review.

In humans, the majority of sustained traumatic brain injuries (TBIs) are classified as 'mild' and most often a result of a closed head injury (CHI). The effects of a non-penetrating CHI are not benign and may lead to chronic pathology and behavioral dysfunction, which could be worsened by repeated head injury. Clinical-neuropathological correlation studies provide evidence that conversion of tau into abnormally phosphorylated proteotoxic intermediates (p-tau) could be part of the pathophysiology triggered by a single TBI and enhanced by repeated TBIs. However, the link between p-tau and CHI in rodents remains controversial. To address this question experimentally, we induced a single CHI or two CHIs to WT or rTg4510 mice. We found that 2× CHI increased tau phosphorylation in WT mice and rTg4510 mice. Behavioral characterization in WT mice found chronic deficits in the radial arm water maze in 2× CHI mice that had partially resolved in the 1× CHI mice. Moreover, using Manganese-Enhanced Magnetic Resonance Imaging with R1 mapping - a novel functional neuroimaging technique - we found greater deficits in the rTg4510 mice following 2× CHI compared to 1× CHI. To integrate our findings with prior work in the field, we conducted a systematic review of rodent mild repetitive CHI studies. Following Prisma guidelines, we identified 25 original peer-reviewed papers. Results from our experiments, as well as our systematic review, provide compelling evidence that tau phosphorylation is modified by experimental mild TBI studies; however, changes in p-tau levels are not universally reported. Together, our results provide evidence that repetitive TBIs can result in worse and more persistent neurological deficits compared to a single TBI, but the direct link between the worsened outcome and elevated p-tau could not be established.

A Concentric Tube Robot System for Rigid Bronchoscopy: A Feasibility Study on Central Airway Obstruction Removal.

New robotic systems have recently emerged to assist with peripheral lung access, but a robotic system for rigid bronchoscopy has yet to be developed. We describe a new robotic system that can deliver thin robotic manipulators through the ports of standard rigid bronchoscopes. The manipulators bend and elongate to provide maneuverability of surgical tools at the endoscope tip, without endoscope motion. We describe an initial feasibility study on the use of this system to bronchoscopically treat a central airway obstruction (CAO). CAO is prevalent and can be life-threatening in patients with large tumors, and conventional rigid bronchoscopic treatments place patients at risk of complications including broken teeth, neck trauma and damage to oropharyngeal structures due to significant forces induced by bronchoscope tilting and manipulation. In this study, we used an ex vivo ovine airway model to demonstrate the ability of a physician using the robotic system to efficiently remove tissue and restore the airway. Pre- and post-operative CT scans showed that the robot was able to reduce the degree of airway obstruction stenosis from 75 to 14% on average for five CAO resections performed in an ex vivo animal model. Using cadaver experiments, we demonstrated the potential of the robotic system to substantially reduce the intraoperative forces applied to the patient's head and neck (from 80.6 to 4.1 N). These preliminary results illustrate that CAO removal is feasible with our new rigid bronchoscopy robot system, and that this approach has the potential to reduce forces applied to the patient due to bronchoscope angulation, and thereby reduce the risk of complications encountered during CAO surgery.

Vitamin A deficiency impairs contextual fear memory in rats: Abnormalities in the glucocorticoid pathway.

Vitamin A and its active metabolite, retinoic acid (RA), play a key role in the maintenance of cognitive functions in the adult brain. Depletion of RA using the vitamin A deficiency (VAD) model in Wistar rats leads to spatial memory deficits in relation to elevated intrahippocampal basal corticosterone (CORT) levels and increased hippocampal 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity. All of these effects are normalised by vitamin A supplementation. However, it is unknown whether vitamin A status also modulates contextual fear conditioning (CFC) in a glucocorticoid-associated fear memory task dependent on the functional integrity of the hippocampus. In the present study, we investigated the impact of VAD and vitamin A supplementation in adult male rats on fear memory processing, plasma CORT levels, hippocampal retinoid receptors and 11ß-HSD1 expression following a novelty-induced stress. We also examined whether vitamin A supplementation or a single injection of UE2316, a selective 11ß-HSD1 inhibitor, known to modulate local glucocorticoid levels, had any beneficial effects on contextual fear memory and biochemical parameters in VAD rats. We provide evidence that VAD rats exhibit a decreased fear conditioning response during training with a poor contextual fear memory 24 hours later. These VAD-induced cognitive impairments are associated with elevated plasma CORT levels under basal conditions, as well as following a stressful event, with saturated CORT release, altered hippocampal retinoid receptors and 11ß-HSD1 expression. Vitamin A supplementation normalises VAD-induced fear conditioning training deficits and all biochemical effects, although it cannot prevent fear memory deficits. Moreover, a single injection of UE2316 not only impairs contextual fear memory, but also reduces plasma CORT levels, regardless of the vitamin A status and decreases slightly hippocampal 11ß-HSD1 activity in VAD rats following stress. The present study highlights the importance of vitamin A status with respect to modulating fear memory conditioning in relation to plasma CORT levels and hippocampal 11ß-HSD1.

Kynurenine 3-monooxygenase is a critical regulator of renal ischemia-reperfusion injury.

Acute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking kynurenine 3-monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active kynurenine metabolites 3-hydroxykynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.

Diclofenac Identified as a Kynurenine 3-Monooxygenase Binder and Inhibitor by Molecular Similarity Techniques.

In this study, we apply a battery of molecular similarity techniques to known inhibitors of kynurenine 3-monooxygenase (KMO), querying each against a repository of approved, experimental, nutraceutical, and illicit drugs. Four compounds are assayed against KMO. Subsequently, diclofenac (also known by the trade names Voltaren, Voltarol, Aclonac, and Cataflam) has been confirmed as a human KMO protein binder and inhibitor in cell lysate with low micromolar KD and IC50, respectively, and low millimolar cellular IC50. Hit to drug hopping, as exemplified here for one of the most successful anti-inflammatory medicines ever invented, holds great promise for expansion into new disease areas and highlights the not-yet-fully-exploited potential of drug repurposing.

Corrigendum: Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness.

This corrects the article DOI: 10.1038/nm.4115.

Exploring N-acyl-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-enes as 11ß-HSD1 Inhibitors.

We recently found that a cyclohexanecarboxamide derived from 4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene displayed low nanomolar inhibition of 11ß-HSD1. In continuation of our efforts to discover potent and selective 11ß-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited potent inhibitory activity against human 11ß-HSD1, although with low selectivity over the isoenzyme 11ß-HSD2, and poor microsomal stability.

Engineered nonlinear materials using gold nanoantenna array.

Gold dipole nanoantennas embedded in an organic molecular film provide strong local electromagnetic fields to enhance both the nonlinear refractive index (n2) and two-photon absorption (2PA) of the molecules. An enhancement of 53× for 2PA and 140× for nonlinear refraction is observed for BDPAS (4,4'-bis(diphenylamino)stilbene) at 600 nm with only 3.7% of gold volume fraction. The complex value of the third-order susceptibility enhancement results in a sign change of n2 for the effective composite material relative to the pure BDPAS film. This complex nature of the enhancement and the tunability of the nanoantenna resonance allow for engineering the effective nonlinear response of the composite film.