Transgenic mice with ocular overexpression of an adrenomedullin receptor reflect human acute angle-closure glaucoma

Glaucoma, frequently associated with high IOP (intra-ocular pressure), is a leading cause of blindness, characterized by a loss of retinal ganglion cells and the corresponding optic nerve fibres. In the present study, acutely and transiently elevated IOP, characteristic of acute angle-closure glaucoma in humans, was observed in CLR (calcitonin receptor-like receptor) transgenic mice between 1 and 3 months of age. Expression of CLR under the control of a smooth muscle alpha-actin promoter in these mice augmented signalling of the smooth-muscle-relaxing peptide adrenomedullin in the pupillary sphincter muscle and resulted in pupillary palsy. Elevated IOP was prevented in CLR transgenic mice when mated with hemizygote adrenomedullin-deficient mice with up to 50% lower plasma and organ adrenomedullin concentrations. This indicates that endogenous adrenomedullin of iris ciliary body origin causes pupillary palsy and angle closure in CLR transgenic mice overexpressing adrenomedullin receptors in the pupillary sphincter muscle. In human eyes, immunoreactive adrenomedullin has also been detected in the ciliary body. Furthermore, the CLR and RAMP2 (receptor-activity-modifying protein 2), constituting adrenomedullin receptor heterodimers, were identified in the human pupillary sphincter muscle. Thus, in humans, defective regulation of adrenomedullin action in the pupillary sphincter muscle, provoked in the present study in CLR transgenic mice, may cause acute and chronic atony and, thereby, contribute to the development of angle-closure glaucoma. The CLR transgenic mice used in the present study provide a model for acute angle-closure glaucoma.     

A novel method to localize antibody-targeted cancer deposits intraoperatively using handheld PET beta and gamma probes

Background Assessing cancer margins, lymph nodes, and small cancer deposits intraoperatively can be challenging. A new device has become available that allows the detection of positron emission tomography (PET) radiotracers through both high-energy gamma and short-range beta emissions. These PET probes are handheld, allowing for real-time evaluation of cancer using a tool that provides surgeons with better intraoperative assessment of tumor sites. Methods Within the context of two institutional review board (IRB)-approved protocols investigating new applications of antibody-labeled PET scanning, ¹²⁴I-labeled humanized monoclonal antibodies specific for colorectal cancer (huA33) and renal tumors (cG250) were constructed. Patients underwent preoperative PET scans, approximately seven days post-tracer infusion, when tumor-to-nontumor ratios were high. Suspected tumor deposits were evaluated intraoperatively with handheld beta and gamma PET probes. Results Handheld PET probes detected emissions from all tumors. Count rates from the gamma probe on tumor ranged from 48 to 306 cps, and for the beta probe ranged from 18 to 190 cps. Gamma and beta emissions exhibited a strong positive correlation. The ratio of gamma and beta counts was at least twice that of the background counts for all tumors evaluated. Conclusions This study is the first to demonstrate the utility of beta probes for the intraoperative detection of radiolabeled antibodies targeting cancer. Importantly, the recorded beta count rates from the beta probe correlate with the count rates from the high-energy gamma probe. Furthermore, the beta probe may offer superior specificity for real-time localization of small tumor deposits, compared to gamma probes. The intraoperative portable PET probe may prove a valuable bridge to combining tumor biology and PET technology to guide surgical therapy.     

Clinical Value of Immunohistochemically Detected Lymphovascular Space Invasion in Early Stage Cervical Carcinoma

Background  This study investigates the clinical significance of lymphovascular space invasion (LVSI) as detected by hematoxylin and eosin (LVSI-H&E) and immunohistochemistry (LVSI-IHC) in early stage cervical carcinoma. Methods  Single representative sections from 97 patients with early stage squamous cell cervical cancer were immunostained with pancytokeratin and CD31 endothelial cell marker antibodies. The H&E sections and their corresponding immunostained sections were reexamined to identify LVSI. Associations between LVSI with clinicopathological factors were sought. Results  Overall, LVSI was present in 29 (29.9%) and absent in 68 (70.1%) by IHC, as compared with 18 cases (18.6%) and 79 cases (81.4%), respectively, by H&E. Statistical analysis revealed a significant association between LVSI-H&E and nodal metastasis (P = .004). Follow-up data were available for 76 patients. The median follow-up period was 64 months. During follow-up, 7 of 24 patients with recurrent disease had evidence of LVSI-H&E as opposed to 3 of 52 cases with no recurrence. There was a significant association between tumor recurrence and LVSI-H&E (P = .009). The 5-year recurrence-free survival was 30% for the group with LVSI-H&E compared with 73% without. There was a significant difference in the recurrence-free survival between the two groups (P = .002). In contrast LVSI-IHC was found to be associated with no pathological factors, and survival analysis revealed no statistically significant association with recurrence or survival. Conclusion  LVSI-H&E in early stage cervical cancer remains an important predictive factor of recurrent disease and reduced disease-free interval. Immunohistochemically detected LVSI is a common event and seems to be of no clinical value.     

The Callender modification of the Macintosh laryngoscope blade reduces the risk of tooth-blade contact in children

Background: Dental injury is well recognized as a potential complication of laryngoscopy and tracheal intubation. The flange of the Macintosh blade may contact teeth during laryngoscopy causing damage. The Callander modification of the Macintosh blade (Callander blade) with a shortened heel at the proximal end has been shown to increase the blade–tooth distance and reduce contact rates in adults. Aim: This study was designed to evaluate the effectiveness of the Callander blade on reducing dental contact in children. Methods: One hundred children, aged 4–14 years, scheduled for general anesthesia requiring endotracheal intubation were studied prospectively. The children were preoperatively evaluated for Mallampati score and dental defects, looseness, and avulsions. Following induction of anesthesia, laryngoscopy was performed twice on each child in succession, once with a standard Macintosh blade and once with a Callander blade of the same size in a random order. The blade–tooth distance and contact rate were compared between the two blades. Results: With the Callander blade, the blade–tooth distance was greater than with the Macintosh (1.78 ± 1.77 vs 0.28 ± 0.76 mm, P = 0.001). The frequency of direct contact was less with the Callander blade than it was with the Macintosh blade (33% vs 86%, respectively, P = 0.008). However, difficult laryngoscopy rate did not differ between the blades. Tracheal intubation was successful in all children and there was no dental injury. Conclusion: Our findings suggest that the Callander blade decreases the risk for dental injury and provides tracheal intubating conditions in children with normal airways similar to those obtained with a traditional Macintosh blade.     

The Width:thickness Ratio of the Patella

Establishing the appropriate size of the patellar implant-bone composite is one of the important steps ensuring functional success in arthroplasty. Conventionally, the patella is measured intraoperatively and its thickness is used to guide the depth of resection. However, in a diseased joint, this may not reflect the native patellar thickness. We studied the relationship between the patellar thickness and various patellar dimensions on three-dimensional reconstructed computed tomographic scans from 37 normal adult knees. Patellar width correlated with thickness. The average patellar width:thickness ratio was 2.0 (standard deviation, 0.106; 95% confidence interval, 1.96–2.03). The cartilage thickness was on average 2.5 mm (standard deviation, 1.0). The width:thickness ratio was similar in 79 digital radiographs taken before TKA of knees without patellofemoral disease (mean, 2.1; standard deviation, 0.28). When compared with the two other methods for calculating patellar resection described in the literature, the width:thickness ratio was more reliable. The width:thickness ratio appears anatomically constant and may be a useful guide for estimating premorbid patellar thickness. Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. Each author certifies that his or her institution has approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained.     

Biphenotypic acute leukaemia: a case series

Biphenotypic acute leukaemia (BAL) is a rare type of leukaemia. Whether patients with BAL should be treated with regimens designed for acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) or both remain unclear. We have reviewed the clinical data for 31 BAL patients. Most patients co-expressed B-lymphoid and myeloid markers. No specific chromosomal abnormality was identified. The majority of the patients were treated with regimens devised for treating ALL. Seven patients were treated with regimens designed for AML. Complete remission (CR) rates of 78% and 57% were noted respectively. The overall survival probability at 2 years was 60%.     

A pilot study of imatinib, low-dose cytarabine and idarubicin for patients with chronic myeloid leukemia in myeloid blast phase

Imatinib is the single most effective agent in chronic myelogenous leukemia (CML) in blast phase (BP), inducing hematologic responses in 30 - 50% of patients. However, only a few of these are complete (CHR) and durable. Imatinib is synergistic with idarubicin and cytarabine. We administered imatinib 600 mg/day, cytarabine 10 mg/day subcutaneous, and idarubicin 12 mg/m² intravenous every 14 days in 19 patients with CML in myeloid BP. Fourteen patients (74%) achieved a hematologic response: CHR in 9 (47%) (3 with complete and 1 with minor cytogenetic responses) and return to chronic phase (RTC) in 5 (26%). Median duration of response was 10 weeks (range, 2 - 89). Six patients received allogeneic stem cell transplantation: 4 CHR, 1 chronic phase and 1 BP. Median survival was 5 months (range, 2 - 20 months). This outpatient regimen is effective and well tolerated and perhaps superior to single-agent imatinib for patients in myeloid BP.     

Applications,functions, and accuracy of artificial intelligence in restorative dentistry: A literature review

Objective

The applications of artificial intelligence (AI) are increasing in restorative dentistry; however, the AI performance is unclear for dental professionals. The purpose of this narrative review was to evaluate the applications, functions, and accuracy of AI in diverse aspects of restorative dentistry including caries detection, tooth preparation margin detection, tooth restoration design, metal structure casting, dental restoration/implant detection, removable partial denture design, and tooth shade determination.

Overview

An electronic search was performed on Medline/PubMed, Embase, Web of Science, Cochrane, Scopus, and Google Scholar databases. English-language articles, published from January 1, 2000, to March 1, 2022, relevant to the aforementioned aspects were selected using the key terms of artificial intelligence, machine learning, deep learning, artificial neural networks, convolutional neural networks, clustering, soft computing, automated planning, computational learning, computer vision, and automated reasoning as inclusion criteria. A manual search was also performed. Therefore, 157 articles were included, reviewed, and discussed.

Conclusions

Based on the current literature, the AI models have shown promising performance in the mentioned aspects when being compared with traditional approaches in terms of accuracy; however, as these models are still in development, more studies are required to validate their accuracy and apply them to routine clinical practice. Clinical Significance: AI with its specific functions has shown successful applications with acceptable accuracy in diverse aspects of restorative dentistry. The understanding of these functions may lead to novel applications with optimal accuracy for AI in restorative dentistry.     

Enhancement of the depigmenting effect of hydroquinone and 4-hydroxyanisole by all-trans-retinoic acid (tretinoin): the impairment of glutathione-dependent cytoprotection?

Many of the well-known depigmenting agents such as hydroquinone and 4-hydroxyanisole are, in fact, melanocytotoxic chemicals which are oxidized in melanocytes to produce highly toxic compounds such as quinones. These cytotoxic compounds are responsible for the destruction of pigment cells, which results in skin depigmentation. However, cells are capable of protecting themselves against cytotoxic agents by intracellular glutathione (GSH). This protection takes place under the enzymatic action of the detoxification enzyme glutathione S-transferase (GST), which is responsible for the conjugation of toxic species to GSH. The depigmenting effect of hydroquinone is shown to be potentiated by buthionine sulfoximine (BSO) and cystamine as the result of the reduction of intracellular levels of GSH by these two agents. Additionally, BSO and cystamine are shown to inhibit the activity of GST. The combination of all-trans-retinoic acid (tretinoin, TRA) with hydroquinone or 4-hydroxyanisole is also known to produce synergetic skin depigmentation. TRA serves as a potent inhibitor of mammalian GSTs and is known to make cells more susceptible to the cytotoxic effect of chemicals by inhibiting the activity of this enzyme. This agent is also shown to reduce the level of intracellular GSH in certain cells. We have proposed that the mechanism of action of TRA to synergistically enhance the melanocytotoxic effect of chemicals involves the inhibition of GST and the impairment of glutathione-dependent cytoprotection against melanocytotoxic agents.     

Bulk collagen incorporation rates into knitted stiff fibre polymer in tissue-engineered scaffolds: the rate-limiting step

Fabrication of tissue-engineered constructs in vitro relies on sufficient synthesis of extracellular matrix (ECM) by cells to form a material suitable for normal function in vivo. Collagen synthesis by human dermal fibroblasts grown in vitro on two polymers, polyethylene terephthalate (PET) and polyglycolic acid (PGA), was measured by high-performance liquid chromatography (HPLC). Cells were either cultured in a dynamic environment, where meshes were loaded onto a pulsing tube in a bioreactor, or in a static environment without pulsing. Collagen synthesis by cells cultured on a static mesh increased by six-fold compared to monolayer culture, and increased by up to a further 5.4-fold in a pulsed bioreactor. However, little of the collagen synthesized was deposited onto the meshes, almost all being lost to the medium. The amount of collagen deposited onto meshes was highest when cells were cultured dynamically on PET meshes (17.6 microg), but deposition still represented only 1.4% of the total synthesized. Although total collagen synthesis was increased by the use of 3D culture and the introduction of pulsing, the results suggest that the limiting factor for fabrication of a tissue-engineered construct within practical timescales is not the amount of collagen synthesized but the quantity retained (i.e. deposited) within the construct during culture. This may be enhanced by systems which promote or assemble true 3D multi-layers of cells.