The phenotypic overlap of syndromes associated with hereditary gingival fibromatosis: follow-up of a family for five years.

Hereditary gingival fibromatosis (HGF) is characterized by the slowly progressive fibrous enlargement of gingival tissue. It usually develops as an isolated disorder but can also be one feature of various syndromes. The currently preferred terminology of these syndromes mainly describes the clinical features of the disorder without identifying the cause. In this report, we present the 5-year follow up of a family with HGF and features of 3 previously described syndromes: Jones syndrome, Zimmerman-Laband syndrome, and HGF-hypertrichosis syndrome. The 45-year-old father had HGF, hypertrichosis, hearing loss, and short stubby fingers and toes with hypoplasia of the terminal phalanges and hypoplasia of the nails on the thumbs. The features of 13-year-old son were almost identical to those of his father except for hypertrichosis, but in addition he was mentally retarded. Although the 10-day-old son had HGF and defective fingers, the mother and 7-year-old daughter were unaffected. Owing to the overlap of these syndromes, we argue that the identification of the genetic pathways and mechanisms will be the most important factor in classifying these disorders, with the phenotype playing a minor role.     

Extended Lateral Supramalleolar Flap for Very Distal Foot Coverage: A Case With Arteriovenous Malformation

Arteriovenous malformation of the foot is very uncommon, and surgical closure after its treatment with embolization and total excision may be challenging for the foot surgeon, particularly in distally localized lesions. A popular method to cover these difficult wounds is free-tissue transfer, which is a highly demanding procedure. Alternatively, distally based regional flaps have been occasionally reported for clinical use in such distant foot defects. Herein, we present a 36-year-old female patient with a diagnosis of arteriovenous malformation arising in the distal medial plantar and dorsal surfaces of the right foot. After surgical resection of the vascular lesion preceded by a misapplied embolization procedure, an extended lateral supramalleolar flap was successfully transferred to the defect area, covering it completely. Functional and aesthetic outcome was satisfactory after 6 months follow-up. Extended lateral supramalleolar flap is a useful and reliable choice for distal foot reconstructions.     

1.25 (OH)2 cholecalciferol pulse therapy and the effects of different dialysis membranes on serum PTH levels of haemodialysis patients

Either oral, intravenous or subcutaneous 1.25 (OH)₂ cholecalciferol is used in the therapy of hyperparathyroidism, which is a serious complication in patients on haemodialysis. We studied a total of 30 patients (10 women and 20 men) and divided them into two groups depending on the different types of dialysis membranes used. In the poly sulfone group, mean age was 43.7±0.97 years and the average dialysis period lasted 29.9±1.23 months. For the 15 cases in which we used cuprophane membrane the mean age was 40.2±1.31 years and the average dialysis period lasted 16.2±0.86 months. The calcium level of the dialysate in both groups was 1.5 mmol/l. According to the study protocol, the determined oral calcitriol dose was 0.07 mg/kg and it was administered intermittently. After one month on high dose calcitriol therapy, treatment was continued with a maintenance dose of 0.03 mg/kg for a further six months. As a phosphate binding agent, daily 3 g calcium carbonate was administered. Before starting this treatment protocol, patients went on a 1 mg/day calcitriol therapy, although the mean PTH level was 424.63 pg/ml and the mean serum alkaline phosphatase level was 290.2 U/l. During the pretreatment period, levels of PTH, alkaline phosphatase, ionized calcium, and total calcium remained significantly within normal limits as a result of the new therapy protocol applied. PTH and phosphorus clearance rates were compared in the patient groups in which different dialysis membranes had been used. PTH and phosphorus clearances were 15.2±3 ml/min and 239.1±19.2 ml/min, respectively, in the polysulfone membrane group, and 1.1±0.3 ml/min and 112.8±9.88 ml/min, respectively, in the cuprophane membrane group (p<0.05).     

Outcomes following adoption of a standardized protocol for abscess drain management in pediatric appendicitis

Background/purposeThough evidence-based clinical pathways for the diagnosis and treatment of pediatric appendicitis have been established, protocols guiding management of percutaneous abscess drains are lacking. We hypothesized a drain management protocol utilizing drain output and clinical factors instead of fluoroscopic drain studies would reduce interventional radiologic procedures without adversely impacting clinical outcomes.MethodsA standardized protocol was uniformly adopted at a tertiary-care children's hospital in April 2016. A retrospective chart review included all cases of appendicitis requiring abscess drainage by interventional radiology three years pre- and postprotocol implementation.ResultsFifty-eight patients (preprotocol = 39, postprotocol = 19) underwent percutaneous abscess drainage, of whom 52 (preprotocol = 34, postprotocol = 18) required a drain. Baseline demographics and clinical presentation were similar across groups. Following protocol implementation, total number of IR procedures decreased from 2.4 to 1.3 per patient (p = 0.004). There was no significant difference in the number of postprocedure diagnostic imaging studies, readmissions, or inpatient days, and there was a trend towards a decrease in number of drain days (10.7 to 5.7, p = 0.067).ConclusionA standardized protocol for management of abscess drains for complicated appendicitis reduced the number of IR procedures without a negative impact on clinical outcomes or increase in alternative imaging studies. This approach may decrease radiation exposure, anesthetic administration, and resource utilization.Type of studyTreatment study (retrospective comparative study).Level of evidenceLevel III.     

Interim report in humans of a previously described technique in an animal model: closure of bladder exstrophy with rectus abdominis muscle flap

The aim of this study was to present the results of a new bladder closure and augmentation technique in children born with bladder exstrophy where primary surgical closure was impossible. The technique was performed in four children with small, noncompliant, inelastic bladders in which secondary changes such as squamous epithelial metaplasia and polypoid transformation had developed. During the opration, a full-thickness rectus abdominis muscle island flap with an intact neurovascular pedicle was prepared from the left abdominal quadrant and rotated to cover the bladder defect and aid in augmentation. The inner layer formed by peritoneum was sutured to the edges of the bladder defect. Postoperative endoscopic and histopathologic investigations revealed the inner, peritoneal layer of the flap to be completely covered by transitional urinary bladder epithelium. Considering the advantages of the technique from this limited experience, the evidence suggests that there is no need for a major gastrointestinal operation for bladder augmentation. A reasonable bladder capacity was available, there was no mucus production from the inner layer of the flap, and metabolic and electrolyte disturbances were reduced.     

Contradictory effects of chlorpromazine on endothelial cells in a rat model of endotoxic shock in association with its actions on serum TNF-alpha levels and antioxidant enzyme activities.

We examined the effects of the phenothiazine derivative, chlorpromazine on thoracic aortic endothelial cell histology (14 h after LPS challenge) in a model of endotoxic shock in rats. Since excessive formation of tumor necrosis factor-alpha (TNF-alpha) and oxygen-derived free radicals contribute to endothelial injury in endotoxemia, we also evaluated the effect of the drug on the activities of antioxidant enzymes superoxide dismutase (SOD) and catalase in liver tissue in this model and tried to find out whether this possible effect was associated with a change in serum TNF-alpha levels (measured 90 min after chlorpromazine administration). Endotoxemia was induced by a single i.p. injection of lipopolysaccharide (LPS) (5 mg kg(-1) in 1.5 ml of saline; LPS from Escherichia coli serotype 055:B5, L-2880, Sigma Chemical Company). Electron microscopic evaluation of the aortas revealed that chlorpromazine (administered 30 min prior to LPS challenge), in smaller doses (3 mg kg(-1)) ameliorated the endothelial cell injury caused by LPS, whereas it caused deterioration of endothelial cell morphology in higher doses (10 and 25 mg kg(-1)). Chlorpromazine administration caused a significant reduction in serum TNF-alpha levels, which was correlated well with an increase in SOD activity in all drug doses (3, 10 and 25 mg kg(-1)). Catalase activity was increased only in the 25 mg kg(-1) chlorpromazine group.     

A Case of Distal Vaginal Agenesis Presenting with Recurrent Urinary Tract Infection and Pyuria in a Prepubertal Girl

Background

Isolated distal vaginal agenesis is a rare anomaly and mostly becomes symptomatic after menarche. We describe an unusual presentation of this anomaly in a prepubertal girl.

Endovascular management of renal angiomyolipomas: Do coils have a benefit in terms of clinical success rates?

PURPOSEThis study evaluated single-center results of endovascular treatment in renal angiomyolipoma (AML) to determine whether there is clinical relevance of adding proximal coil embolization to distal particle embolization in terms of safety, efficacy, and retreatment rates.METHODSA retrospective analysis was performed to evaluate patients undergoing transarterial embolization for renal AMLs from January 2007 to October 2020. Parameters regarding patient and tumor characteristics, embolization technique, treatment outcome, and complications were recorded. Patients were divided into 2 groups as A (only particle group) and B (particle + coil group) based on the type of embolic agent used for treatment. Comparative analysis was performed between the 2 groups in terms of tumor size reduction, retreatment, and complication rates. RESULTSIn this study, 42 patients (37 (88.1%) females and 5 (11.9%) males) harboring 48 AMLs were included. The mean age was 43.46 (range, 20-78). The technical success rate was 95.8% (46 of 48 procedures). The mean size reduction was 1.94 ± 1 cm (P  < .001) after treatments; however, no significant difference was seen between groups in terms of tumor size reduction. Retreatment rates were 3.1% (1 of 32 cases) in group A and 14.3% (2 of 14 cases) in group B (P  = .21). No significant difference was found between groups in terms of bleeding and complication rates during the perioperative period. Mean follow-up duration was 26.48 ± 25.71 (range, 2-102) months.CONCLUSIONIn this study, no clear supplementary benefit was observed in terms of safety and efficacy with the adjunction of coils to distal particle embolization in the management of AMLs.

Main points

• Transarterial embolization is safe and effective in reducing lesion size and bleeding rates in the management of angiomyolipomas.
• Lesion size reduction can be achieved with both techniques; solely microparticle embolization or distal microparticle embolization plus proximal coil embolization.
• Proximal coil embolization does not provide an additional benefit with lesions having intratumoral microaneurysms ≥5 mm as the study showed no difference in complication and bleeding rates.

Renal angiomyolipoma (AML) is one of the most common benign tumors of the kidney, with an incidence of 0.4% in the general population.^1,2 AMLs are seen in 2 forms; sporadic and tuberosclerosis (TSC) related. Sporadic form accounts for 80% of the AML cases. TSC-related AMLs tend to be bilateral, multifocal, larger with a faster growth rate and are more symptomatic than the sporadic type.³ AMLs have slow growth rates and rarely necessitate invasive treatment at all times.⁴ Historical data suggest that AMLs equal to or larger than 4 cm and those that have 5 mm or larger microaneurysms tend to be more symptomatic and prone to hemorrhage.^5,6 Although a treatment indication based on tumor size larger than 4 cm is subject to dispute,⁷ treatment decisions are often made using these cut-off values in the literature. Treatment options consist of medical treatment, surgery, transarterial embolization (TAE), and thermal ablation with no definitive recommendation on the first-line treatment choice.^8,9 However, because of its less-invasive nature, TAE is a favored choice in the management of AMLs over surgery. So far, various embolic agents (ethanol, microparticles, coils, gel foam, etc.) have been used in the management of patients with AML.¹⁰ Concerning the embolic materials, Patatas et al.¹¹ compared solely coil embolization with solely microparticle embolization in transarterial embolization of AMLs. They found similar reduction rates on computed tomography (CT) follow-up between the 2 groups. Ewalt et al.¹² showed that microparticle plus coil embolization is effective in terms of size reduction in large (>4 cm) and symptomatic and TSC-related AMLs. Although based on the literature, coils, microparticles, and microparticle + coil embolization are all safe and efficient, there are no clear data on the additional benefit of adding coil embolization to microparticle embolization in terms of treatment efficacy. Therefore, this study aimed to evaluate within single-center results whether there is clinical relevance of adding proximal coil embolization to distal microparticle embolization in terms of safety, efficacy, and retreatment rates.     

Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2

The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small-molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic, there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high-resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 153 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated conformational changes within the active site, and key inhibitor motifs that will template future drug development against Mac1.

The macrodomain of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) nonstructural protein 3 (NSP3) (Mac1) presents an intriguing target for drug discovery (1–5). Upon viral infection, host cells initiate an innate interferon-mediated immune response leading to the expression of poly-(ADP-ribose)-polymerases (PARPs), which catalyze the antiviral posttranslational addition of ADP-ribose (ADPr) to a large range of target proteins (6). Mac1 enzymatically reverses this mono-ADP-ribosylation, counteracting immune signaling (7). Promisingly, inactivation of Mac1 by single-point mutations in the ADPr-binding site significantly reduced lethality and pathogenicity in mice after SARS-CoV infection (8). Small-molecule inhibitors of SARS-CoV-2 Mac1 should therefore offer novel therapeutics to mitigate COVID-19 (9, 10).A challenge for the development of such inhibitors has been the lack of small-molecule modulators of macrodomain activity, other than ADPr; indeed, only recently have quantitative assays been developed (10, 11). This is true not only for Mac1 from SARS-CoV-2, but also for the overall family of enzymes, which lack good chemical matter by which their activity can be probed, despite their importance in several areas of health and diseases. Accordingly, to map the recognition determinants of Mac1, we adopted a biophysical approach, screening for fragment ligands using protein crystallography, molecular docking, isothermal titration calorimetry (ITC), differential scanning fluorimetry (DSF), and a binding assay based on homogeneous time-resolved fluorescence (HTRF) (12). Mac1 proved to be unusually amenable to structure determination, enabling us to determine the structures of over 230 fragment complexes, typically to ultra-high resolution (often better than 1.1 Å), affording us a detailed map of enzyme hot spots with chemical matter of sufficient potency with which to optimize a quantitative assay (12, 13).Nevertheless, our best fragments remained of modest potency, with none more potent than 180 µM. Here, we describe the discovery and optimization of potent macrodomain ligands using two strategies (Fig. 1). In the first, we sought to link and merge pairs of fragments to create larger molecules that exploited multiple hot spots, so reaching higher affinities. This used a fragment-linking method (12), adapted to explore a virtual library of 22 billion readily synthesizable molecules (14). In the second approach, we exploited the hot spots revealed by the initial fragments to guide computational docking of ultra-large chemical libraries of lead-like molecules, potentially more potent than the fragments docked in our original study (12). Both approaches ultimately led to compounds with IC₅₀ values as low as 0.4 µM for the merged fragments and as low as 1.7 µM for the docking hits (Fig. 1). These represent the most potent inhibitors reported for any member of the broad family of macrodomains. Furthermore, the many X-ray crystal structures determined here provide an extensive resource for drug development campaigns against this promising antiviral target.Open in a separate windowFig. 1.Overview of the structure-based strategies used to discover ligands that bind to the NSP3 macrodomain of SARS-CoV-2 (Mac1).     

Early osteoblastic activity on TiO2 thin films decorated with flower-like hierarchical Au structures

Titanium alloys are the most commonly used dental and orthopedic implant materials due to their proven biocompatibility and mechanical properties. The native oxide layer (TiO₂ layer) formed on such Ti-based implants acts as the self-protecting layer against possible ion release. Increasing the oxide layer thickness further on such TiO₂ implants even opens the triggering of the osseointegration process if the oxide layer is having a certain degree of roughness, preferably higher. This work reports a novel photocatalytic patterning of sputter deposited TiO₂ layers with flower-like Au structures to enhance the early osteoblastic activity. The prepared hierarchical Au structures, composed of micro- and nanoscale features on the top, lead to improved number of filopodia formation. This suggest that proposed Au–TiO₂ surface may foster the cell attachment and as well as cell proliferation.

Flower-like hierarchical Au structures, composed of micro- and nanoscale features, lead to higher number of filopodia formation on TiO₂ thin films.