Alveolar Bone Grafting in Cleft Patients from Bone Defect to Dental Implants

Cleft lip and palate is the most common congenital deformity affecting craniofacial structures. Orofacial clefts have great impact on the quality of life which includes aesthetics, function, psychological impact, dental development and facial growth. Incomplete fusion of facial prominences during the fourth to tenth week of gestation is the main cause. Cleft gaps are closed with alveolar bone grafts in surgical procedure called osteoplasty. Autogenic bone is taken from the iliac crest as the gold standard. The time of grafting can be divided into two stages: primary and secondary. The alveolar defect is usually reconstructured between 7 and 11 years and is often related to the development of the maxillary canine root. After successful osteoplasty, cleft defect is closed but there is still a lack of tooth. The space closure with orthodontic treatment has 50-75% success. If the orthodontic treatment is not possible, in order to replace the missing tooth there are three possibilities: adhesive bridgework, tooth transplantation and implants. Dental implant has the role of holding dental prosthesis, prevents pronounced bone atrophy and loads the augmentation material in the cleft area. Despite the fact that autologous bone from iliac crest is the gold standard, it is not a perfect source for reconstruction of the alveolar cleft. Bone morphogenic protein (BMP) is appropriate as an alternative graft material. The purpose of this review is to explain morphology of cleft defects, historical perspective, surgical techniques and possibilities of implant and prosthodontic rehabilitation.Key words: Cleft Lip, Cleft Palate, Alveolar bone grafting, Bone Morphogenic Proteins, Dental implants, Dental prosthesis, Orthodontic Space Closure     

In vivo toxicity evaluation of two polyoxotungstates with potential antidiabetic activity using Wistar rats as a model system

In this study, the in vivo hypoglycemic effect of a donut-shaped polyanion salt (NH₄)₁₄[Na@P₅W₃₀O₁₁₀]·31H₂O {NaP₅W₃₀} and its Ag-containing derivative K₁₄[Ag@P₅W₃₀O₁₁₀]·22H₂O·6KCl {AgP₅W₃₀}, as well as their hepatotoxicity and nephrotoxicity, was evaluated. In the screening hypoglycemic study, Wistar albino rats with streptozotocin induced diabetes were treated intraperitoneally with three single doses (5, 10, and 20 mg per kg per b.w.) of both investigated polyoxotungstates. The blood glucose levels, measured before and after 2, 4 and 6 h polyoxotungstate application, showed that both studied compounds induced the most pronounced and time dependent glucose lowering effects at the doses of 20 mg kg⁻¹. Thus, daily doses of 20 mg kg⁻¹ were administered to Wistar albino rats orally for 14 days in further toxicity examinations. The serum glucose concentration and biochemical parameters of kidney and liver function, as well as a histopathological analysis of kidney and liver tissues were evaluated 14 days after the polyoxotungstate administration. Both investigated compounds did not induce statistically significant alterations of the serum glucose and uric acid concentrations, as well as some of the liver function markers (serum alanine and aspartate aminotransferases, and alkaline phosphatase activities). However, the significant decrease in serum total protein and albumin concentrations and the increase in biochemical parameters of renal function – serum urea (up to 63.1%) and creatinine concentrations (up to 23.3%) were observed for both polyoxotungstates. In addition, the detected biochemical changes were in accordance with kidney and liver histhopathological analysis. Accordingly, the hepatotoxic and nephrotoxic effects of these potential antidiabetic polyoxotungstates could be considered as mild.

Study of the in vivo hypoglycemic effect, hepatotoxicity and nephrotoxicity of a donut-shaped polyanion salt (NH₄)₁₄[Na@P₅W₃₀O₁₁₀]·31H₂O {NaP₅W₃₀} and its Ag-containing derivative K₁₄[Ag@P₅W₃₀O₁₁₀]·22H₂O·6KCl {AgP₅W₃₀}.     

Pimecrolimus cream 1% in the treatment of lichen sclerosus

BACKGROUND: Lichen sclerosus (LS) is a chronic inflammatory skin condition, which most commonly causes dysuria, pruritus and soreness of the vulval and perianal areas. Potent topical corticosteroids are used for the treatment of LS, but it is well known that they inhibit collagen synthesis and cause skin atrophy as a side effect. METHODS: The present pilot study evaluated the efficacy and safety of pimecrolimus cream 1% applied twice daily for up to 6 months in 29 women with severe LS. RESULTS: Of the 26 subjects who completed the follow-up period, 42% (11/26) were in complete remission with relief from itchiness, pain and inflammation. A 3.5-fold increase in type I collagen synthesis and a 7.5-fold increase in type III collagen synthesis of the affected areas was detected after 2 months of pimecrolimus treatment. There were no systemic adverse reactions, although mild local skin reactions were reported by 50% of the patients. Blood concentrations of pimecrolimus were checked in 10/26 patients (39%) and were undetectable in all cases. CONCLUSIONS: Patient-applied 1% pimecrolimus cream is safe and effective for the treatment of LS.     

Clinical Impacts of Copy Number Variations in B-cell Differentiation and Cell Cycle Control Genes in Pediatric B-cell Acute Lymphoblastic Leukemia: a Single Centre Experience

BackgroundIKZF1 gene deletions have been identified as a poor prognostic factor in pediatric B-cell acute lymphoblastic leukemia (B-ALL), especially in the presence of co-occurring deletions (IKZF1^plus profile). This study aimed to determine the frequency of IKZF1 deletions and deletions in other B-cell differentiation and cell cycle control genes, and their prognostic impact in Slovenian pediatric B-ALL patients.Patients and methodsWe studied a cohort of 99 patients diagnosed with B-ALL from January 2012 to December 2020 and treated according to the ALL IC-BFM 2009 protocol. Eighty-eight bone marrow or peripheral blood samples were analysed for copy number variations (CNVs) using the SALSA MLPA P335 ALL-IKZF1 probemix.ResultsAt least one CNV was detected in more than 65% of analysed samples. The most frequently altered genes were PAX5 and CDKN2A/B (30.7%, 26.1%, and 25.0%, respectively). Deletions in IKZF1 were present in 18.2% of analysed samples and were associated with an inferior 5-year event-free survival (EFS; 54.8% vs. 85.9%, p = 0.016). The IKZF1^plus profile was identified in 12.5% of the analysed samples, and these patients had an inferior 5-year EFS than those with deletions in IKZF1 only and those without deletions (50.8% vs. 75.0% vs. 85.9%, respectively, p = 0.049). Overall survival (OS) was also worse in patients with the IKZF1^plus profile than those with deletions in IKZF1 only and those without deletions (5-year OS 76.2% vs. 100% vs. 93.0%, respectively). However, the difference between the groups was not statistically significant.ConclusionsOur results are in concordance with the results obtained in larger cooperative clinical trials. Copy number variations analysis using the SALSA MLPA kit is a reliable tool for initial diagnostic approach in children with B-ALL, even in smaller institutions in low- and middle-income countries.Key words: B-acute lymphoblastic leukemia, IKZF1 deletions, IKZF1 ^plus , MLPA, pediatric, copy number variations (CNVs)     

Murine Recombinant Angiotensin-Converting Enzyme 2: Effect on Angiotensin II-Dependent Hypertension and Distinctive Angiotensin-Converting Enzyme 2 Inhibitor Characteristics on Rodent and Human Angiotensin-Converting Enzyme 2

A newly produced murine recombinant angiotensin (Ang)-converting enzyme 2 (ACE2) was characterized in vivo and in vitro. The effects of available ACE2 inhibitors (MLN-4760 and 2 conformational variants of DX600, linear and cyclic) were also examined. When murine ACE2 was given to mice for 4 weeks, a marked increase in serum ACE2 activity was sustainable. In acute studies, mouse ACE2 (1 mg/kg) obliterated hypertension induced by Ang II infusion by rapidly decreasing plasma Ang II. These effects were blocked by MLN-4760 but not by either form of DX600. In vitro, conversion from Ang II to Ang-(1-7) by mouse ACE2 was blocked by MLN-4760 (10(-6) m) but not by either form of DX600 (10(-5) m). Quantitative analysis of multiple Ang peptides in plasma ex vivo revealed formation of Ang-(1-9) from Ang I by human but not by mouse ACE2. Both human and mouse ACE2 led to the dissipation of Ang II with formation of Ang (1-7). By contrast, mouse ACE2-driven Ang-(1-7) formation from Ang II was blocked by MLN-4760 but not by either linear or cyclic DX600. In conclusion, sustained elevations in serum ACE2 activity can be accomplished with murine ACE2 administration, thereby providing a strategy for ACE2 amplification in chronic studies using rodent models of hypertension and cardiovascular disease. Human but not mouse ACE2 degrades Ang I to form Ang-(1-9). There are also species differences regarding rodent and human ACE2 inhibition by known inhibitors such that MLN-4760 inhibits both human and mouse ACE2, whereas DX600 only blocks human ACE2 activity.     

Value of posttransplant protocol biopsies in 2 biliary autoimmune liver diseases: A step toward personalized immunosuppressive treatment

The value of protocol liver graft biopsies with good liver function was evaluated in patients with primary sclerosing cholangitis (PSC) or primary biliary cholangitis (PBC).A total of 250 protocol liver biopsy reports from 182 PSC and PBC patients were compared. Overall histopathological findings and those leading to changes in immunosuppression therapy were retrospectively analyzed.The mean time to first protocol biopsy after transplantation was 5.5 (±4.5) years for PSC patients and 9.3 (±6.6) years for PBC patients. More than 1 abnormal histopathological parameter was found in 43% and 62% of PSC and PBC patients, respectively. However, the histology was interpreted as normal by the pathologist in 78% of PSC and 60% of PBC patients. Immunosuppression therapy was reduced in 10% and increased in 6% patients due to protocol biopsy findings. Biopsies leading to increased immunosuppression therapy had more portal (P = .004), endothelial (P = .008), interphase (P = .021), and lobular (P = .000) inflammation.Mild histopathological findings were frequently found in the protocol biopsies despite the normal biochemistry. PBC patients had more histological abnormalities than those transplanted due to PSC; however, PBC patients had longer follow-up times. Immunosuppression therapy could be safely increased or decreased according to protocol biopsy findings after multidisciplinary meeting discussions.     

New Drugs on the Block—Emerging Treatments for Nonalcoholic Steatohepatitis

Patients with nonalcoholic steatohepatitis (NASH) are at higher risk of progression to advanced stages of fibrosis, cirrhosis, hepatocellular carcinoma and othe...     

Can Fasting Curb the Metabolic Syndrome Epidemic?

Metabolic syndrome (MetS) represents a cluster of metabolic abnormalities that includes hypertension, central obesity, insulin resistance, and atherogenic dyslipidemia. Due to the high prevalence (around 1/3 of the world population) economic burden of MetS, there is a need for new dietary, lifestyle, and therapeutic options. Recently, fasting emerged as a dietary method proposed for controlling metabolic risk factors. Intermittent fasting (IF), or time-restricted feeding (TRF), describes an array of feeding patterns in which calorie intake is restricted to a specific time period. Hence, this review aimed to elucidate the latest data on MetS and explore the viability of simple management options, such as IF and TRF. Preclinical studies have shown how IF/TRF exerts beneficial effects on the gut microbiota, glucose and insulin metabolism, weight and visceral fat, and lipid metabolism. However, the results obtained from human studies are somewhat conflicting, as weight loss was achieved in all studies, whereas in some studies, there was no significant effect on insulin resistance, cholesterol/lipid metabolism, or blood pressure. Nevertheless, as only very few human studies were performed, there is a need for more randomized control trials on larger cohorts of patients with MetS to gather higher-yield evidence to clarify whether IF/TRF are suitable dietary patterns for this population.     

Chemoselective synthesis of multifunctional ferrocene-containing derivatives by the cross Rauhut–Currier reaction

A simple protocol has been developed for the chemoselective synthesis of ferrocene-containing Rauhut–Currier adducts from 1-ferrocenyl-2-nitroethene and vinyl ketones using 20 mol% of triphenylphosphine. Multifunctional ferrocene derivatives were obtained in moderate to high yields (51–92%) by the coupling between the α-position of vinyl ketones and the β-position of the nitroalkene. The study of the Rauhut–Currier reaction under the described conditions showed that the strong electron-donating group at the β-position of nitroalkenes plays a significant role in the reaction outcome due to prevention of polymerization and stabilization of the zwitterionic intermediate. Additionally, a preparative synthesis of 4-ferrocenyl-3-methylene-5-nitropentan-2-one was carried out and its synthetic transformations showed easy conversion to other useful building blocks.

A simple method has been developed for the chemoselective synthesis of ferrocene-containing Rauhut–Currier adducts from 1-ferrocenyl-2-nitroethene and vinyl ketones catalyzed by triphenylphosphine.