Modelling the dynamics of expiratory airflow to describe chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by expiratory airflow limitation, but current diagnostic criteria only consider flow till the first second and are therefore strongly debated. We aimed to develop a data-based individualized model for flow decline and to explore the relationship between model parameters and COPD presence. A second-order transfer function model was chosen and the model parameters (namely the two poles and the steady state gain (SSG)) from 474 individuals were correlated with COPD presence. The capability of the model to predict disease presence was explored using 5 machine learning classifiers and tenfold cross-validation. Median (95 % CI) poles in subjects without disease were 0.9868 (0.9858–0.9878) and 0.9333 (0.9256–0.9395), compared with 0.9929 (0.9925–0.9933) and 0.9082 (0.9004–0.9140) in subjects with COPD (p < 0.001 for both poles). A significant difference was also found when analysing the SSG, being lower in COPD group 3.8 (3.5–4.2) compared with 8.2 (7.8–8.7) in subjects without (p < 0.0001). A combination of all three parameters in a support vector machines corresponded with highest sensitivity of 85 %, specificity of 98.1 % and accuracy of 88.2 % to COPD diagnosis. The forced expiration of COPD can be modelled by a second-order system which parameters identify most COPD cases. Our approach offers an additional tool in case FEV₁/FVC ratio-based diagnosis is doubted.     

Long lasting near-obstruction stenosis of mesencephalic aqueduct without development of hydrocephalus – case report

The aim of this study is to present the five-year longitudinal magnetic resonance imaging (MRI) follow up of a patient with incidental finding of near-obstruction stenosis of the aqueduct of Sylvius due to a large pineal cyst. The patient was scanned 3 times on a 3T MR device using a set of standard structural sequences supplemented with high-resolution constructive interference of steady state (CISS) T2 sequence for precise delineation of the aqueduct of Sylvius and cardiac-gated phase-contrast sequences for the analysis of cerebrospinal fluid (CSF) movement. On all MR scans, the size of the pineal cyst and severity of near-obstruction aqueductal stenosis did not show any morphological changes. There was no significant ventricular enlargement although structural CISS sequence showed a near-obstruction stenosis and cardiac-gated phase-contrast sequences did not detect CSF movement through the aqueduct of Sylvius. Our findings are contradictory to the classic hypothesis of CSF physiology based on secretion, circulation, and absorption of CSF, which states that the impairment of CSF circulation through the aqueduct of Sylvius inevitably leads to a hypertensive hydrocephalus development involving the third and the lateral ventricle. Our research group previously proposed a new hypothesis of CSF physiology, which offers more suitable explanation for such clinical cases.Clinical practice has shown that an aqueduct of Sylvius obstruction or severe stenosis (tumoral compression, intrinsic non-tumoral pathology) could lead to a development of the triventricular hypertensive hydrocephalus (1). According to the classic hypothesis of CSF physiology, CSF is secreted inside the brain ventricles and flows unidirectionally along the subarachnoid space to be absorbed into the dural venous sinuses or into perineural lymphatic system (2,3). Therefore, a blockade of CSF flow from the third to the fourth lateral ventricle at the aqueduct of Sylvius level inevitably leads to the triventricular hypertensive hydrocephalus development. It is assumed that CSF is formed by an active secretion mainly by the choroid plexuses against hydrostatic pressure inside the CSF system, so any blockade between the site of secretion and the site of absorption will lead to CSF accumulation, CSF system enlargement, and subsequently to the development of hydrocephalus proximal to the obstruction site (1).The aqueduct of Sylvius is a narrow canal inside the mesencephalon that connects the third and the fourth lateral ventricle, thus, according to the classic hypothesis, its passability is of key importance for normal CSF physiology (2,3). An aqueduct of Sylvius stenosis sometimes leads to the compensatory changes of the CSF system that are known as “arrested hydrocephalus” (4). The compensatory mechanisms of this state are still unclear. We present a patient with long lasting near-obstruction stenosis without detectable CSF movement through the aqueduct of Sylvius, which has some similarities with the “arrested hydrocephalus” condition. Despite the functional blockade of CSF movement, no significant ventricular enlargement was observed during the follow up period of 5 years. Such findings are contradictory to the classic hypothesis of CSF hydrodynamics and classic circulatory hypothesis of hydrocephalus development. However, the new hypothesis of CSF physiology proposed by our team (Bulat, Orešković and Klarica hypothesis) (5-7) states that stenosis/blockade of aqueduct of Sylvius could favor but does not necessarily lead to the development of hydrocephalus (6,8). In this case report, we discuss pathophysiological mechanisms of hydrocephalus development from the perspective of both classic and new microcirculatory hypothesis of CSF physiology (5-7).     

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}.     

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...     

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.     

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.     

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.