Biomechanical comparison of titanium alloy additively manufactured and conventionally manufactured plate-screw constructs.

AIM: To biomechanically compare the bending stiffness, strength, and cyclic fatigue of titanium additively manufactured (AM) and conventionally manufactured (CM) limited contact plates (LCP) of equivalent dimensions using plate-screw constructs. METHODS: Twenty-four 1.5/2.0-mm plate constructs (CM: n = 12; AM: n = 12) were placed under 4-point bending conditions. Data were collected during quasi-static single cycle to failure and cyclic fatigue testing until implants plastically deformed or failed. Bending stiffness, bending structural stiffness, and bending strength were determined from load-displacement curves. Fatigue life was determined as number of cycles to failure. Median test variables for each method were compared using the Wilcoxon rank sum test within each group. Fatigue data was also analysed by the Kaplan-Meier estimator of survival function. RESULTS: There was no evidence for a difference in bending stiffness and bending structural stiffness between AM and CM constructs. However, AM constructs exhibited greater bending strength (median 3.07 (min 3.0, max 3.4) Nm) under quasi-static 4-point bending than the CM constructs (median 2.57 (min 2.5, max 2.6) Nm, p = 0.006). Number of cycles to failure under dynamic 4-point bending was higher for the CM constructs (median 164,272 (min 73,557, max 250,000) cycles) than the AM constructs (median 18,704 (min 14,427, max 33,228) cycles; p = 0.02). Survival analysis showed that 50% of AM plates failed by 18,842 cycles, while 50% CM plates failed by 78,543 cycles. CONCLUSION AND CLINICAL RELEVANCE: Additively manufactured titanium implants, printed to replicate a conventional titanium orthopaedic plate, were more prone to failure in a shorter fatigue period despite being stronger in single cycle to failure. Patient-specific implants made using this process may be brittle and therefore not comparable to CM orthopaedic implants. Careful selection of their use on a case/patient-specific basis is recommended.

Disseminated Rasamsonia argillacea infection in a dog.

CASE HISTORY: A 4-year-old, male neutered Borzoi presented for unlocalised pain and frequent episodes of vocalisation. CLINICAL FINDINGS: Pain was localised to the lumbar spine and radiographs revealed a L3-L4 lesion consistent with discospondylitis. The dog was treated for presumptive bacterial discospondylitis with surgical debridement, spinal stabilisation, and cephalexin. Samples collected from the affected intervertebral disc at the time of surgery revealed lymphoplasmacytic inflammation with no causative agent identified on histopathology or bacterial culture. After an initial period of improvement, signs recurred despite an 8-week antibiotic course, with the development of inappetence, weight loss, polydipsia, and polyuria. Repeat radiographs revealed a new cervical intervertebral lesion, and concurrent pyelonephritis was diagnosed based on blood and urine results. Fungal culture of urine resulted in growth of Rasamsonia argillacea species complex and disseminated fungal disease was clinically diagnosed. Antifungal treatment was commenced, however the dog deteriorated, and euthanasia was performed. PATHOLOGICAL FINDINGS: Multifocal white plaques were grossly visualised in the spleen, mesenteric lymph nodes, cervical vertebrae, and kidneys. Periodic acid-Schiff-positive, fine, parallel-walled, occasionally branching, septate hyphae 5-10 µm in diameter, and conidia 5-7 µm in diameter were found on sectioning all organs. R. argillacea species complex was identified by fungal culture of urine and was considered the species of fungal organism seen histologically. The isolate was subsequently confirmed as R. argillacea by DNA sequencing. DIAGNOSIS: Disseminated Rasamsonia argillacea infection. CLINICAL RELEVANCE: Rasamsonia argillacea species complex is a recognised invasive mycosis in veterinary medicine, with disseminated disease causing significant clinical complications and death. This is believed to be the first report of infection caused by R. argillacea in a dog in Australasia and highlights the importance of awareness of a potential fungal aetiology in dogs with discospondylitis.Abbreviations: CLSI: Clinical and Laboratory Standards Institute; CRI: Constant rate infusion; MEC: Minimum effective concentration; MIC: Minimum inhibitory concentration; PAS: Periodic acid-Schiff.

A mechanistic physiologically based model to assess the effect of study design and modified physiology on formulation safe space for virtual bioequivalence of dermatological drug products.

Physiologically based pharmacokinetic (PBPK) models are widely accepted tools utilised to describe and predict drug pharmacokinetics (PK). This includes the use of dermal PBPK models at the regulatory level including virtual bioequivalence (VBE) studies. The current work considers the Topicort® Spray formulation, which contains 0.25% desoximetasone (DSM), as an example formulation. Quantitative formulation composition and in vitro permeation testing (IVPT) data were obtained from the public literature to develop a mechanistic model using the multi-phase, multi-layer (MPML) MechDermA IVPT module in the Simcyp Simulator. In vitro-in vivo extrapolation functionality was used to simulate in vivo PK for various scenarios and predict a 'safe space' for formulation bioequivalence using the VBE module. The potential effect of vasoconstriction, impaired barrier function, and various dosing scenarios on the formulation safe space was also assessed. The model predicted 'safe space' for formulation solubility suggesting that a 50% change in solubility may cause bio-in-equivalence, whereas viscosity could deviate by orders of magnitude and the formulation may still remain bioequivalent. Evaporation rate and fraction of volatile components showed some sensitivity, suggesting that large changes in the volume or composition of the volatile fraction could cause bio-in-equivalence. The tested dosing scenarios showed decreased sensitivity for all formulation parameters with a decreased dose. The relative formulation bioequivalence was insensitive to vasoconstriction, but the safe space became wider with decreased barrier function for all parameters, except viscosity that was unaffected.

Scanning electron microscopic study of the human uterine tube epithelial lining: surgical biopsy samples and epithelial cell culture.

This article summarizes the importance of the exact morphology of human uterine/fallopian tube epithelium at the scanning electron microscopy (SEM) level for the clinical outcome even nowadays. Visual referential micrographs from SEM reflect two ways to view human epithelial cell lining surfaces: the surface epithelial uterine tube from surgical tissue biopsy and human fallopian tube epithelial cells (HFTEC) culture monolayer surface. One colorized image visualizes ciliated cells, distinguishes them from non-ciliated cells, and provides an educational benefit. A detailed description of the ultrastructure in referential and pathologic human uterine tube epithelium is important in defining the morphological basis of high-grade carcinomas, in the mechanism of pathophysiology, and in discussing options for its prevention. Cell cultures of human fallopian tube epithelial cells offer new approaches in simulating the mechanisms of cancer genesis or may help to elucidate the genetic basis of several diagnoses. New technical approaches in SEM provide higher resolution and detailed surface images. The SEM modality is still one of the current options in diagnostics and may be useful for advancing human reproductive organ cancer research.

Surgical management of superficial digital flexor tendon luxation in dogs: 48 cases (2005-2020).

OBJECTIVES: To report the outcome, frequency of complications and potential prognostic factors associated with surgical repair of superficial digital flexor tendon (SDFT) luxation in dogs. MATERIALS AND METHODS: Medical records from 10 referral hospitals were reviewed retrospectively for cases of SDFT luxation in dogs that underwent surgical stabilisation. Signalment, clinical presentation, diagnostic imaging, surgical method, type and length of post-operative limb immobilisation, nature of and length of exercise restriction, presence of post-operative complications and outcomes were recorded. Data were summarised descriptively and prognostic risk factors assessed for association with surgical outcome using risk ratios. RESULTS: Forty-eight cases were included. A successful surgical outcome was recorded in 35 of 48 (73%) cases. Re-luxation of the SDFT occurred in seven of 48 (15%). Six out of 48 (13%) had a persistent lameness despite a stable non-luxating SDFT. A high frequency of post-operative complications occurred (71%), with the majority resolved medically. The risk of surgical failure was 60% higher (risk ratio 1.6, 95% confidence interval 1.1 to 2.4) where absorbable suture material was used compared to non-absorbable suture material. Surgical failure was more common in cases managed with non-rigid immobilisation post-operatively (57% failure) compared to cases managed with rigid immobilisation (19% failure), although this result was not statistically significant. Limb immobilisation of 6 weeks or longer did not significantly affect surgical outcome, compared to shorter periods of exercise restriction or limb immobilisation. CLINICAL SIGNIFICANCE: A good outcome can be expected following surgical stabilisation of SDFT luxation. The use of non-absorbable suture was associated with a more successful surgical outcome.

Electron microscope images of human coronaviruses - Reality versus illusion.

Since the outbreak of COVID-19 as a pandemic disease earlier in 2020, several publications reported the electron microscope images of SARS-CoV-2. This article reviews 73 articles from March 1956 till April 2021, focusing on the ultrastructure characteristics of the coronaviruses. We present the scientific debate and provide an opinion on the current controversy of electron microscopic images interpreted as SARS-CoV-2 particles in specimens from patients with COVID-19. Finally, we report our findings in a post-mortem lung specimen of a COVID-19 patient. With this we hope to facilitate accurate interpretation of TEM findings, and contribute to the building of a unified database in the face of COVID-19 (Tab. 2, Fig. 8, Ref. 81). Keywords.

Few Insights on the problem of COVID-19.

The recent Coronavirus 2019 outbreak took the world by surprise and called for global drastic measures. At this early point in the timeline of the pandemic, several questions remain open until the results of large scale studies become available. This article offers few insights on scattered issues; including the clinical characteristics, pathology and diagnosis, as well as treatment perspectives and public health approach. Focusing healthcare resources on necessary treatment and prevention and combining efforts for developing feasible solutions will be decisive for time needed to achieve worldwide containment (Tab. 1, Ref. 23). Keywords: COVID-19, Coronavirus 2019, pandemic, public health.

Ependymal cells surface of human third brain ventricle by scanning electron microscopy.

OBJECTIVES: The ependymal lining of the human brain ventricular system displays distinct structural differences and functional heterogeneity among individual ependymal cells (ECs). To date, multi-ciliated ECs (E1 cells), bi-ciliated ECs (E2 cells), uni-ciliated ECs (E3 cells), ECs without cilia, and ECs with cytoplasmic protrusions have been described in human brain ventricles. METHOD: Using scanning electron microscopy (SEM), we evaluated ependymal samples from 6 defined regions of the third ventricle from 9 human brains. These regions were strictly defined according to the periventricular structures they neighbour with. RESULTS: We observed different structures on the apical surface of the ECs. Various ECs differed from each other by the presence of microvilli, secretory bodies, and a variable number of cilia, which led us to divide the ECs into several exactly specified types according to their apical morphology. CONCLUSION: We found all types of ECs in every examined region with a predominance of particular types of apical surface of ECs in the individual areas (Tab. 4, Fig. 7, Ref. 22).

Iron-oxide minerals in the human tissues.

Iron is critically important and highly regulated trace metal in the human body. However, in its free ion form, it is known to be cytotoxic; therefore, it is bound to iron storing protein, ferritin. Ferritin is a key regulator of body iron homeostasis able to form various types of minerals depending on the tissue environment. Each mineral, e.g. magnetite, maghemite, goethite, akaganeite or hematite, present in the ferritin core carry different characteristics possibly affecting cells in the tissue. In specific cases, it can lead to disease development. Widely studied connection with neurodegenerative conditions is widely studied, including Alzheimer disease. Although the exact ferritin structure and its distribution throughout a human body are still not fully known, many studies have attempted to elucidate the mechanisms involved in its regulation and pathogenesis. In this review, we try to summarize the iron uptake into the body. Next, we discuss the known occurrence of ferritin in human tissues. Lastly, we also examine the formation of iron oxides and their involvement in brain functions.

Fertility maintenance in male oncological patients: current state and future perspectives.

Growing cancer incidence in reproductive age goes hand in hand with a rising survival rate of patients who underwent anticancer therapy. This trend points to the necessity of discussion regarding the fertility maintenance. The patient´s future with respect to his reproductive ability has to be addressed properly to achieve a complex approach to cancer management. The germinal epithelium of the testes is highly susceptible to deleterious effects of chemotherapy. After the administration of gonadotoxic chemotherapeutic agents, a patient can develop oligospermia, or even azoospermia. Similarly, radiation exposure can damage spermatogenesis, while higher doses lead to azoospermia. This review brings an overview of the methods of assisted reproduction, which are currently in use for fertility maintenance in oncological patients, but also in those with non-malignant indications. Also, novel, yet still experimental, methods are discussed, which represent promising technologies applicable to prepubertal oncological patients. We also discuss historical milestones in the development of assisted reproduction, summarize the options of semen analysis, and we present a practical guide through the process of sperm cryopreservation and subsequent in vivo or in vitro fertilisation. We deem that fertility maintenance should be an integral part of the health care in oncological patients in reproductive age (Tab. 1, Ref. 85). Keywords: assisted reproduction technique, sperm cryopreservation, testicular tissue cryopreservation, spermatogenesis, sperm quality in oncological patients.

The effect of GnRH agonists on angiogenesis and its implications for the myocardium in patients with cardiac risk.

Gonadotropin-releasing hormone agonists were described as anti-angiogenic factors in tumors. Simultaneously they were associated with increased cardiovascular risk in patients treated for prostate cancer, especially in those with preexisting cardiac disease. Studies aiming to elucidate the mechanisms by which androgen deprivation therapy causes cardiovascular effects are rare. We believe that gonadotropin-releasing hormone agonists can impair myocardial angiogenesis. That, in patients with myocardial disease can deepen hypoxia, significantly worsen the condition of the myocardium, and therefore increase the risk of cardiac failure. Careful assessment of the myocardial status and consequent timing and typing of therapy can minimalize the adverse effects. Ideally through close cooperation between cardiologists and oncologists (Fig. 1, Ref. 25). Keywords: angiogenesis, cardiovascular risk, follicle stimulating hormone, GnRH agonist, testosterone.

Sentinel lymph node - historical background and current views on its significance in complex management of breast cancer patients.

Nowadays, breast cancer is the leading oncological diagnosis in women worldwide. On the other hand, breast cancer treatment can be considered one of the most progressive therapeutic approach in the medical field of oncology. The invasive types of breast cancer have a tendency to spread via lymphatic route, what brings in the issue of sentinel lymph node - the first node into which the lymph drains from a given anatomical location. This review paper discusses the historical background of the concept of sentinel lymph node and focuses on clinical significance of the positivity of sentinel lymph node(s) as well. Modern-day conservative therapeutic surgery of breast cancer should be in accordance with diagnostic and preventive interventions in the axilla, whose rate of invasiveness and morbidity must be also attenuated without worsening the patient´s prognosis and survival rate. Formerly, a complete axillary lymph node dissection was routinely performed for prophylactic and cancer staging purposes. The indiscriminate application of this approach was replaced by sentinel lymph node biopsy. Along with common histopathological examination, immunohistochemistry, as well as modern techniques of molecular biology are often employed. These state-of-the-art methods enabled the identification of micrometastases, or even nanometastases, though their real prognostic value is yet to be concluded (Ref. 52). Keywords: sentinel node, breast cancer, biopsy, historical background.

Artificial intelligence in service of medicine.

The race to make the dream of artificial intelligence a reality comes parallel with the increasing struggle of health care systems to cope with information overload and translational pressure. It is clear that a shift in the way data is generated requires a shift in the way they are processed. This is where AI comes with great promises to solve the problem of volume versus applicability of information in science. In medicine, AI is showing exponential progress in the fields of predictive analysis and image recognition. These promises however, come with an intricate package of ethico-social, scientific and economic implications, towards which a reductionist approach leads to distorted and dramatic predictions. All this, in a time when the growing pressure on healthcare systems towards defensive medicine begs the question of the true need for AI for good medical practice.This article examines the concept and achievements of AI and attempts to offer a complex view on the realistic expectations from it in medicine, in the context of current practice (Ref. 38). Keywords: algorithms, artificial intelligence, image recognition, neural networks, predictive analysis.

Elevated age-related cortical iron, ferritin and amyloid plaques in APP(swe)/PS1(deltaE9) transgenic mouse model of Alzheimer's disease.

Iron is very important element for functioning of the brain. Its concentration changes with aging the brain or during disease. The aim of our work was the histological examination of content of ferritin and free iron (unbound) in brain cortex in association with Abeta plaques from their earliest stages of accumulation in amyloid plaque forming APP/PS1 transgenic mice. Light microscopy revealed the onset of plaques formation at 8-monthage. Detectable traces of free iron and no ferritin were found around plaques at this age, while the rate of their accumulation in and around Abeta plaques was elevated at 13 months of age. Ferritin accumulated mainly on the edge of Abeta plaques, while the smaller amount of free iron was observed in the plaque-free tissue, as well as in and around Abeta plaques. We conclude that free iron and ferritin accumulation follows the amyloid plaques formation. Quantification of cortical iron and ferritin content can be an important marker in the diagnosis of Alzheimer's disease.

Labelling of individual ependymal areas in lateral ventricles of human brain: ependymal tables.

Different types of ependymal areas were studied and labelled in the human brain lateral ventricle. Periventricular structures were included in coining the names of the ependymal areas because they represent a basic and stable part of brain nerve structures suitable for the sake of clarity of localization of the ependyma. The labelling of individual ependymal areas was composed from letters: "Lv" (lateral ventricle); "E" (ependymal area) and letters for abbreviations of the closest periventricular structure, e.g. the septum pellucidum is "sp". The labelling for ependymal area over the septum pellucidum is thus "LvE-sp". The studied types of ependymal areas were arranged in so­called ependymal tables for cornu anterius, pars centralis, cornu inferius and cornu posterius of the human lateral ventricle. Labelling of individual ependymal areas allows for better localization and characterisation of these areas in future studies carried out by various methods (e.g. morphological, biological, molecular) and will prevent from using misnomers with different types of ependymal areas in norm as well as in pathology (Tab. 5, Fig. 6, Ref. 22). Text in PDF www.elis.sk.

Iron deposition in rabbit cerebellum after exposure to generated and mobile GSM electromagnetic fields.

BACKGROUND: Mobile phone application may cause structural, functional changes and accumulation of toxic elements in brain. OBJECTIVES: The aim of this study was to investigate iron accumulation in rabbit cerebellum after exposure to RF EMF with light and scanning electron microscopy. MATERIALS AND METHODS: Histochemical analysis of iron distribution by light and electron microscopy with energy-dispersive microanalysis was used. RESULTS: Light microscopy revealed dystrophic changes of Purkinje cells in irradiated groups and iron deposits located in various parts of cerebellum. Deposits consists of C, O, Na, Mg, Al, Si, P, S, Cl, Ca and Fe. CONCLUSION: Our experiment revealed structural changes of Purkinje cells and iron and aluminium accumulations in stratum granulosum of rabbit's cerebellum after exposure to RF EMF (Fig. 6, Ref. 33).

Comparative analysis of human omental milky spots between the patients with colon cancer and the control group.

AIM: Morphological description of milky spots (MSs) in the human greater omentum. METHOD: Samples of the greater omentum collected during surgical procedures were subjected to further histological analysis. Two groups of patients were studied. Group A consisted of patients with colon cancer and peritonitis (stimulated MSs), group B consisted of patients without colon cancer and without peritonitis (unstimulated MSs). In the research, we focused on the cellular composition and differences between stimulated and unstimulated MSs. RESULTS: MSs detected in the study were predominantly oval (67 %), round (12 %) or irregular in shape (21 %). The average number of immune cells found in one milky spot (MS) in the group A was 454 (209-694), consisted of T cells in 44.7 % (27-55 %), B cells in 26.8 % (16-34 %), macrophages in 18.3 % (12-27 %) and other immune cells in 10.2 % (6-18 %). The average number of immune cells found in one MS in the group B was 58 (42-100 %), consisted of T cells in 21.1 % (16-22 %), B cells in 18.7 % (13-22 %), macrophages in 46.9 % (33-60 %) and other immune cells in 13.3 % (1-22 %). The average size of MSs in the group A was significantly higher than in the group B: 768 µm (313-1075) to 293 µm (197-421). The results showed that there were significant differences in terms of strong predominance of macrophages in unstimulated milky spots and strong predominance of T cells in stimulated milky spots. CONCLUSION: MSs are specific immune active lymphatic structures on the greater omentum. They play a key role in defense mechanism, especially in peritonitis. Their function is not completely clear in cancer, some authors suggest they might play a significant role in omental metastasis. Further analysing of the morphology and cells interactions of MSs is needed (Tab. 2, Fig. 6, Ref. 20).

[Omentum majus and milky spots as an important part of the immune system]. / Omentum majus a mliecne skvrny ako významná súcast imunitného systému.

INTRODUCTION: Description and analysis of human omental milky spots is still not sufficiently clarified. In our study we describe the morphology of human omental milky spots and we also bring together a summary of the current knowledge of their function based on the available literature. METHOD: Samples of the omentum majus were collected preoperatively during surgical procedures in Vítkovice Hospital and subsequently subjected to further processing and histological analysis. Histological sections were stained with hematoxylin and eosin with a focus on the milky spots morphology and comparison of two groups of patients. RESULTS: Milky spots detected in the study were predominantly oval 56% (n=10), irregular in shape 28% (n=5) and round 16% (n=3). The average number of immune cells found in one milky spot in group A was 435 (194620). The average number of immune cells found in one milky spot in group B was 54 (40112). All milky spots were unencapsulated, macroscopically, they appear as furtive structures resembling white cotton balls. 72% (n=13) of milky spots were covered by mesothelial cells. CONCLUSION: Milky spots are small submesothelial lymphatic structures found in the omentum majus. They are in contact with the peritoneal cavity. They have their own vascular supply and no capsule. Our results show that the number and size of omental milky spots increase in patients with peritonitis.Key words: omentum majus milky spots - morphology surgery.

Induced pluripotent stem cells in modeling and cell-based therapy of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by neuromuscular degeneration and the progressive loss of upper and lower motor neurons (MNs), causing weakness and paralysis. However, the underlying mechanisms of this disease are still unknown and there is no cure, or even treatment to stop or reverse its pathology. Consequently, most ALS patients die within 3 - 5 years after disease onset. While considerable progress has been made in studying animal models of ALS, they lack clinical suitability due to genetic differences. However, the recent development of induced pluripotent stem cells (iPSCs) has made it possible to study human disease-specific neuronal and glial cells to identify disease mechanisms and develop phenotypic screens for drug discovery. iPSCs provide researchers with a model of naturally occurring pathology under the human genetic background and MNs differentiated from human iPSCs bearing ALS-associated mutations offer a powerful model to study disease pathology. This paper reviews recent methods of differentiating iPSCs into neuronal cells and suggests further applications of these iPSCs-derived cells for ALS disease modeling, drug screening, and possible cell-based therapy.

Interaction Between Domperidone and Ketoconazole: Toward Prediction of Consequent QTc Prolongation Using Purely In Vitro Information.

We aimed to investigate the application of combined mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation in predicting the domperidone (DOM) triggered pseudo-electrocardiogram modification in the presence of a CYP3A inhibitor, ketoconazole (KETO), using in vitro-in vivo extrapolation. In vitro metabolic and inhibitory data were incorporated into physiologically based pharmacokinetic (PBPK) models within Simcyp to simulate time course of plasma DOM and KETO concentrations when administered alone or in combination with KETO (DOM+KETO). Simulated DOM concentrations in plasma were used to predict changes in gender-specific QTcF (Fridericia correction) intervals within the Cardiac Safety Simulator platform taking into consideration DOM, KETO, and DOM+KETO triggered inhibition of multiple ionic currents in population. Combination of in vitro-in vivo extrapolation, PBPK, and systems pharmacology of electric currents in the heart was able to predict the direction and magnitude of PK and PD changes under coadministration of the two drugs although some disparities were detected.