Tic Cough in an Adolescent with Organic Brain Pathology-A Case Report and Literature Review.

Chronic cough in children and adolescents can be troublesome both to the patient and the whole family. The most common causes of chronic cough in children are protracted bacterial bronchitis and bronchial asthma. However, differential diagnostic workup and treatment can become complicated when a cough of different etiology is encountered, especially in a child having a complex medical history for an unrelated pathology. A cough lacking any identified somatic cause and response to medical treatment in combination with core clinical features of tics that include suppressibility, distractibility, suggestibility, variability, and the presence of a premonitory sensation is labeled tic cough. Here we discuss a case of an adolescent who had atrophy of the corpus callosum and a history of ventriculoperitoneal shunting due to hydrocephalus caused by stenosis of the sylvian aqueduct, but now presented with a debilitating dry cough lasting for several months. After physical causes of cough were ruled out, the diagnosis of tic cough was reached, and multidisciplinary treatment ensured complete recovery. To the best of our knowledge, this is the first reported case showing coincidence of tic cough and hydrocephalus. The co-occurrence of non-syndromic corpus callosum atrophy and tic cough might hypothetically suggest a predisposing pathogenetic link via reduced signaling through cortical inhibitory neurons; further studies are needed. The importance of careful assessment of medical history, clinical picture, and features of the cough itself are emphasized in order to reach the correct diagnosis. Increased awareness of medical society is mandatory to recognize tic cough and to distinguish it from the neurologic manifestations of organic brain pathology.

Cancer Stem Cells in Pancreatic Ductal Adenocarcinoma.

The first discovery of cancer stem cells (CSCs) in leukaemia triggered active research on stemness in neoplastic tissues. CSCs represent a subpopulation of malignant cells, defined by unique properties: a dedifferentiated state, self-renewal, pluripotency, an inherent resistance to chemo- and radiotherapy, the presence of certain epigenetic alterations, as well as a higher tumorigenicity in comparison with the general population of cancer cells. A combination of these features highlights CSCs as a high-priority target during cancer treatment. The presence of CSCs has been confirmed in multiple malignancies, including pancreatic ductal adenocarcinoma, an entity that is well known for its dismal prognosis. As the aggressive course of pancreatic carcinoma is partly attributable to treatment resistance, CSCs could contribute to adverse outcomes. The aim of this review is to summarize the current information regarding the markers and molecular features of CSCs in pancreatic ductal adenocarcinoma and the therapeutic options to remove them.

The Main Theories on the Pathogenesis of Endometriosis.

Endometriosis is a complex disease, which is defined by abnormal growth of endometrial tissue outside the uterus. It affects about 10% of women of reproductive age all over the world. Endometriosis causes symptoms that notably worsen patient's well-being-such as severe pelvic pain, dysfunction of the organs of pelvic cavity, infertility and secondary mental issues. The diagnosis of endometriosis is quite often delayed because of nonspecific manifestations. Since the disease was defined, several different pathogenetic pathways have been considered, including retrograde menstruation, benign metastasis, immune dysregulation, coelomic metaplasia, hormonal disbalance, involvement of stem cells and alterations in epigenetic regulation, but the true pathogenesis of endometriosis remains poorly understood. The knowledge of the exact mechanism of the origin and progression of this disease is significant for the appropriate treatment. Therefore, this review reports the main pathogenetic theories of endometriosis based on current studies.

Pathological Changes in the Lungs of Patients with a Lethal COVID-19 Clinical Course.

The novel coronavirus SARS-CoV-2 was identified in 2019 and quickly became the cause of the fifth worst pandemic in human history. Our goal for this research paper was to examine the morphology of the lungs in 88 patients that died from COVID-19 in Latvia, thus increasing the data available about the histological characteristics of SARS-CoV-2-induced disease. Lung tissue samples from 88 autopsies were visualized in hematoxylin-eosin and assessed by light microscopy. The male-to-female ratio was 56:32, and the mean age was 62 years ± 15.5 years (22-94 years). Clinically important laboratory data were assessed, including leucocyte count, CRP (C-reactive protein) and D-dimer levels. Signs of diffuse alveolar damage were found in 83/88 (94.3%; 95% CI 87.0-97.9) of patients, 38/88 (43.2%; 95% CI 33.3-53.6) in the exudative phase, and 45/88 (51.1%; 95% CI 40.8-61.3) in the proliferative phase. Vascular damage was identified in 70/88 (79.5%; 95% CI 69.9-86.7) of patients, and 83/88 (94.3%; 95% CI 87.0-97.9) had signs of thrombosis. A sparse inflammatory infiltrate of lymphocytes and macrophages was a common finding aside from cases with an identified coinfection. Eighty patients had significant co-morbidities, including coronary heart disease (49), primary arterial hypertension (41), and diabetes mellitus (34). Since our group's demographic profile and spectrum of co-morbidities were analogous to other reports, the histological findings of marked diffuse alveolar damage, widespread vascular lesions, and active thrombosis can be considered representative of severe COVID-19.

Role of Endomyocardial Biopsy in Diagnostics of Myocarditis.

Endomyocardial biopsy as the cornerstone of diagnostics has been re-evaluated throughout the years, leaving unanswered questions on the precedence of it. The reported incidence of myocarditis has increased during the pandemic of coronavirus disease 2019 (COVID-19), reinforcing discussions on appropriate diagnostics of myocarditis. By analysis of evidence-based literature published within the last demi-decade, we aimed to summarize the most recent information in order to evaluate the current role of endomyocardial biopsy in diagnostics and management of myocarditis. For the most part, research published over the last five years showed ongoing uncertainty regarding the use, informativeness, safety and necessity of performing a biopsy. Special circumstances, such as fulminant clinical course or failure to respond to empirical treatment, were reconfirmed as justified indications, with a growing applicability of non-invasive diagnostic approaches for most other cases. We concluded that endomyocardial biopsy, if performed properly and with adjunct diagnostic methods, holds a critical role for treatment correction in specific histological subtypes of myocarditis and for differential diagnosis between immune-mediated myocarditis and secondary infections due to immunosuppressive treatment. A high level of possible misdiagnosing was detected, indicating the need to review terminology used to describe findings of myocardial inflammation that did not meet Dallas criteria.

Immunohistochemical Profile of Parathyroid Tumours: A Comprehensive Review.

Immunohistochemistry remains an indispensable tool in diagnostic surgical pathology. In parathyroid tumours, it has four main applications: to detect (1) loss of parafibromin; (2) other manifestations of an aberrant immunophenotype hinting towards carcinoma; (3) histogenesis of a neck mass and (4) pathogenetic events, including features of tumour microenvironment and immune landscape. Parafibromin stain is mandatory to identify the new entity of parafibromin-deficient parathyroid neoplasm, defined in the WHO classification (2022). Loss of parafibromin indicates a greater probability of malignant course and should trigger the search for inherited or somatic CDC73 mutations. Aberrant immunophenotype is characterised by a set of markers that are lost (parafibromin), down-regulated (e.g., APC protein, p27 protein, calcium-sensing receptor) or up-regulated (e.g., proliferation activity by Ki-67 exceeding 5%) in parathyroid carcinoma compared to benign parathyroid disease. Aberrant immunophenotype is not the final proof of malignancy but should prompt the search for the definitive criteria for carcinoma. Histogenetic studies can be necessary for differential diagnosis between thyroid vs. parathyroid origin of cervical or intrathyroidal mass; detection of parathyroid hormone (PTH), chromogranin A, TTF-1, calcitonin or CD56 can be helpful. Finally, immunohistochemistry is useful in pathogenetic studies due to its ability to highlight both the presence and the tissue location of certain proteins. The main markers and challenges (technological variations, heterogeneity) are discussed here in the light of the current WHO classification (2022) of parathyroid tumours.

Non-Aziridination Approaches to 3-Arylaziridine-2-carboxylic Acid Derivatives and 3-Aryl-(aziridin-2-yl)ketones.

Highly functionalized aziridines, including compounds with aromatic moieties, are attractive substrates both in synthetic and medical areas of chemistry. There is a broad and interesting set of synthetic methods for reaching these compounds. Aziridination represents the most explored tool, but there are several other more specific, less well-known, but highly promising approaches. Therefore, the current review focuses on recently described or updated ways to obtain 3-arylated aziridines via different non-aziridination-based synthetic methods, reported mainly since 2000. The presented methods belong to two main directions of synthesis, namely, cyclization of open-chain substrates and rearrangement of other heterocycles. Cyclization of open-chain substrates includes the classic Gabriel-Cromwell type cyclization of halogenated substrates with amines, base-promoted cyclization of activated aminoalcohols (or its analogues), and the oxidative cyclization of ß-dicarbonyls. Rearrangements of other heterocycles are presented as the Baldwin rearrangement of 4-isoxazolines, the cycloaddition of 1.3-dipoles or dienes to 2H-azirines, and the addition of C- and N-nucleophiles to the double bond of azirines.

Stemness, Inflammation and Epithelial-Mesenchymal Transition in Colorectal Carcinoma: The Intricate Network.

In global cancer statistics, colorectal carcinoma (CRC) ranks third by incidence and second by mortality, causing 10.0% of new cancer cases and 9.4% of oncological deaths worldwide. Despite the development of screening programs and preventive measures, there are still high numbers of advanced cases. Multiple problems compromise the treatment of metastatic colorectal cancer, one of these being cancer stem cells-a minor fraction of pluripotent, self-renewing malignant cells capable of maintaining steady, low proliferation and exhibiting an intriguing arsenal of treatment resistance mechanisms. Currently, there is an increasing body of evidence for intricate associations between inflammation, epithelial-mesenchymal transition and cancer stem cells. In this review, we focus on inflammation and its role in CRC stemness development through epithelial-mesenchymal transition.

An Easy Route to Aziridine Ketones and Carbinols.

N,N-Dimethylaziridine-2-carboxamides react with organolithium reagents yielding 2-aziridinylketones. The reaction with one equivalent of organolithium compound is selective to amide carbonyl at a low (-78 °C) temperature. These ketones, in reaction with organolithium reagents, give symmetrical and unsymmetrical aziridinyl carbinols. The usage of excess phenyllithium may serve as a special N-Boc-protecting group cleavage method for acid-sensitive substrates.

Molecular profile of parathyroid tissues and tumours: a heterogeneous landscape.

Advances in laboratory diagnostics and surgical treatment of primary hyperparathyroidism have ensured solid basis for research in parathyroid pathology in order to specify key molecules in pathogenesis and morphological diagnostics of difficult cases. The aim of this study was to assess the molecular landscape and its heterogeneity in primary parathyroid hyperplasia (PPH) and adenoma, compared to carcinoma and normal glands. In a retrospective analysis of 179 surgically removed parathyroid glands (102 adenomas; 27 PPH; 45 normal glands; 5 carcinomas), expression of Ki-67, p21, p27, p53, cyclin D1, Bcl-2 protein, vimentin, cytokeratin (CK) 19, E-cadherin, CD56, CD44 and parafibromin was detected by immunohistochemistry, followed by computer-assisted assessment of mean values and heterogeneity measures. Descriptive statistics and Kruskal-Wallis test were applied. Significant differences were disclosed regarding the mean and highest fraction of Ki-67 (both p < 0.001), p21 (both p < 0.001), cyclin D1 (p = 0.002) and p27-expressing cells (p = 0.010). Proliferative lesions (PPH, adenoma and carcinoma) showed statistically significantly up-regulated CK19 (p = 0.012), decreased E-cadherin levels and distinctive patterns of vimentin. CD44, CD56 and p53 were almost absent from parathyroid tissues. All carcinomas lacked parafibromin contrasting with invariable positivity in adenomas. Remarkable heterogeneity of cell cycle markers and intermediate filaments must be accounted for in scientific studies and elaboration of diagnostic cut-offs.

3-Arylaziridine-2-carboxylic Acid Derivatives and (3-Arylaziridin-2-yl)ketones: The Aziridination Approaches.

Aziridination reactions represent a powerful tool in aziridine synthesis. Significant progress has been achieved in this field in the last decades, whereas highly functionalized aziridines including 3-arylated aziridine-2-carbonyl compounds play an important role in both medical and synthetic chemistry. For the reasons listed, in the current review we have focused on the ways to obtain 3-arylated aziridines and on the recent advances (mainly since the year 2000) in the methodology of the synthesis of these compounds via aziridination.

Acute Appendicitis in the Elderly: A Literature Review on an Increasingly Frequent Surgical Problem.

With increased life expectancy and the growing total population of elderly patients, there has been rise in the number of cases of acute appendicitis in elderly people. Although acute appendicitis is not the most typical pathological condition in the elderly, it is not uncommon. Most of these patients require surgical treatment, and as with any acute surgical pathology in advanced age, treatment possibilities are affected by comorbidities, overall health status, and an increased risk of complications. In this literature review we discuss differences in acute appendicitis in the elderly population, with a focus on clinical signs, diagnostics, pathogenesis, treatment, and results.

Cancer Stem Cells: Significance in Origin, Pathogenesis and Treatment of Glioblastoma.

Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic tumors and soon after in solid malignancies. CSCs have attracted remarkable research interest due to their role in tumor resistance to chemotherapy and radiation treatment as well as recurrence. Extensive research has been devoted to the role of CSCs in glioblastoma multiforme (GBM), the most common primary brain tumor in adults, which is characterized by a dismal prognosis because of its aggressive course and poor response to treatment. The aim of the current paper is to provide an overview of current knowledge on the role of cancer stem cells in the pathogenesis and treatment resistance of glioblastoma. The six regulatory mechanisms of glioma stem cells (GSCs)-tumor microenvironment, niche concept, metabolism, immunity, genetics, and epigenetics-are reviewed. The molecular markers used to identify GSCs are described. The role of GSCs in the treatment resistance of glioblastoma is reviewed, along with future treatment options targeting GSCs. Stem cells of glioblastoma thus represent both a driving mechanism of major treatment difficulties and a possible target for more effective future approaches.

The Association Between Inflammation, Epithelial Mesenchymal Transition and Stemness in Colorectal Carcinoma.

BACKGROUND: Inflammation plays an important albeit dual role in carcinogenesis. Survival studies have highlighted the prognostic significance of peritumorous inflammation. Currently, the theoretical background allows inflammation, epithelial mesenchymal transition (EMT) and the closely associated stem cell differentiation in colorectal carcinoma (CRC) to be linked. However, there is scarce direct morphological evidence. PURPOSE AND METHODS: The aim of our study was to investigate the role of inflammation in cancer growth and invasion by analyzing the association between inflammation and known morphological prognostic features of colorectal cancer, EMT, stemness and mismatch repair (MMR) protein expression. The study was designed as a retrospective morphological and immunohistochemical assessment of 553 consecutive cases of surgically treated primary CRC. RESULTS: There were statistically significant associations between high-grade inflammation and lower pT (p = 0.002), absence of lymph node metastases (p < 0.001) and less frequent lymphatic (p = 0.003), venous (p = 0.017), arterial (p = 0.012), perineural (p = 0.001) and intraneural (p = 0.01) invasion. In contrast, Crohn's like reaction (CLR) by density of lymphoid follicles in the invasive front lacked significant differences in regard to pT, pN, tumor invasion into surrounding structures (blood or lymphatic vessels, nerves), grade or necrosis (all p > 0.05). The expression of E-cadherin, CD44 and MMR proteins yielded no statistically significant associations with peritumorous inflammation by Klintrup-Mäkinen score or the density of lymphoid follicles. Nevertheless, E-cadherin levels were significantly associated with the density of eosinophils (p = 0.007). CONCLUSION: High-grade peritumorous inflammation is associated with beneficial morphologic CRC features, including less frequent manifestations of invasion, and is not secondary to tissue damage and necrosis. CLR is not associated with cancer spread by pTN; this finding indirectly suggests an independent role of CLR in carcinogenesis. Further, inflammation by Klintrup-Mäkinen grade and CLR is not dependent on epithelial-mesenchymal transition and stem cell differentiation. Our study highlights the complex associations between inflammation, tumor morphology, EMT, stemness and MMR protein expression in human CRC tissues.

HIV-1 Reverse Transcriptase Promotes Tumor Growth and Metastasis Formation via ROS-Dependent Upregulation of Twist.

HIV-induced immune suppression results in the high prevalence of HIV/AIDS-associated malignancies including Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer. HIV-infected people are also at an increased risk of "non-AIDS-defining" malignancies not directly linked to immune suppression but associated with viral infections. Their incidence is increasing despite successful antiretroviral therapy. The mechanism behind this phenomenon remains unclear. Here, we obtained daughter clones of murine mammary gland adenocarcinoma 4T1luc2 cells expressing consensus reverse transcriptase of HIV-1 subtype A FSU_A strain (RT_A) with and without primary mutations of drug resistance. In in vitro tests, mutations of resistance to nucleoside inhibitors K65R/M184V reduced the polymerase, and to nonnucleoside inhibitors K103N/G190S, the RNase H activities of RT_A. Expression of these RT_A variants in 4T1luc2 cells led to increased production of the reactive oxygen species (ROS), lipid peroxidation, enhanced cell motility in the wound healing assay, and upregulation of expression of Vimentin and Twist. These properties, particularly, the expression of Twist, correlated with the levels of expression RT_A and/or the production of ROS. When implanted into syngeneic BALB/C mice, 4T1luc2 cells expressing nonmutated RT_A demonstrated enhanced rate of tumor growth and increased metastatic activity, dependent on the level of expression of RT_A and Twist. No enhancement was observed for the clones expressing mutated RT_A variants. Plausible mechanisms are discussed involving differential interactions of mutated and nonmutated RTs with its cellular partners involved in the regulation of ROS. This study establishes links between the expression of HIV-1 RT, production of ROS, induction of EMT, and enhanced propagation of RT-expressing tumor cells. Such scenario can be proposed as one of the mechanisms of HIV-induced/enhanced carcinogenesis not associated with immune suppression.

Molecular classification of diffuse gliomas.

In this study we assessed whether gliomas could be subdivided into different molecular subtypes by immunohistochemistry (IHC) reminiscent of those first described by Verhaak et al. in 2010 (classical, proneural, mesenchymal and neural). We also evaluated the prognostic significance of single molecular factors and searched for significant correlations between markers. In this study, we included 146 patients with glioblastomas (GBMs) and 26 with diffuse astrocytomas (DAs). The glioma samples were tested for PDGFRA, IDH1 R132H, CD44, p53, Ki-67, p21 and p27 expression. We found that gliomas could be subdivided into molecular subtypes by IHC. Fifty per cent of GBMs were of the proneural subtype, 18.5% of mesenchymal subtype and 31.5% were not otherwise classified. However, most of the DAs (92.3%) belonged to the proneural subtype. No prognostic role was found for the molecular subtypes, but predictive roles were noted. Both proneural and mesenchymal molecular subtypes showed a benefit from the addition of chemotherapy and radiotherapy; however, the mesenchymal subtype showed a greater response. Interestingly, the mesenchymal subtype did not receive any benefit from the addition of radiotherapy compared with palliative management and surgery alone. Regarding single molecular markers, only IDH1 R132H was found to have a prognostic role for GBMs. There was a trend towards better survival in tumours with lower PDGFRA expression (p = 0.066). In DAs, PDGFRA and Ki-67 expression had prognostic roles. The following statistically significant correlations were found in GBMs: Ki-67/p53, Ki-67/p27 and p53/PDGFRA; in DAs: p53/PDGFRA, CD44/PDGFRA, and p21/PDGFRA.

Novel Variant of the Androgen Receptor Gene in a Patient With Complete Androgen Insensitivity Syndrome and Polyorchidism.

Introduction: Complete androgen insensitivity (CAIS) in 65-95% cases is caused by pathogenic allelic variants (mutations) in the gene encoding androgen receptor (AR gene) and is characterized by female phenotype development with a male karyotype (46, XY). Patients are usually diagnosed during puberty and undergo gonadectomy due to increased testicular germ cell tumor risk. Only a few outcomes have been reported in older individuals with postponed gonadectomy. Case presentation: A 48-year-old CAIS patient presented with polyorchidism (four testes) without gonadal malignancies. Genetic testing identified a novel allelic variant in the AR gene [c.2141T>G (p.Phe805Cys)] causing the clinical symptoms. Conclusion: We have described a unique patient with CAIS and polyorchidism without malignancies in her late 40's bearing a novel likely pathogenic variant in the AR gene.

Laparoscopic Cholecystectomy for a Patient with a Lumboperitoneal Shunt: A Rare Case.

A rare factor that can complicate the perioperative course of laparoscopic cholecystectomy is previous placement of a lumboperitoneal (LP) shunt. Thus far, only two articles describing this situation have been published. Here, we report on a 41-year-old female patient with gallstone disease and a LP shunt placement in the preceding year due to idiopathic intracranial hypertension. It is a syndrome of increased intracranial pressure without any known cause that mainly affects young obese women. The patient was operated upon using standard port placement and peritoneal insufflation. The postoperative period was uneventful and the patient was discharged shortly after the procedure. Due to the increasing incidence and prevalence of obesity, the number of general surgical patients with a LP shunt will likely increase. Based on our experience and evidence in the literature, we conclude that performing a laparoscopy for a patient with a LP shunt is safe.

Evaluation of malignant parathyroid tumours in two European cohorts of patients with sporadic primary hyperparathyroidism.

PURPOSE: Parathyroid carcinoma (PC) is remarkable for its rare occurrence and challenging diagnostics. PC accounts for 0.1-5 % cases of primary hyperparathyroidism (PHPT). The differentiation from benign tumours is difficult even by morphological criteria. To address these issues, we assessed the PC frequency in two separate European PHPT cohorts and evaluated the demographic, clinical, morphological and molecular background. METHODS: A retrospective study was carried out, using continuously maintained database (2005-2014) of PHPT patients from two tertiary referral university hospitals in Europe. The demographic, clinical data and frequency of PC among surgically treated PHPT was detected. Immunohistochemistry (IHC) was performed to detect parafibromin, representing protein product of HRPT2 gene and proliferation marker Ki-67. RESULTS: Both PHPT cohorts were characterised by close mean age values (58.6 and 58.0 years) and female predominance. The frequency of PC differed significantly between the cohorts: 2.1 vs. 0.3 %; p = 0.004. PC was characterised by invariable complete loss of parafibromin contrasting with parathyroid adenomas. The proliferation fraction was similar in both PC cohorts (10.6 and 11.0 %). PC showed significantly higher proliferation fraction than typical parathyroid adenomas (1.6 %), atypical adenomas (1.6 %) or adenomas featuring focal loss of parafibromin (2.2 %). CONCLUSIONS: PC frequency can range significantly between the two European cohorts. The differences can be attributable to selection bias of patients referred for surgery and are not caused by discordant definition of malignant parathyroid histology. Diffuse loss of parafibromin and increased proliferation fraction by Ki-67 are valuable adjuncts in PC diagnostics due to significant differences with various clinical and morphological subtypes of adenoma.

Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms.

The study represents a comprehensive retrospective morphological and immunohistochemical profiling of pancreatic neuroendocrine neoplasms (PNENs) in order to reveal the associations between morphological and molecular parameters. The local tumour spread (T), presence of metastases in regional lymph nodes (N) and distant organs (M), tumour grade (G) and resection line status (R) by pathology findings (pTNMGR), mitotic activity, perineural, vascular and lymphatic invasion were assessed in 16 surgically resected PNENs. By immunohistochemistry, expression of Ki-67, p53, p27, p21, cyclin D1, Bcl-2, E-cadherin, CD44, vimentin, cyclooxygenase 2 (COX-2), microvascular density, and cytokeratin (CK) spectrum, along with neuroendocrine, intestinal and squamous markers were detected. Descriptive statistics, Chi-square test, Spearman's rank correlation, Mann-Whitney and Kruskal-Wallis methods were applied; p<0.05 was considered significant. Ki-67, CK19, p63, vimentin and COX-2 were significantly up-regulated in PNENs in comparison to benign pancreatic islets. A complex network of morphological and molecular associations was identified. Ki-67 correlated with PNEN size (p=0.022), the World Health Organization 2004 and 2010 classification grades (p=0.021 and p=0.002), stage (p=0.028) and mitotic count (p=0.007) but among molecular markers--with CK19 (p=0.033) and vimentin (p=0.045). CK19 was significantly up-regulated in PNENs, having higher pT (p=0.018), pR (p=0.025), vascular (p=0.020), perineural (p=0.026) and lymphatic invasion (p=0.043). In conclusion, proliferation activity (by Ki-67), E-cadherin, vimentin and CK19 are important molecular characteristics of PNENs due to significant associations with morphological tumour characteristics, pTNMGR and invasive growth.