Medical Sciences

Pulmonary hypertension (PH) is a rare disease with a high morbidity and mortality rate. A number of systemic diseases and genetic mutations are known to lead to PH. The main features of PH are altered vascular relaxation responses and the activation of proliferative and anti-apoptotic pathways, resulting in pulmonary vascular remodeling, elevated pulmonary artery pressure, and right ventricular hypertrophy, ultimately leading to right heart failure and premature death. Important advances have been made in the field of pulmonary pathobiology, and several deregulated signaling pathways have been shown to be associated with PH. Clinical and experimental studies suggest that, irrespective of the underlying disease, endothelial cell disruption and/or dysfunction play a key role in the pathogenesis of PH. Endothelial caveolin-1, a cell membrane protein, interacts with and regulates several transcription factors and maintains homeostasis. Disruption of endothelial cells leads to the loss or dysfunction of endothelial caveolin-1, resulting in reciprocal activation of proliferative and inflammatory pathways, leading to cell proliferation, medial hypertrophy, and PH, which initiates PH and facilitates its progression. The disruption of endothelial cells, accompanied by the loss of endothelial caveolin-1, is accompanied by enhanced expression of caveolin-1 in smooth muscle cells (SMCs) that leads to pro-proliferative and pro-migratory responses, subsequently leading to neointima formation. The neointimal cells have low caveolin-1 and normal eNOS expression that may be responsible for promoting nitrosative and oxidative stress, furthering cell proliferation and metabolic alterations. These changes have been observed in human PH lungs and in experimental models of PH. In hypoxia-induced PH, there is no endothelial disruption, loss of endothelial caveolin-1, or enhanced expression of caveolin-1 in SMCs. Hypoxia induces alterations in membrane composition without caveolin-1 or any other membrane protein loss. However, caveolin-1 is dysfunctional, resulting in cell proliferation, medial hypertrophy, and PH. These alterations are reversible upon removal of hypoxia, provided there is no associated EC disruption. This review examined the role of caveolin-1 disruption and dysfunction in PH. Full article

Despite the changing paradigms of melanoma treatment in recent years, there remains a relative paucity of data regarding subungual melanoma in the literature. From 2002–2018, 25 patients with subungual melanoma were surgically treated at our facility. A retrospective chart review was conducted to collect relevant demographic, clinical, pathologic, and outcomes data. The median age at diagnosis was 69 years. Most patients (60%) were male, and the melanoma lesion was most often located on the foot (68%). Acral-lentiginous was the most common histologic subtype (59%), and the median Breslow thickness was 3.4 mm. Fifteen patients (63%) underwent a sentinel lymph node biopsy as part of their surgical resection, and four of these patients (27%) had metastatic disease in the lymph nodes. In total, 10 patients underwent lymph node dissection of the involved basin. The median follow up was 21 months in this patient population. Age, gender, tumor location, ulceration, and lesion histology were not significantly associated with recurrence free survival (RFS). Increasing Breslow thickness was found to be significantly associated with shorter RFS (HR: 1.07, CI: 1.03–1.55). In total, 13 patients developed a disease recurrence, and RFS rates were 66% at 1 year and 40% at 3 years. Additionally, 91 and 37% of patients were alive at one year and three years, respectively. Subungual melanomas are rare lesions that often have a more advanced stage at diagnosis, which contributes to the poor prognosis of these cutaneous malignancies. Full article

Rapamycin is an exogenous compound that has been shown to improve cognition in Alzheimer’s disease mouse models and can regulate pathways downstream of the insulin receptor signaling pathway. Insulin is also known to improve cognition in rodent models of Alzheimer’s disease. Central nervous system (CNS) insulin must first cross the blood–brain barrier (BBB), a specialized network of brain endothelial cells. This transport process is regulated by physiological factors, such as insulin itself, triglycerides, cytokines, and starvation. Since rapamycin treatment can alter the metabolic state of rodents, increase the circulating triglycerides, and acts as a starvation mimetic, we hypothesized rapamycin could alter the rate of insulin transport across the BBB, providing a potential mechanism for the beneficial effects of rapamycin on cognition. Using young male and female CD-1 mice, we measured the effects of rapamycin on the basal levels of serum factors, insulin receptor signaling, vascular binding, and BBB pharmacokinetics. We found chronic rapamycin treatment was able to affect basal levels of circulating serum factors and endothelial cell insulin receptor signaling. In addition, while acute rapamycin treatment did affect insulin binding at the BBB, overall transport was unaltered. Chronic rapamycin slowed insulin BBB transport non-significantly (p = 0.055). These results suggest that rapamycin may not directly impact the transport of insulin at the BBB but could be acting to alter insulin signaling within brain endothelial cells, which can affect downstream signaling. Full article

A large number of models are now available for the investigation of skin wound healing. These can be used to study the processes that take place in a phase-specific manner under both physiological and pathological conditions. Most models focus on wound closure, which is a crucial parameter for wound healing. However, vascular supply plays an equally important role and corresponding models for selective or parallel investigation of microcirculation regeneration and angiogenesis are also described. In this review article, we therefore focus on the different levels of investigation of skin wound healing (in vivo to in virtuo) and the investigation of angiogenesis and its parameters. Full article

Background: The German S3- guideline on local therapy of leg ulcers and diabetic foot ulcers is in the process of being updated. Major goals are to improve the guidelines’ applicability and to take steps towards a living guideline according to current methodological standards. The aim of this article is to describe the main measures to achieve these goals. Methods: The context of the guideline in the field of local wound care and the stakeholder requirements are briefly described. Based on a derived framework, the project team adjusted the methods for the guideline. Results: Main adjustments are more specific inclusion criteria, online consensus meetings and the use of an authoring and publication platform to provide information in a multi-layered format. A new set of practice-oriented key questions were defined by the guideline panel to foster the formulation of action-oriented recommendations. Conclusions: The set of new key questions addressing practical problems and patients’ preferences as well as the adjustments made to improve not only the guidelines’ applicability, but also the feasibility of the further dynamic updating processes in the sense of a living guideline, should be steps in the right direction. Full article

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a new pathogen agent causing the coronavirus infectious disease (COVID-19). This novel virus originated the most challenging pandemic in this century, causing economic and social upheaval internationally. The extreme infectiousness and high mortality rates incentivized the development of vaccines to control this pandemic to prevent further morbidity and mortality. This international scenario led academic scientists, industries, and governments to work and collaborate strongly to make a portfolio of vaccines available at an unprecedented pace. Indeed, the robust collaboration between public systems and private companies led to resolutive actions for accelerating therapeutic interventions and vaccines mechanism. These strategies contributed to rapidly identifying safe and effective vaccines as quickly and efficiently as possible. Preclinical research employed animal models to develop vaccines that induce protective and long-lived immune responses. A spectrum of vaccines is worldwide under investigation in various preclinical and clinical studies to develop both individual protection and safe development of population-level herd immunity. Companies employed and developed different technological approaches for vaccines production, including inactivated vaccines, live-attenuated, non-replicating viral vector vaccines, as well as acid nucleic-based vaccines. In this view, the present narrative review provides an overview of current vaccination strategies, taking into account both preclinical studies and clinical trials in humans. Furthermore, to better understand immunization, animal models on SARS-CoV-2 pathogenesis are also briefly discussed. Full article

Despite recent advances in immune-modulatory drugs, pharmacological therapies have been proven ineffective in severe presentations of multiple sclerosis (MS), including secondary progressive MS. At present, therapeutic interventions’ performance is primarily focused on ameliorating symptoms to improve the patient’s quality of life (QOL). Among complementary treatments, nutrition has been considered a decisive factor to control symptoms and enhance the wellness of MS patients. Although no special diets are associated with MS, the impact of diet and dietary supplements on the course of progressive forms of the disease has been studied during the last few years. Fatigue is among the most common and disabling symptoms reported by MS patients. Fatigue has been defined in the Multiple Sclerosis Council for Clinical Practice Guidelines (MSCCPG, 1998) as a “subjective lack of physical and/or mental energy that the individual perceives as an interference with habitual and desired activities”. This study aimed to compare the psychometric functioning of the “Fatigue Severity Scale” (FSS) and the “Modified Fatigue Impact Scale” (MFIS) in our sample of people with MS. Specifically, during chronic treatment, the change in these two parameters with two vitamin-rich dietary supplements (Citozym^® and Ergozym^®) was evaluated. The impact of these nutritional supplements revealed differences in antioxidant and anti-inflammatory parameters among the volunteers in the treatment group, with a subsequent improvement in fatigue. In conclusion, the results obtained have confirmed the effectiveness of complementary nutritional therapies, evaluated essentially based on hematological biomarkers, through which it is possible to act on disability to improve the QOL of MS patients. Full article

Cutaneous burn injury is associated with epidermal loss in the zone of coagulation zone and delayed tissue loss in the zone of stasis. Thus, thermal stress can trigger both necrosis and regulated cell death (RCD) or apoptosis. Experimental in vitro and in vivo work has clearly demonstrated apoptotic events of thermally injured keratinocytes that are accompanied by morphological and biochemical markers of regulated cell death. However, in vivo data for the different pathways of regulated cell death are sparse. In vitro experiments with heat-stressed human keratinocytes have demonstrated death receptor involvement (extrinsic apoptosis), calcium influx, and disruption of mitochondrial membrane potential (intrinsic apoptosis) in regulated cell death. In addition, caspase-independent pathways have been suggested in regulated cell death. Keratinocyte heat stress leads to reduced proliferation, possibly as a result of reduced keratinocyte adhesion (anoikis) or oncogene involvement. Understanding the underlying mechanisms of RCD and the skin’s responses to thermal stress may lead to improved strategies for treating cutaneous burn trauma. Full article

Background: This study aimed to investigate the association between endocrine therapy and weight gain with a history of breast cancer. Methods: This was a retrospective cohort study. Recruited patients consisted of those receiving endocrine therapy and those not receiving endocrine therapy. Weight at diagnosis was collected from medical records, and current body mass was measured using a digital scale (time since diagnosis was 4.0 ± 1.9 years). Moreover, we measured current physical activity using an accelerometer and dietary intake using a validated questionnaire. The primary analysis was a t-test for the body-mass change after diagnosis between the two groups. Results: We recruited 300 patients and collected data from 292. Mean weight gain after diagnosis was 1.3 ± 3.9 kg, and the change in body mass of patients taking endocrine therapy (1.3 ± 4.0 kg) was not significantly different from that of patients not taking endocrine therapy (1.4 ± 3.8 kg, p = 0.92). There was no association of endocrine therapy, physical activity, and dietary intake with a 5% weight gain after adjusting confounding factors (e.g., breast cancer stage and chemotherapy). Conclusions: Caution is required with generalization because of sampling bias and ethnic differences. Full article

Aim: To determine the frequency, mode of transmission, and outcome of Coronavirus Disease 2019 (COVID-19) among healthcare workers (HCWs) in a tertiary care cardiac center in the Kingdom of Saudi Arabia (KSA). Methods: This is a retrospective study of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infected HCWs and was conducted from 2 March to 31 December 2020. Data related to the presence of COVID-19 symptoms, mode of transmission, hospitalization, and mortality were collected from the patients’ medical records. Results: Of the 4462 patients tested for COVID-19 by real-time reverse transcriptase polymerase chain reaction (RT-PCR), 203 (4.5%) HCWs were positive; of these, 125 (61.6%) were males, and the most common age group was <40 years. The most commonly encountered health professionals were nurses (74, 36.4%), followed by therapists/technicians (48, 23.6%), housekeepers (25, 12.3%), and physicians (21, 10.4%). The majority (184, 90.6%) of the HCWs contracted COVID-19 in the community, and only 19 (9.4%) were healthcare-associated infections. Of the infected HCWs, 169 (83.3%) had mild symptoms and were managed in home isolation. The most common symptoms were fever (128, 63.1%), body ache (124, 61.8%), headache (113, 55.7%), dry cough (123, 60.6%), sore throat (97, 47.8%), body weakness (97, 47.8%), and fatigue (94, 46.3%). Comparing males and females, there was a significantly higher number of female nurses; in contrast, there was a higher number of male physicians, housekeepers, therapists/technicians, and other specialty HCWs. A significantly lower number of nurses, therapists/technicians were infected in the ≥40 years age group compared to <40 years. Furthermore, a significantly higher difference was observed among non-Saudi nurses compared to Saudi nurses. No mortality was documented among the included HCWs. Conclusions: In the largest tertiary cardiac center in KSA, most HCWs who contracted COVID-19 developed mild symptoms; nurses and those aged <40 years were most commonly infected, and most infections were acquired in the community. HCWs’ adherence to mitigation measures outside of the workplace is vital to curb the current pandemic and decrease nosocomial transmission risk. Full article

Type-2 diabetes (T2DM) is a risk factor for the development of pancreatic ductal adenocarcinoma (PDAC) and is characterized by insulin resistance and hyperinsulinemia. Besides the well-known growth-promoting activity of insulin or the other members of the Insulin/Insulin-like Growth factor (IGF) axis, we here describe an inducing effect of insulin on PD-L1 expression in PDAC cells. Treatment of the PDAC cell lines BxPc3, A818-6, and T3M4 with insulin increased PD-L1 expression in a time- and dose dependent fashion, as shown by Western blot and qPCR analysis. siRNA mediated knock-down showed that the effects of insulin on PD-L1 depend on the insulin and IGF receptors (InsR and IGFR, respectively). In addition, a crosstalk of insulin-induced ERK activation and Epidermal Growth Factor (EGF) triggered PD-L1 expression. This involves different mechanisms in the three cell lines including upregulation of InsR-A expression in A818-6 and modulation of the adaptor protein Gab1 in BxPc3 cells. As a consequence of the insulin-induced PD-L1 expression, PDAC cells suppress the proliferation of activated human CD8+ T-cells in coculture experiments. The suppression of CD8+ cell proliferation by insulin-pretreated PDAC cells was reversed by PD-1 blockade with Pembrolizumab or by PD-L1 siRNA. Furthermore, the clinical relevance of these observations was supported by detecting a coexpression of cytoplasmic InsR (characteristic for its activation) and PD-L1 in tumor tissues from PDAC patients. Our findings provide a novel insight into the protumorigenic role of insulin in PDAC. Recognizing the impact of insulin on PD-L1 expression as part of the immune privilege, strategies to interfere with this mechanism could pave the way towards a more efficient immunotherapy of PDAC. Full article

Background: Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) represent a rare tumor composed of adenocarcinoma and neuroendocrine carcinoma components. This study reports a case series of gastric MiNEN and discusses issues related to its diagnosis, management, and outcomes. Methods: We retrospectively analyzed data from patients with gastric MiNEN who underwent surgical resection at our service from 2009 to 2020. Patients with gastric adenocarcinoma served as a comparison group. Clinical, pathologic, and surgical characteristics were compared. Results: During the selected period, 5 gastric MiNEN patients and 597 patients with gastric adenocarcinoma were included. Among the clinical variables, age, sex, BMI, and laboratory exams were similar between the two groups. Only ASA classification was different (p = 0.015). Pathological variables such as tumor size, lymphovascular invasion, number of retrieved lymph nodes, and pTNM staging were also similar between both groups. Lastly, early surgical outcomes and long-term survival did not differ between gastric MiNEN and adenocarcinoma patients. Conclusion: A MiNEN is a rare tumor that represents less than 1% of GC patients undergoing curative treatment, and demonstrated clinicopathological characteristics and outcomes similar to gastric adenocarcinoma. Full article

Background: Mounting data suggest that exposure to chronic stress is associated with worse breast cancer outcomes. This study aimed to explore the impact of social environmental adversity (SEA, e.g., child abuse, crime, sexual, and physical violence), depressive symptomatology, and anxiety on immune cell infiltration into the breast tumor microenvironment. Methods: Participants (n = 33) completed a series of surveys assessing depression and anxiety symptoms, adverse childhood events (ACE), and trauma history. Tumor-associated macrophages (CD68+), B cells (CD19+), and T cells (CD3+) were identified by immunohistochemical analyses of formalin-fixed paraffin-embedded tumor samples and quantified. Spearman rank tests were used to explore the relationships between the variables studied. Results: Exposure to SEA was high (ACE = 72%, exposure to crime = 47%, and exposure to physical/sexual assault = 73%) among participants. Moreover, 30% reported a comorbid history of depression and ACE; 39% reported one or more traumatic events, and clinically significant depression symptomatology, while 21% reported trauma history and significant anxiety symptomatology. Increased tumor-infiltrating B cells were significantly correlated with exposure to crime, anxiety symptoms, and exposure to an ACE. The ACE plus anxiety group presented the highest infiltration of B cells, T cells, and macrophages. Conclusion: These findings support a role for SEA, anxiety symptoms, and depression as potential modulators of the immune tumor microenvironment in breast cancer. Full article

Usually, cutaneous wound healing does not get impeded and processes uneventfully, reaching wound closure easily. The goal of this repair process is to restore the integrity of the body surface by creating a resilient and stable scar. Surgical practice and strategies have an impact on the course of wound healing and the later appearance of the scar. By considering elementary surgical principles, such as the appropriate suture material, suture technique, and timing, optimal conditions for wound healing can be created. Wounds can be differentiated into clean wounds, clean–contaminated wounds, contaminated, and infected/dirty wounds, based on the degree of colonization or infection. Furthermore, a distinction is made between acute and chronic wounds. The latter are wounds that persist for longer than 4–6 weeks. Care should be taken to avoid surgical site infections in the management of wounds by maintaining sterile working conditions, using antimicrobial working techniques, and implementing the principles of preoperative antibiotics. Successful wound closure is influenced by wound debridement. Wound debridement removes necrotic tissue, senescent and non-migratory cells, bacteria, and foreign bodies that impede wound healing. Additionally, the reconstructive ladder is a viable and partially overlapping treatment algorithm in plastic surgery to achieve successful wound closure. Full article

Putrescine, spermine, and spermidine are the important polyamines (PAs), found in all living organisms. PAs are formed by the decarboxylation of amino acids, and they facilitate cell growth and development via different cellular responses. PAs are the integrated part of the cellular and genetic metabolism and help in transcription, translation, signaling, and post-translational modifications. At the cellular level, PA concentration may influence the condition of various diseases in the body. For instance, a high PA level is detrimental to patients suffering from aging, cognitive impairment, and cancer. The levels of PAs decline with age in humans, which is associated with different health disorders. On the other hand, PAs reduce the risk of many cardiovascular diseases and increase longevity, when taken in an optimum quantity. Therefore, a controlled diet is an easy way to maintain the level of PAs in the body. Based on the nutritional intake of PAs, healthy cell functioning can be maintained. Moreover, several diseases can also be controlled to a higher extend via maintaining the metabolism of PAs. The present review discusses the types, important functions, and metabolism of PAs in humans. It also highlights the nutritional role of PAs in the prevention of various diseases. Full article

Background and Objectives: Hemoglobin A1c (HbA1c) is widely used for the monitoring and management of diabetes mellitus. The aim of this study is to investigate the influence of hemoglobin (Hb) variants on the measurement of HbA1c. Materials and Methods: HbA1c levels of 845 blood samples obtained from diabetic patients with various hemoglobin types were measured using a turbidimetric inhibition immunoassay and capillary electrophoresis. Results: Of 845 patients with diabetes, 65.7% (555/845) have the normal hemoglobin type (A₂A) and 34.3% (290/845) have various abnormal hemoglobin types, including heterozygous HbE 30.2% (255/845), homozygous HbE 1.9 % (16/845), Hb Constant Spring (CS) trait 1.4% (12/845), CSEA Bart’s 0.2% (2/845), and beta-thalassemia trait 0.6% (5/845). In most of the patients with diabetes, HbA1c levels determined by two different methods, inhibition immunoassay and capillary electrophoresis, gave strong positive correlation (R = 0.901, P < 0.001), except for those with homozygous HbE (N = 16) and CSEA Bart’s (N = 2). In all 18 patients with homozygous HbE and CSEA Bart’s, the HbA1c was undetectable by capillary electrophoresis, meaning that their estimated average glucose was undeterminable, although their HbA1c levels could be measured using an inhibition immunoassay. The discrepancy of HbA1c results obtained from two different methods is noted in patients without HbA. Conclusions: We have demonstrated the erroneous nature of HbA1c measurement in patients with hemoglobin variants, especially in those without HbA expression. Therefore, in the population with a high prevalence of hemoglobinopathies, hemoglobin typing should be considered as basic information prior to HbA1c measurement. Full article

Background: Aromatase inhibitors (AIs) are associated with musculoskeletal pain in one third (20–47%) of breast cancer patients. Recently, CDK4/6 inhibitors have emerged as a new therapeutic approach in hormone receptor (HR)-positive breast cancer. While hematological and gastrointestinal toxicities are frequently reported during treatment with CDK4/6 inhibitors, musculoskeletal symptoms are less commonly encountered. Methods: Herein, we present a retrospective study of 47 breast cancer patients who received CDK4/6 inhibitors along with endocrine therapy in our department between 01/01/2018 and 01/09/2020. Results: Median age at diagnosis was 58 years (29–81). Median duration of treatment was 8.76 months (SD: 7.68; 0.47–30.13 months). Median PFS was 24.33 months (95% CI; 1.71–46.96). Overall, toxicity was reported in 61.7% of the cases (29/47). Arthralgia was reported in 6.4% (3/47) of the patients. Hematological toxicity was reported in 51.1% (24/47) of the patients. Neutropenia was the main hematological toxicity observed (86.8%; 22/47) along with anemia (4.3%; 2/47), thrombocytopenia (2.1%; 1/47), and leukopenia (4.2%; 1/24). Conclusions: Though our data reflect a small sample size, we report a reduced arthralgia rate (6.4%) during treatment with CDK4/6 inhibitors compared with that reported in studies of AIs (20–47%). Full article

The direct-acting oral anticoagulant (DOAC) has become an alternative to low-molecular-weight heparin (LMWH) for treatment and prophylaxis of venous thromboembolism (VTE) in cancer patients. The clinicians are, however, faced with difficult decisions regarding DOAC treatment: Which patients cannot use DOACs? Should incidental VTE be treated similar to symptomatic VTE? Is it safe to give DOACs to patients with gastrointestinal or urogenital cancers? How about drug–drug interactions? Should all cancer patients receive thromboprophylaxis? Is arterial thrombosis a problem? The current article reviews the available literature regarding these questions and aims to provide practical solutions based on data from the clinical trials and new guidelines. Full article

Background: An outbreak of an unknown respiratory illness caused by a novel coronavirus, SARS-CoV-2, emerged in the city of Wuhan in Hubei Province, China, in December 2019 and was referred to as coronavirus disease-2019 (COVID-19). Soon after, it was declared as a global pandemic by the World Health Organization (WHO) in March 2020. SARS-CoV-2 mainly infects the respiratory tract with different outcomes ranging from asymptomatic infection to severe critical illness leading to death. Different SARS-CoV-2 variants are emerging of which three have raised concerns worldwide due to their high transmissibility among populations. Objective: To study the prevalence of COVID-19 in the region of Nabatieh-South Lebanon during the past year and assess the presence of SARS-CoV-2 variants and their effect on the spread of infection during times of lockdown. Methods: In our study, 37,474 nasopharyngeal swab samples were collected and analyzed for the detection of SARS-CoV-2 virus in suspected patients attending a tertiary health care center in South Lebanon during the period between 16 March 2020 and 21 February 2021. Results: The results demonstrated a variation in the prevalence rates ranging from less than 1% during full lockdown of the country to 8.4% upon easing lockdown restrictions and reaching 27.5% after the holidays and 2021 New Year celebrations. Interestingly, a new variant(s) appeared starting January 2021 with a significant positive association between the prevalence of positive tests and the percentage of the variant(s). Conclusions: Our results indicate that the lockdown implemented by the Lebanese officials was an effective intervention to contain COVID-19 spread. Our study also showed that lifting lockdown measures during the holidays, which allowed indoor crowded gatherings to occur, caused a surge in COVID-19 cases and rise in the mortality rates nationwide. More importantly, we confirmed the presence of a highly transmissible SARS-CoV-2 variant(s) circulating in the Lebanese community from at least January 2021 onwards. Full article