Life, Volume 14, Issue 5 (May 2024) – 91 articles

Fryns syndrome (FS) is a multiple congenital anomaly syndrome with different multisystemic malformations. These include congenital diaphragmatic hernia, pulmonary hypoplasia, and craniofacial dysmorphic features in combination with malformations of the central nervous system such as agenesis of the corpus callosum, cerebellar hypoplasia, and enlarged ventricles. We present a non-consanguineous northern European family with two recurrent cases of FS: a boy with multiple congenital malformations who died at the age of 2.5 months and a female fetus with a complex developmental disorder with similar features in a following pregnancy. Quad whole exome analysis revealed two likely splicing-affecting disease-causing mutations in the PIGN gene: a synonymous mutation c.2619G>A, p.(Leu873=) in the last nucleotide of exon 29 and a 30 bp-deletion c.996_1023+2del (NM_176787.5) protruding into intron 12, with both mutations in trans configuration in the affected patients. Exon skipping resulting from these two variants was confirmed via RNA sequencing. Our molecular and clinical findings identified compound heterozygosity for two novel splice-affecting variants as the underlying pathomechanism for the development of FS in two patients. Full article

Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease that affects more than 2 million people worldwide. It manifests through vasculopathy, an abnormal immunological response, and fibrosis leading to dysfunction of the multiple organs. The disease is categorized into two subtypes: limited cutaneous SSc and diffuse cutaneous SSc. Scleroderma can affect vital organs with respiratory, cardiac, renal, ocular, and dermatological complications. The ocular manifestations of the disease can occur in the anterior and posterior segments of the eye. Changes in the anterior segment related to the disease include eyelid skin remodeling, dry eye syndrome, and conjunctival abnormalities. The disease’s impact on the posterior segment of the eye mostly causes pathologies in the retinal microcirculatory system and abnormalities in the optic nerve. This review provides detailed insights into ocular complications associated with scleroderma. Full article

Familial Alzheimer’s disease (FAD) can be caused by mutations in PSEN1 that encode presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca²⁺) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD; however, it has been difficult to assess in humans whether or not these phenotypes are the result of amyloid or tau pathology. This study aimed to assess the early calcium and glutamate phenotypes of FAD by measuring the Ca²⁺ response of induced pluripotent stem cell (iPSC)-derived neurons bearing PSEN1 mutations to glutamate and the ionotropic glutamate receptor agonists NMDA, AMPA, and kainate compared to isogenic control and healthy lines. The data show that in early neurons, even in the absence of amyloid and tau phenotypes, FAD neurons exhibit increased Ca²⁺ responses to glutamate and AMPA, but not NMDA or kainate. Together, this suggests that PSEN1 mutations alter Ca²⁺ and glutamate signaling as an early phenotype of FAD. Full article

Neovascular age-related macular degeneration (AMD) is a major cause of irreversible blindness in elderly populations in developed countries. AMD’s etiopathology is multifactorial, with strong environmental and genetic components, but the exact molecular pathomechanisms underlying the disease are still unknown. In this study, we analyzed blood serum collected from 74 neovascular AMD patients and 58 healthy controls to identify proteins that may serve as potential biomarkers and expand our knowledge about the etiopathogenesis of the disease. The study revealed 17 differentially expressed proteins—11 up-regulated and 6 down-regulated—in neovascular AMD, which are involved in the biological processes previously linked with the disease—oxidative stress and persistent inflammation, impaired cellular transport, lipid metabolism and blood coagulation. In conclusion, the differences in the expressions of the proteins identified in this study may contribute to our understanding of the mechanisms underlying AMD and possibly serve in future as promising biomarkers. Full article

This retrospective cohort study evaluates the safety and efficacy of replacement therapy with regard to pregnancy outcomes in hemophilia carriers. Hemophilia carriers face elevated bleeding risks during pregnancy, necessitating meticulous management, including replacement therapy with clotting factors. This research examines the records of 64 pregnant hemophilia carriers at King Fahad Medical City, Riyadh, from January 2010 to December 2023, analyzing their demographic details, hemophilia type and severity, replacement therapy specifics, and pregnancy outcomes. The study found that 62.5% of the participants had hemophilia A, with 43.8% categorized as severe. Most subjects (87.5%) received recombinant factor VIII at a median dosage of 30 IU/kg weekly. Adverse pregnancy outcomes included gestational hypertension (15.6%), preterm labor (18.8%), and postpartum hemorrhage (12.5%). The cesarean section rate was 28.1%. Neonatal outcomes were generally favorable, with median birth weights at 3100 g and mean Apgar scores of 8.2 and 9.1 at 1 and 5 min, respectively. Logistic regression analysis revealed no significant association between adverse events and therapy type or dosage, though a trend towards significance was noted with once-weekly administration (p = 0.082). The study concludes that replacement therapy is a viable method for managing hemophilia in pregnant carriers, leading to generally favorable maternal and neonatal outcomes. However, it underscores the importance of individualized treatment plans and close monitoring to effectively manage the risks associated with hemophilia during pregnancy. Full article

Aim. To identify subgroups of patients with primary osteoarthritis of the hip joint (pHOA) with similar imaging and laboratory findings, disease evolution, and response to conventional therapies. Methods. We performed further statistical analyses on patient data from two published, double-blind, randomized, and placebo-controlled studies (DB-RCTs), which examined the effects of intra-articular corticosteroids (ia-CSs), hyaluronic acid (ia-HA)—KИ-109-3-0008/14.01.2014, and intravenous bisphosphonates (iv-BPs) -KИ- 109-3-0009/14.01.2014 compared to the country’s standard pHOA therapy. The data span an 8-year follow-up of 700 patients with pHOA, including: 1. Clinical parameters (WOMAC-A, B, C, and T; PtGA). 2. Laboratory markers (serum calcium and phosphate levels; 25-OH-D and PTH, markers for bone sCTX-I and cartilage uCTX-II turnover). 3. Radiological indicators: X-ray stage (Kellgren-Lawrence (K/L) and model (Bombelli/OOARSI), width (mJSW), speed (JSN mm/year), and zone of maximum narrowing of the joint space (max-JSN)—determining the type of femoral head migration (FHM). 4. DXA indicators: bone geometry (HAL; NSA; and MNW); changes in regional and total bone mineral density (TH-BMD, LS-BMD, and TB-BMD). 5. Therapeutic responses (OARSI/MCII; mJSW; JSNmm/yearly) to different drug regimens (iv-BP -zoledronic acid (ZA/-5 mg/yearly for 3 years)); ia-CS 40 mg methylprednisolone acetate, twice every 6 months; and ia-HA with intermediate molecular weight (20 mg/2 mL × 3 weekly applications, two courses every 6 months) were compared to standard of care therapy (Standard of Care/SC/), namely D3-supplementation according to serum levels (20–120 ng/mL; target level of 60 ng/mL), simple analgesics (paracetamol, up to 2.0 g/24 h), and physical exercises. The abovementioned data were integrated into a non-supervised hierarchical agglomerative clustering analysis (NHACA) using Ward’s linkage method and the squared Euclidean distance to identify different endophenotypes (EFs). Univariate and multivariate multinomial logistic regression analyses were performed to determine the impact of sex and FHM on clinical and radiographic regression of pHOA. Results. A baseline cluster analysis using incoming (M0) patient data identified three EFs: hypertrophic H-HOA, atrophic A-HOA, and intermediate I-HOA. These EFs had characteristics that were similar to those of patients grouped by radiographic stage and pattern (‘H’-RPs, ‘I’-RPs, and ‘A’-RPs), p < 0.05). The repeated cluster analysis of M36 data identified four EF pHOAs: 1. Hypertrophic (slow progressors, the influence of the type of femoral head migration (FHM) outweighing the influence of sex on progression), progressing to planned total hip replacement (THR) within 5 (K/LIII) to 10 (K/LII) years. 2. Intermediate (sex is more important than the FHM type for progression) with two subgroups: 2#: male-associated (slow progressors), THR within 4 (K/LIII) to 8 years. (K/LII). 2* Female-associated (rapid progressors), THR within 3 (K/LIII) to 5 (K/LII) years. 3. Atrophic (rapid progressors; the influence of FHM type outweighs that of sex), THR within 2 (K/LIII) to 4 (K/LII) years. Each EF, in addition to the patient’s individual progression rate, was also associated with a different response to the aforementioned therapies. Conclusions. Clinical endophenotyping provides guidance for a personalized approach in patients with pHOA, simultaneously assisting the creation of homogeneous patient groups necessary for conducting modern genetic and therapeutic scientific studies. Full article

Atrial fibrillation (AF) commonly occurs in approximately 2% of cancer patients, and the incidence of AF among cancer patients is greater than in the general population. This observational study presented the incidence risk of AF among cancer patients, including specific cancer types, using a population database. The Taiwan Cancer Registry was used to identify cancer patients between 2008 and 2017. The diagnosis of AF was based on the International Classification of Diseases codes (ICD-9-CM: 427.31 or ICD-10-CM: I48.0, I48.1, I48.2, and I48.91) in Taiwan national health insurance research datasets. The incidence of developing AF in the cancer population was calculated as the number of new-onset AF cases per person-year of follow-up during the study period. The overall incidence of AF among cancer patients was 50.99 per 100,000 person-years. Patients aged older than 65 years and males had higher AF incidence rates. Lung cancer males and esophageal cancer females showed the highest AF incidence risk (185.02 and 150.30 per 100,000 person-years, respectively). Our findings identified esophageal, lung, and gallbladder cancers as the top three cancers associated with a higher incidence of AF. Careful monitoring and management of patients with these cancers are crucial for early detection and intervention of AF. Full article

Uncontrollable bleeding is recognized as the leading cause of preventable death among trauma patients. Early transfusion of blood products, especially plasma replacing crystalloid and colloid solutions, has been shown to increase survival of severely injured patients. However, the requirements for cold storage and thawing processes prior to transfusion present significant logistical challenges in prehospital and remote areas, resulting in a considerable delay in receiving thawed or liquid plasma, even in hospitals. In contrast, freeze- or spray-dried plasma, which can be massively produced, stockpiled, and stored at room temperature, is easily carried and can be reconstituted for transfusion in minutes, provides a promising alternative. Drawn from history, this paper provides a review of different forms of dried plasma with a focus on in vitro characterization of hemostatic properties, to assess the effects of the drying process, storage conditions in dry form and after reconstitution, their distinct safety and/or efficacy profiles currently in different phases of development, and to discuss the current expectations of these products in the context of recent preclinical and clinical trials. Future research directions are presented as well. Full article

Scopolamine and atropine are two medicinal alkaloids derived from Datura stramonium L. with anticholinergic properties. This study explored how methyl jasmonate (MJ), a plant growth regulator, affects the biosynthesis and accumulation of these alkaloids in different plant tissues. The expression levels of putrescine N-methyltransferase (PMT), tropinone reductase I (TR1), and hyoscyamine 6β-hydroxylase (h6h), three critical enzymes in the biosynthetic pathway, were also analyzed. The results indicated that MJ at 150 µM increased the production of scopolamine and atropine in both leaves and roots, while MJ at 300 µM had an adverse effect. Furthermore, MJ enhanced the expression of PMT, TR1, and h6h genes in the roots, the primary site of alkaloid synthesis, but not in the leaves, the primary site of alkaloid storage. These results imply that MJ can be applied to regulate the biosynthesis and accumulation of scopolamine and atropine in D. stramonium, thereby improving their production efficiency. Full article

Chronic kidney disease (CKD) and cardiovascular disease (CVD) are highly prevalent conditions, each significantly contributing to the global burden of morbidity and mortality. CVD and CKD share a great number of common risk factors, such as hypertension, diabetes, obesity, and smoking, among others. Their relationship extends beyond these factors, encompassing intricate interplay between the two systems. Within this complex network of pathophysiological processes, vitamin D has emerged as a potential linchpin, exerting influence over diverse physiological pathways implicated in both CKD and CVD. In recent years, scientific exploration has unveiled a close connection between these two prevalent conditions and vitamin D, a crucial hormone traditionally recognized for its role in bone health. This article aims to provide an extensive review of vitamin D’s multifaceted and expanding actions concerning its involvement in CKD and CVD. Full article

This review provides an overview of current knowledge regarding the adaptive effects of physical training on the endothelium. The endothelium plays a crucial role in maintaining the health of vessel walls and regulating vascular tone, structure, and homeostasis. Regular exercise, known for its promotion of cardiovascular health, can enhance endothelial function through various mechanisms. The specific health benefits derived from exercise are contingent upon the type and intensity of physical training. The review examines current clinical evidence supporting exercise’s protective effects on the vascular endothelium and identifies potential therapeutic targets for endothelial dysfunction. There is an urgent need to develop preventive strategies and gain a deeper understanding of the distinct impacts of exercise on the endothelium. Full article

BRCA1 and BRCA2 mutations are responsible for a higher incidence of breast and ovarian cancer (from 55% up to 70% vs. 12% in the general population). If their functions have been widely investigated in the onset of these malignancies, still little is known about their role in fertility impairment. Cancer patients treated with antineoplastic drugs can be susceptible to their gonadotoxicity and, in women, some of them can induce apoptotic program in premature ovarian follicles, progressive depletion of ovarian reserve and, consequently, cancer treatment-related infertility (CTRI). BRCA variants seem to be associated with early infertility, thus accelerating treatment impairment of ovaries and making women face the concrete possibility of an early pregnancy. In this regard, fertility preservation (FP) procedures should be discussed in oncofertility counseling—from the first line of prevention with risk-reducing salpingo-oophorectomy (RRSO) to the new experimental ovarian stem cells (OSCs) model as a new way to obtain in vitro-differentiated oocytes, several techniques may represent a valid option to BRCA-mutated patients. In this review, we revisit knowledge about BRCA involvement in lower fertility, pregnancy feasibility, and the fertility preservation (FP) options available. Full article

(1) Background: Infections caused by multidrug-resistant (MDR) bacteria represent one of the major global public health problems of the 21st century. Beta-lactam antibacterial agents are commonly used to treat infections due to Gram-negative pathogens. New β-lactam/β-lactamase inhibitor combinations are urgently needed. Combining relebactam (REL) with imipenem (IMI) and cilastatin (CS) can restore its activity against many imipenem-nonsusceptible Gram-negative pathogens. (2) Methods: we performed a systematic review of the studies reporting on the use of in vivo REAL/IPM/CS. (3) Results: A total of eight studies were included in this review. The primary diagnosis was as follows: complicated urinary tract infection (n = 234), complicated intra-abdominal infections (n = 220), hospital-acquired pneumonia (n = 276), and ventilator-associated pneumonia (n = 157). Patients with normal renal function received REL/IPM/CS (250 mg/500 mg/500 mg). The most frequently reported AEs occurring in patients treated with imipenem/cilastatin plus REL/IPM/CS were nausea (11.5%), diarrhea (9.8%), vomiting (9.8%), and infusion site disorders (4.0%). Treatment outcomes in these high-risk patients receiving REL/IPM/CS were generally favorable. A total of 70.6% of patients treated with REL/IPM/CS reported a favorable clinical response at follow-up. (4) Conclusions: this review indicates that REL/IPM/CS is active against important MDR Gram-negative organisms. Full article

Tumoral calcinosis is an extremely rare genetic disease caused by mutations in three genes, GALNT3, FGF23, and KL, which disrupt phosphorus metabolism. The hallmark of this condition is the formation of tumors in the soft tissues around the joints. Other phenotypic features of tumoral calcinosis are dental involvement and brain and vascular calcifications. The clinical case reported herein presents for the first time to the scientific community the c.202A>G (p.Thr68Ala) mutation of the FGF23 gene, associated with a hyperphosphatemic variant of tumoral calcinosis and multiple severe vascular aneurysms. A female patient underwent multiple surgeries for tumor formations in her soft tissues that first appeared at the age of 12 months. On this occurrence, the patient was found to have hyperphosphatemia, low phosphate clearance, increased tubular reabsorption with normal levels of total and ionized calcium, vitamin D3, and parathyroid hormone, and no effect of treatment with sevelamer hydrochloride and a low-phosphate diet. At the age of 39, the patient underwent imaging studies due to edema and a pulsating formation in the neck area, which revealed multiple vascular aneurysms with thrombosis, for which she received operative and interventional treatment. In this connection, and because of the established phosphorus metabolism disturbance, a genetic disease was suspected. The sequence analysis and deletion/duplication testing of the 358 genes performed on this occasion revealed that the woman was homozygous for a variant of the c.202A>G (p.Thr68Ala) mutation of the FGF23 gene. The established mutation is not present in population databases. The presented clinical case is the first and only one in the world to demonstrate the role of this type of FGF23 gene mutation in the development of a hyperphosphatemic variant of tumoral calcinosis characterized by aggressive formation of multiple vascular aneurysms. Full article

For patients with chronic pain and persistent physical symptoms, understanding the mechanism of central sensitisation may help in understanding how symptoms persist. This cross-sectional study investigated the association of central sensitisation with depression, anxiety, and somatic symptoms. Four hundred and fifteen adults attending an outpatient psychosomatic clinic were evaluated. Participants completed the Hospital Anxiety and Depression Scale, Somatic Symptom Scale 8, and the Central Sensitisation Inventory. The relationships between these factors were examined using descriptive statistics and multiple logistic regression analyses. The mean age was 42.3 years, and 59% were female. The disorders included adjustment disorders (n = 70), anxiety disorders (n = 63), depressive disorders (n = 103), feeding and eating disorders (n = 30), sleep–wake disorders (n = 37), somatic symptoms and related disorders (n = 84), and others (n = 28). In multiple logistic regression analyses, higher central sensitisation was associated with more severe anxiety, depression, and somatic symptoms after controlling for potential confounders. In the disease-specific analysis, somatic symptoms correlated more positively with central sensitisation than with depression or anxiety. Central sensitisation and depression, anxiety, and somatic symptoms were associated with patients attending an outpatient clinic. These findings highlight the importance of evaluating depression, anxiety, and somatic symptoms when assessing central sensitisation. Full article

Resveratrol, a polyphenolic compound found primarily in red grapes and pomegranates is known as an antioxidant but can act as a pro-oxidant when copper ions are present. Here, resveratrol is demonstrated to reduce cell growth (as evaluated by MTT assay) and promote apoptosis-like cell death (as measured by Histone/DNA ELISA) in prostate cancer cell lines PC3 and C42B. This effect is effectively inhibited by a copper chelator (neocuproine) and reactive oxygen species (ROS) scavengers (thiourea for hydroxyl radical, superoxide dismutase for superoxide anion, and catalase for hydrogen peroxide). These inhibitory effects provide evidence that intracellular copper reacts with resveratrol within cancer cells, resulting in DNA damage via the generation of reactive oxygen species. Additionally, it has been demonstrated that non-tumorigenic epithelial cell lines (MCF-10A) grown in media supplemented with copper are more susceptible to growth inhibition by resveratrol, as confirmed by the observed reduction in cell proliferation. Copper supplementation induces enhanced expression of the copper transporter CTR1 in MCF-10A cells, which is reduced by the addition of resveratrol to the media. The selective cell death of cancer cells generated by copper-mediated and ROS mechanisms may help to explain the anticancer properties of resveratrol. Full article

Multidrug-resistant bacterial pathogens, such as E. coli, represent a major human health threat. Due to the critical need to overcome this dilemma, since the drug efflux pump has a vital function in the evolution of antimicrobial resistance in bacteria, we have investigated the potential of Mentha essential oil major constituents (1–19) as antimicrobial agents via their ability to inhibit pathogenic DNA gyrase and, in addition, their potential inhibition of the E. coli AcrB-TolC efflux pump, a potential target to inhibit MDR pathogens. The ligand docking approach was conducted to analyze the binding interactions of Mentha EO constituents with the target receptors. The obtained results proved their antimicrobial activity through the inhibition of DNA gyrase (1kzn) with binding affinity ΔG values between −4.94 and −6.49 kcal/mol. Moreover, Mentha EO constituents demonstrated their activity against MDR E. coli by their ability to inhibit AcrB-TolC (4dx7) with ΔG values ranging between −4.69 and −6.39 kcal/mol. The antimicrobial and MDR activity of Mentha EOs was supported via hydrogen bonding and hydrophobic interactions with the key amino acid residues at the binding site of the active pocket of the targeted receptors. Full article

Alopecia constitutes one of the most common dermatological disorders, and its steadily increasing prevalence is a cause for concern. Alopecia can be divided into two main categories, cicatricial/scarring and non-cicatricial/non-scarring, depending on the causes of hair loss and its patterns. The aim of this study was to investigate the relationship between anthropometric and nutritional laboratory parameters in Caucasian adult women and men with non-cicatricial alopecia. A total of 50 patients (37 with non-cicatricial alopecia and 13 healthy controls) were included in the study. Clinical examination and scalp trichoscopy were performed. The anthropometric and nutritional laboratory parameters were collected and analyzed. No statistically significant differences in the laboratory findings were found. The patients with non-cicatricial alopecia were statistically significantly younger as compared to the controls. An elevated risk of hair loss, which was detected among the younger participants, might be associated with a modern lifestyle and the so-called ‘Western diet’. It seems safe to assume that suboptimal nutrition and poor eating habits during childhood might constitute risk factors for early hair loss. Full article

Introduction: Non-infectious erythema, or Red Breast Syndrome (RBS), has been observed on the skin where acellular dermal matrix was implanted, although the exact cause is yet to be determined. Patients and Methods: A total of 214 female patients underwent breast-conserving surgery (BCS) and volume replacement using diced acellular dermal matrix (dADM) for breast cancer between December 2017 and December 2018. After collecting and evaluating relevant clinical data, inflammation markers, along with NK cell status presented by IFN-γ secretion assay, were measured using ELISA. Results: Nineteen patients (8.88%) presented with RBS after BCS and dADM use. A significant increase of platelet-to-lymphocyte ratio was noted in the non-RBS group (p = 0.02). Compared to the RBS group (p = 0.042), the WBC level of the non-RBS group showed significant decrease over time. Eosinophil counts increased significantly at follow-up but went up higher in the RBS group. Multivariate analysis showed preoperative chemotherapy significantly increased the hazard of RBS (OR 3.274, p = 0.047 and OR 17.098, p < 0.001, respectively). Discussion: Though no causal relationship between RBS and immune status was proven, the results suggest an association between preoperative chemotherapy and RBS in addition to the possible role of eosinophilia in leading to eosinophilic dermatoses, which warrants further exploration and elucidation. Full article

Humanity’s strive to understand why and how life appeared on planet Earth dates back to prehistoric times. At the beginning of the 19th century, empirical biology started to tackle this question yielding both Charles Darwin’s Theory of Evolution and the paradigm that the crucial trigger putting life on its tracks was the appearance of organic molecules. In parallel to these developments in the biological sciences, physics and physical chemistry saw the fundamental laws of thermodynamics being unraveled. Towards the end of the 19th century and during the first half of the 20th century, the tensions between thermodynamics and the “organic-molecules-paradigm” became increasingly difficult to ignore, culminating in Erwin Schrödinger’s 1944 formulation of a thermodynamics-compliant vision of life and, consequently, the prerequisites for its appearance. We will first review the major milestones over the last 200 years in the biological and the physical sciences, relevant to making sense of life and its origins and then discuss the more recent reappraisal of the relative importance of metal ions vs. organic molecules in performing the essential processes of a living cell. Based on this reassessment and the modern understanding of biological free energy conversion (aka bioenergetics), we consider that scenarios wherein life emerges from an abiotic chemiosmotic process are both thermodynamics-compliant and the most parsimonious proposed so far. Full article

Colorectal cancer (CRC) is a heterogenous pathology with high incidence and mortality rates globally, but it is also preventable so finding the most promising candidates (natural compounds or repurposed drugs) to be chemopreventive alternatives has become a topic of interest in recent years. The present work aims to elucidate the potential effects of a combination between genistein (GEN), an isoflavone of natural origin, and aspirin (ASA) in CRC prevention/treatment by performing an in vitro evaluation in human colorectal cancer cells (HCT-116) and an in ovo analysis using the chick embryo chorioallantoic membrane (CAM) model. Cell viability was verified by an MTT (migratory potential by scratch) assay, and the expressions of MMP-2 and MMP-9 were analyzed using RT-qPCR. Our results indicated a dose-dependent cytotoxic effect of ASA (2.5 mM) + GEN (10–75 µM) combination characterized by reduced cell viability and morphological changes (actin skeleton reorganization and nuclei deterioration), an inhibition of HCT-116 cells’ migratory potential by down-regulating MMP-2 and MMP-9 mRNA expressions, and an antiangiogenic effect by modifying the vascular network. These promising results raise the possibility of future in-depth investigations regarding the chemopreventive/therapeutical potential of ASA+GEN combination. Full article

The aim of this study was to conduct salivary, microbiological, and caries risk assessments in relation to caries experience among individuals with intellectual disability in an institutional center in the Al-Baha region, Saudi Arabia. A cross-sectional study was conducted among 89 patients residing in special care homes in the Al-Baha region, Saudi Arabia, from October 2023 to February 2024. The demographic details of all participants were recorded. Clinical oral examinations were performed for the decayed, missing, or filled teeth (DMFT) and plaque indices. Salivary and microbiological assessments were also carried out. The mean age of the study sample was 30.11 ± 4.39 years, and the mean duration of years spent residing in the facility was 26.49 ± 4.66. There was no significant difference observed across plaque scores, S. mutans colony count, salivary rate, pH, DFMT, and caries experience when they were compared across the levels of severity of intellectual disability. Statistically significant differences were observed across diet score, circumstance score, and chances to avoid caries and were found to be correlated with the severity of intellectual disability (p = 0.001, p = 0.001, and p = 0.002), respectively. The cariogram revealed that participants in this study had poor oral health status, with participants with severe intellectual disability having higher diet scores, frequency scores, and susceptibility scores; hence lesser chances to avoid dental caries. Regular dental check-ups, including cleanings and other treatments if necessary, seem to be fundamental to prevent dental issues and maintain healthy teeth and gums for this group of people. Developing interventions that focus on improving oral health status among intellectually disabled individuals may be recommended to ensure the optimum level of support and reduce the burden of dental decay among those individuals. Full article

Due to its variety of signs and symptoms, there have been numerous attempts to treat fibromyalgia (FM), but a cure has yet to be established. The aim of this study was to evaluate the effects of a complex kinetic therapy program and a combined physical modality program on pain and other common symptoms of FM. Patients and methods: A total of 78 female patients were included in this study; 39 subjects underwent a kinesiotherapy (KT) intervention (combining aerobic and Pilates exercises), and 39 participated in a physical modality (PM) program (including electrotherapy (TENS and low-laser therapy) and thermotherapy). Results: Regarding the parameter of pain assessment, kinesiotherapy demonstrated its superiority both during the treatment period and in the evaluation 3 months after therapy cessation. Both in terms of patient-reported pain (inter-group comparisons: p = 0.000 at T3) and the examination of tender points (inter-group comparisons: p = 0.000 at T3), as well as the algometric assessment, pain was alleviated by the two forms of applied kinetic therapy. The observed functional impairment was statistically significantly influenced (p = 0.001) at the end of the kinetic program application, while for the perceived functional impairment, neither therapy proved superiority over the other at any point of evaluation (inter-group comparisons: p = 0.715 at T3). Regarding the influence of the emotional consequences implied by fibromyalgia, neither the forms of kinesiotherapy nor the chosen physical modalities proved superiority at any point of evaluation (HAQ anxiety inter-group comparisons: p = 0.000 at T3). In conclusion, even though kinesiotherapy had superior influences on fibromyalgia pain in the studied group, the current research lends credence to the significance of non-pharmacological therapy in managing fibromyalgia. Participants demonstrated positive advancements in subjective and objective pain assessments, as well as improvements in functional and emotional well-being. Full article

Our study aims to evaluate the effect of everolimus treatment on lung function in lung transplant (LT) patients with established chronic lung allograft dysfunction (CLAD). Methods: This retrospective study included LT patients in two reference LT units who started everolimus therapy to treat CLAD from October 2008 to October 2016. We assessed the variation in the maximum forced expiratory volume in the first second (FEV₁) before and after the treatment. Results: Fifty-seven patients were included in this study. The variation in the FEV₁ was −102.7 (149.6) mL/month before starting everolimus compared to −44.7 (109.6) mL/month within the first three months, +1.4 (63.5) mL/month until the sixth month, and −7.4 (46.2) mL/month until the twelfth month (p < 0.05). Glomerular filtrate remained unchanged after everolimus treatment [59.1 (17.5) mL/min per 1.73 m² at baseline and 60.9 (19.6) mL/min per 1.73 m², 57.7 (20.5) mL/min per 1.73 m², and 57.3 (17.8) mL/min per 1.73 m², at 1, 3, and 6 months, respectively] (p > 0.05). Everolimus was withdrawn in 22 (38.6%) patients. The median time to withdrawal was 14.1 (5.5–25.1) months. Conclusions: This study showed an improvement in FEV₁ decline in patients with CLAD treated with everolimus. However, the drug was withdrawn in a high proportion of patients. Full article

Forests appeared during the Middle to Late Devonian, but Devonian forests and their compositions are still rarely known. Xinhang forest was reported as the largest Devonian forest, with lycopsid trees of Guangdedendron micrum Wang et al. A fern-like plant Xinhangia spina Yang and Wang with shoots and anatomy, was previously described from this forest, but its habit and ecology remain unclear. From Xinhang forest, we now report more specimens of fern-like plants including X. spina and some unnamed plants in several beds. Prominent adventitious roots, spines and secondary xylem indicate that the stems of X. spina are largely procumbent to function as anchorage, absorption and support. Other fern-like plants with distinct roots or multiple slender branches also suggest procumbent habits. Xinhang forest is thus reconsidered as multispecific with a canopy of lycopsid trees and understory of diverse fern-like plants, which are adapted to the disturbed coastal environment. The composition of Xinhang forest may indicate a structural transition of the early forests’ dominator from fern-like plants to lycopsids. Full article

Fixed nitrogen species generated by the early Earth’s atmosphere are thought to be critical to the emergence of life and the sustenance of early metabolisms. A previous study estimated nitrogen fixation in the Hadean Earth’s N₂/CO₂-dominated atmosphere; however, that previous study only considered a limited chemical network that produces NO_x species (i.e., no HCN formation) via the thermochemical dissociation of N₂ and CO₂ in lightning flashes, followed by photochemistry. Here, we present an updated model of nitrogen fixation on Hadean Earth. We use the Chemical Equilibrium with Applications (CEA) thermochemical model to estimate lightning-induced NO and HCN formation and an updated version of KINETICS, the 1-D Caltech/JPL photochemical model, to assess the photochemical production of fixed nitrogen species that rain out into the Earth’s early ocean. Our updated photochemical model contains hydrocarbon and nitrile chemistry, and we use a Geant4 simulation platform to consider nitrogen fixation stimulated by solar energetic particle deposition throughout the atmosphere. We study the impact of a novel reaction pathway for generating HCN via HCN₂, inspired by the experimental results which suggest that reactions with CH radicals (from CH₄ photolysis) may facilitate the incorporation of N into the molecular structure of aerosols. When the HCN₂ reactions are added, we find that the HCN rainout rate rises by a factor of five in our 1-bar case and is about the same in our 2- and 12-bar cases. Finally, we estimate the equilibrium concentration of fixed nitrogen species under a kinetic steady state in the Hadean ocean, considering loss by hydrothermal vent circulation, photoreduction, and hydrolysis. These results inform our understanding of environments that may have been relevant to the formation of life on Earth, as well as processes that could lead to the emergence of life elsewhere in the universe. Full article

Most of the annual 10 million cancer-related deaths are caused by metastatic disease. Survival rates for cancer are strongly dependent on the type of cancer and its stage at detection. Early detection remains a challenge due to the lack of reliable biomarkers and cost-efficient screening methods. Phage biosensors can offer a solution for early detection using non-invasive liquid biopsies. Here, we report the first results of the bifunctional phage biosensor to detect metastatic urological cancers from urine. A dye-sensitized phage library was used to select metastasis-related phage binders. After selection rounds, the most promising phage candidate was used to classify metastatic cancer from controls. Additionally, we applied one chemical sensor (phenoxazine non-fluorescent dye) to classify cancer from urine. A statistical significance (p = 0.0002) was observed between metastatic and non-metastatic cancer, with sensitivity of 70% and specificity of 79%. Furthermore, the chemical sensor demonstrated significance in detecting cancer (p < 0.0001) with a sensitivity of 71% and a specificity of 75%. Our data suggest a new promising field for urine biomarker research, and further evaluation with prospectively collected samples is ongoing. In conclusion, we report, for the first time, the potential of a chemical- and phage-based biosensor method to detect metastatic cancer using urine. Full article

Research progresses have led to the development of different kinds of nanoplatforms to deliver drugs through different biological membranes. Particularly, nanocarriers represent a precious means to treat skin pathologies, due to their capability to solubilize lipophilic and hydrophilic drugs, to control their release, and to promote their permeation through the stratum corneum barrier. A crucial point in the development of nano-delivery systems relies on their characterization, as well as in the assessment of their interaction with tissues, in order to predict their fate under in vivo administration. The size of nanoparticles, their shape, and the type of matrix can influence their biodistribution inside the skin strata and their cellular uptake. In this respect, an overview of some characterization methods employed to investigate nanoparticles intended for topical administration is presented here, namely dynamic light scattering, zeta potential, scanning and transmission electron microscopy, X-ray diffraction, atomic force microscopy, Fourier transform infrared and Raman spectroscopy. In addition, the main fluorescence methods employed to detect the in vitro nanoparticles interaction with skin cell lines, such as fluorescence-activated cell sorting or confocal imaging, are described, considering different examples of applications. Finally, recent studies on the techniques employed to determine the nanoparticle presence in the skin by ex vivo and in vivo models are reported. Full article