Objectives: This study aimed to showcase how implementing a patient blood management (PBM) program effectively cuts unnecessary red blood cell (RBC) transfusions in a New York City urban community teaching hospital. Methods: Analyzing seven years from 2013 to 2019, a retrospective review of RBC transfusions was conducted. Results: Following the introduction of PBM, considerable improvements were observed annually. These included a drop in mean pretransfusion hemoglobin levels from 7.26 g/dL (2013) to 6.58 g/dL (2019), a 34% reduction in yearly RBC unit transfusions, and fewer units given to patients with pre-Hgb levels ≥ 7 g/dL (from 1210 units in 2013 to 310 units in 2019). Furthermore, this study noted a decline in two-unit RBC orders when Hgb levels were ≥ 7 g/dL from 65 orders in 2013 to merely 3 in 2019. The estimated total cost savings attributed to the six-year PBM program duration after full implementation in 2014 amounted to USD 2.1 million. Conclusions: Overall, PBM implementation significantly decreased RBC transfusions and enhanced transfusion practices. The findings emphasize that successful PBM strategies do not always necessitate extensive resources or increased budgets but instead rely on the application of intuitive methods, as evidenced by this study. Full article

Maintenance of the health of our oceans is critical for the survival of the oceanic food chain upon which humanity is dependent. Zooplanktonic copepods are among the most numerous multicellular organisms on earth. As the base of the primary consumer food web, they constitute a major biomass in oceans, being an important food source for fish and functioning in the carbon cycle. The potential impact of climate change on copepod populations is an area of intense study. Omics technologies offer the potential to detect early metabolic alterations induced by the stresses of climate change. One such omics approach is lipidomics, which can accurately quantify changes in lipid pools serving structural, signal transduction, and energy roles. We utilized high-resolution mass spectrometry (≤2 ppm mass error) to characterize the lipidome of three different species of copepods in an effort to identify lipid-based biomarkers of copepod health and viability which are more sensitive than observational tools. With the establishment of such a lipid database, we will have an analytical platform useful for prospectively monitoring the lipidome of copepods in a planned long-term five-year ecological study of climate change on this oceanic sentinel species. The copepods examined in this pilot study included a North Atlantic species (Calanus finmarchicus) and two species from the Gulf of Mexico, one a filter feeder (Acartia tonsa) and one a hunter (Labidocerca aestiva). Our findings clearly indicate that the lipidomes of copepod species can vary greatly, supporting the need to obtain a broad snapshot of each unique lipidome in a long-term multigeneration prospective study of climate change. This is critical, since there may well be species-specific responses to the stressors of climate change and co-stressors such as pollution. While lipid nomenclature and biochemistry are extremely complex, it is not essential for all readers interested in climate change to understand all of the various lipid classes presented in this study. The clear message from this research is that we can monitor key copepod lipid families with high accuracy, and therefore potentially monitor lipid families that respond to environmental perturbations evoked by climate change. Full article

Background: Aging is associated with cognitive decline, leading to cognitive and physical impairments, which are risk factors for loss of independence and dementia development. Early diagnosis is beneficial for both, the patient and their family, to avoid long-term consequences. The aim of this study was to analyze the frequency of depressive disorders and their influence on cognitive and physical function of older people in early dementia detection. Methods: There were 852 patients, aged at least 60 years, from the Central Teaching Hospital. The study was conducted between September 2022 and June 2023. The qualified participants were examined using four tools: Geriatric Depression Scale (GDS), Instrumental Activities of Daily Living (IADL), Timed Up and Go (TUG) and Schulman’s Clock-Drawing Test. Results: Over one-third had depressive disorders. A relationship with p < 0.05 was observed between GDS and IADL: r = −0.61. A relationship with p > 0.05 was observed between GDS and TUG: r = −024. A relationship with p < 0.05 was observed between GDS and CDT: r = 0.74. Conclusions: The first signs of depressive disorders in older people may be considered an indication for further diagnosis of dementia. Full article

Introduction: In some cases, there may be a discrepancy between the symptomatology alleged by Crohn’s disease (CD) patients and the results of laboratory tests or imaging investigations. Ileocolonoscopy with biopsy is the primary investigation for diagnosing and monitoring CD patients. Cross-sectional imaging techniques such as CT or MR enterography (MRE) and intestinal ultrasonography (IUS) have been proposed as complementary methods to colonoscopy for a complete evaluation of this category of patients. This study aims to identify the role of IUS, contrast-enhanced ultrasound (CEUS) and MRE in evaluating ileal CD activity, using clinical severity scores (Crohn’s disease activity index—CDAI, Harvey–Bradshaw index—HBI) and faecal calprotectin or C-reactive protein (CRP) levels as reference methods. Materials and Methods: A total of 44 adult patients with ileal CD confirmed using an ileocolonoscopy with biopsy and histopathological examination were assessed by IUS, CEUS and MRE. The evaluation of the disease activity based on the results obtained from the cross-sectional imaging tests was carried out by using some severity scores available in the literature. The sensitivity and specificity of IUS + CEUS and MRE for differentiating active from inactive forms of CD were determined using CDAI, HBI, faecal calprotectin and CRP as reference methods. The accuracy of the results was assessed by the receiver operating characteristics method. The Pearson correlation coefficient was used to determine the types of correlation. A p-value less than 0.05 suggested a statistically significant relationship. Results: Compared to CDAI, the best correlation was identified for Limberg score (r = 0.667, 95% confidence interval (CI) [0.46, 0.8], p < 0.001), followed by MaRIAs score (r = 0.614, 95% CI [0.39, 0.77], p < 0.001). A sensitivity of 93.33% and a specificity of 71.43% (AUC = 0.98) were demonstrated in the case of Limberg score for differentiating patients with active disease from those in remission and for MaRIAs score a sensitivity of 100.00% and a specificity of 57.14% (AUC = 0.97). Regarding HBI, the best correlation was observed for MaRIAs score (r = 0.594, 95% CI [0.36, 0.76], p < 0.001). Also, faecal calprotectin showed the best correlation with MaRIAs score (r = 0.697, 95% CI [0.46, 0.84], p < 0.001), but in the case of CRP, there was only a weak correlation for all evaluated scores. Conclusions: Although magnetic resonance imaging does not appear to be superior to ultrasonography in terms of accuracy for differentiating active forms of CD from those in remission, the results of our study suggest that MRE associates a better correlation with clinical severity scores and faecal calprotectin levels compared to ultrasonography. More studies are needed to validate these results. Full article

Background: The presence of side effects and low bioavailability of rhein has limited its use in the treatment of osteoarthritis. We aimed to evaluate the in vitro response of human articular chondrocytes to the presence of the combination of platelet-rich plasma (PRP) and rhein. Methods: Solutions of rhein were prepared to assess solubility and select a working concentration. A stimulus with interleukin-1β (IL-β, 10 ng/mL) was induced for 24 h on human chondrocytes. Five treatment groups were established: control, IL-β control, PRP, rhein, and PRP + rhein. Cell viability, cell migration, nitric oxide (NO) production, tumor necrosis factor-α (TNF-α), and gene expression analyses were carried out. Results: A concentration of 50 mg/L was selected after a dose–response curve assay. Both NO and tumor TNF-α production significantly decreased after PRP and PRP + rhein treatments at 24 and 48 h. The wound healing assay revealed a significant stimulation of migration after 72 h with the PRP and PRP + rhein treatments. Expression of IL-1β, IL-6, MMP-13, and ADAMTS-5 was significantly downregulated, particularly after treatment with the combination of PRP + rhein. Conclusions: Much of the determinations denoted a better performance of the combination of PRP and rhein in decreasing the levels of the different targets evaluated; however, this was not great enough to detect a significant difference in comparison with the PRP treatment alone. Full article

Free play in kindergarten can be roughly divided into fine and gross motor activities, but the effects of these activities on improving handgrip strength are unknown. Therefore, we aimed to compare one-year changes in handgrip strength and forearm flexor muscle size in children separated by preferred play in a kindergarten. One hundred and eleven children were recruited from a local kindergarten. They underwent handgrip strength and forearm muscle thickness measurements, and 95 (49 boys and 46 girls) underwent a second measurement one year after the first measurement. Class teachers assessed the physical activity of everyone in their class after the second measurement. Using three evaluation scores by the class teachers, we divided children into three groups based on the children’s preference to play in kindergarten (fine movement vs. gross motor movement). Handgrip strength did not change differently between groups across one year. However, children who liked active playing outside (i.e., gross motor activity) were stronger than others. Furthermore, children who like playing outside observed greater changes than the other groups in the ulna (right hand) and radius muscle thickness (left hand), suggesting that changes in forearm muscle size might be incongruent with changes in handgrip strength among the three activity groups. Full article

For children born with congenital heart defects (CHDs), extracorporeal life support may be necessary. This retrospective single-center study aimed to investigate the outcomes of children with CHDs on extracorporeal membrane oxygenation (ECMO), focusing on various risk factors. Among the 88 patients, 36 (41%) had a single-ventricle heart defect, while 52 (59%) had a biventricular defect. In total, 25 (28%) survived, with 7 (8%) in the first group and 18 (20%) in the latter. A p-value of 0.19 indicated no significant difference in survival rates. Children with biventricular hearts had shorter ECMO durations but longer stays in the intensive care unit. The overall rate of complications on ECMO was higher in children with a single ventricle (odds ratio [OR] 1.57, 95% confidence interval [CI] 0.67–3.7); bleeding was the most common complication in both groups. The occurrence of a second ECMO run was more frequent in patients with a single ventricle (22% vs. 9.6%). ECMO can be effective for children with congenital heart defects, including single-ventricle patients. Bleeding remains a serious complication associated with worse outcomes. Patients requiring a second ECMO run within 30 days have lower survival rates. Full article

Decoy cells that can be detected in the urine sediment of immunosuppressed patients are often caused by the uncontrolled replication of polyomaviruses, such as BK-Virus (BKV) and John Cunningham (JC)-Virus (JCV), within the upper urinary tract. Due to the wide availability of highly sensitive BKV and JCV PCR, the diagnostic utility of screening for decoy cells in urine as an indicator of polyomavirus-associated nephropathy (PyVAN) has been questioned by some institutions. We hypothesize that specific staining of different infection time-dependent BKV-specific antigens in urine sediment could allow cell-specific mapping of antigen expression during decoy cell development. Urine sediment cells from six kidney transplant recipients (five males, one female) were stained for the presence of the early BKV gene transcript lTag and the major viral capsid protein VP1 using monospecific antibodies, monoclonal antibodies and confocal microscopy. For this purpose, cyto-preparations were prepared and the BK polyoma genotype was determined by sequencing the PCR-amplified coding region of the VP1 protein. lTag staining began at specific sites in the nucleus and spread across the nucleus in a cobweb-like pattern as the size of the nucleus increased. It spread into the cytosol as soon as the nuclear membrane was fragmented or dissolved, as in apoptosis or in the metaphase of the cell cycle. In comparison, we observed that VP1 staining started in the nuclear region and accumulated at the nuclear edge in 6–32% of VP1⁺ cells. The staining traveled through the cytosol of the proximal tubule cell and reached high intensities at the cytosol before spreading to the surrounding area in the form of exosome-like particles. The spreading virus-containing particles adhered to surrounding cells, including erythrocytes. VP1-positive proximal tubule cells contain apoptotic bodies, with 68–94% of them losing parts of their DNA and exhibiting membrane damage, appearing as “ghost cells” but still VP1⁺. Specific polyoma staining of urine sediment cells can help determine and enumerate exfoliation of BKV-positive cells based on VP1 staining, which exceeds single-face decoy staining in terms of accuracy. Furthermore, our staining approaches might serve as an early readout in primary diagnostics and for the evaluation of treatment responses in the setting of reduced immunosuppression. Full article

The neonicotinoid imidacloprid is a widely used insecticide worldwide. We assessed the effects of acute and chronic imidacloprid exposure on the social behavior of adult zebrafish. We assembled simple apparatus to detect 2D locomotion: a single camera capture system and two specially designed water tanks. We then used the tracking and heat maps of the behavior trajectories of zebrafish subjected to sham and imidacloprid exposure and compared their social behavior. Furthermore, histomorphology and immunohistochemistry of their brain tissue sections were performed to clarify possible neurotoxicity due to imidacloprid exposure in our adult zebrafish. Our results showed that imidacloprid exposure significantly reduced the zebrafish’s swimming speed, distance traveled, acceleration, and deceleration. The longer the imidacloprid exposure, the more severe the locomotor behavior disability. Furthermore, imidacloprid exposure significantly reduced heterosexual attractive behavior between the different sexes, as well as defensive alert behavior among males. Our histomorphology and immunohistochemistry evidence showed imidacloprid exposure may lead to neuronal oxidative stress, inflammation, apoptosis, and damage in the telencephalon of adult zebrafish. Thus, we suggested that neonicotinoid imidacloprid exposure can damage the telencephalon neurons of adult zebrafish through oxidative stress, inflammation, and apoptosis and then affect the social behavior of adult zebrafish. Full article

Nitrogen-containing bisphosphonates lead to the depletion of geranylgeranyl pyrophosphate involved in the mevalonate pathway. The effect of geranylgeraniol (GGOH) on human osteoblast and osteoclast activities suppressed by zoledronate was investigated in this study. The effect of GGOH on human osteoblasts and osteoclasts subjected to treatment with zoledronate was analyzed by assessing cell viability, osteoclast differentiation, resorption ability, gene expression, and protein synthesis. Cell viability suppressed by bisphosphonates in osteoblasts and osteoprogenitor cells was restored with GGOH. Osteoclast differentiation was analyzed by vitronectin receptor immunofluorescence staining, and the addition of GGOH to zoledronate significantly increased osteoclast differentiation compared with zoledronate alone. A trend of reversal of osteoclast resorption by GGOH was observed; however, it was not significant in all groups. The expression of ALP, type 1 collagen, and RUNX2 in osteoblasts was recovered by the addition of GGOH. Only CALCR expression in osteoclasts was significantly recovered by GGOH addition in the zoledronate group. Although the activities of osteoblasts and osteoclasts were not entirely restored, the possibility that the topical application of GGOH in MRONJ patients or patients with dental problems and bisphosphonates might lessen the risk of development and recurrence of MRONJ is shown. Full article

We evaluated the therapeutic effects of bone-marrow-derived mesenchymal stem cells (BMSCs) on behavioral and cognitive function in a mouse model of mild subarachnoid hemorrhage (SAH) and explored the underlying mechanisms in conjunction with the HMGB1–RAGE axis. The SAH models were generated in a total of 126 male C57BL/6J mice via endovascular perforation and evaluated 24 h and 72 h after the intravenous administration of BMSCs (3 × 10⁵ cells). The BMSCs were administered once, at 3 h, or twice, at 3 h and 48 h after the model induction. The therapeutic effects of the BMSCs were compared to those of the saline administration. Compared to saline-treated SAH-model mice, at 3 h, the mice with mild SAH treated with the BMSCs showed significant improvements in their neurological scores and cerebral edema. The administration of the BMSCs decreased the mRNA expression of HMGB1, RAGE, TLR4, and MyD88, as well as the protein expression of HMGB1 and phosphorylated NF-kB p65. Furthermore, the numbers of slips per walking time, impairments in short-term memory, and the recognition of novel objects were improved. There was some improvement in inflammatory-marker levels and cognitive function according to the BMSCs’ administration times, but no large differences were seen. The administration of BMSCs improved behavioral and cognitive dysfunction by ameliorating HMGB1–RAGE axis-mediated neuroinflammation after SAH. Full article

The anabolic effects of WNT16 on osteoblasts are well established, however, little is known regarding the role of WNT16 in chondrocytes. In this study, we evaluated Wnt16 expression and its biological effects on mouse articular chondrocytes (ACs), since these cells are key to the development of osteoarthritis. While ACs derived from the long bone epiphysis of 7-day old C57BL/6J mice express multiple Wnts, Wnt5b and Wnt16 represent the two most highly expressed Wnts (expressed at several-fold higher levels than other Wnts). Treatment of serum-free AC cultures, with 100 ng/mL of recombinant human (rh) WNT16 for 24 h (hrs), increased proliferation (20%, p < 0.05) and expression levels of makers (Sox9 and Col2) of immature chondrocytes at both 24 h and 72 h, while Acan increased at 72 h. Expression of Mmp9, a marker of mature chondrocytes was decreased at 24 h. Additionally, WNT16 treatment regulated expression levels of Wnt ligands in a biphasic manner, inhibiting its expression at 24 h, while stimulating expression at 72 h. To determine whether WNT16 exerted anabolic effects on the AC phenotype, ex vivo cultures of tibial epiphyses were treated with rhWNT16 or vehicle for 9 days, and the articular cartilage phenotype was evaluated by safranin O cartilage staining and expression of articular cartilage marker genes. Both articular cartilage area and expression levels of AC markers were increased after rhWNT16 treatment. Our data suggest that Wnt16 expressed in ACs may play a role in regulating joint cartilage homeostasis via its direct effect, as well as through modulating the expression of other Wnt ligands. Full article

Neutrophil Extracellular Traps (NETs) are large neutrophil-derived structures composed of decondensed chromatin, cytosolic, and granule proteins. NETs play an important role in fighting infection, inflammation, thrombosis, and tumor progression processes, yet their fast and reliable identification has been challenging. Smudge cells (SCs) are a subcategory of white cells identified by CellaVision^®, a hematology autoanalyzer routinely used in clinical practice that uses digital imaging to generate “manual” differentials of peripheral blood smears. We hypothesize that a proportion of cells identified in the SC category by CellaVision^® Hematology Autoanalyzers are actually NETs. We demonstrate that NET-like SCs are not present in normal blood samples, nor are they an artifact of smear preparation. NET-like SCs stain positive for neutrophil markers such as myeloperoxidase, leukocyte alkaline phosphatase, and neutrophil elastase. On flow cytometry, cells from samples with high percent NET-like SCs that are positive for surface DNA are also positive for CD45, myeloperoxidase and markers of neutrophil activation and CD66b. Samples with NET-like SCs have a strong side fluorescent (SFL) signal on the white count and nucleated red cells (WNR) scattergram, representing cells with high nucleic acid content. When compared to patients with low percent SCs, those with a high percentage of SCs have a significantly higher incidence of documented bacterial and viral infections. The current methodology of NET identification is time-consuming, complicated, and cumbersome. In this study, we present data supporting identification of NETs by CellaVision^®, allowing for easy, fast, cost-effective, and high throughput identification of NETs that is available in real time and may serve as a positive marker for a bacterial or viral infections. Full article

Mathematical and computational models are used to describe biomechanical processes in multicellular systems. Here, we develop a model to analyse how two types of epithelial cell layers interact during tissue invasion depending on their cellular properties, i.e., simulating cancer cells expanding into a region of normal cells. We model the tissue invasion process using the cellular Potts model and implement our two-dimensional computational simulations in the software package CompuCell3D. The model predicts that differences in mechanical properties of cells can lead to tissue invasion, even if the division rates and death rates of the two cell types are the same. We also show how the invasion speed varies depending on the cell division and death rates and the mechanical properties of the cells. Full article

Accumulating data suggest an important role of growth factors in autoimmune diseases and parasitic nematode infections. Nematodes are used in clinical studies of autoimmune diseases and parasite-derived molecules are widely studied for their therapeutic potential in various types of disorders. However, the effect of nematode infection on growth factors in autoimmune disorders has not been studied. The objective of this study was to evaluate the influence of infection with the intestinal nematode Heligmosomoides polygyrus in murine autoimmune models on the production of growth factors. Here, the level of a variety of growth factors related mainly to angiogenesis was evaluated by protein array in the intestinal mucosa of C57BL/6 dextran sodium sulfate-induced colitic mice and in cerebral spinal fluid of experimental autoimmune encephalomyelitis (EAE) mice infected with nematodes. In addition, vessel formation was evaluated in the brains of EAE mice infected with H. polygyrus. A significant influence of nematode infection on the level of angiogenic factors was observed. Parasitic infection of colitic mice resulted in upregulation of mucosal AREG, EGF, FGF-2, and IGFBP-3 in the intestine of the host and better adaptation (infectivity). In EAE mice, infection increased the level of FGF-2 and FGF-7 in CSF. In addition, remodeling of brain vessels was observed, with a higher density of long vessels. Nematode-derived factors are promising tools to fight autoimmune diseases and to study angiogenesis. Full article

This study examined the effects of obesity on cartilage mechanics and longitudinal failure probability at the medial tibiofemoral compartment, using combined musculoskeletal simulation and probabilistic failure modelling approaches. The current investigation examined twenty obese females (BMI > 30.0 kg/m²) and 20 healthy weight (BMI < 25.0 kg/m²) females. Walking kinematics were obtained via an 8-camera optoelectric system, and a force plate was used to collect ground reaction forces. Musculoskeletal simulation and probabilistic failure modelling were utilized to explore medial tibiofemoral forces and cartilage probability. Comparisons between groups were undertaken using linear mixed-effects models. Net peak cartilage forces, stress and strain were significantly larger in the obese group (force = 2013.92 N, stress = 3.03 MPa & strain = 0.25), compared to health weight (force = 1493.21 N, stress 2.26 MPa & strain = 0.19). In addition, medial tibiofemoral cartilage failure probability was also significantly larger in the obese group (42.98%) compared to healthy weight (11.63%). The findings from the current investigation show that obesity has a profoundly negative influence on longitudinal medial knee cartilage health and strongly advocates for the implementation of effective weight management programs into long-term musculoskeletal management strategies. Full article

We aimed to assess the association between rice intake and cognitive function among Qatari adults and test the interactions with health conditions. Data from 1000 adults aged ≥18 years old who attended the Qatar Biobank (QBB) study were used. Rice dietary intake was measured by a food frequency questionnaire (FFQ), and mean reaction time (MRT) was used as an indicator of cognitive function. Linear regression and structure equation models were used. The mean rice consumption was 7.6 times/week (SD 2.0). The sample had a mean MRT of 717 milliseconds (SD 205). Rice consumption was positively associated with MRT. Across the quartiles of rice intake, the regression coefficients (95% CI) for MRT were 0.0 (reference), 22.4 (−7.8, 52.6), 36.3 (5.1, 67.5), and 34.5 (2.6, 66.4). There was a significant interaction between rice intake and hypertension, BMI, and blood lipids in relation to MRT. The association between rice intake and MRT was only observed among those with hypertension, overweight/obesity, low LDL, and low total cholesterol levels. Serum magnesium did not mediate the association. High rice consumption was associated with a higher MRT, especially among those with hypertension, overweight/obesity, low LDL, and or low total cholesterol levels. Further longitudinal studies are needed to confirm the findings. Full article

The objective of this study was to analyze the neurostructural abnormalities of brain areas responsible for the acquisition and maintenance of fear in small animal phobia by comparing gray matter volume (GMV) in individuals with phobia and non-fearful controls. Structural magnetic resonance imaging was obtained from 62 adults (79% female) assigned to one of two groups: 31 were diagnosed with small animal phobia and 31 were non-fearful controls. To investigate structural alterations, a whole-brain voxel-based morphometry analysis was conducted to compare the GMV of the brain areas involved in fear between both groups. The results indicated that individuals with a small animal specific phobia showed smaller GMV in cortical regions, such as the orbitofrontal (OFC) and medial frontal cortex, and greater GMV in the putamen than non-fearful controls. These brain areas are responsible for avoidant behavior (putamen) and emotional regulation processes or inhibitory control (prefrontal cortex (PFC)), which might suggest a greater vulnerability of phobic individuals to acquiring non-adaptive conditioned responses and emotional dysregulation. The findings provide preliminary support for the involvement of structural deficits in OFC and medial frontal cortex in phobia, contributing to clarify the neurobiological substrates for phobias. Full article

The critical importance of hypoxia-inducible factor (HIF)s in the regulation of endochondral bone formation is now well established. HIF protein levels are closely regulated by the prolyl hydroxylase domain-containing protein (PHD) mediated ubiquitin-proteasomal degradation pathway. Of the three PHD family members expressed in bone, we previously showed that mice with conditional disruption of the Phd2 gene in chondrocytes led to a massive increase in the trabecular bone mass of the long bones. By contrast, loss of Phd3 expression in chondrocytes had no skeletal effects. To investigate the role of Phd1 expressed in chondrocytes on skeletal development, we conditionally disrupted the Phd1 gene in chondrocytes by crossing Phd1 floxed mice with Collagen 2α1-Cre mice for evaluation of a skeletal phenotype. At 12 weeks of age, neither body weight nor body length was significantly different in the Cre⁺; Phd1^flox/flox conditional knockout (cKO) mice compared to Cre⁻; Phd1^flox/flox wild-type (WT) control mice. Micro-CT measurements revealed significant gender differences in the trabecular bone volume adjusted for tissue volume at the secondary spongiosa of the femur and the tibia for both genotypes, but no genotype differences were found for any of the trabecular bone measurements of either femur or tibia. Similarly, cortical bone parameters were not affected in the Phd1 cKO mice compared to control mice. Histomorphometric analyses revealed no significant differences in bone area, bone formation rate or mineral apposition rate in the secondary spongiosa of femurs between cKO and WT control mice. Loss of Phd1 expression in chondrocytes did not affect the expression of markers of chondrocytes (collage 2, collagen 10) or osteoblasts (alkaline phosphatase, bone sialoprotein) in the bones of cKO mice. Based on these and our published data, we conclude that of the three PHD family members, only Phd2 expressed in chondrocytes regulates endochondral bone formation and development of peak bone mass in mice. Full article

The aim of this pilot study was to investigate whether polymorphisms in the gene encoding heat shock factor 1 (HSF1), a transcriptional activator of molecular chaperones, play a role in the development of type 2 diabetes (T2D). A total of 3229 unrelated individuals of Slavic origin, including 1569 T2D patients and 1660 age- and sex-matched healthy controls, were enrolled for the study. Five common single nucleotide polymorphisms (SNPs) of the HSF1 gene were genotyped using the MassArray-4 system. SNPs rs7838717 (p = 0.002) and rs3757971 (p = 0.005) showed an association with an increased risk of T2D in females with a body mass index ≥ 25 kg/m². The rs7838717T-rs4279640T-rs3757971C and rs7838717T-rs4279640T-rs3757971T haplotypes were associated with increased and decreased disease risk in overweight or obese females, respectively. The associations were replicated as disease susceptibility genes in large cohorts from the UK Biobank (p = 0.008), DIAMANTE (p = 2.7 × 10⁻¹³), and DIAGRAM (p = 0.0004) consortiums. The functional annotation of the SNPs revealed that the rs7838717-T and rs3757971C alleles correlated with increased expression of the genes involved in unfolded protein response. The present study showed, for the first time, that genetic variation of HSF1 is associated with the risk of type 2 diabetes, supporting a role for impaired protein folding in disease pathogenesis. Full article

We investigated the role of vitamin D in the risk of tuberculosis (TB) among patients with end-stage kidney disease (ESKD). The retrospective cohort was conducted with data of 20,985 patients with kidney disease and 20,985 controls without kidney disease (1:1 matching on age of cohort entry and sex) in the duration of 1997–2010 from the Taiwan National Health insurance database. Then, by a case–cohort study, among 20,985 kidney disease, 3194 ESKD patients were identified with matched 3194 non-ESKD patients. Multivariate analyses revealed a significant association between kidney disease and tuberculosis (adjusted incidence rate ratio (IRR) 1.57 (1.33–1.86)), and the risk increased after 3 years of follow-up the (adjusted IRR 3.79 (2.55–5.62)), but after more years of follow-up no significance was observed. We also found that ESKD increases the risk of tuberculosis (adjusted IRR 3.67 (2.27–5.93)). However, vitamin D usage was not related with the tuberculosis risk in ESKD patients (p > 0.1783). Our study showed increased risk of tuberculosis in kidney disease and ESKD patients, and vitamin D was not beneficial in ESKD. Full article

Fibrosis is a hallmark of progressive kidney diseases. The overexpression of profibrotic cytokine, namely transforming growth factor β (TGF-β) due to excessive inflammation and tissue damage, induces kidney fibrosis. The inhibition of TGF-β signaling is markedly limited in experimental disease models. Targeting TGF-β signaling, therefore, offers a prospective strategy for the management of kidney fibrosis. Presently, the marketed drugs have numerous side effects, but plant-derived compounds are relatively safer and more cost-effective. In this study, TGFβR-1 was targeted to identify the lead compounds among flavonoids using various computational approaches, such as ADME/T (absorption, distribution, metabolism, and excretion/toxicity) analysis, molecular docking, and molecular dynamics simulation. ADME/T screening identified a total of 31 flavonoids with drug-like properties of 31 compounds, a total of 5 compounds showed a higher binding affinity to TGFβR-1, with Epicatechin, Fisetin, and Luteolin ranking at the top three (−13.58, −13.17, and −10.50 kcal/mol, respectively), which are comparable to the control drug linagliptin (−9.074 kcal/mol). The compounds also exhibited outstanding protein–ligand interactions. The molecular dynamic simulations revealed a stable interaction of these compounds with the binding site of TGFβR-1. These findings indicate that flavonoids, particularly Epicatechin, Fisetin, and Luteolin, may compete with the ligand-binding site of TGFβR-1, suggesting that these compounds can be further evaluated for the development of potential therapeutics against kidney fibrosis. Further, in-vitro and in-vivo studies are recommended to support the current findings. Full article

EVs are membranous subcellular structures originating from various cells, including platelets which consist of biomolecules that can modify the target cell’s pathophysiological functions including inflammation, cell communication, coagulation, and metastasis. EVs, which are known to allow the transmission of a wide range of molecules between cells, are gaining popularity in the fields of subcellular treatment, regenerative medicine, and drug delivery. PEVs are the most abundant EVs in circulation, being produced by platelet activation, and are considered to have a significant role in coagulation. PEV cargo is extremely diverse, containing lipids, proteins, nucleic acids, and organelles depending on the condition that induced their release and can regulate a wide range of biological activities. PEVs, unlike platelets, can overcome tissue barriers, allowing platelet-derived contents to be transferred to target cells and organs that platelets cannot reach. Their isolation, characterization, and therapeutic efficacy, on the other hand, are poorly understood. This review summarizes the technical elements of PEV isolation and characterization methods as well as the pathophysiological role of PEVs, including therapeutic potential and translational possibility in diverse disciplines. Full article

Ozone (O₃) is a reactive oxygen species (ROS) that can interact with cellular components and cause oxidative stress. Following said logic, if O₃ induces such a stressful milieu, how does it exert antioxidant functions? This is mediated by controlled toxicity produced by low concentrations of O₃, which enhance the cell’s suppliance of antioxidant properties without causing any further damage. Therapeutic concentrations vary extensively, although 50 µg/mL is commonly used in experimental and clinical procedures, given that augmented concentrations might work as germicides or cause endogenous damage. O₃ therapy has been shown to be effective when applied before or after traumatic renal procedures, whether caused by ischemia, xenobiotics, chronic damage, or other models. In this review, we focus on discussing the role of O₃ therapy in different models of kidney damage associated with fibrosis, apoptosis, oxidative stress, and inflammation. We integrate and report knowledge about O₃ in renal therapy, debunking skepticism towards unconventional medicine, explaining its proven therapeutic properties, and thus providing background for its use in further research as well as in clinical settings. Full article

Significant cross talk occurs between inflammation and coagulation. Thus, coagulopathy is common in sepsis, potentially aggravating the prognosis. Initially, septic patients tend to exhibit a prothrombotic state through extrinsic pathway activation, cytokine-induced coagulation amplification, anticoagulant pathways suppression, and fibrinolysis impairment. In late sepsis stages, with the establishment of disseminated intravascular coagulation (DIC), hypocoagulability ensues. Traditional laboratory findings of sepsis, including thrombocytopenia, increased prothrombin time (PT) and fibrin degradation products (FDPs), and decreased fibrinogen, only present late in the course of sepsis. A recently introduced definition of sepsis-induced coagulopathy (SIC) aims to identify patients at an earlier stage when changes to coagulation status are still reversible. Nonconventional assays, such as the measurement of anticoagulant proteins and nuclear material levels, and viscoelastic studies, have shown promising sensitivity and specificity in detecting patients at risk for DIC, allowing for timely therapeutic interventions. This review outlines current insights into the pathophysiological mechanisms and diagnostic options of SIC. Full article

Osteoarthritis (OA) is the most common degenerative disease of the connective tissue of the human musculoskeletal system. Despite its widespread prevalence, there are many limitations in its diagnosis and treatment. OA diagnosis currently relies on the presence of clinical symptoms, sometimes accompanied by changes in joint X-rays or MRIs. Biomarkers help not only to diagnose early disease progression but also to understand the process of OA in many ways. In this article, we briefly summarize information on articular joints and joint tissues, the pathogenesis of OA and review the literature about biomarkers in the field of OA, specifically inflammatory cytokines/chemokines, proteins, miRNA, and metabolic biomarkers found in the blood, synovial fluid and in extracellular vesicles. Full article

Background: Therapeutic exercise has an important role to manage chemotherapy-induced peripheral neuropathy symptoms. However, there is little evidence of its effectiveness. Objective: To synthesize the evidence regarding therapeutic exercise during chemotherapy to improve peripheral neuropathy symptoms. Databases: PubMed, CINAHL, Cochrane Library, PEDro, ScienceDirect, Scopus, Web of Science and BIREME. Methodology: Randomized clinical trials were included. GRADE was used to synthesize evidence and an inverse variance model for meta-analysis. Results: Up to May 2022, 2172 references were analyzed and 14 studies that evaluated 1094 participants were included. The exercises were highly effective in improving pain threshold and moderately effective in improving peripheral neuropathy symptoms at the 8-week follow-up and the 4–24 weeks. Furthermore, the evidence was low in improving thermal threshold, tactile and vibratory sensitivity. Conclusion: Therapeutic exercise generates a significant reduction in peripheral neuropathy symptoms in patients in short- and long-term follow-up with a moderate level of evidence quality. Full article

Defects in signaling pathways are the root cause of many disorders. These malformations come in a wide variety of types, and their causes are also very diverse. Some of these flaws can be brought on by pathogenic organisms and viruses, many of which can obstruct signaling processes. Other illnesses are linked to malfunctions in the way that cell signaling pathways work. When thinking about how errors in signaling pathways might cause disease, the idea of signalosome remodeling is helpful. The signalosome may be conveniently divided into two types of defects: phenotypic remodeling and genotypic remodeling. The majority of significant illnesses that affect people, including high blood pressure, heart disease, diabetes, and many types of mental illness, appear to be caused by minute phenotypic changes in signaling pathways. Such phenotypic remodeling modifies cell behavior and subverts normal cellular processes, resulting in illness. There has not been much progress in creating efficient therapies since it has been challenging to definitively confirm this connection between signalosome remodeling and illness. The considerable redundancy included into cell signaling systems presents several potential for developing novel treatments for various disease conditions. One of the most important pathways, NF-κB, controls several aspects of innate and adaptive immune responses, is a key modulator of inflammatory reactions, and has been widely studied both from experimental and theoretical perspectives. NF-κB contributes to the control of inflammasomes and stimulates the expression of a number of pro-inflammatory genes, including those that produce cytokines and chemokines. Additionally, NF-κB is essential for controlling innate immune cells and inflammatory T cells’ survival, activation, and differentiation. As a result, aberrant NF-κB activation plays a role in the pathogenesis of several inflammatory illnesses. The activation and function of NF-κB in relation to inflammatory illnesses was covered here, and the advancement of treatment approaches based on NF-κB inhibition will be highlighted. This review presents the temporal behavior of NF-κB and its potential relevance in different human diseases which will be helpful not only for theoretical but also for experimental perspectives. Full article

Background: As pediatric BOLD Signal Variability (SV) analysis is relatively novel, there is a need to provide a foundational framework that gives researchers an entry point into engaging with the topic. This begins with clarifying the definition of BOLD signal variability by identifying and categorizing the various metrics utilized to measure BOLD SV. Methods: A systematic review of the literature was conducted. Inclusion criteria were restricted to studies utilizing any metric of BOLD SV and with individuals younger than 18 in the study population. The definition of BOLD SV was any measure of intra-individual variability in the BOLD signal. Five databases were searched: Psychinfo, Healthstar, MEDLINE, Embase, and Scopus. Results: A total of 17 observational studies, including male (n = 1796) and female (n = 1324) pediatric participants were included. Eight studies quantified variability as the amount of deviation from the average BOLD signal, seven used complexity-based metrics, three used correlation measures of variability, and one used the structure of the hemodynamic response function. In this study, 10 methods of quantifying signal variability were identified. Associations and trends in BOLD SV were commonly found with age, factors specific to mental and/or neurological disorders such as attention deficit disorder, epilepsy, psychotic symptoms, and performance on psychological and behavioral tasks. Conclusions: BOLD SV is a potential biomarker of neurodevelopmental and neurological conditions and symptom severity in mental disorders for defined pediatric populations. Studies that establish clinical trends and identify the mechanisms underlying BOLD SV with a low risk of bias are needed before clinical applications can be utilized by physicians. Full article

SEIC is a non-invasive lesion of the endometrial epithelium considered to be the precursor to uterine serous carcinoma (USC) and is just as aggressive as USC. Currently, there are no reliable data about the behavior and prognosis of SEIC; therefore, the therapeutic management approach is not clear. Method: A systematic search of the Pubmed, Scopus and Embase databases was conducted, following the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: Of the 296 studies that matched the search criteria, only 9 met the inclusion criteria, covering a total of 81 patients. The main disease-presenting pattern was AUB (abnormal uterine bleeding). In 31 cases, SEIC was associated with extrauterine disease. All patients underwent hysterectomy and salpingo-oophorectomy, while only 15 of the 81 patients received adjuvant treatments. In the patients receiving adjuvant therapy, the RR was 42.67%, the DFS was 35.71% and the OS was 57.13%. In patients subjected to follow-up alone, the RR was only 28.78%, the DFS was 59.1% and the OS was 66.6%. Conclusions: The presence of an extrauterine disease significantly worsens outcomes, regardless of adjuvant treatment. In cases of disease confined to the uterine mucosa alone, the prognosis is good and follow-up allows a good control of the disease; however, adjuvant therapy could further increase survival rates and reduce relapse rates. Full article

Prior studies have shown that among patients with chronic kidney disease not yet on dialysis, the faster progression of kidney injury in men than in women is, at least partly, explained by sex differences in ambulatory blood pressure (BP) control. The present study aimed to investigate potential differences in the levels of ambulatory BP and intensity of antihypertensive treatment between men and women with end-stage kidney disease undergoing long-term peritoneal dialysis (PD). In a case-control design, 48 male PD patients were matched for age and heart failure status with 48 female patients in a 1:1 ratio. Ambulatory BP monitoring was performed with an oscillometric device, the Mobil-O-Graph (IEM, Stolberg, Germany). The BP-lowering medications actually taken by the patients were prospectively recorded. No gender-related differences were observed in 24 h systolic BP (129.0 ± 17.9 vs. 128.5 ± 17.6 mmHg, p = 0.890). In contrast, 24 h diastolic BP was higher in men than in women (81.5 ± 12.1 vs. 76.8 ± 10.3 mmHg, p = 0.042). As compared with women, men were being treated with a higher average number of antihypertensive medications daily (2.4 ± 1.1 vs. 1.9 ± 1.1, p = 0.019) and were more commonly receiving calcium-channel-blockers (70.8% vs. 43.8%, p = 0.007) and β-blockers (85.4% vs. 66.7%, p = 0.031). In conclusion, the present study shows that among PD patients, the levels of ambulatory BP and intensity of antihypertensive treatment are higher in men than in women. Longitudinal studies are needed to explore whether these gender-related differences in the severity of hypertension are associated with worse cardiovascular outcomes for male patients undergoing PD. Full article

Central centrifugal cicatricial alopecia (CCCA) is a lymphocytic scarring alopecia that predominantly affects women of African descent. Recent studies have demonstrated prevalence in children and adolescents, as well as Asian populations. A thorough search of Pubmed, Cochrane Database of Systematic Reviews, OVID Medline and Google Scholar was conducted using keywords such as “central centrifugal cicatricial alopecia”, “scarring hair loss”, “scarring alopecia”, “hot comb alopecia”, “pediatric” and “adolescent”. The results yielded few articles in the literature that directly addressed CCCA in the adolescent population, with three articles providing details of the presentation in the form of case series and retrospective reviews. The presentation in the adolescent population was found to be varied, ranging from asymptomatic to symptomatic and involving diffuse to patchy hair loss in only the vertex and/or frontal and parietal scalp. Genetic and environmental etiologies were found to be statistically significant, and markers of metabolic dysregulation predisposing patients to diabetes mellitus and breast cancer were also uncovered. The differential diagnosis of patients who present with hair loss in the adolescent population should therefore be broad, and a low threshold for biopsies should be adopted to confirm CCCA in suspected patients. This will have future implications for reduced morbidity and public health. Full article

Immunoglobulin G4-related disease (IgG4-RD) is a rare fibro-inflammatory condition characterized by IgG4-expressing plasma cell infiltration of the skin and other organs, leading to profound itchiness. Oral corticosteroids are the first-line therapy for IgG4-RD but relapses and potential side effects are common. In this case, we discuss a patient with a hyperpigmented, scaling dermatitis on his arms, back, and chest with lichen amyloidosis (LA) that incompletely responded to corticosteroids. He had reduced quality of life secondary to chronic pruritus. Dupilumab, an IL-4 and IL-13 inhibitor, was initiated. He experienced a transient worsening, followed by complete resolution of his itch with remission of his rash. While the pathogenesis of IgG4-RD is not entirely understood, a T-helper 2 (Th2) immune response has been implicated, with interleukins (IL) 4, 5, 10, and 13 playing a role in IgG4 class switch, resulting in eosinophilia and elevated IgE. The strong response of dupilumab in this case may provide evidence in favor of the involvement of IL-4 and IL-13 in the pathogenesis of cutaneous IgG4-RD. Future clinical studies involving larger patient populations may be warranted. Full article

We propose a theoretical basis for analyzing several features of genetic diseases caused by dominant alleles, including: disease prevalence, genotype penetrance, and the relationship between causal genotype frequency and disease frequency. In addition, we provide a theoretical framework for accurate diagnosis and clinical approaches for disease study, including two examples in which inaccurate and incomplete diagnoses affect the estimates of disease prevalence: First, the disease iceberg effect shows that disease prevalence is often underestimated due to errors introduced by inaccurate diagnosis; second, because lifetime risk of disease is cumulative, and therefore an increasing function of age, measurements of prevalence are inaccurate if people of all ages are not included. Finally, we discuss the aggregation of genetic diseases. We identify theoretical and computational deficiencies associated with using the sibling recurrence-risk ratio as a measure of familial aggregation. We develop an alternative concept of aggregation and propose an associated measure that does not experience the deficiencies. Throughout, we provide clinicians and researchers practical implications of our theoretical framework. Full article