Healthy Control Individuals Research Articles

Proinflammatory cytokine profiles in prediabetic Saudi patients

Prediabetes is an increase-risk state for diabetes that is associated with an increase in blood glucose levels to more than normal, but not increased enough to be termed as type 2 diabetes mellitus (T2DM). A timely intervention and management of prediabetes can stop its further progression to the diabetic state. Many cytokines are involved in diseases including diabetes, however, their role in prediabetes is unknown. In this study, we attempted to analyze numerous proinflammatory cytokines in prediabetic patients. A total of 60 adult Saudi prediabetes patients and healthy control individuals were included in this study. To better understand the role of the proinflammatory cytokines in prediabetes patients and its potential link to the disease outcome, the variations in the levels of these cytokines were investigated using Multi-Analyte ELISA technique. The T helper cells (Th1 and Th2) immune response expression profiling of 84 genes was done using Real Time-quantitative PCR (RT-qPCR) technique. The present finding showed that serum Interleukin IL-2, IL-1β, and IL-1α levels of all prediabetes patients were increased when compared with healthy control cases (P < 0.05). Inductions of proinflammatory cytokines and upregulation of Th1 and Th2 immune genes might play a potential role during prediabetes status and may be linked to the disease outcome. Further studies are needed to investigate the underlying mechanism of these proinflammatory cytokines in diabetes development. A strong positive correlation was found between IL and 1α with glucose levels than with IL-1β and IL-2. In conclusion, cytokines, especially IL-1, may play a critical role in the development of diabetes.

STUDY THE EXPRESSION OF IL-22 GENE IN AUTOIMMUNE HYPOTHYROIDISM IN IRAQ

This study was aimed to assess expression of IL-22 gene in patients with newly diagnosed autoantibodies against the thyroid antigens; anti-thyroglobulin (anti-TG), and anti-thyroid peroxidase (anti-TPO) in comparison with patients previously diagnosed and treated for autoimmune hypothyroidism as well as healthy control individuals. Twenty-eight patients with positive anti-TG and/or anti-TPO were enrolled in this study along with twelve age- and gender-matched healthy controls. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to assess gene expression and fold change among the study groups. Results revealed anti-TG concentration ranges of 134.3 to 2998.9 IU/mL and anti-TPO concentration ranges of 41.6 to 1018.4 IU/mL in patients while control group individuals were negative for these autoantibodies. The mean fold change of IL-22 expression (2-∆∆Ct) was the highest in newly diagnosed patients compared to patients on treatment for autoimmune hypothyroidism and healthy controls indicating the potential role of IL-22 in the early stages of the disease and its contribution in immune imbalance.

Selective perforant-pathway atrophy in Huntington disease: MRI analysis of hippocampal subfields.

While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions. We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months. Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group. Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.

Short-term fasting lowers glucagon levels under euglycemic and hypoglycemic conditions in healthy humans.

Fasting is associated with increased susceptibility to hypoglycemia in people with type 1 diabetes, thereby making it a significant health risk. To date, the relationship between fasting and insulin-induced hypoglycemia has not been well characterized, so our objective was to determine whether insulin-independent factors, such as counterregulatory hormone responses, are adversely impacted by fasting in healthy control individuals. Counterregulatory responses to insulin-induced hypoglycemia were measured in 12 healthy people during 2 metabolic studies. During one study, participants ate breakfast and lunch, after which they underwent a 2-hour bout of insulin-induced hypoglycemia (FED). During the other study, participants remained fasted prior to hypoglycemia (FAST). As expected, hepatic glycogen concentrations were lower in FAST, and associated with diminished peak glucagon levels and reduced endogenous glucose production (EGP) during hypoglycemia. Accompanying lower EGP in FAST was a reduction in peripheral glucose utilization, and a resultant reduction in the amount of exogenous glucose required to maintain glycemia. These data suggest that whereas a fasting-induced lowering of glucose utilization could potentially delay the onset of insulin-induced hypoglycemia, subsequent reductions in glucagon levels and EGP are likely to encumber recovery from it. As a result of this diminished metabolic flexibility in response to fasting, susceptibility to hypoglycemia could be enhanced in patients with type 1 diabetes under similar conditions.

Construction of a Diagnostic Model and a lncRNA-Associated ceRNA Network Based on Apoptosis-Related Genes for Schizophrenia.

Gene expression profiles and apoptosis-related data were downloaded from the Gene Expression Omnibus and Molecular Signature databases, respectively. Apoptosis-related differentially expressed mRNAs (DEGs) and miRNAs (DEMs) from blood samples between the schizophrenia and healthy control individuals were screened. A diagnostic model was developed using the data from univariate and least absolute shrinkage and selection operator (LASSO) regression analyses, followed by validation using the GSE38485 dataset. Cases were divided into low-risk (LR) and high-risk (HR) groups based on the risk score of the model, and differences in immune gene sets and pathways between these two groups were compared. Finally, a ceRNA network was constructed by integrating long non-coding RNAs (lncRNAs), DEMs, and DEGs. A diagnostic model containing 15 apoptosis-related genes was developed and its diagnostic efficiency was found to be robust. The HR group was correlated with higher immune scores of chemokines, cytokines, and interleukins; it was also significantly involved in pathways such as pancreatic beta cells and early estrogen response. A ceRNA network composed of 2 lncRNAs, 14 miRNAs, and 5 mRNAs was established. The established model is a potential tool to improve the diagnostic efficiency of patients with schizophrenia, and the nodes included in the ceRNA network might serve as biomarkers and therapeutic targets for schizophrenia.

Investigating the effect of MAP2K1 gene (MEK1) in MAPK pathway in the induction of adult T-cell leukemia/lymphoma (ATLL).

HTLV-1 is responsible for two important diseases, HAM/TSP and ATLL. Approximately 10 to 20 million people are infected with HTLV-1 worldwide. Identifying altered genes in different cancers is crucial for finding potential treatment strategies. One of the proteins of the RAS/MAPK signaling pathway is MEK1, which is made from the MAP2K1 gene. The effects of the MAP2K1 gene on the MAPK signaling pathway are not yet fully elucidated. The current study aims to determine the MAP2K1 gene mutations and the level of MAP2K1 gene expression in ATLL patients compared to healthy individuals. Ten ATLL and 10 healthy control individuals were investigated in this study. We used ELISA test to screen anti-HTLV-I antibodies and PCR for confirmation of infection. Then, we extracted total RNA from fresh whole blood, and cDNA was synthesized. The expression levels of the MAP2K1 gene were examined by qRT-PCR, and to check possible mutations in the MAP2K1 gene; all samples were sequenced and analyzed by BioEdite Software. MAP2K1 gene expression in the ATLL group was significantly higher than in the healthy control (P=0.001). The mutational sequencing analysis showed nucleotide 212 (S→R) change and identification mutations at different nucleotides that were entirely different from the nucleotide mutations defined in the UniProt database. These results could be a perspective in the prevention, prognosis, and targeted treatment of diseases in which the MAP2K1 gene plays a vital role.

Attenuation of Anxiety-Potentiated Startle After Treatment With Escitalopram or Mindfulness Meditation in Anxiety Disorders

BackgroundBiological markers for anxiety disorders may further understanding of disorder pathophysiology and suggest potential targeted treatments. The fear-potentiated startle (FPS) (a measure of startle to predictable threat) and anxiety-potentiated startle (APS) (startle to unpredictable threat) laboratory paradigm has been used to detect physiological differences in individuals with anxiety disorders compared with nonanxious control individuals, and in pharmacological challenge studies in healthy adults. However, little is known about how startle may change with treatment for anxiety disorders, and no data are available regarding alterations due to mindfulness meditation training. MethodsNinety-three individuals with anxiety disorders and 66 healthy individuals completed 2 sessions of the neutral, predictable, and unpredictable threat task, which employs a startle probe and the threat of shock to assess moment-by-moment fear and anxiety. Between the two testing sessions, patients received randomized 8-week treatment with either escitalopram or mindfulness-based stress reduction. ResultsAPS, but not FPS, was higher in participants with anxiety disorders compared with healthy control individuals at baseline. Further, there was a significantly greater decrease in APS for both treatment groups compared with the control group, with the patient groups showing reductions bringing them into the range of control individuals at the end of the treatment. ConclusionsBoth anxiety treatments (escitalopram and mindfulness-based stress reduction) reduced startle potentiation during unpredictable (APS) but not predictable (FPS) threat. These findings further validate APS as a biological correlate of pathological anxiety and provide physiological evidence for the impact of mindfulness-based stress reduction on anxiety disorders, suggesting that there may be comparable effects of the two treatments on anxiety neurocircuitry.

Electrochemical impedance-based biosensor for label-free determination of plasma P-tau181 levels for clinically accurate diagnosis of mild cognitive impairment and Alzheimer's disease

Plasma phosphorylated-tau threonine 181 (p-tau181) is a promising biomarker for predicting Alzheimer's disease (AD) and mild cognitive impairment (MCI), which is the symptomatic pre-dementia stage of AD. To date, there are limitations in the current diagnosis and classification of the two stages of MCI and AD in clinical practice remain a dilemma. In this study, we aimed to discriminate and diagnose patients with MCI, AD, and healthy participants based on the accurate, label-free, and ultrasensitive detection of p-tau181 levels in human clinical plasma samples using our developed electrochemical impedance-based biosensor, which allows to detect p-tau181 at a very low concentration of 0.92 fg mL−1. Human plasma samples were collected from 20 patients with AD, 20 patients with MCI, and 20 individuals with healthy control. The change in charge-transfer resistance of the developed impedance-based biosensor caused by capturing p-tau181 in plasma samples was recorded to evaluate the determination of plasma p-tau181 levels in human clinical samples for discrimination and diagnosis of AD, MCI, and healthy control individuals, respectively. Receiver operating characteristic (ROC) curve, a standard analysis to judge the clinically diagnostic capability of our biosensor platform based on the estimated levels of plasma p-tau181, resulted a sensitivity of 95%, a specificity of 85%, the area under the ROC curve (AUC) value of 0.94 of the accuracy for discriminating AD patients from healthy controls; a sensitivity of 70%, a specificity of 70%, the AUC of 0.75 to discriminate MCI patients from healthy controls. Statistical analysis (one-way analysis of variance (ANOVA)) was used to compare the estimated plasma p-tau181 levels in clinical samples, indicated significantly higher for AD patients with healthy controls (***p ≤ 0.001), AD with MCI patients (***p ≤ 0.001), and MCI patients with healthy controls (*p ≤ 0.05), respectively. In addition, we compared our sensor to the global cognitive function scales and discovered that it performed noticeably improvement in diagnosing the stages of AD. These results demonstrated the good application of our developed electrochemical impedance-based biosensor in the identification of clinical disease stages. Moreover, in this study, a small dissociation constant (KD) of 0.533 pM was first determined to evaluate the high binding affinity between the p-tau181 biomarker and its antibody, providing a reference parameter for future studies of the p-tau181 biomarker and AD.

Circulating Anti-GB3 Antibody as a Biomarker of Myocardial Inflammation in Patients with Fabry Disease Cardiomyopathy.

Fabry disease cardiomyopathy (FDCM) has manifested some resistance to enzyme replacement therapy (ERT), particularly in its advanced phase. Recently, myocardial inflammation of autoimmune origin has been demonstrated in FDCM. The objective of this study was the assessment of circulating anti-globotriaosylceramide (GB3) antibodies as potential biomarkers of myocardial inflammation in FDCM, defined by the additional presence of ≥CD3+ 7 T lymphocytes/low-power field associated with focal necrosis of adjacent myocytes. Its sensitivity was based on the evidence of overlapping myocarditis at left ventricular endomyocardial biopsy. From January 1996 to December 2021, 85 patients received a histological diagnosis of FDCM in our department and 48 (56.5%) of them had an overlapping myocardial inflammation with negative PCR for common cardiotropic viruses, positive antiheart, and antimyosin abs. The presence of anti-GB3 antibodies was evaluated with an in-house ELISA assay (BioGeM scarl Medical Investigational Research, MIR-Ariano Irpino, Italy), along with antiheart and antimyosin abs, in the FDCM patients and compared with control healthy individuals. The correlation between levels of circulating anti-GB3 autoantibody myocardial inflammation and FDCM severity was assessed. Anti-Gb3 antibodies were above the positivity cut-off in 87.5% of FDCM subjects with myocarditis (42 out of 48), while 81.1% of FDCM patients without myocarditis were identified as negative for Gb3 antibodies. Positive anti-Gb3 abs correlated with positive antiheart and antimyosin abs. The present study suggests a potential positive role of anti-GB3 antibodies as a marker of overlapping cardiac inflammation in patients with FDCM.

#5592 THE SODIUM PHOSPHATE COTRANSPORTER NAPI-IIB IS UPREGULATED AND EXPRESSED DE NOVO IN KIDNEYS OF PATIENTS WITH CHRONIC KIDNEYS DISEASE

Abstract Background and Aims Renal reabsorption of phosphate is mediated by 3 main transporters located in the luminal brush border membrane of the proximal tubule, namely NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit2 (SLC20A2). The expression of all three proteins has been shown to be reduced in animal models of kidney disease [1]. Recently, we demonstrated that NaPi-IIb, a paralogue of the SLC34 subfamily that is mostly expressed in small intestine and lungs, is also expressed in the loop of Henle. Its mRNA expression is enhanced in rodent models of kidney injury. However, the expression of NaPi-IIb has not been characterized in humans and it is unknown whether NaPi-IIb is also upregulated in chronic kidney disease (CKD). Method In this study, we examined the localization of NaPi-IIa, IIb, and IIc in kidneys of control healthy individuals (kidney donors) (eGFR: 111.6 ± 22.9 ml/min/1.73m2) and patients with diabetic nephropathy (eGFR: 31.9 ± 7.7 ml/min/1.73m2), anti-glomerular basement membrane nephritis (anti-GMB) (eGFR: 27.2 ± 22.6 ml/min/1.73m2), and hypertensive nephropathy (eGFR: 31.5 ± 5.3 ml/min/1.73m2) by immunofluorescence. Moreover, we analyzed data from various transcriptome data bases from healthy individuals and patients with CKD. Results In kidneys from healthy donors, NaPi-IIb staining was restricted to thin and thick limbs of the loop of Henle, while AQP1 was observed in proximal tubules and descending thin limbs. NaPi-IIc was abundantly found in proximal tubule cells. In biopsies from patients, NaPi-IIb signal was also found in addition to thin and thick limbs in cells of the collecting duct and in many proximal tubules. In contrast, the staining of NaPi-IIc was reduced in all groups of patients with CKD. RNA expression data from the European Renal cDNA Bank (ERCB) confirmed our immunofluorescence findings. SLC34A2 (NaPi-IIb) mRNA was progressively more expressed in kidneys of patients with kidney disease of tubulointerstitial origin from CKD stages 1 to 5, while it was strongly upregulated from stage 4 onwards in CKD of glomerular origin. Single cell RNA sequencing data of patients with acute kidney injury and CKD [2] showed elevation of SLC34A2 expression in injured thick ascending limb, degenerative proximal tubule cells (14x higher, adj. p≪0.0001) (de novo expression), and descending thin limb (3.7x higher, adj. p≪0.0001). SLC34A1 (NaPi-IIa) expression levels were reduced in whole kidneys (ERCB data) and SLC34A1 and SLC34A3 expression also decreased in proximal tubule cells of patients with CKD. Conclusion The phosphate transporter NaPi-IIb is highly upregulated in kidneys from patients with various etiologies of CKD and its expression spreads to proximal tubule and collecting duct. In contrast, the expression of the main physiological phosphate transporters NaPi-IIa and NaPi-IIc is reduced in CKD. These findings may have implications for the development and maintenance of hyperphosphatemia in CKD patients and limit the use of specific NaPi-IIa and/or NaPi-IIc inhibitors in patients with CKD.

A comparative study of serum Zn, Cu, Mg, Mn, Cr, and Fe levels and their association with the vulnerability of Iraqi COVID-19 patients

For the immune system to protect the body from infectious diseases such as COVID-19, it needs the ideal amount of vital trace elements. Trace element levels, especially, zinc (Zn), copper (Cu), magnesium (Mg), manganese (Mn), chromium (Cr), and iron (Fe) levels, may affect how sensitive an individual is to COVID-19 and other viruses. The current study evaluated the level of those trace elements during stays in the isolation center and investigated their association with vulnerability to COVID-19. A total of 120 individuals, 49 males and 71 females aged between 20 and 60 years, were included in this study. Forty individuals infected with COVID-19, 40 individuals who had recovered from it, and 40 healthy individuals, were all evaluated and studied. By using a flame atomic absorption spectrophotometer, levels of Zn, Cu, and Mg were assessed for all samples, whereas levels of Mn, and Cr were determined by a flameless atomic absorption spectrophotometer. The infected individuals had significantly lower levels of Zn, Mg, Mn, Cr, and Fe than recovered individuals and healthy control individuals (P<0.0001). On the other hand, the total number of infected patients was found to have much higher levels of Cu than those in the recovered group and the control group. For the recovered and healthy control groups, no significant differences were observed in the levels of trace elements (P>0.05), except for Zn (P<0.01). Also, the findings indicated no association of trace elements with age and BMI (P>0.05). These results show that an imbalance in the levels of essential trace elements could be associated with increasing the risk of COVID-19 infection. However, additional thorough research of greater scope is required considering the severity of the infection.

Inflammation biomarkers IL‑6 and IL‑10 may improve the diagnostic and prognostic accuracy of currently authorized traumatic brain injury tools.

Traumatic brain injury (TBI) is currently one of the leading causes of mortality and disability worldwide. At present, no reliable inflammatory or specific molecular neurobiomarker exists in any of the standard models proposed for TBI classification or prognostication. Therefore, the present study was designed to assess the value of a group of inflammatory mediators for evaluating acute TBI, in combination with clinical, laboratory and radiological indices and prognostic clinical scales. In the present single-centre, prospective observational study, 109 adult patients with TBI, 20 adult healthy controls and a pilot group of 17 paediatric patients with TBI from a Neurosurgical Department and two intensive care units of University General Hospital of Heraklion, Greece were recruited. Blood measurements using the ELISA method, of cytokines IL-6, IL-8 and IL-10, ubiquitin C-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein, were performed. Compared with those in healthy control individuals, elevated IL-6 and IL-10 but reduced levels of IL-8 were found on day 1 in adult patients with TBI. In terms of TBI severity classifications, higher levels of IL-6 (P=0.001) and IL-10 (P=0.009) on day 1 in the adult group were found to be associated with more severe TBI according to widely used clinical and functional scales. Moreover, elevated IL-6 and IL-10 in adults were found to be associated with more serious brain imaging findings (rs<0.442; P<0.007). Subsequent multivariate logistic regression analysis in adults revealed that early-measured (day 1) IL-6 [odds ratio (OR)=0.987; P=0.025] and UCH-L1 (OR=0.993; P=0.032) are significant independent predictors of an unfavourable outcome. In conclusion, results from the present study suggest that inflammatory molecular biomarkers may prove to be valuable diagnostic and prognostic tools for TBI.

Robust immunogenicity to the H3N2 component of influenza A vaccine in primary Sjögren syndrome.

Influenza A (H3N2) virus is the major cause of morbidity/mortality due to seasonal influenza over 50years. Data about the safety/immunogenicity of influenza A/Singapore (H3N2) vaccine are scarce in primary Sjögren syndrome (pSS). Twenty-one consecutive pSS patients and 42 HC (healthy control individuals) were immunized with influenza A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus. Rates of SP (seroprotection) and SC (seroconversion), GMT (geometric mean titers), FI-GMT (factor increase in GMT), ESSDAI (EULAR Sjögren's Syndrome Disease Activity Index), and adverse events were appraised before and 4weeks post-vaccination. pSS and HC had similar mean age (51.2 ± 14.2 vs. 50.6 ± 12.1years, p = 0.886). Pre-vaccination SP rates were high in pSS and HC (90.5% vs. 71.4%, p = 0.114), and GMT were higher in pSS [80.0 (52.4-160.0) vs. 40.0 (20.0-80.0), p = 0.001]. The percentage of influenza vaccination in the preceding two years was elevated and similar in pSS and HC (94.1% vs. 94.6%, p = 1.000). GMT values augmented in both groups four weeks after vaccination and persisted higher in the first group [160.0 (80.0-320.0) vs. 80.0 (40.0-80.0), p < 0.001] with equivalent FI-GMT [1.4 (1.0-2.8) vs. 1.4 (1.0-2.0), p = 0.410]. Both groups had low and similar SC rates (19.0% vs. 9.5%, p = 0.423). ESSDAI values persisted steadily during the study (p = 0.313). No serious adverse events have occurred. The novel demonstration that the influenza A/Singapore (H3N2) vaccine induces a different pattern of immunogenicity from other influenza A constituents in pSS, featured by a desirable high pre- and post-vaccination immunogenicity, is in line with reported differences in immune responses between strains in trivalent vaccines and may be related to pre-existing immunity. gov: #NCT03540823. Key Points • This prospective study demonstrated a robust pre- and post-vaccination immunogenicity to influenza A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus in primary Sjögren's syndrome (pSS). • This high immunogenicity pattern may be related to pre-existing immunization, or else it is related to immunogenicity differences of each strain. • This vaccine had an adequate safety profile in pSS, with no impact on disease activity.

Predominantly defective CD8+ T cell immunity to SARS-CoV-2 mRNA vaccination in lung transplant recipients

BackgroundAlthough mRNA vaccines have overall efficacy preventing morbidity/mortality from SARS-CoV-2 infection, immunocompromised persons remain at risk. Antibodies mostly prevent early symptomatic infection, but cellular immunity, particularly the virus-specific CD8+ T cell response, is protective against disease. Defects in T cell responses to vaccination have not been well characterized in immunocompromised hosts; persons with lung transplantation are particularly vulnerable to vaccine failure with severe illness.MethodsComparison groups included persons with lung transplantation and no history of COVID-19 (21 and 19 persons after initial mRNA vaccination and a third booster vaccination respectively), 8 lung transplantation participants recovered from COVID-19, and 22 non-immunocompromised healthy control individuals after initial mRNA vaccination (without history of COVID-19). Anti-spike T cell responses were assayed by stimulating peripheral blood mononuclear cells (PBMCs) with pooled small overlapping peptides spanning the SARS-CoV-2 spike protein, followed by intracellular cytokine staining (ICS) and flow cytometry for release of cytokines in response to stimulation, including negative controls (no peptide stimulation) and positive controls (phorbol myristate acetate [PMA] and ionomycin stimulation). To evaluate for low frequency memory responses, PBMCs were cultured in the presence of the mRNA-1273 vaccine for 14 days before this evaluation.ResultsIonophore stimulation of PBMCs revealed a less inflammatory milieu in terms of interleukin (IL)-2, IL-4, and IL-10 profiling in lung transplantation individuals, reflecting the effect of immunosuppressive treatments. Similar to what we previously reported in healthy vaccinees, spike-specific responses in lung transplantation recipients were undetectable (< 0.01%) when tested 2 weeks after vaccination or later, but were detectable after in vitro culture of PBMCs with mRNA-1273 vaccine to enrich memory T cell responses. This was also seen in COVID-19-recovered lung transplantation recipients. Comparison of their enriched memory responses to controls revealed relatively similar CD4+ T cell memory, but markedly reduced CD8+ T cell memory both after primary vaccination or a booster dose. These responses were not correlated to age or time after transplantation. The vaccine-induced CD4+ and CD8+ responses correlated well in the healthy control group, but poorly in the transplantation groups.ConclusionsThese results reveal a specific defect in CD8+ T cells, which have key roles both in transplanted organ rejection but also antiviral effector responses. Overcoming this defect will require strategies to enhance vaccine immunogenicity in immunocompromised persons.

Quadriceps Neuromuscular Function During and After Exercise-Induced Fatigue in Patients With Patellofemoral Pain.

Exercise-induced fatigue reduces muscle force production and motoneuron pool excitability. However, it is unclear if patients with patellofemoral pain (PFP) experience further loss in quadriceps neuromuscular function due to fatigue during exercise and postexercise. To observe how quadriceps maximal strength, activation, and force-generating capacity change during and after repetitive bouts of isokinetic knee-extension exercise in patients with PFP. Cross-sectional study. Laboratory. Twenty-two patients with PFP (visual analog scale mean pain severity = 4.2 of 10 cm, mean symptom duration = 38.6 months) and 19 healthy control individuals matched on age and body mass index. Quadriceps peak torque (PT), central activation ratio (CAR), and rate of torque development (RTD) were assessed at baseline and immediately after every 5 sets of knee-extension exercise (times 1-5). Participants continued knee-extension exercises until the baseline quadriceps PT dropped below 50% for 3 consecutive contractions. No group-by-time interaction was observed for quadriceps PT (F5,195 = 1.03, P = .40). However, group-by-time interactions were detected for quadriceps CAR (F5,195 = 2.63, P= .03) and RTD (F5,195 = 3.85, P = .002). Quadriceps CAR (-3.6%, P = .04, Cohen d = 0.53) and RTD (-18.9%, P = .0008, Cohen d = 1.02) decreased between baseline and time 1 in patients with PFP but not in their healthy counterparts (CAR -1.9%, P = .86; RTD -9.8%, P = .22). Quadriceps RTD also decreased between times 4 and 5 in patients with PFP (-24.9%, P = .002, Cohen d = 0.89) but not in the healthy group (-0.9%, P = .99). Patients with PFP appeared to experience an additional reduction in quadriceps activation, force-generating capacity, or both during the early and late stages of exercise compared with healthy individuals. Clinicians should be aware of such possible acute changes during exercise and postexercise and use fatigue-resistant rehabilitation programs for patients with PFP.

Hemiplejik hastalarda plantar fasya kalınlığının ultrasonografik değerlendirilmesi

Aims: In hemiplegic patients, changes in load distribution due to spasticity and paralysis cause trauma due to increased pressure and biomechanical problems in the plantar fascia on both sides. The aim of this study was to evaluate the plantar fascia thickness on both plegic and non-plegic sides by ultrasound in hemiplegic patients.&#x0D; Material and Methods: This cross-sectional study included patients with chronic hemiplegia (&gt;6 months) and healthy control individuals. Clinical and demographic features were noted. Plantar fascia was visualized as hyperechoic fibrils by ultrasound. The thickness was measured in both sides and at one cm after the calcaneal connection.&#x0D; Results: We included forty hemiplegic patients (22 males, 18 females) with a mean age of 58.60 ± 11.8 years; and thirty-six age, sex, and body mass index (BMI) matched healthy subjects. Plantar fascia thickness values were significantly higher on the non-plegic side (3.82 ± 0.1 mm) compared to that of plegic side (2.83 ± 0.6 mm) and healthy groups sides ( (right side:2.82 ± 0,50; left side: 2.81 ± 0,6) (p0,05). We also found significantly positive correlation between plantar fascia thickness of the non-plegic side and time since stroke (r=0.538, p

Changes of microbiota level in urinary tract infections: A meta-analysis.

No consensus has been reached on the dysbiosis signs of microbiota in patients with urinary tract infections (UTIs). This meta-analysis aimed to verify the relationship between microbiota levels and UTIs. PubMed, Web of Science, and Embase databases were retrieved for related articles published from inception until October 20, 2021. The standardized mean difference (SMD) and its related 95% confidence intervals (CIs) of the microbiota diversity and abundance were pooled under a random-effects model. Twelve studies were included in this meta-analysis. The pooled analysis revealed that the microbiota diversity was lower in patients with UTIs than in healthy individuals (SMD = -0.655, 95% CI = -1.290, -0.021, I 2 = 81.0%, P = 0.043). The abundance of specific bacteria was higher in UTI subjects compared with healthy control individuals (SMD = 0.41, 95% CI = 0.07-0.74, P = 0.017), especially in North America patients with UTIs. Similar results were also found in studies with the total sample size being greater than 30. Importantly, Escherichia coli levels were increased in patients with UTI, whereas Lactobacillus levels decreased. E. coli and Lactobacilli have huge prospects as potential microbiota markers in the treatment of UTIs.

Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing.

Pulmonary atresia (PA) is a severe cyanotic congenital heart disease. Although some genetic mutations have been described to be associated with PA, the knowledge of pathogenesis is insufficient. The aim of this research was to use whole-exome sequencing (WES) to determine novel rare genetic variants in PA patients. We performed WES in 33 patients (27 patient-parent trios and 6 single probands) and 300 healthy control individuals. By applying an enhanced analytical framework to incorporate de novo and case-control rare variation, we identified 176 risk genes (100 de novo variants and 87 rare variants). Protein‒protein interaction (PPI) analysis and Genotype-Tissue Expression analysis revealed that 35 putative candidate genes had PPIs with known PA genes with high expression in the human heart. Expression quantitative trait loci analysis revealed that 27 genes that were identified as novel PA genes that could be affected by the surrounding single nucleotide polymorphism were screened. Furthermore, we screened rare damaging variants with a threshold of minor allele frequency at 0.5% in the ExAC_EAS and GnomAD_exome_EAS databases, and the deleteriousness was predicted by bioinformatics tools. For the first time, 18 rare variants in 11 new candidate genes have been identified that may play a role in the pathogenesis of PA. Our research provides new insights into the pathogenesis of PA and helps to identify the critical genes for PA.

Single-cell RNA sequencing defines disease-specific differences between chronic nodular prurigo and atopic dermatitis

Chronic nodular prurigo (CNPG) is an inflammatory skin disease that is maintained by a chronic itch-scratch cycle likely rooted in neuroimmunological dysregulation. This condition may be associated with atopy in some patients, and there are now promising therapeutic results from blocking type 2 cytokines such as IL-4, IL-13, and IL-31. This study aimed to improve the understanding of pathomechanisms underlying CNPG as well as molecular relationships between CNPG and atopic dermatitis (AD). We profiled skin lesions from patients with CNPG in comparison with AD and healthy control individuals using single-cell RNA sequencing combined with T-cell receptor sequencing. We found type 2 immune skewing in both CNPG and AD, as evidenced by CD4+ helper T cells expressing IL13. However, only AD harbored an additional, oligoclonally expanded CD8A+IL9R+IL13+ cytotoxic T-cell population, and immune activation pathways were highly upregulated in AD, but less so in CNPG. Conversely, CNPG showed signatures of extracellular matrix organization, collagen synthesis, and fibrosis, including a unique population of CXCL14-IL24+ secretory papillary fibroblasts. Besides known itch mediators such as IL31 and oncostatin M, we also detected increased levels of neuromedin Bin fibroblasts of CNPG lesions compared with AD and HC, with neuromedin B receptors detectable on some nerve endings. These data show that CNPG does not harbor the strong disease-specific immune activation pathways that are typically found in AD but is rather characterized by upregulated stromal remodeling mechanisms that might have a direct impact on itch fibers.

Longitudinal change in neurocognitive functioning in children and adolescents at clinical high risk for psychosis: a systematic review.

Clinical high risk of psychosis (CHR-P) population has become an attractive area of interest in preventing transitions to psychosis. The consequences of developing a psychotic disorder may be worse in cases of early onset. Thus, childhood and adolescence represent a critical developmental window, where opportunities to gain social and adaptive abilities depend on the individuals' neurocognitive performance. There have been previous syntheses of the evidence regarding neurocognitive functioning in CHR-P individuals and its longitudinal changes. However, there has been less focus on children and adolescents at CHR-P. A multistep literature search was performed from database inception until July 15th, 2022. PRIMSA/MOOSE compliant systematic review and PROSPERO protocol were used to identify studies reporting on longitudinal changes in neurocognitive functioning in children and adolescents (mean age of sample ≤ 18years) at CHR-P and matched healthy control (HC) group. A systematic review of identified studies was then undertaken. Three articles were included, resulting in a total sample size of 151 CHR-P patients [mean (SD) age, 16.48 (2.41) years; 32.45% female] and 64 HC individuals [mean (SD) age, 16.79 (2.38) years; 42.18% female]. CHR-P individuals had worse outcomes in verbal learning, sustained attention and executive functioning domains compared to HC. Individuals taking antidepressants had better outcomes in verbal learning in contrast with those taking antipsychotics. In children and adolescents, neurocognition may be already impaired before the psychosis onset, and remains stable during the transition to psychosis. Further study should be performed to obtain more robust evidence.