Mitochondrial control of lymphocyte homeostasis.

Mitochondria play a multitude of essential roles within mammalian cells, and understanding how they control immunity is an emerging area of study. Lymphocytes, as integral cellular components of the adaptive immune system, rely on mitochondria for their function, and mitochondria can dynamically instruct their differentiation and activation by undergoing rapid and profound remodelling. Energy homeostasis and ATP production are often considered the primary functions of mitochondria in immune cells; however, their importance extends across a spectrum of other molecular processes, including regulation of redox balance, signalling pathways, and biosynthesis. In this review, we explore the dynamic landscape of mitochondrial homeostasis in T and B cells, and discuss how mitochondrial disorders compromise adaptive immunity.

Dynamic mitochondrial transcription and translation in B cells control germinal center entry and lymphomagenesis.

Germinal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription factor A, mitochondrial (TFAM). TFAM, while also necessary for normal B cell development, is required for entry of activated GC precursor B cells into the germinal center reaction; deletion of Tfam significantly impairs GC formation, function and output. Loss of TFAM in B cells compromises the actin cytoskeleton and impairs cellular motility of GC B cells in response to chemokine signaling, leading to their spatial disorganization. We show that B cell lymphoma substantially increases mitochondrial translation and that deletion of Tfam in B cells is protective against the development of lymphoma in a c-Myc transgenic mouse model. Finally, we show that pharmacological inhibition of mitochondrial transcription and translation inhibits growth of GC-derived human lymphoma cells and induces similar defects in the actin cytoskeleton.

Potential role of the geriatric nutritional risk index as a novel risk factor for the development of non-valvular atrial fibrillation in patients with heart failure.

PURPOSE: The geriatric nutritional risk index (GNRI) is a simple and objective nutritional assessment tool for elderly patients. Lower GNRI values are associated with a worse prognosis in heart failure with reduced ejection fraction (HFrEF). Our aim is to investigate the relationship between malnutrition and follow-up cardiovascular (CV) events in HFrEF. METHODS: A retrospective study was performed on 362 patients with HFrEF. The baseline GNRI was calculated at the first visit. The patients were divided into three groups according to the GNRI: >98, no-risk group; 92 to ≤98, low risk group; 82 to <92, moderate­to­high­risk group. The study endpoint was a composite of follow-upCV events, including all-cause mortality, non-valvular atrial fibrillation (NVAF) , need for cardioverter defibrillator (ICD) therapy, HfrEF­related hospitalizations and need for percutaneous coronary interventions (PCIs). RESULTS: Follow-up data showed that the group with moderate-to-high risk had a significantly higher incidence of NVAF, PCIs and all-cause mortality compared to other groups (p<0.001, p: 0.026 and p0.05). Mean GNRI value was 83.3 in NVAF patients and 101.1 in patients without NVAF (p<0.001). Kaplan Meier survival analysis showed that patients from the group with moderate-to-high risk had a significantly worse survival rate (p < 0.001). In the multivariate Cox regression analysis, the group with moderate-to­high risk (HR=3.872) and ICD implantations (HR=4.045) were associated with increased mortality. CONCLUSION: The GNRI value may have a potential role for predicting future events, especially NVAF in patients with HfrEF (Tab. 4, Fig. 2, Ref. 27).

Loss of hnRNPLL-dependent splicing of Ptprc has no impact on B-cell development, activation and terminal differentiation into antibody-secreting cells.

The RNA-binding protein heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) controls alternative splicing of protein tyrosine phosphatase receptor type C (Ptprc) which encodes CD45. hnRNPLL deficiency leads to a failure in silencing Ptprc exons 4-6 causing aberrant expression of the corresponding CD45 isoforms, namely, CD45RA, RB and RC. While an N-ethyl-N-nitrosourea-induced point mutation in murine Hnrnpll results in loss of peripheral naïve T cells, its role in B-cell biology remains unclear. Here, we demonstrate that B-cell development in the bone marrow of Hnrnpllthu/thu mice is normal and the number of mature B-cell subsets in the spleen and peritoneal cavity is comparable to control littermates. In response to in vivo immunization, Hnrnpllthu/thu mice were deficient in generating germinal center (GC) B cells, and analysis of mixed bone marrow chimeras revealed that the GC B-cell deficiency was a B-cell extrinsic effect of the hnRNPLL mutation. Mature Hnrnpllthu/thu B cells proliferated normally in response to various B-cell receptor- and Toll-like receptor-mediated stimuli. Similarly, in vitro stimulation of mutant B cells led to normal generation of plasmablasts, but mutant plasmablasts failed to downregulate B220 expression because of the inability of cells to undergo proper CD45 pre-messenger RNA alternative splicing. These findings collectively suggest that, like in T and natural killer T cells, the mutation disrupts hnRNPLL-mediated alternative splicing of the Ptprc gene in plasmablasts, but this dysregulation of Ptprc alternative splicing does not affect the development and function of B cells.

Monocyte/HDL ratio predicts hypertensive complications.

OBJECTIVE: We aimed to investigate whether a simple and easily calculated parameter such as monocyte/ HDL ratio (MHR) may be used in predicting non-dipper (NDHT)-dipper HT (DHT) end organ damage. METHODS: 70 NDHT and 73 DHT patient groups were included in the study according to ambulatory blood pressure screening results. Basic laboratory parameters and spot urine samples were evaluated. Transthoracic echocardiography and ophthalmological examination were performed for end-organ damages. RESULTS: The MHR among the groups was higher in the NDHT group; which was statistically significant (p≤0.001). In the NDHT group, albumin, creatinine, protein values, protein/creatinine ratio in the spot urine were significantly higher than in the DHT group (p≤0.05). Left ventricular hypertrophy (LVH) and retinopathy were also more frequently observed in the NDHT group (p≤0.001 and p=0.001, respectively). MHR in patients with LVH and retinopathy was significantly higher than in those without these complications (p=0.001). CONCLUSION: Easy to use, non-invasive and simple calculation, MHR can be used to predict end organ damage in hypertensive cases, and can be also used to distinguish between DHT/NDHT groups. This data supports the role of inflammation (Tab. 7, Ref. 14).

Improvement of anti-biofouling properties of hollow fiber membranes with bismuth-BAL chelates (BisBAL).

In this study, hollow fiber membranes with and without bismuth dimercaptopropanol (Bis-BAL) additive were fabricated. Membranes were characterized in terms of permeability, surface properties, anti-biofouling and antibacterial properties. Membranes were operated in a lab-scale submerged membrane bioreactor (MBR). During the MBR operation, flux, chemical oxygen demand, volatile suspended solids and suspended solids were calculated for 30 days. Results showed that extracellular polymeric substance and soluble microbial product amounts were decreased in BisBAL-containing membranes. BisBAL-added membranes had the ability to inhibit the growth of Escherichia coli. BisBAL as an additive for membranes was found to be an effective, cheap alternative for enhancing anti-biofouling properties of the membranes.

Unraveling Key Players of Humoral Immunity: Advanced and Optimized Lymphocyte Isolation Protocol from Murine Peyer's Patches.

In the gut mucosa, immune cells constitute a unique immunological entity, which promotes immune tolerance while concurrently conferring immune defense against pathogens. It is well established that Peyer's patches (PPs) have an essential role in the mucosal immune network by hosting several effector T and B cell subsets. A certain fraction of these effector cells, follicular T helper (TFH) and germinal center (GC) B cells are professionalized in the regulation of humoral immunity. Hence, the characterization of these cell subsets within PPs in terms of their differentiation program and functional properties can provide important information about mucosal immunity. To this end, an easily applicable, efficient and reproducible method of lymphocyte isolation from PPs would be valuable to researchers. In this study, we aimed to generate an effective method to isolate lymphocytes from mouse PPs with high cell yield. Our approach revealed that initial tissue processing such as the use of digestive reagents and tissue agitation, as well as cell staining conditions and selection of antibody panels, have great influence on the quality and identity of the isolated lymphocytes and on experimental outcomes. Here, we describe a protocol enabling researchers to efficiently isolate lymphocyte populations from PPs allowing reproducible flow cytometry-based assessment of T and B cell subsets primarily focusing on TFH and GC B cell subsets.

The novel diagnostic marker in low-LVEF heart failure patients.

OBJECTIVE: The structural and compositional changes in the myocardium seem to have a major role in the development of heart failure (HF).Imbalance between production and degradation in extracellular collagen results in increase of collagen synthesis biomarkers in the circulation as the carboxy-terminal propeptide of type I procollagen (PIP). Here we aimed to determine role of PIP in the diagnosis of chronic HF. MATERIAL AND METHODS: 87 patients with HF group and 80 healthy subjects were enrolled into the study. Echocardiographic examination was performed.At the beginning of the study, serum B type natriuretic peptide (BNP), PIP, high sensitive C-reactive protein (hs-CRP) were measured . The subjects were followed for one year then after. RESULTS: Average PIP value of HF group was significantly higher than that of the control group (p < 0.001). Both hs-CRP and BNP values were well correlated to PIP values (p < 0.001). In the HF group, PIP value of patients who died at the end of one year was similar to that of patients who survived at the end of first year. CONCLUSION: PIP may not mirror acute events in follow-up of chronic heart failure but it is a very beneficial biomarker in diagnosis of low-LVEF heart failure with high sensitivity and specificity (Tab. 2, Fig. 1, Ref. 16).

Effects of parenteral papaverine and piracetam administration on cochlea following acoustic trauma.

INTRODUCTION: Noise exposure, the main cause of hearing loss in countries with lot of industries, may result both in temporary or permanent hearing loss. The goal of this study was to investigate the effects of parenteral papaverine and piracetam administration following an acoustic trauma on hearing function with histopathologic correlation. MATERIALS AND METHODS: Eighteen Wistar albino rats exposed to noise for 8 h in a free environment were included. We divided the study population into three groups, and performed daily intraperitoneal injections of papaverine, piracetam, and saline, respectively, throughout the study. We investigated the histopathologic effects of cellular apoptosis on inner hair cells (IHCs) and outer hair cells (OHCs) and compared the distortion product otoacoustic emissions (DPOAEs) thresholds among the groups. RESULTS AND DISCUSSION: On the 3rd and 7th days, DPOAE thresholds at 8 kHz were significantly higher both in papaverine and piracetam groups compared with the control group (P = 0.004 for 3rd day, P = 0.016 and P = 0.028 for 7th day, respectively). On the 14th day, piracetam group had significantly higher mean thresholds at 8 kHz (P = 0.029); however, papaverine group had similar mean thresholds compared to the control group (P = 0.200). On the 3rd and 7th days following acoustic trauma, both IHC and OHC loss were significantly lower in both papaverine and piracetam groups. On the 7th day, the mean amount of apoptotic IHCs and OHCs identified using Caspase-3 method were significantly lower in both groups, but the mean amount identified using terminal deoxynucleotidyl transferase dUTP nick end labeling method were similar in both groups compared to the control group. CONCLUSION: We demonstrated the effects of papaverine and piracetam on the recovery of cochlear damage due to acoustic trauma on experimental animals using histopathologic and electrophysiologic examinations.

eNOS and XRCC4 VNTR variants contribute to formation of nicotine dependence and/or schizophrenia.

BACKGROUND: This study aimed to evaluate whether VNTR variants in the Endothelial Nitric Oxide Synthase (eNOS) and the XRCC4 gene play any role in nicotine dependence (ND) and/or Schizophrenia+ND (Sch+ND) ethiopathogenesis. METHODS: Present study included 100 individuals with ND, 60 patients with Sch+ND, and 70 healthy controls. These variants were analyzed using PCR. RESULTS: The cases with ND had higher eNOS VNTR-BB genotype than the healthy control subjects (p = 0.001). eNOS-AA genotype was lower in cases with Sch+ND and ND groups compared to the controls (p = 0.001, p = 0.001, respectively). eNOS-B allele was found significantly more frequently in Sch+ND group compared to the controls (p = 0.001). eNOS-A allele was significantly lower in ND group than the controls (p = 0.001). XRCC4-ID genotype was more common in the ND group than the control group (p = 0.001) as heterozygosity disadvantage. XRCC4-DD genotype was more common in the Sch+ND group compared to the controls (p = 0.035). The frequency of XRCC4-I allele was lower in the Sch+ND group compared to the controls (p = 0.012). CONCLUSIONS: Our results showed that eNOS and XRCC4 VNTR variants might play a potential role in Sch+ND and/or ND pathophysiology (Tab. 2, Ref. 48).

Effects of thiocolchicoside, a commonly used myorelaxant, on the acoustic reflex.

OBJECTIVE: To determine whether thiocolchicoside, a commonly used myorelaxant, may impair the acoustic reflex. METHODS: Forty-two patients scheduled to receive thiocolchicoside treatment for different reasons were enrolled in the study. Acoustic reflex thresholds at 500, 1000, 2000 and 4000 Hz were determined and analysed statistically pre-treatment and on the 5th day of treatment. RESULTS: Increases were observed in the mean acoustic reflex thresholds on the 5th day of treatment compared to pre-treatment, at all frequencies, except right contralateral thresholds at 500 and 2000 Hz. These increases were statistically significant for right ipsilateral thresholds at 2000 and 4000 Hz, left ipsilateral thresholds at 500, 1000, 2000 and 4000 Hz, and left contralateral thresholds at 2000 and 4000 Hz (p ≤ 0.05), but not at other frequencies (p > 0.05). CONCLUSION: Muscle relaxant drugs, especially those affecting the central nervous system, may weaken the stapedial muscle so that the ability of noise to cause acoustic trauma may become evident. For this reason, physicians should advise their patients to avoid loud noises when muscle relaxant therapy is prescribed.

Atherogenic index of plasma may be strong predictor of subclinical atherosclerosis in patients with Behçet disease.

OBJECTIVES: Behcet's disease (BD) is a systemic vasculitis characterized by cardiovascular complications. Early diagnosis of these complications can reduce morbidity and mortality. Carotid artery intima-media thickness (cIMT) and the logarithmic value of triglyceride to high density lipoprotein ratio (atherogenic index of plasma, AIP) are good markers of atherosclerosis. The purpose of this study was to investigate whether AIP is a predictive marker of subclinical atherosclerosis in BD patients. PATIENTS AND METHODS: A total of 84 BD patients (60 male, 24 female) and 84 healthy control individuals (58 male, 26 female) were included in this study. cIMT measurements were made, and AIP values were calculated. RESULTS: cIMT (p < 0.001) and AIP (p < 0.001) values of the BD patients were higher than those of the control group. A strong independent relationship was found between the AIP value and cIMT (ß = 0.232, p = 0.018). In the subgroup analysis, the cIMT and AIP values of male BD patients were higher than those of female BD patients. CONCLUSION: Increased AIP and cIMT values can be a good marker for subclinical atherosclerosis in BD patients, especially in male BD patients.

An unusual case report of gingival overgrowth associated with the use of leflunomide.

Leflunomide is an immunomodulatory agent with antiproliferative activity that is used for the treatment of rheumatoid arthritis. Leflunomide induced side effects are hepatotoxicity, immunosuppression, skin reactions, peripheral neuropathy, hypertension, diarrhea, interstitial lung disease, and rarely oral mucosal lesions. Here, we presented an unusual case of gingival overgrowth associated with the use of leflunomide, which improved after ceasing the drug.

Spinal cord injury resulting from gunshot wounds: a comparative study with non-gunshot causes.

STUDY DESIGN: Retrospective, comparative 7-year study. OBJECTIVES: To identify the clinical characteristics of patients with spinal cord injury (SCI) resulting from gunshot wound (GSW). SETTING: Turkish Armed Forces Rehabilitation Center, Ankara, Turkey. METHODS: The study included 1043 consecutive patients with SCI who were divided into two groups according to etiology: patients with gunshot-induced spinal cord injury (GSWSCI) constituted the study group, and randomly selected patients with non-gunshot-induced spinal cord injury (NGSWSCI) who were matched for gender and for week of admission constituted the control group. The demographic and clinical characteristics of the patients were recorded, compared and analyzed. RESULTS: The study group included 102 patients (mean age: 26.93±9.11 years). The vast majority of the patients were aged 16-30 years (68.6%) and 90.2% were male. The majority of the lesions were at the thoracic level (58.8%) and a complete injury (60.8%). Surgical stabilization of the spine was performed in 50 patients (49%). The most prevalent associated injury was intra-abdominal injury followed by chest injury. Compared with the NGSWSCI group, the GSWSCI patients were more likely to have a complete lesion (60.8% vs 45.1%, P=0.025), had a lower rate of surgical stabilization (49 vs 88.2%, P=0.0001) and had a higher rate of associated injuries (54.9% vs 25.5%, P=0.0001). Compared with the civilian GSWSCI group, the military GSWSCI patients had a higher rate of surgical stabilization and associated injuries (60% vs 40%, P=0.049, 68.9% vs 43.9%, P=0.012, respectively). CONCLUSION: The results revealed that GSWSCI and military GSWSCI patients may have different demographic and clinical features compared with NGSWSCI and civilian GSWSCI patients, respectively.

Exacerbation of myasthenia gravis by alendronate.

Myasthenia gravis is an important indication for the long-term prescription of corticosteroids. We present a patient with myasthenia gravis who had worsening of symptoms associated with the use of alendronate. A 24-year-old patient with myasthenia gravis had been administered oral systemic corticosteroid (deflazacort 40 mg/day) for 3 years in order to control his myasthenic symptoms. One year earlier, his lumbar spine bone mineral density was decreased. He was started on oral calcium/vitamin D3 and alendronate (70-mg tablets once a week) for osteoporosis. He reported an exacerbation of muscle weakness and extreme fatigue on days when he took alendronate. He could not work on these days and has to be on leave. Alendronate was stopped, and he was started on intravenous ibandronate injections given every 3 months. He did not experience muscle weakness and fatigue with ibandronate therapy. Alendronate should be used with caution in patients with myasthenia gravis who have corticosteroid-induced osteoporosis.

Relationship between coronary in-stent restenosis and plasma urotensin II level.

AIM: In-stent restonosis is an important limitation for coronary stenting. The cause of in-stent restenosis is neointimal hyperplasia developed from smooth muscle and matrix. We aimed to investigate the association between urotensin II (U-II) and in-stent restenosis after coronary stenting, which causes endothelial and muscle proliferation and accumulation of collagen. METHODS: Total 153 patient was enrolled to the study who meet criteria for angiographic indication underwent coronary artery angiography. All patients have history undergone for coronary stent implantation 3 to 9 months ago. In-stent restenosis is identified as ≥50% narrowing inside the stent. In-stent restenosis was observed in 73 and remaining of 80 patients revealed no critical lesion in stent on angiographic evaluation. Plasma level measurement of U-II was performed in all subjects. RESULTS: Urotensin II levels were found to be significantly higher in Group I compared to Group II (1.44±0.74 ng/mL and 1.21±0.59 ng/mL, respectively, P=0.03). In a subgroup analysis, U-II levels were significantly higher in group I than group II in patients treated with bare metal stent (BMS) (1.50±0.76 ng/mL and 1.18±0.56 ng/mL, P=0.016); however, there was not significant change in patients treated with drug-eluted stent (1.26±0.64 ng/mL and 1.27±0.63 ng/mL, P=0.9). Multivariate statistical significance: negative correlation was found between in-stent restenosis and renin-angiotensin-system (RAS) blocker usage (P=0.040) and right coronary artery (RCA) lesion interventions (P=0.018). CONCLUSION: This study revealed high plasma U-II level might be accepted as a risk factors for in-stent restenosis with BMS. In-stent restenosis is less developed after RCA interventions and taking drug of RAS blockages. Our study findings need to be confirmed in further studies.

Spontaneous healing of occlusive type F coronary artery dissection.

In the presence of resistance to circumferential expansion of atherosclerotic plaques due to mechanical dilation high shear stresses between stiff plaques and normal vessel segments may occur and thus may result in coronary dissection. Limited data are available on the clinical and angiographic outcome of severe (type E, type F) coronary dissections. Herein, we report a case of type F dissection (causing total occlusion) of proximal right coronary artery during balon angioplasty which healed spontaneously. In conclusion, although the type F dissection has worse prognosis due to complete cessation of distal vessel perfusion, the possibility of spontaneous healing should be kept in mind after unsuccessful intervention.