Chronic stress targets mitochondrial respiratory efficiency in the skeletal muscle of C57BL/6 mice.

Episodes of chronic stress can result in psychic disorders like post-traumatic stress disorder, but also promote the development of metabolic syndrome and type 2 diabetes. We hypothesize that muscle, as main regulator of whole-body energy expenditure, is a central target of acute and adaptive molecular effects of stress in this context. Here, we investigate the immediate effect of a stress period on energy metabolism in Musculus gastrocnemius in our established C57BL/6 chronic variable stress (Cvs) mouse model. Cvs decreased lean body mass despite increased energy intake, reduced circadian energy expenditure (EE), and substrate utilization. Cvs altered the proteome of metabolic components but not of the oxidative phosphorylation system (OXPHOS), or other mitochondrial structural components. Functionally, Cvs impaired the electron transport chain (ETC) capacity of complex I and complex II, and reduces respiratory capacity of the ETC from complex I to ATP synthase. Complex I-OXPHOS correlated to diurnal EE and complex II-maximal uncoupled respiration correlated to diurnal and reduced nocturnal EE. Bioenergetics assessment revealed higher optimal thermodynamic efficiencies (ƞ-opt) of mitochondria via complex II after Cvs. Interestingly, transcriptome and methylome were unaffected by Cvs, thus excluding major contributions to supposed metabolic adaptation processes. In summary, the preclinical Cvs model shows that metabolic pressure by Cvs is initially compensated by adaptation of mitochondria function associated with high thermodynamic efficiency and decreased EE to manage the energy balance. This counter-regulation of mitochondrial complex II may be the driving force to longitudinal metabolic changes of muscle physiological adaptation as the basis of stress memory.

Catheter Ablation of Atrial Tachycardia after Pulmonary Vein Isolation in a Patient with Common Ostium of Inferior Pulmonary Veins: Case Report.

Background and Objectives: Atrial fibrillation (AF), a prevalent cardiac arrhythmia, significantly impacts the quality of life of those affected. The preferred treatment for symptomatic AF, particularly when pharmacological methods fall short, is catheter ablation with pulmonary vein isolation (PVI). While common pulmonary vein (PV) anatomical variants, such as the right accessory pulmonary vein and the common ostium of left pulmonary veins (LCPV), have been studied extensively, their impact on the long-term outcome of PVI is known to be minimal. However, data on less common anomalies, like the common ostium of the left and right inferior pulmonary vein (CIPV), remain scarce in the medical literature. This report aims to shed light on the challenges and outcomes of catheter ablation in a patient with a rare CIPV anomaly. By presenting this case, we contribute to the limited knowledge about the management of such unique anatomical variations in AF treatment and discuss the importance of individualized treatment approaches. Case Presentation: We present a case involving a 56-year-old male diagnosed with AF in 2018. Initial PVI treatment was successful, but the patient experienced symptom recurrence after three years. A preprocedural CT scan before the second ablation revealed a CIPV anomaly. During the repeat procedure, a right superior pulmonary vein (RSPV) reisolation was performed due to identified gaps in the previous ablation line. Post-procedure, the patient maintained a sinus rhythm and reported no further symptoms. Conclusions: This case highlights the importance of recognizing rare PV anatomies like CIPV in the effective management of AF. Tailored ablation strategies, accounting for unique anatomical conditions, can lead to successful long-term outcomes, reinforcing the need for personalized approaches in AF treatment, especially in cases involving complex anatomical variations.

Transcript CD81-215 may be a long noncoding RNA of stromal origin with tumor-promoting role in colon cancer.

The role of tetraspanin CD81 in malignant transformation is best studied in colorectal cancer, and it appears that other transcripts beside the fully coding mRNA may also be dysregulated in malignant cells. Recent data from a comprehensive pan-cancer transcriptome analysis demonstrated differential activity of two alternative CD81 gene promoters in malignant versus nonmalignant gut mucosa. The promoter active in gut mucosa gives rise to transcripts CD81-203 and CD81-213, while the promoter active in colon and rectal cancer gives rise to transcripts CD81-205 and CD81-215. Our study aimed to explore the biomarker potential of the transcripts from the alternative CD81 gene promoters in colon cancer, as well as to investigate their structure and potential function using in silico tools. The analysis of the transcripts' expression in several colon cell lines cultivated in 2D and 3D and a set of colon cancer and healthy gut mucosa samples by qPCR and RNA sequencing suggested their low expression and stromal origin. Expression patterns in tumor and nontumor tissue along with in silico data suppose that the transcript CD81-215 may be a noncoding RNA of stromal origin with possible involvement in signaling related to malignant transformation.

Eurasian consumers' food safety beliefs and trust issues in the age of COVID-19: evidence from an online survey in 15 countries.

BACKGROUND: This investigation provides an important insight into Eurasian consumers' food safety beliefs and trust issues influenced by the COVID-19 pandemic. An online survey was conducted in 15 European and Asian countries involving more than 4000 consumers. RESULTS: It has confirmed that different socioeconomic characteristics, cultural aspects and education levels shape food safety perceptions within Eurasian countries. The COVID-19 pandemic influenced their beliefs and trust in food safety, which is relatively low on average. However, it is significantly higher for European consumers (especially European Union ones) compared to their Asian counterparts. Both Asian and European respondents agreed that food fraud and climate changes represent a food safety issue. However, European consumers were less concerned regarding the food safety of genetically modified foods and meat and dairy analogs/hybrids. Asian consumers were, to a greater extent, worried about the risk of getting COVID-19 from food, restaurants, food retail establishments and home food deliveries. CONCLUSION: Eurasian consumers have put their greatest extent of trust, when food safety assurance is concerned, into food scientists and food producers holding a food safety certificate. Broadly, they are uncertain to what extent their federal governments and food inspectors are competent, able and efficient in ensuring food safety. Higher education of Eurasian consumers was followed by increased food safety confidence in all parts of the food chain. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

SMAD4-201 transcript as a putative biomarker in colorectal cancer.

BACKGROUND: Transcripts with alternative 5'-untranslated regions (UTRs) result from the activity of alternative promoters and they can determine gene expression by influencing its stability and translational efficiency, thus executing complex regulation of developmental, physiological and pathological processes. Transcriptional regulation of human SMAD4, a key tumor suppressor deregulated in most gastrointestinal cancers, entails four alternative promoters. These promoters and alternative transcripts they generate remain unexplored as contributors to the SMAD4 deregulation in cancer. The aim of this study was to investigate the relative abundance of the transcript SMAD4-201 in colorectal cell lines and tissues in order to establish if its fluctuations may be associated with colorectal cancer (CRC). METHODS: Relative abundance of SMAD4-201 in total SMAD4 mRNA was analyzed using quantitative PCR in a set of permanent human colon cell lines and tumor and corresponding healthy tissue samples from patients with CRC. RESULTS: The relative abundance of SMAD4-201 in analyzed cell lines varied between 16 and 47%. A similar relative abundance of SMAD4-201 transcript was found in the majority of analyzed human tumor tissue samples, and it was averagely 20% lower in non-malignant in comparison to malignant tissue samples (p = 0.001). Transcript SMAD4-202 was not detectable in any of the analyzed samples, so the observed fluctuations in the composition of SMAD4 transcripts can be attributed to transcripts other than SMAD4-201 and SMAD4-202. CONCLUSION: The expression profile of SMAD4-201 in human tumor and non-tumor tissue samples may indicate the translational potential of this molecule in CRC, but further research is needed to clarify its usability as a potential biomarker for early diagnosis.

Inappropriate shock delivery as a result of electromagnetic interference originating from the faulty electrical installation.

We present a case report of a 74-year-old male patient with an implantable cardioverter defibrillator who suffered an inappropriate defibrillation shock while bathing in the tub. Insight in the ICD stored electrogram episodes revealed electromagnetic interferences, with a typical 50 Hz electrical artifact mimicking fast ventricular tachycardia as a device misinterpreted. After this event, the maintenance workers investigated the electrical installation in the bathroom and revealed that there was voltage leaking between electrical installation and metal pipes. After the repair was completed without any additional programming, the patient has had no subsequent shocks.

Prognostic potential of circulating miR-93-5p in patients with colorectal cancer liver metastases.

This study aimed to examine the expression pattern of tumoral and circulating miR-93-5p in patients with colorectal cancer (CRC) liver metastasis (CRLM) and to explore its predictive and prognostic potential. CRLM tissue, surrounding non-tumor liver tissue, and serum were obtained from 35 patients with CRLM. The expression pattern of tissue and circulating miR-93-5p in patients with CRLM was determined using quantitative polymerase chain reaction, using miR-16-5p for normalization. Sample-based cut-off values for CRLM and serum miR-93-5p expression were calculated using Receiver Operating Characteristic curve analysis to stratify the patients into high and low miR-93-5p expression groups which were that compared with patients' clinicopathological data, therapy response, one-year disease-free survival, and disease recurrence. Relative miR-93-5p expression was higher in CRLM in comparison to the non-metastatic liver tissue (p<0.001). CRLM miR-93-5p expression showed moderate negative correlation with carcinoembryonic antigen levels (r=-0.406; p=0.016). There were no differences in high-/low-miR-93-5p expression and therapy responders vs. non-responders, which was confirmed in vitro using metastatic and normal colonic cells SW620 and HCEC-1CT, respectively. No difference was observed in one-year recurrence-free survival in patients with high vs. low miR-93-5p expression in CRLM or serum. However, high miR-93-5p serum levels were significantly associated with early disease recurrence (p=0.035). In conclusion, miR-93-5p serum levels could be potentially used as a prognostic factor for early disease recurrence in CRLM patients.

Prognostic relevance of autophagy-related markers p62, LC3, and Beclin1 in ovarian cancer.

AIM: To analyze the expression of autophagy markers p62, LC3, and Beclin1 in ovarian cancer tissue and evaluate the prognostic potential of these markers. METHODS: The study enrolled 328 patients: 122 with epithelial ovarian carcinoma, 42 with atypical proliferative tumor, and 164 with benign epithelial ovarian tumor. The expression of p62, LC3, and Beclin1 was analyzed in central and invasive tumor segments with immunohistochemistry combined with tissue microarray. The expression levels of the analyzed markers were correlated with relevant histopathology parameters. RESULTS: The expression of all analyzed markers was most remarkable in epithelial ovarian carcinoma. There was a strong positive correlation between the expressions of p62 and LC3, while these two markers negatively correlated with Beclin1. High-grade serous carcinoma had higher p62 and LC3 levels, and lower Beclin1 levels than other tumor types. This expression profile was also observed in more advanced tumor stages. CONCLUSION: Prominent p62 and LC3 expression in combination with weak Beclin1 expression in high-grade serous carcinoma indicates potential for the application of autophagy inhibitors in patients with this tumor subtype.

Adaptation of Oxidative Phosphorylation Machinery Compensates for Hepatic Lipotoxicity in Early Stages of MAFLD.

Alterations in mitochondrial function are an important control variable in the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), while also noted by increased de novo lipogenesis (DNL) and hepatic insulin resistance. We hypothesized that the organization and function of a mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. We addressed this question using a transgenic mouse model with increased hepatic insulin resistance and DNL due to constitutively active human SREBP-1c. The abundance of ETC complex subunits and components of key metabolic pathways are regulated in the liver of these animals. Further omics approaches combined with functional assays in isolated liver mitochondria and primary hepatocytes revealed that the SREBP-1c-forced fatty liver induced a substrate limitation for oxidative phosphorylation, inducing enhanced complex II activity. The observed increased expression of mitochondrial genes may have indicated a counteraction. In conclusion, a shift of available substrates directed toward activated DNL results in increased electron flows, mainly through complex II, to compensate for the increased energy demand of the cell. The reorganization of key compounds in energy metabolism observed in the SREBP-1c animal model might explain the initial increase in mitochondrial function observed in the early stages of human MAFLD.

SMAD7 and SMAD4 expression in colorectal cancer progression and therapy response.

Inhibitory SMAD7 and common mediator SMAD4 play crucial roles in SMAD-dependent TGF-ß signaling that is often disrupted in colorectal cancer (CRC). This study aimed to profile the expression of SMAD7 and SMAD4 in primary and metastatic CRC and to evaluate their significance in disease progression and therapy response. The expression of SMAD7 and SMAD4 genes was analyzed by quantitative real-time PCR in tissues from 35 primary and metastatic CRC patients and in vitro in 7 human cell lines originating from colon tissue. Expression levels of SMAD7 and SMAD4, as well as their ratio, were determined and their association with tumor characteristics and response to therapy were evaluated. SMAD4 level was significantly lower in tumors compared to non-tumor tissues in both primary (p = 0.001) and metastatic (p = 0.001) CRC patients, while tumor expression of SMAD7 was significantly lower from non-tumor tissue only in metastatic patients (p = 0.017). SMAD7/SMAD4 ratio was elevated in CRC primary tumor tissues and cell lines compared to corresponding non-tumor tissues and cell line, respectively (p = 0.003). SMAD7 expression was significantly elevated in primary tumor tissues obtained from responders to neoadjuvant chemoradiotherapy (nCRT) compared to non-responders (p = 0.014). Alterations of expression and ratio of SMAD7 and SMAD4 in CRC cell lines, primary rectal cancer, and liver metastasis emphasize the importance of these genes in different stages of disease progression. Differential expression of SMAD7 in responders versus non-responders to nCRT should be further investigated for its potential predictive value.

Early Selective C-Reactive Protein Apheresis in a Patient with Acute ST Segment Elevation Myocardial Reinfarction.

The patient was admitted for urgent coronary angiography following an acute anterior ST segment elevation myocardial reinfarction (STEMI) caused by acute stent thrombosis. A stent had been implanted 10 days prior to the reinfarction for an acute anterior STEMI. However, the patient had stopped taking ticagrelor post-discharge. Primary percutaneous coronary intervention of the left anterior descending artery was performed. Subsequently, due to a high C-reactive protein (CRP) level, 3 CRP apheresis sessions were performed, with the first session starting 12 h after the onset of symptoms. A significant drop in CRP was noted after each apheresis. The post-procedural course was uneventful.

Covid-19 pandemic effects on food safety - Multi-country survey study.

This study provides an important insight into the response of food safety systems during the first months of the pandemic, elevating the perspective of preventing Covid-19 within conventional food safety management systems. A multi-country survey was conducted in 16 countries involving 825 food companies. Based on the results of the survey, it is obvious that the level of maturity of a food safety system in place is the main trigger in classifying companies and their responses to the pandemic challenge. Staff awareness and hygiene are the two most important attributes in combating Covid-19, opposed to temperature checking of workers in food establishment and health protocols from the World Health Organization, recognized as attributes with limited salience and importance. Companies confirmed implementation of more restrictive hygiene procedures during the pandemic and the need for purchasing more additional personal protective equipment. Retailers were identified as the food supply chain link mostly affected by the pandemic opposed to food storage facilities ranked as least affected. During this challenging period, all companies declared that food safety has not been compromised at any moment. It is important to note that less than a half of the food companies had documented any emergency plans associated with pandemics and health issues in place.

A Promising Innovative Treatment for ST-Elevation Myocardial Infarction: The Use of C-Reactive Protein Selective Apheresis: Case Report.

BACKGROUND: In patients with ST-elevation myocardial infarction (STEMI), C-reactive protein (CRP) levels are associated with larger infarct size, transmural extent, and poor function of left ventricle and independently predict 30-day mortality. CRP-apheresis following STEMI showed to be feasible, safe, and has significant beneficial effect both on myocardial infarction size and wall motion. To the best of our knowledge, this is only the second published clinical evaluation of the efficacy and safety of selective CRP-apheresis in the STEMI treatment using Spectra-Optia and Pentrasorb CRP-adsorber systems. CASE REPORT: A 53-year-old female was referred with anterior STEMI. After percutaneous coronary intervention, patient received standard post-STEMI therapy according to current guidelines. Selective therapeutic plasma exchange (TPE) was performed using Spectra-Optia (Terumo BCT; USA) and Pentrasorb CRP-adsorber (Pentracor GmbH; Germany) systems. Antecubital veins were used for vascular access and acid-citrate-dextrose solution (ACD formula A; total volume = 1,026 mL) was utilized as anticoagulant. The volume of processed blood was 15,600 mL. The removed "natural" plasma (total volume = 8,329 mL) was replaced with CRP-depleted autologous plasma (total volume = 8,085 mL). This intensive TPE-treatment was well tolerated, without adverse effects, or complications. The CRP plasma levels were: initial = 4.2 mg/L 6 h after acute myocardial infarction (AMI), pre-apheresis = 16.4 mg/L, and post-apheresis = 4.59 mg/L (CRP-depletion = 72%). There were neither significant changes observed in biochemistry nor any alterations in plasma hemostatic activity investigated before and after CRP-adsorption performed. CONCLUSION: Early performed CRP-apheresis is a promising innovative therapeutic approach for STEMI treatment that could provide a reduced size of infarction zone - with inferior occurrence of heart failure after AMI. However, precise and complete evaluation of the efficacy and safety of this treatment requires further multicenter randomized and larger clinical studies.

Physiological Disturbance in Fatty Liver Energy Metabolism Converges on IGFBP2 Abundance and Regulation in Mice and Men.

Fatty liver occurs from simple steatosis with accumulated hepatic lipids and hepatic insulin resistance to severe steatohepatitis, with aggravated lipid accumulation and systemic insulin resistance, but this progression is still poorly understood. Analyses of hepatic gene expression patterns from alb-SREBP-1c mice with moderate, or aP2-SREBP-1c mice with aggravated, hepatic lipid accumulation revealed IGFBP2 as key nodal molecule differing between moderate and aggravated fatty liver. Reduced IGFBP2 expression in aggravated fatty liver was paralleled with promoter hypermethylation, reduced hepatic IGFBP2 secretion and IGFBP2 circulating in plasma. Physiologically, the decrease of IGFBP2 was accompanied with reduced fatty acid oxidation and increased de novo lipogenesis potentially mediated by IGF1 in primary hepatocytes. Furthermore, methyltransferase and sirtuin activities were enhanced. In humans, IGFBP2 serum concentration was lower in obese men with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) compared to non-obese controls, and liver fat reduction by weight-loss intervention correlated with an increase of IGFBP2 serum levels. In conclusion, hepatic IGFBP2 abundance correlates to its circulating level and is related to hepatic energy metabolism and de novo lipogenesis. This designates IGFBP2 as non-invasive biomarker for fatty liver disease progression and might further provide an additional variable for risk prediction for pathogenesis of fatty liver in diabetes subtype clusters.

Neutrophil extracellular traps-associated markers are elevated in patients with systemic lupus erythematosus.

Neutrophil extracellular traps (NETs) are the main source of autoantigens in systemic lupus erythematosus (SLE). The aim of this study was to evaluate the clinical importance of NETs-associated markers in SLE. We compared NETs-associated markers in SLE patients (n = 111) with healthy controls (n = 50). Moreover, in 35 patients with drug-naïve SLE (n = 35), we investigated correlation between NETs-associated markers [DNase I concentration, myeloperoxidase (MPO) activity, anti-MPO antibodies, cell-free DNA (cfDNA), NETolytic activity] with serological parameters [anti-dsDNA antibodies, C3, C4 and B-cell activating factor (BAFF) levels] and disease activity measured by modified SLE Disease Activity Index (M-SLEDAI-2K). In comparison with healthy controls, SLE patients had higher cfDNA, MPO activity, anti-MPO antibodies (p < 0.001), BAFF and DNase I concentration (p < 0.01). Contrary, NETolytic activity was lower in SLE patients (p < 0.05), despite higher concentration of DNase I. MPO activity and cfDNA levels showed correlation with DNase I concentration (p < 0.001, p < 0.01, respectively). BAFF levels correlated with cfDNA, DNase I concentration and MPO activity (p < 0.05). Anti-dsDNA antibodies showed correlation with MPO activity (p < 0.01), cfDNA and BAFF levels (p < 0.001). Anti-dsDNA and C3 levels were independent predictors of M-SLEDAI-2K in multivariate analysis (p < 0.01). We demonstrated that sera of SLE patients have decreased NETolytic activity, leading to increased levels of various NETs-associated markers, which correlate with anti-dsDNA antibodies in drug-naïve SLE. We showed that BAFF participates in a complex relationship between NETosis and anti-dsDNA antibodies production. These findings have important implications for a better understanding of SLE pathogenesis and development of therapy that inhibits NETs persistence and disease progression.

Effects of Temperature Abuse on the Growth and Staphylococcal Enterotoxin A Gene (sea) Expression of Staphylococcus aureus in Milk.

The aim of this study was to determine the effects of different temperatures and storage time on Staphylococcus aureus growth, sea gene expression, and synthesis of staphylococcal enterotoxin A (SEA) in the pasteurized and UHT-pasteurized milk. Pasteurized and UHT-pasteurized milk were inoculated with 3.98 log10 CFU/mL of S. aureus (ATCC 13565). Inoculated milk samples were stored at 8°C, 15°C, and 22°C for 24, 48, and 72 h, respectively. SEA synthesis was detected with a fully automated miniVIDAS instrument using the Enzyme-Linked Fluorescent Assay (ELFA) technology. The patterns of gene regulation were detected by quantitative reverse transcriptase PCR. The 2-ΔΔCT method has been used as a relative quantification strategy for gene expression responses data analysis. The results indicated that growth rate, sea gene expression, and SEA synthesis were influenced by type of milk, storage time, and temperature. Incubation of milk at different temperatures (15°C and 22°C) and times was used to simulate inadequate transport and storage conditions. Storage of pasteurized milk at 22°C for 24 h significantly upregulated the expression of sea gene compared with milk stored at 8°C, which coincides with the achieved S. aureus number of 105 CFU/mL and detected amount of SEA. In addition, storage of UHT-pasteurized milk at 22°C for 24 h and at 15°C for 48 h significantly upregulated the sea gene expression compared with milk stored at 8°C, which coincides with the detected amount of SEA and the dynamics of S. aureus number change. It can, therefore, be concluded that implementing good hygiene practices to avoid pre- and post-heat treatment milk contamination and maintaining the cold chain at temperature <8°C throughout the entire dairy production chain are of paramount importance to decrease the risk of staphylococcal food poisoning.

Breast cancer and its impact in male transsexuals.

INTRODUCTION: Lesbian, gay, and bisexuals have unique healthcare needs. Breast cancer is leading cancer in women, worldwide, accounting for 25% of all cases. Annual incidence rates increased significantly in all countries and age groups. The occurrence of breast cancer is rare in transgender population. As they have very limited access to medical care, it is much less likely to pursue breast cancer screening than in other individuals not identified as transgender. REVIEW OF THE CASES FROM LITERATURE: Up to date, only 13 cases of the breast cancer transsexuals (female to male) have been reported in six published papers worldwide. Histological examination of the breast tumor in female-to-male transgender showed progesterone/estrogen-positive invasive ductal carcinoma. DISCUSSION: Gender identity describes a person's inherent sense of being a woman, man, or of neither gender, whereas sexual orientation refers to how people identify their physical and emotional attraction to others. Gender reassignment surgery, as series of complex surgical genital and non-genital procedures, is recognized as the most effective treatment for patients with gender dysphoria. The two main principles of hormone therapy for transgender patients are to reduce endogenous hormone levels and their associated sex characteristics and replace them with hormones of the preferred sex. Breast cancer infrequently occurs in transgender patients. Even breast core biopsies can be difficult for interpreting after changes in breast tissue in female-to-male transsexuals following gender reassignment. CONCLUSION: Reviewing the literature, so many different data concerning probability of breast cancer in sexual minority can be found. Breast cancer screening program should be offered to all transgender individuals according to national guidelines. Very important is to take into consideration a transgender person's natal and surgical anatomy, unique clinical concerns for depression and anxiety, risk of suicide together with risk factors including experiences of harassment or physical or sexual violence, low education level, and unemployment. Understanding the need for mammography in these often marginalized groups is very important in addressing breast cancer disparities despite differences in insurance coverage in some countries and greater concern for the cancer of the breast in residual breast tissue. The best screening rule, ever, for breast cancer in male transsexuals and other similar population should be, besides surgical history and hormonal status, "Screen Now, Screen Regularly and Screen What You Have."

25(OH) vitamin D deficiency in lymphoid malignancies, its prevalence and significance. Are we fully aware of it?

INTRODUCTION: Vitamin D has a role in cellular differentiation, proliferation, apoptosis, and angiogenesis and therefore is studied as a prognostic factor in cancer. The aim of our study was to assess the prevalence and significance of 25(OH)D deficiency in patients with lymphoid malignancies. METHODOLOGY: Between January 2014 and June 2016 at the Clinic for Hematology, Clinical Center of Serbia, Belgrade, the pretreatment serum level of 25(OH)D was determined in 133 (62 women/71 men, median age 58 (18-84) years) previously untreated patients with lymphoid malignancy using a chemiluminescent immunoassay. From their medical records, we noted the age, clinical stage, Eastern Cooperative Oncology Group Performance Scale (ECOG PS), nutritional status using the Nutritional Risk Score 2002 (NRS2002), the time of year, comorbidity index, progression, and progression-free survival (PFS) for a median of 20 (1-32) months. The optimal cutoff point for prediction of outcome was determined using the Maximally Selected Rank Statistics. RESULTS: There were 37 (27.8%) patients with the severe 25(OH)D deficiency ≤ 25 nmol/l, 80 (60.2%) with 25(OH)D deficiency 25-50 nmol/l, and 16 (12%) with 25(OH)D insufficiency 50-75 nmol/l. None of the patients had the desired normal level. There were significant differences between groups in regard to ECOG PS, NRS2002, type of lymphoma, and progression. The severely 25(OH)D-deficient patients had a shorter mean time until progression (P = 0.018). Cox regression analysis showed that 25(OH)D < 19.6 nmol/l remained the only significant parameter for PFS (HR = 2.921; 95% CI 1.307-6.529). CONCLUSION: The prevalence of 25(OH)D deficiency in the analyzed group of patients with lymphoid malignancies is high and greater in malnourished individuals. Patients with pretreatment serum 25(OH)D < 19.6 nmol/l had a significantly shorter PFS.

Pathophysiology and Genetics of Bronchiectasis Unrelated to Cystic Fibrosis.

Bronchiectasis is characterized by deregulated inflammatory response and recurrent bacterial infection resulting in progressive lung damage and an irreversible dilatation of bronchi and bronchioles. Generally accepted model of the development of bronchiectasis is the "vicious cycle hypothesis" that proposes compromising of the mucociliary clearance by an initial event, which leads to the infection of the respiratory tract followed by further impairment of mucociliary function, bacterial proliferation, and more inflammation. Bronchiectasis is a very common symptom in patients with cystic fibrosis (CF), while bronchiectasis unrelated to CF is heterogeneous pathology of unknown cause with a large number of potential contributory factors and poorly understood pathogenesis. It is presumed that bronchiectasis unrelated to CF is a multifactorial condition predisposed by genetic factors. Different molecules have been implicated in the onset and development of idiopathic bronchiectasis, as well as modulation of the disease severity and response to therapy. Most of these molecules are involved in the processes that contribute to the homeostasis of the lung tissue, especially mucociliary clearance, protease-antiprotease balance, and immunomodulation. Evaluation of the studies performed towards investigation of the role these molecules play in bronchiectasis identifies genetic variants that may be of potential importance for clinical management of the disease, and also of interest for future research efforts. This review focuses on the molecules with major roles in lung homeostasis and their involvement in bronchiectasis unrelated to CF.

The Variants in the 3' Untranslated Region of the Matrix Metalloproteinase 9 Gene as Modulators of Treatment Outcome in Children with Asthma.

PURPOSE: The maintaining of asthma control is difficult due to high variability in response to therapy among patients. Since matrix metalloproteinase 9 (MMP9) is implicated in inflammation and remodeling of asthmatic airways, it could be associated with adequate response to asthma therapy. The aim of this study was to investigate whether variants in 3' end of the MMP9 gene are associated with clinical phenotype and responsiveness to treatment in children with asthma. METHODS: The study included 127 asthmatic children from Slovenia. Variants in the 3' end of the MMP9 gene were analyzed by direct DNA sequencing and the obtained results were correlated with clinical parameters. RESULTS: Two variants were detected, rs13925 and rs20544. For the variant rs20544, statistically significant difference in airway hyperresponsiveness (p = 0.011) and asthma control (p = 0.049) between genotypes was found. Patients with TT genotype had lower airway sensitivity, and after 12 months of treatment showed significant improvement in Asthma Control Test (ACT) scores compared to CC and CT genotype. For the variant rs13925, the association with lung function was observed. The carriers of A allele showed noticeable improvement of lung function after the first 6 months of treatment in comparison to the carriers of G allele (p = 0.046). CONCLUSION: The main finding of our study is the association of MMP9 genotypes rs20544 TT and rs13925 AA and AG with better asthma control, and indirectly better response to treatment. Based on these results, MMP9 deserves further research as a potential predictive biomarker for asthma.