Exhaled IL-8 in Systemic Lupus Erythematosus with and without Pulmonary Fibrosis

The purpose of this study is to evaluate the relationship between the concentration of interleukin-8 (IL-8) in exhaled breath condensate (EBC) and bronchoalveolar lavage fluid (BALF) with the disease activity score and pulmonary function of systemic lupus erythematosus (SLE) patients with and without pulmonary fibrosis. Thirty-four SLE patients and 31 healthy controls were enrolled and evaluated using high-resolution computed tomography (HRCT), pulmonary function tests, systemic lupus activity measure (SLAM), assessing BALF and EBC. IL-8 levels in BALF and EBC samples were measured with an enzyme-immunosorbent assay kit. The mean (±SEM) IL-8 concentrations in BALF and EBC were higher in SLE patients compared to healthy controls (34.84 ± 95.0 vs. 7.65 ± 21.22 pg/ml, p < 0.001; 3.82 ± 0.52 pg/m vs. 1.7 ± 1.7 pg/ml, p < 0.001, respectively). SLE patients had increased percentage of neutrophils in BALF when compared with control group (1.00 ± 5.99 vs. 0.00 ± 0.56 %, p = 0.0003). Pulmonary fibrosis in HRCT was found in 50 % of SLE patients. The disease activity scored by SLAM was significantly higher and total lung capacity was significantly lower in SLE patients with pulmonary fibrosis (8.00 ± 3.17 vs. 6.00 ± 2.31, p = 0.01; 88.00 ± 28.29 vs. 112.00 ± 21.08 % predicted, p = 0.01, respectively). In SLE patients with pulmonary fibrosis, correlations were found between SLAM and IL-8 concentration in BALF, forced expiratory volume in 1 s and forced vital capacity (r = 0.65, p = 0.006; r = ?0.53, p = 0.035; r = ?0.67, p = 0.006, respectively). Our results indicate that IL-8 plays an important role in the pathogenesis of SLE. An increased concentration of IL-8 according to BALF could be considered as a useful biomarker of SLE activity and pulmonary fibrosis in SLE.     

Is the polycystic ovary syndrome associated with chronic inflammation per se?

OBJECTIVE: The aim of the present study was to evaluate serum concentrations of tumor necrosis factor-alpha (TNF-alpha), TNF-soluble receptors, and IL-6 in obese women without additional diseases and obese women with polycystic ovary syndrome (PCOS). STUDY DESIGN: The study group consisted of 39 obese women with PCOS and 34 age-matched obese women without additional disease were included as controls. Blood glucose, total cholesterol, HDL-cholesterol, and triglycerides were measured by the enzymatic procedure. Plasma insulin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEAS), androstenedione, total and free testosterone, cortisol, progesterone, 17OH-progesterone, estradiol, and sex hormone binding globulin (SHBG) were measured by a commercial radioimmunoassay (RIA). Tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors (sTNFRs), and IL-6 were determined by an ELISA. RESULTS: We did not observe any differences in serum concentrations of TNF-alpha between obese women with and without PCOS. Serum concentrations of sTNFR1 and sTNFR2 were significantly higher in PCOS patients compared with controls; however, serum concentrations of IL-6 were significantly lower in PCOS patients. CONCLUSIONS: Our findings suggest that PCOS is not associated with chronic inflammation.     

MTHFD 1958G>A and MTR 2756A>G polymorphisms are associated with bipolar disorder and schizophrenia

BACKGROUND: The etiology of bipolar disorder (BD) and schizophrenia is very complex. Polymorphic variants of genes encoding enzymes of the monoaminergic may be involved in development of BD and schizophrenia. Therefore, we examined the prevalence of 1958G>A polymorphism of MTHFD1 gene, encoding trifunctional folate enzyme 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase (MTHFD1), and 2756A>G variant of methionine synthase (MTR) gene in patients with BD (n=200), schizophrenia (n=200) and in controls (n=300). OBJECTIVE: We investigated the genotypic and allelic frequencies of MTHFD1 1958G>A (R653Q) and MTR 2756A>G (D919G) gene polymorphisms in a group of bipolar (n=200) and schizophrenic patients (n=200), as well as in controls (n=300). METHODS: The distributon of genotypes in all groups was tested for deviation from Hardy-Weinberg equilibrium (HWE). The Pearson's chi-square (chi) test and Fisher's exact test were applied to assess differences in the genotypic and allelic (respectively) distribution between groups of patients and controls. MAIN RESULTS: We found that MTHFD1 1958AA or 1958AG genotypes constitute risk factors for development of bipolar disorder type I (BDI) or schizophrenia with odds ratios (OR)=1.743 (95% CI=1.211-2.508; P=0.0027; P (corr)=0.0054) and 2.667 (95% CI=1.845-3.854; P=0.0001; P (corr)=0.0002), respectively. In the same groups, the MTR 2756GG or 2756AG genotypes also constitute significant risk factors in occurrence of BDI and schizophrenia with OR=1.621 (95% CI=1.130-2.326; P=0.0086; P (corr)=0.0172) and 1.556 (95% CI=1.085-2.232; P=0.0160; P (corr)=0.032), respectively. Gender classification of patients indicated significant association only of MTHFD1 1958A allele with BDI and schizophrenia in the male patients OR=1.838 (95% CI=1.114-3.031; P=0.0166; P (corr)=0.0332) and OR=3.964 (95% CI=2.358-6.663; P=0.0001 P (corr)=0.0002), respectively. CONCLUSION: Since MTHFD and MTR genes are located in 14q24 and 1q43 loci, our findings support the significance of chromosomes 14q and 1q in etiopathogenesis of bipolar disorder and schizophrenia.     

The variability of clinical presentation of chronic obstructive pulmonary disease in patients with hereditary alpha-1 antitrypsin deficiency

Four patients with alpha-1 antitrypsin (alpha-1 AT) deficiency are presented: one woman with severe (phenotype PiZ) and 3 men with moderate (phenotype PiMZ) deficiency of alpha-1 AT. The variability of clinical presentation of hereditary emphysema is described. In all patients tobacco smoking history, spirometric and 6-minutes walking tests as well as HRCT of the lung were performed and compared. The influence of smoking on the functional status is underlined.     

Myeloperoxidase (MPO) as a marker of neutrophil influx into nasal mucosa after recombinant IL-8 challenge

Myeloperoxidase (MPO) has been proposed to mirror the degree of neutrophil activation, however its role as a marker of the participation of neutrophils in allergic inflammation is still unclear as the literature is controversial. The aim of this study was to evaluate the MPO levels and neutrophil influx in nasal lavage after recombinant Il-8 challenge. Eight patients suffering from seasonal allergic rhinitis, hypersensitive to grass pollens, with average age 30.1 +/- 2.67 were challenged both with Il-8 and diluent for Il-8 on a subsequent day, in two phases: before the pollen season (unprimed mucosa) and during the season (primed mucosa). Nasal lavage with saline were collected before, during Il-8 or placebo challenge and 30 minutes, 2 hours and 3 hours after the challenge. The number of neutrophils and MPO levels in the nasal fluid were determined. After the challenge with Il-8 of primed mucosa the number of neutrophils increased from 28250 cells/ml at the baseline to 28778, 251020 and 333660 at 0, 5, 2 and 3 hours respectively. There was a statistically significant difference between cells number after diluent and Il-8 challenge (p < 0.05, Wilcoxon rank-sum test). The number of neutrophils in the nasal lavage of primed mucosa after Il-8 challenge was significantly higher (p < 0.005) at all time points in comparison with the diluent and Il-8 challenges in the unprimed mucosa. There was no difference (p < 0.05) in MPO levels in the nasal lavage between Il-8 (mean 17.43 ng/ml +/- 10.98) and diluent challenge (20.98 ng/ml +/- 11.89) of unprimed mucosa. In the primed mucosa fluid we observed a peak of MPO level at 2 hours time point, however that was not significant as compared to diluent challenge (p = 0.465). We did not find the relationship between MPO levels and the neutrophils number in the lavage (rank Spearman factor, rs = 0.258, p = 0.42). Due to the lack of statistically confirmed relationship between MPO level and the number of neutrophils, MPO seems to be of little value as a marker of neutrophil influx into nasal mucosa.     

Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs

An approximately 4-Mb genomic segment on chromosome 17p11.2, commonly deleted in patients with the Smith-Magenis syndrome (SMS) and duplicated in patients with dup(17)(p11.2p11.2) syndrome, is flanked by large, complex low-copy repeats (LCRs), termed proximal and distal SMS-REP. A third copy, the middle SMS-REP, is located between them. SMS-REPs are believed to mediate nonallelic homologous recombination, resulting in both SMS deletions and reciprocal duplications. To delineate the genomic structure and evolutionary origin of SMS-REPs, we constructed a bacterial artificial chromosome/P1 artificial chromosome contig spanning the entire SMS region, including the SMS-REPs, determined its genomic sequence, and used fluorescence in situ hybridization to study the evolution of SMS-REP in several primate species. Our analysis shows that both the proximal SMS-REP (approximately 256 kb) and the distal copy (approximately 176 kb) are located in the same orientation and derived from a progenitor copy, whereas the middle SMS-REP (approximately 241 kb) is inverted and appears to have been derived from the proximal copy. The SMS-REP LCRs are highly homologous (>98%) and contain at least 14 genes/pseudogenes each. SMS-REPs are not present in mice and were duplicated after the divergence of New World monkeys from pre-monkeys approximately 40-65 million years ago. Our findings potentially explain why the vast majority of SMS deletions and dup(17)(p11.2p11.2) occur at proximal and distal SMS-REPs and further support previous observations that higher-order genomic architecture involving LCRs arose recently during primate speciation and may predispose the human genome to both meiotic and mitotic rearrangements.     

Verification of the exponential model of body temperature decrease after death in pigs

The authors have conducted a systematic study in pigs to verify the models of post-mortem body temperature decrease currently employed in forensic medicine. Twenty-four hour automatic temperature recordings were performed in four body sites starting 1.25 h after pig killing in an industrial slaughterhouse under typical environmental conditions (19.5-22.5 degrees C). The animals had been randomly selected under a regular manufacturing process. The temperature decrease time plots drawn starting 75 min after death for the eyeball, the orbit soft tissues, the rectum and muscle tissue were found to fit the single-exponential thermodynamic model originally proposed by H. Rainy in 1868. In view of the actual intersubject variability, the addition of a second exponential term to the model was demonstrated to be statistically insignificant. Therefore, the two-exponential model for death time estimation frequently recommended in the forensic medicine literature, even if theoretically substantiated for individual test cases, provides no advantage as regards the reliability of estimation in an actual case. The improvement of the precision of time of death estimation by the reconstruction of an individual curve on the basis of two dead body temperature measurements taken 1 h apart or taken continuously for a longer time (about 4 h), has also been proved incorrect. It was demonstrated that the reported increase of precision of time of death estimation due to use of a multiexponential model, with individual exponential terms to account for the cooling rate of the specific body sites separately, is artifactual. The results of this study support the use of the eyeball and/or the orbit soft tissues as temperature measuring sites at times shortly after death. A single-exponential model applied to the eyeball cooling has been shown to provide a very precise estimation of the time of death up to approximately 13 h after death. For the period thereafter, a better estimation of the time of death is obtained from temperature data collected from the muscles or the rectum.     

Plasma levels of alpha beta peptides are altered in amnestic mild cognitive impairment but not in sporadic Alzheimer's disease

Plasma alpha beta levels have been examined in sporadic Alzheimer's disease yielding conflicting results; both no difference and an increase in plasma concentrations of alpha beta42 and alpha beta40 in sporadic cases of AD as compared to controls have been reported. Elevated plasma alpha beta42 levels may be detected several years before the onset of symptoms (in mild cognitive impairment stadium). Levels of alpha beta40 and alpha beta42 were measured in plasma from 54 patients with AD, 39 subjects with MCI and 35 controls using a commercially available ELISA. Mean plasma alpha beta42 levels were significantly higher in MCI as compared to both AD (P < 0.001) and control subjects (P < 0.001), while alpha beta40 did not differ between the groups. No correlations were observed between alpha beta levels and age, MMSE scores or gender. According to ROC curve analysis the maximum accuracy in discriminating MCI versus both controls and AD subjects has been achieved using a cut-off value of 3.8.     

Sleep disturbances in women with polycystic ovary syndrome

Sleep disturbances in women with Polycystic Ovary Syndrome (PCOS) have been reported in recent years. The majority of published studies are related to Obstructive Sleep Apnea (OSA) while not many researches have analyzed any other causes of sleep disturbances. A group of ninety five women with Polycystic Ovary Syndrome were enrolled into the study. Sleep disturbances were assessed using validated questionnaires. On the grounds of Athens Insomnia Scale (AIS) evaluation a clinically significant insomnia was ascertained in 12.6% of women with PCOS, while according to Insomnia Severity Index (ISI) in 10.5%. Clinically significant insomnia according to both AIS and ISI, occurred significantly more often in women with PCOS than in women without PCOS based on the chi-square test. The Mann–Whitney U test revealed statistically significant difference between women with and without PCOS based on total values of ISI. An excessive daytime sleepiness occurred at 7.4% of women with PCOS. Statistically significant dependance between: clinically significant insomnia in both AIS and ISI and excessive daytime sleepiness indicated by Epworth Sleepiness Scale (ESS) was observed. Sleep disorders are common in women with PCOS. Screening assessment of sleep disturbances should be a part of medical diagnostics in women with PCOS.     

Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype

PurposeHaploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS.MethodsWe report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status.ResultsThe expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes.ConclusionWe refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.