Lung ultrasound is a promising screening tool to rule out interstitial lung disease in patients with rheumatoid arthritis.

BACKGROUND AND OBJECTIVE: It is still controversial how to screen for interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). We aimed to evaluate the performance of lung ultrasound (LUS) as a screening tool for RA-ILD and to compare it with the performance of chest auscultation, chest x-ray and pulmonary function tests (PFTs). METHODS: Cross-sectional study of consecutive RA patients evaluated at a Rheumatology Clinic in Buenos Aires between January and December 2022. High-resolution computed tomography (HRCT) was the gold standard for diagnosing ILD and was performed within 30 days of the LUS, chest x-ray and PFTs. Investigators were blinded to HRCT results and patients' clinical data. LUS was performed by exploring 14 areas and was considered positive when the sum of B lines was ≥5. Performance for the diagnosis of ILD was reported for each diagnostic test. RESULTS: One hundred and six patients were included; 87 (82%) were women. Median age was 60.9 (±9.5) years-old. A total of 32 (30.2%, 95% CI: 21.6%-39.9%) had ILD. The sensitivity and negative predictive value of LUS were 90.6% (95% CI 75.0%-98.0%) and 94.7% (95% CI 85.4%-98.9%), respectively. LUS performance was superior to that of the other evaluated diagnostic tests for screening ILD. CONCLUSIONS: Given that the US is a low-cost point-of-care tool with a high negative predictive value, it is emerging as a valuable tool for ruling out ILD in patients with RA.

Efficacy of a new nutraceutical formulation: L-tryptophan, probiotics, charcoal, chamomile, mint, and licorice (COLONIR®) in the improvement of gastrointestinal symptoms in subjects with irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders. IBS is characterized by recurrent chronic abdominal pain and altered bowel habits in the absence of organic damage. Although there are reviews and guidelines for treating IBS, the complexity and diversity of IBS presentation make treatment difficult. Treatment of IBS focuses on relieving symptoms as mild signs and symptoms can often be controlled by managing stress and by making changes in diet and lifestyle. The use of nutraceutical compounds has been advocated as a possible alternative treatment in patients with IBS. COLONIR® (Omega Pharma Srl, Milan, Italy) may be an alternative or adjuvant treatment in patients with gastrointestinal symptoms. This study aimed to evaluate the effect of this new nutraceutical formulation in inducing symptoms remission and improve gastrointestinal habits. METHODS: An initial cohort of 1004 consecutive patients referred to 25 different Units of Internal Medicine a/o Gastroenterology in Italy to perform colonoscopy for intestinal symptoms was asked to participate. Patients were treated for 2 months with two doses of nutraceuticals/day during meals namely COLONIR®. Patients were assessed at baseline and after 2 months to evaluate the frequency and severity of gastrointestinal symptoms in the past seven days with a questionnaire based on ROMA IV criteria. RESULTS: After 2 months, 899 patients completed the follow-up. COLONIR® achieved a statistically significant reduction of severity of symptoms in the study population without any documented side effects. CONCLUSIONS: These promising results, here reported, need to be confirmed, valuating the efficacy of COLONIR® in relieving gastrointestinal symptoms in IBS patients in further studies.

Prognostic value of static and dynamic biomarkers in COVID-19 patients: a prospective cohort study.

OBJECTIVE: The aim of this study was to analyze in a prospective cohort of hospitalized COVID-19 patients the relationship between biomarkers levels and their variation within the first 4 days since admission, and prognosis. METHODS: Prospective cohort study. Individuals with confirmed diagnosis of covid-19 admitted in our hospital were included. Blood samples were obtained systematically on days 1 and 4 of hospitalization. Levels of RCP, LDH, Ferritin and D-dimer, together with platelets, lymphocytes and neutrophils counts were measured. A combined outcome that included ICU admission and death was considered the primary outcome. Logistic regression analysis was performed. RESULTS: We included 335 patients with confirmed COVID-19. During their hospitalization, 23 (6.8%) needed ICU admission, and 10 (2.9%) died. In the multivariate analysis, a value of RCP greater than 10 mg/dl (OR 8.69, CI95% 1.45-52), an increase in RCP greater than 20% (OR 26.08, CI 95% 3.21-211.3), an increase in LDH greater than 20% (OR 6.29, CI 95% 1.84-21.44), a count of lymphocytes lower than 1500/mm3 (OR 2.74, CI 95% 1.04-7.23), a D-dimer value greater than 550 ng/ml (OR 9.8, CI 95% 1.78-53.9) and a neutrophil/lymphocyte index greater than 3(OR 4.5, CI 95% 1.43-14.19) were all associated with the primary outcome. CONCLUSIONS: Our study shows that the utilization of static and dynamic biomarkers may represent an important tool to assess prognosis of COVID-19 patients.

Pre-treatment plasma proteomic markers associated with survival in oesophageal cancer.

BACKGROUND: The incidence of oesophageal adenocarcinoma is increasing worldwide but survival remains poor. Neoadjuvant chemotherapy can improve survival, but prognostic and predictive biomarkers are required. This study built upon preclinical approaches to identify prognostic plasma proteomic markers in oesophageal cancer. METHODS: Plasma samples collected before and during the treatment of oesophageal cancer and non-cancer controls were analysed by surface-enhanced laser desorption/ionisation time-of-flight (SELDI-TOF) mass spectroscopy (MS). Protein peaks were identified by MS in tryptic digests of purified fractions. Associations between peak intensities obtained in the spectra and clinical endpoints (survival, disease-free survival) were tested by univariate (Fisher's exact test) and multivariate analysis (binary logistic regression). RESULTS: Plasma protein peaks were identified that differed significantly (P<0.05, ANOVA) between the oesophageal cancer and control groups at baseline. Three peaks, confirmed as apolipoprotein A-I, serum amyloid A and transthyretin, in baseline (pre-treatment) samples were associated by univariate and multivariate analysis with disease-free survival and overall survival. CONCLUSION: Plasma proteins can be detected prior to treatment for oesophageal cancer that are associated with outcome and merit testing as prognostic and predictive markers of response to guide chemotherapy in oesophageal cancer.

Detection of oesophageal cancer biomarkers by plasma proteomic profiling of human cell line xenografts in response to chemotherapy.

BACKGROUND: The incidence of oesophageal adenocarcinoma is increasing worldwide but survival remains poor. Neoadjuvant chemotherapy may improve survival, but targeting treatment to patients who respond to chemotherapy could be improved by the availability of markers of response. This study sought proteomic markers of therapeutic response using an adenocarcinoma xenograft model. METHODS: Epirubicin, cisplatin or 5-fluorouracil was administered to severe combined immune-deficient mice bearing OE19 oesophageal adenocarcinoma xenografts. Murine plasma samples from treated and untreated xenografts were analysed by surface-enhanced laser desorption/ionisation time-of-flight mass spectroscopy, and panels of peaks were found using class prediction models that distinguished treatment groups. Proteins in these peaks were identified by mass spectroscopy in tryptic digests of purified fractions. Five paired samples from oesophageal cancer patients before and after chemotherapy were analysed using the same methodology. RESULTS: Plasma protein peaks were identified that differed significantly (P<0.05, ANOVA) between the treated xenograft and control groups. Marker panels predicted treated vs untreated xenografts with sensitivities of 100%, specificities of 86-100% and test efficiencies of 89-100%. Three of the proteins identified in these panels, apolipoprotein A-I, serum amyloid A and transthyretin were confirmed in the clinical samples. CONCLUSION: Plasma protein markers can be detected in response to chemotherapy in oesophageal adenocarcinoma xenografts and in clinical samples, and have the potential to monitor response and guide chemotherapy in oesophageal adenocarcinoma.

Successful management of intrauterine twin and concomitant cervical pregnancy: a case report.

Use of in vitro fertilization techniques increases the frequency of pathological implantation. However, simultaneous pregnancies are a rarity. Ectopic implantation of the embryo may occur in the cervical canal. This is the first case report, which describes successful management of an intrauterine twin pregnancy which occurred simultaneously with a cervical pregnancy. Diagnostic and therapeutic options are discussed along with the outcome of pregnancies. The cervical pregnancy was removed by aspiration, without dilation of cervical canal, which saved the lives of intrauterine fetuses and preserved fertility for following pregnancies. Finally we review the advanced methods in the literature.

The effects of postmenopausal hormone replacement therapy on hemostatic variables: a meta-analysis of 46 studies.

The aim of the study was to summarize and reanalyze all available data from the literature to study the overall effect of postmenopausal hormone replacement therapy (HRT) and its various forms on hemostatic variables. Studies were identified from literature searches by Medline and Index Medicus, review articles and personal communications. Reference lists of all articles were checked to find additional studies. Principal investigators were contacted and asked to provide additional data if required. Data were collected separately for each factor of the hemostatic system. Studies written in any language were included. Each collection of studies was analyzed using standard methods for meta-analysis. A total of 76 arms of 48 studies were eligible for analysis. This included 6,119 women using HRT and 24,974 non-users. The age of investigated women was 40-68 years. HRT was associated with significantly decreased levels of fibrinogen, factor VIII, antithrombin III, and proteins C and S, but significantly increased plasminogen levels. HRT with estrogen alone or in combination with progestins, oral vs. transdermal regimens, different estrogen preparations and various progestins induced significantly different changes in many cases. In conclusion, HRT was associated with changes that could explain the increased rate of venous thrombotic events, and also with some changes that could account for beneficial vascular effects. Surprisingly, the addition of progestins induced favorable changes in many cases. Also, transdermal use was associated with more beneficial effects than oral regimens in some cases.

Eukaryotic initiation factor 2B: identification of multiple phosphorylation sites in the epsilon-subunit and their functions in vivo.

Eukaryotic initiation factor (eIF) 2B is a heteromeric guanine nucleotide exchange factor that plays an important role in regulating mRNA translation. Here we identify multiple phosphorylation sites in the largest, catalytic, subunit (epsilon) of mammalian eIF2B. These sites are phosphorylated by four different protein kinases. Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro. Glycogen synthase kinase 3 (GSK3) is responsible for phosphorylating Ser535. This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo. The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1. All five sites are phosphorylated in the eIF2B complex in vivo.

[Increased fetal risk of primary venous thrombosis presenting at a young age]. / A fiatalkori primer vénás thrombosis fokozott magzati kockázata.

Based on the hypothesis that the predisposition to thrombosis in women suffering from deep venous thrombosis at young age can disturb also the uteroplacental circulation, the authors retrospectively analyzed the fetal outcome of 333 pregnancies in 101 women with thromboembolic event before 40 years of age and compared it to the fetal outcome of 2943 pregnancies in 1000 randomly selected obstetrical patients without thrombosis. The relative risks of adverse fetal outcomes in thromboembolic women were as follows: 1.85 (95% C.I.: 1.35-2.55) for the spontaneous miscarriage, 3.9 (95% C.I.: 2.20-6.93) for the second-trimester miscarriage, 1.74 (95% C.I.: 1.15-2.64) for the low birth weight, 2.82 (95% C.I.: 1.28-6.30) for the perinatal loss and 7.17 (95% C.I.: 2.64-19.47) for the abruption of placentae. Data obtained suggest that women with deep venous thrombosis at young age should encounter a higher risk of the uteroplacental thrombosis which results in increasing fetal morbidity and mortality during the second and third trimesters of gestation.

Eukaryotic translation initiation factor 5 (eIF5) acts as a classical GTPase-activator protein.

GTP hydrolysis occurs at several specific stages during the initiation, elongation, and termination stages of mRNA translation. However, it is unclear how GTP hydrolysis occurs; it has previously been suggested to involve a GTPase active center in the ribosome, although proof for this is lacking. Alternatively, it could involve the translation factors themselves, e.g., be similar to the situation for small G in which the GTPase active site involves arginine residues contributed by a further protein termed a GTPase-activator protein (GAP). During translation initiation in eukaryotes, initiation factor eIF5 is required for hydrolysis of GTP bound to eIF2 (the protein which brings the initiator Met-tRNA(i) to the 40S subunit). Here we show that eIF5 displays the hallmarks of a classical GAP (e.g., RasGAP). Firstly, its interaction with eIF2 is enhanced by AlF(4)(-). Secondly, eIF5 possesses a conserved arginine (Arg15) which, like the "arginine fingers" of classical GAPs, is flanked by hydrophobic residues. Mutation of Arg15 to methionine abolishes the ability of eIF5 either to stimulate GTP hydrolysis or to support mRNA translation in vitro. Mutation studies suggest that a second conserved arginine (Arg48) also contributes to the GTPase active site of the eIF2.eIF5 complex. Our data thus show that eIF5 behaves as a classical GAP and that GTP hydrolysis during translation involves proteins extrinsic to the ribosome. Indeed, inspection of their sequences suggests that other translation factors may also act as GAPs.

Clinical importance of vascular LH/hCG receptors--a review.

It was believed for a long time that functional LH/hCG receptors were present only in gonads. Recent studies have demonstrated, however, that these receptors are also present in several nongonadal organs in the human body. Uterus is one of them. Besides two uterine layers, endothelial cells and smooth muscle of blood vessels in the uterus also contain these receptors. In vivo administration of hCG decreased vascular resistance in the human uterus and in vitro treatment increased vasodilatory and decreased vasoconstrictive eicosanoids in the vessels. These findings led us to investigate whether hCG administration to patients with signs of threatened abortion has any beneficial effect. Patients were treated with either magnesium or progesterone and/or hCG. The results showed that the frequency of patients reaching second trimester was higher when hCG was used, which was paralleled by a significant decrease in uterine vascular resistance. Patients who reached term after treatment had decreased incidence of preterm delivery and intrauterine growth retardation. In conclusion, we suggest that uterine vascular LH/hCG receptors play an important role in the peri-implantation period by increasing uterine blood flow through vasodilatation and also perhaps through angiogenesis and trophoblast invasion, resulting in therapeutic benefit.

A mutation in the c-myc-IRES leads to enhanced internal ribosome entry in multiple myeloma: a novel mechanism of oncogene de-regulation.

The 5' untranslated region of the proto-oncogene c-myc contains an internal ribosome entry segment (IRES) (Nanbru et al., 1997; Stoneley et al., 1998) and thus c-myc protein synthesis can be initiated by a cap-independent as well as a cap-dependent mechanism (Stoneley et al., 2000). In cell lines derived from patients with multiple myeloma (MM) there is aberrant translational regulation of c-myc and this correlates with a C-T mutation in the c-myc-IRES (Paulin et al., 1996). RNA derived from the mutant IRES displays enhanced binding of protein factors (Paulin et al., 1998). Here we show that the same mutation is present in 42% of bone marrow samples obtained from patients with MM, but was not present in any of 21 controls demonstrating a strong correlation between this mutation and the disease. In a tissue culture based assay, the mutant version of the c-myc-IRES was more active in all cell types tested, but showed the greatest activity in a cell line derived from a patient with MM. Our data demonstrate that a single mutation in the c-myc-IRES is sufficient to cause enhanced initiation of translation via internal ribosome entry and represents a novel mechanism of oncogenesis.

Postmenopausal hormone replacement therapy and cardiovascular mortality in Central-Eastern Europe.

BACKGROUND: The leading cause of death among elderly women is cardiovascular (CV) disease in the United States and in Western Europe as well. The protective effect of postmenopausal hormone replacement therapy (HRT) on coronary heart disease has been verified in epidemiologic studies. There are no data available on the rate of HRT use in Eastern Europe. Our goals were to study the rates of HRT in Eastern Europe, to compare them to those of the United States and Western Europe, as well as to compare their CV mortality rates. METHODS: The use of HRT in Eastern Europe was calculated from sales records obtained from all pharmaceutical companies that ship HRT preparations to the given area. Data on HRT in Western countries were taken from the literature. Mortality rates were obtained from the World Health Organization. RESULTS: The rate (mean +/- SD) of HRT in Eastern Europe was 2.88 +/- 2.67%, whereas 12.67 +/- 9.97% in Western Europe and the United States, p < .05. The cardiovascular mortality rate per 100,000 women older than 45 years in Eastern Europe was higher (1766 +/- 158.3) than in the Western countries (1155 +/- 164.1, p < .001). CONCLUSIONS: The rate of HRT is markedly lower. whereas CV mortality rates are notably higher in Eastern Europe than in the United States or Western Europe. Because HRT seems to be underutilized in Eastern Europe, to increase its use might be an important tool to improve CV mortality rates. However, due to the risks associated with HRT, other measures to prevent coronary heart disease, such as smoking cessation programs, and other efforts should also be considered in Eastern Europe.

Urodynamic investigation of women operated on for genuine stress incontinence.

Anterior colporrhaphy (Kelly-Stoeckel suture) was performed on 22 women suffering from grade-I or grade-II genuine stress incontinence. Urodynamic investigation was performed on every patient before surgery and 6 months postoperatively. 21 patients were cured and 1 patient improved. After operation the functional urethral length was increased by 28.8%, and urethrovesical pressure transmission was improved by 22.9%. Maximum urethral closure pressure decreased postoperatively by 21.1%. Pressure transmission was clearly improved by the surgical intervention and urinary continence was restored in spite of the fact that maximal urethral closure pressure decreased. Based on these results it is suggested to consider performing anterior colporrhaphy in cases of weak urethral closure pressure, because of the increased risk of worsening the complaints of these patients.

A single nucleotide change in the c-myc internal ribosome entry segment leads to enhanced binding of a group of protein factors.

A 340 nucleotide section of the c- myc 5' untranslated region (UTR) contains an internal ribosome entry segment. We have described previously a mutation in this region of RNA in cell lines derived from patients with multiple myeloma (MM) which exhibit increased expression of c- myc protein by an aberrant translational mechanism. In this study we show by electrophoretic mobility shift assays (EMSA), north-western blotting and UV cross-linking that radiolabelled c- myc 5' UTR RNA transcripts which harbour the mutation cause enhanced binding of cellular proteins. In addition, we also demonstrate that an MM derived cell line possesses an altered repertoire of RNA binding proteins. Our data suggest that the deregulated expression of c -myc in MM could result both from the effect of the mutation and the additional proteins which are present in these cell types.

[Severe genital mycoplasma infection following cesarean section]. / Genitális mycoplasmák által okozott súlyos fertözés sectio caesareát követöen.

Authors report a serious case of post-caesarean delivery endometritis caused, probably exclusively, by genital mycoplasmas: Ureaplasma urealyticum and Mycoplasma hominis. The initial treatment of the patient with various penicillins, ceftriaxone, gentamicin, metronidazole and nystatine proved ineffective. Subsequently, as microbiological tests turned out positive for genital mycoplasmas, a therapy of doxycyclin was introduced and a full recovery could be attained. Authors' experience is consistent with the observation of American scientists that U. urealyticum is an important pathogen in post-caesarean delivery endometritis. Since the carriage of U. urealyticum in women is frequent in Hungary, it is suggested that microbiological investigations related to sectio caesarea always include tests for genital mycoplasmas.

[Systemic lupus erythematosus and pregnancy (effect of pre-conception hematologic disorders on fetal outcome)]. / Szisztémás lupus erythematosus és terhesség (prekoncepcionális haematológiai rendellenességek hatása a magzati eredményekre).

The aim of the study was to determine the fetal and neonatal outcomes of pregnancies conceived during the inactive phase of systemic lupus erythematosus (SLE). Fetal and neonatal outcomes in 75 pregnancies of 33 patients with SLE were analyzed. In 19 patients (57.6%) the SLE also had hematological autoimmune presentations prior to gestation, such as anemia, thrombopenia, garnulocytopenia, and antiphospholipid antibody and/or lupus anticoagulant (APA). Out of 75 pregnancies, 19 elective terminations were carried out because the disease was active or for non-medical reasons. The adverse fetal outcomes of those 56 pregnancies which occurred during the inactive phase were compared with those of the control patients. In SLE, the rates of spontaneous abortions (46.4%) and newborns with low (< 2500 gr) birthweight (36.7%) were found to increase roughly three times that of the controls and the perinatal fetal loss (16.7%) also increased significantly as compared with the control group (28.5 per thousand). APA noted at any time before pregnancy increased the low birthweight rate (75%) six fold and the perinatal loss (33.3%) more than ten fold but did not affect the rate of spontaneous abortions. Any kind of hemocytopenias without APA, noted before pregnancy did not worsen the fetal outcome in SLE. Neonatal lupus was diagnosed in 2 out of the 30 newborns. Our results suggest that among the hematologic manifestations of SLE presenting before pregnancy, APA can predict the high risks of low birthweight and perinatal fetal loss as opposed to hemocytopenias.

C-Myc 5' untranslated region contains an internal ribosome entry segment.

Translation in eukaryotic cells is generally initiated by ribosome scanning from the 5' end of the capped mRNA. However, initiation of translation may also occur by a mechanism which is independent of the cap structure and in this case ribosomes are directed to the start codon by an internal ribosome entry segment (IRES). Picornaviruses represent the paradigm for this mechanism, but only a few examples exist which show that this mechanism is used by eukaryotic cells. In this report we show data which demonstrate that the 5' UTR of the proto-oncogene c-myc contains an IRES. When a dicistronic reporter vector, with c-myc 5' UTR inserted between the two cistrons, was transfected into both HepG2 and HeLa cells, the translation of the downstream cistron was increased by 50-fold, demonstrating that translational regulation of c-myc is mediated through cap-independent mechanisms. This is the first example of a proto-oncogene regulated in this manner and suggests that aberrant translational regulation of c-myc is likely to play a role in tumorigenesis.

[Therapeutic importance of the diagnosis of Kallmann syndrome]. / A Kallmann-kór kórismézésének terápiás jelentósége.

Hyposmia with hypogonadotropic hypogonadism was diagnosed as Kallmann syndrome in a 24 years old dizygotic female twin. This syndrome indicates the importance of smell in the sexual development through the progenitor cells in the olfactory placode because luteinizing-hormone-releasing hormone (LHRH) secreting cells of hypothalamus arise from these cells. In addition, substitution therapy may be successful in the treatment of the lack of secondary sex traits and primary amenorrhoea as the presented case demonstrated.

Investigation of aberrant translational control of c-myc in cell lines derived from patients with multiple myeloma.

In cell lines derived from patients with multiple myeloma (MM) we have found an elevation in the amount of the c-myc protein which is not accompanied by an increase in the level of mRNA or a change in the half-life of the protein. There is a 3.4 fold enhancement in the degree of association of the c-myc message with polysomes. This is not accompanied by an alteration in polysome size or a change in the transit time of the c-myc mRNA on the polysomes thus suggesting that there is in increase in the degree of mobilisation of the c-myc message. Sequencing of the c-myc 5'UTR has revealed the presence of a mutation in all the MM cell lines studied and we demonstrate that this mutation causes altered binding of cellular proteins to this RNA species.