Association of heart structure and function abnormalities with laboratory findings in patients with systemic lupus erythematosus.

Conventional risk factors of coronary artery disease fail to explain the increased frequency of cardiovascular morbidity in patients with systemic lupus erythematosus (SLE). The study was conducted to determine possible association between the heart structure and function abnormalities with established prognostic value assessed by non-invasive imaging techniques and markers of autoimmune and inflammatory phenomena typical for SLE. Echocardiography and single photon emission computerized tomography (SPECT; Tc-99m-MIBI) at rest were performed in 60 SLE patients in a stable clinical condition of their disease. Laboratory evaluation included serum levels of C-reactive protein (CRP), complement C3c and C4 components and antiphospholipid antibodies (aPL). The latter included serum anticardiolipin (aCL) and anti-ß2-glycoprotein I (antiß2GPI) antibodies, both of IgG and IgM class, and lupus anticoagulant (LA) in plasma. Echocardiography revealed pathologic thickening of valvular leaflets and/or pericardium in more than 60% of patients. Right ventricular systolic pressure (RVSP) was elevated (>30 mmHg) in 16.7%. Myocardial perfusion defects were present in 36.7% of patients, despite normal ECG recordings and a lack of clinical symptoms of myocardial ischaemia. There was a significant association between thickening of valvular leaflets and/or pericardium and high CRP and low C3c and C4 concentrations. On the other hand, increased RVSP and the presence of myocardial perfusion defects were associated with the presence of anticardiolipin and antiß2GPI antibodies of the IgG class. Increased anticardiolipin IgG levels predicted perfusion defects in SPECT study with 100% sensitivity and 68% specificity, whereas elevated antiß2GPI IgG levels predicted RVSP elevation (>30 mmHg) with 100% sensitivity and 78% specificity. In stable SLE patients pericardial and valve abnormalities may be associated with markers of an ongoing inflammation. Also, pulmonary systolic pressure elevation and myocardial perfusion defects are combined with elevated levels of anticardiolipin and antiß2GPI antibodies of the IgG class. These results indicate that even clinically silent pulmonary hypertension and myocardial perfusion defects in SLE patients could be causally related to the presence of antiphospholipid antibodies.

An exploration of the impact of ethanol diluent on breath alcohol concentration in patients receiving paclitaxel chemotherapy.

PURPOSE: This study aimed to provide a better understanding of the impact of paclitaxel chemotherapy on breath alcohol in an Irish population. METHODS: Patients attending the Oncology Day Unit at Beaumont Hospital were invited to participate on the day of their treatment. The brand of paclitaxel used was Actavis Pharma Inc and contained 6 mg/mL paclitaxel in 50% Ethanol/ 50% Cremophor EL. Breath alcohol concentration was measured using the AlcoSense ™ Breathalyser on three separate visits. The primary end-point was the number of patients who were above the legal threshold for drink driving in Ireland. RESULTS: In total, 50 patients were recruited. 36 (68%) were female. The most common diagnosis was breast cancer (56%). Ten (20%) patients had metastatic disease and 4 (8%) had liver metastases. The mean paclitaxel dose administered was 118 mg. The mean amount of ethanol infused was 7.7 g. 27 patients had a detectable breath alcohol level on at least one visit. The mean breath alcohol concentration was 2 mcg/100 mL or 0.02 mg/L of breath. The maximum concentration of ethanol in exhaled breath was 11 mcg/100 mL or 0.11 mg/L which is 50% of the statutory limit for drink driving in Ireland. A weak correlation was observed between ethanol concentration in exhaled breath and the total amount of ethanol administered. Although no patient exceeded the general limit for drink driving in Ireland, three (6%) participants had a breath alcohol concentration above the threshold for professional, learner or novice drivers. CONCLUSION: Although definitive conclusions are limited by relatively small numbers, it seems unlikely that weekly paclitaxel infusions pose any significant risk to patients driving.

A PDZ-interacting domain in CFTR is an apical membrane polarization signal.

Polarization of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel, to the apical plasma membrane of epithelial cells is critical for vectorial transport of chloride in a variety of epithelia, including the airway, pancreas, intestine, and kidney. However, the motifs that localize CFTR to the apical membrane are unknown. We report that the last 3 amino acids in the COOH-terminus of CFTR (T-R-L) comprise a PDZ-interacting domain that is required for the polarization of CFTR to the apical plasma membrane in human airway and kidney epithelial cells. In addition, the CFTR mutant, S1455X, which lacks the 26 COOH-terminal amino acids, including the PDZ-interacting domain, is mispolarized to the lateral membrane. We also demonstrate that CFTR binds to ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50), an apical membrane PDZ domain-containing protein. We propose that COOH-terminal deletions of CFTR, which represent about 10% of CFTR mutations, result in defective vectorial chloride transport, partly by altering the polarized distribution of CFTR in epithelial cells. Moreover, our data demonstrate that PDZ-interacting domains and PDZ domain-containing proteins play a key role in the apical polarization of ion channels in epithelial cells.

Clinical characteristics of carriers of a GAG deletion in the DYT1 gene amongst Polish patients with primary dystonia.

DYT1 primary torsion dystonia is an autosomal dominant disorder caused by deletion of a GAG triplet in exon 5 of the DYT1 gene. A significant proportion of individuals with early-onset generalized dystonia is believed to be DYT1 mutation carriers. We assessed the frequency of the GAG deletion in the DYT1 gene in a group of 61 Polish probands with clinical diagnosis of primary dystonia. The deletion was identified in four probands presenting with early-onset generalized disease (7%). Further studies in probands' families revealed two symptomatic and nine asymptomatic mutation carriers. We tested all mutation-positive individuals for the presence of some common polymorphisms within the DYT1 gene. Two of the 15 mutation-positive individuals additionally carried polymorphisms in 3'-UTR of the gene. Early onset in a limb and progression toward a generalized form, but not family history of dystonia, are indicative of DYT1 dystonia in Polish dystonic individuals.

Characteristics of the adenohypophyseal Ca2+-phospholipid-dependent protein kinase.

The Ca2+-phospholipid-dependent protein kinase, initially described by Takai et al. (J. Biol. Chem. 254, 3692-3695, 1979), has been identified in the anterior pituitary gland of the rat and sheep. The enzyme is essentially undetectable in initial cell extracts but marked activity is manifest following DEAE chromatography, suggesting the potential presence of an endogenous inhibitor of this enzyme. Two forms of this protein kinase exist in both sheep and rat anterior pituitary gland, both of which are similarly dependent upon Ca2+, phosphatidyl serine and diacylglycerol. Several endogenous substrates for this protein kinase have been observed in both the pars distalis and pars tuberalis of the sheep adenohypophysis.

Frequency of Fra X syndrome among institutionalized mentally retarded males in Poland.

Results of cytogenetic studies, performed in a group of 201 institutionalized mentally retarded males, are presented. At least two cytogenetic methods for eliciting the Xq27.3 fragile site, recommended by the Fourth International Workshop on the Fra X Syndrome were used. A subgroup of 67 out of 201 studied males was also examined using molecular methods. In 6 (2.9%) males fra X syndrome was diagnosed. All cytogenetic positive results were confirmed by molecular analysis. Five patients had full expansion CGG repeats and one had both premutation and full mutation. Postulated frequency of fra X syndrome in Polish population being 0.2-0.4/1,000 males seems to be lower than it could be expected on the basis of previous literature data.

Analysis of unstable DNA sequence in FMR1 gene in Polish families with fragile X syndrome.

The unstable DNA sequence in the FMR1 gene was analyzed in 85 individuals from Polish families with fragile X syndrome in order to characterize mutations responsible for the disease in Poland. In all affected individuals classified on the basis of clinical features and expression of the fragile site at X(q27.3) a large expansion of the unstable sequence (full mutation) was detected. About 5% (2 of 43) of individuals with full mutation did not express the fragile site. Among normal alleles, ranging in size from 20 to 41 CGG repeats, allele with 29 repeats was the most frequent (37%). Transmission of premutated and fully mutated alleles to the offspring was always associated with size increase. No change in repeat number was found when normal alleles were transmitted.

Oxygen delivery with a single cannula tidal flow venovenous system for extracorporeal membrane oxygenation.

Venovenous tidal flow perfusion for extracorporeal membrane oxygenation via a single lumen cannula in the right atrium avoids the sacrifice of a carotid artery inherent in venoarterial systems, and eliminates the problems of two cannula venovenous perfusion. Oxygen delivery and hemodynamic effects of a single cannula, single lumen system with tidal flows directed by alternating tubing occluders were studied in six newborn lambs to define optimal system performance and possible adverse hemodynamic effects. The ratio of drainage to infusion time was fixed at 2:1 to avoid excessive reinfusion pressures. Total length of the in/out cycle was varied from 2-6 sec, resulting in a cycling frequency of 30 to 10 cycles/min and a tidal volume of 17-50 ml. Systemic arterial, mixed venous, and pre and post oxygenator partial pressure of oxygen and oxygen saturation were measured. Recirculation, oxygen delivery, and effective bypass flow (total flow--recirculated flow) were calculated. With slower cycling frequency, recirculation progressively fell, and effective flow and oxygen delivery increased (p < 0.001 for each parameter across the cycle length). In these animals, oxygen delivery was limited by low oxygen carrying capacity (mean hemoglobin, 8.1 g/dl). The authors concluded that with longer cycles, the system minimizes recirculation without apparent adverse hemodynamic consequences, achieving sufficient effective bypass flow to assure adequate oxygen delivery when hemoglobin levels are normal.

[Lipoproteins (A) after a history of myocardial infarction, arteriosclerosis obliterans, hypertension and hyperlipidemia]. / Lipoproteina(A) po przebytym zawale serca, w miazdzycy tetnic obwodowych, nadcisnieniu tetniczym i hiperlipidemii.

Serum lipoprotein(a) concentration in men with hypertension, arteriosclerosis obliterans, hypercholesterolemia and after myocardial infarction was measured using Laurell's immunoelectrophoresis. Lp(a) distribution and mean serum concentrations did not differ significantly from the controls, with the exception of a group of premature myocardial infarction (age below 45), in which high values were more frequent.

[Inter-generational transmission of mutations responsible for fragile X syndrome]. / Miedzypokoleniowe przekazywanie mutacji warunkujacych zespól lamliwego chromosomu X.

Inter-generational transmission of normal and mutated (CGG)n sequences in the FMR1 gene was studied in 17 Polish fragile X families. All normal alleles were stable when transmitted to the progeny. Twenty-five of the 26 transmitted maternal premutations expanded to full mutation level. No correlation between the number of CGG repeats in the maternal premutation and the size of the mutation in the offspring was found. Analysis of the mutation size in siblings revealed that the length of full mutations is sex-dependent. The average length of the (CGG)n sequence in sons of fragile X female carriers was larger than in daughters.

[Immunologic tests in patients with idiopathic uveitis--preliminary reports]. / Badania immunologiczne u chorych z samoistnym zapaleniem tylnego odcinka blony naczyniowej--doniesienie wstepne.

AIM: This study aimed to evaluate the immune system function in patients with uveitis of unknown aetiology. METHODS: The clinical material comprised 19 patients with endogenous uveitis. In all cases the following immunological tests were performed: serum immunoglobulins A, G, M, total IgE, circulating immune complexes, complement components C3c and C4-all determined by laser nephelometry; antinuclear antibodies assessed with indirect immunofluorescence method using HEp-2 cell lines; and antineutrophil cytoplasmic antibodies using indirect immunofluorescence test. In 4 cases lupus anticoagulant was measured with APTT and dRVVT assays. RESULTS: Among our 19 examined patients immunological abnormalities were found in 12 cases. Changes in immunoglobulin concentrations were found in 8 cases. In 4 patients abnormalities of the complement system were observed. Antinuclear antibodies with speckled pattern in indirect immunofluorescence were present in 7 cases. CONCLUSION: In a proportion of patients with endogenous uveitis mild immunological abnormalities were present, suggesting an autoimmune background of the disease. Studies of the immunological profile can therefore help in better evaluation of the patients. It remains to be determined whether the observed immunological alterations are of any importance in the pathogenesis of the studied disease.

Spectroscopic and HPLC studies of photodegradation of nilvadipine.

Photochemical decomposition of nilvadipine (NV), a derivative of 1,4-dihydropyridine (DHP), was studied. Photodegradation was carried out in the conditions recommended in the first version of the document issued by the International Conference on Harmonization (ICH), currently in force in the studies of photochemical stability of drugs and therapeutic substances. Methanol solutions of NV were irradiated with a high-pressure mercury arc lamp, type HBO 200 (300-400 nm). The maximum absorption of radiation at 365 nm was achieved by applying the interference filter and Wood's filter. The assessment of NV photodegradation was made on the basis of the UV spectrophotometric and high-performance liquid chromatographic (HPLC) methods. Quantitatively, the process was described with the calculated rate constants of decomposition k, time of decomposition of 50% of the compound to 5, and time of decomposition of 10% of the compound t(0.1). The two methods applied allowed a determination of the kinetic parameters of NV photodegradation from the relationship ln c = f(t). Using the Reinecke salt as a chemical actinometer, apparent quantum yields of photodegradation were obtained; after extrapolation to the time of irradiation zero, these gave the actual quantum yield (phi = 7.3 10(-5)). The quantum yield of fluorescence at lambda(exc) = 375 nm was about 9.3 x 10(-4) The methods used for evaluation of NV photodegradation were subjected to validation, and results of the analytical methods were statistically assessed by Snedecor F and Student t tests. The former test revealed no statistically significant difference between the variances obtained by the HPLC and UV spectrophotometric methods. Also, verification of the zero hypothesis of the Student t test on equality of means of the results obtained gave no significant diferences between the two methods.

Nasal provocation test with lysine-aspirin for diagnosis of aspirin-sensitive asthma.

Nasal provocation tests (NPTs) with lysine-aspirin (L-ASA) have been recently introduced for assessment of aspirin-induced asthma (AIA). They differ in dose and means of aspirin instillation, duration of observation period, and criteria for positivity. Thus far they have not become a routine part of clinical diagnosis. Fifty-one patients with AIA, confirmed by oral challenge test, were recruited to undergo diagnostic NPTs with L-ASA. In 10 of these patients (19.6%), NPTs could not be performed because of total obstruction of at least one nostril or marked fluctuations in nasal flows, leaving 41 patients with AIA for the study. Control groups consisted of 13 aspirin-tolerant asthmatic patients and 10 healthy subjects. L-ASA at a total dose of 16 mg of acetylsalicylic acid applied bilaterally into the inferior nasal conchae caused significant fall in inspiratory nasal flow in at least one nostril (>40%), which was measured by anterior rhinomanometry, and clinical symptoms of watery discharge and nasal blockage in 35 of 41 patients with AIA, one of 10 healthy subjects, and none of 13 aspirin-tolerant asthmatic patients. No relationship was found between the baseline nasal flow values and the intensity of response to L-ASA. No systemic reactions, including bronchospasm, were noticed, even in patients whose initial FEV1 was lower than 70% of predicted value. This test is highly specific (95.7%) and sensitive (86.7%), but negative results do not exclude possible intolerance to aspirin (predictive value of a negative result 78.6%). In conclusion, the NPT described is a simple, safe, and quick test for diagnosis of AIA. It can be used in patients with unstable asthma. It may be a method of choice to confirm hypersensitivity to aspirin manifested only by symptoms from the upper respiratory tract. Patients suspected of aspirin intolerance who have negative NPT results should undergo bronchial or oral challenge tests with aspirin.

Biosynthesis of N-glycolyneuraminic acid. The primary site of hydroxylation of N-acetylneuraminic acid is the cytosolic sugar nucleotide pool.

N-Glycolylneuraminic acid (Neu5Gc) is an oncofetal antigen in humans and is developmentally regulated in rodents. We have explored the biology of N-acetylneuraminic acid hydroxylase, the enzyme responsible for conversion of the parent sialic acid, N-acetylneuraminic acid (Neu5Ac) to Neu5Gc. We show that the major sialic acid in all compartments of murine myeloma cell lines is Neu5Gc. Pulse-chase analysis in these cells with the sialic acid precursor [6-3H]N-acetylmannosamine demonstrates that most of the newly synthesized Neu5Gc appears initially in the cytosolic low-molecular weight pool bound to CMP. The percentage of Neu5Gc on membrane-bound sialic acids closely parallels that in the CMP-bound pool at various times of chase, whereas that in the free sialic acid pool is very low initially, and rises only later during the chase. This implies that conversion from Neu5Ac to Neu5Gc occurs primarily while Neu5Ac is in its sugar nucleotide form. In support of this, the hydroxylase enzyme from a variety of tissues and cells converted CMP-Neu5Ac to CMP-Neu5Gc, but showed no activity towards free or alpha-glycosidically bound Neu5Ac. Furthermore, the majority of the enzyme activity is found in the cytosol. Studies with isolated intact Golgi vesicles indicate that CMP-Neu5Gc can be transported and utilized for transfer of Neu5Gc to glycoconjugates. The general properties of the enzyme have also been investigated. The Km for CMP-Neu5Ac is in the range of 0.6-2.5 microM. No activity can be detected against the beta-methylglycoside of Neu5Ac. On the other hand, inhibition studies suggest that the enzyme recognizes both the 5'-phosphate group and the pyrimidine base of the substrate. Taken together, the data allow us to propose pathways for the biosynthesis and reutilization of Neu5Gc, with initial conversion from Neu5Ac occurring primarily at the level of the sugar nucleotide. Subsequent release and reutilization of Neu5Gc could then account for the higher steady-state level of Neu5Gc found in all of the sialic acid pools of the cell.

[Spontaneous pneumomediastinum with subcutaneous emphysema and pneumothorax as the initial manifestation of bronchial asthma. Case report]. / Samoistna odma sródpiersia, tkanki podskórnej i oplucnej pierwszym przejawem astmy oskrzelowej. Opis przypadku.

Spontaneous emphysema is not only the rate complication of bronchial asthma but may also be the first, atypical manifestation of the disease. We have presented here the case report of a young man in whom the occurrence of spontaneous pneumomediastinum with subcutaneous emphysema and pneumothorax led to the diagnosis of bronchial asthma.

Effects of cystic fibrosis and congenital bilateral absence of the vas deferens-associated mutations on cystic fibrosis transmembrane conductance regulator-mediated regulation of separate channels.

The protein defective in cystic fibrosis (CF), the CF transmembrane-conductance regulator (CFTR), functions as an epithelial chloride channel and as a regulator of separate ion channels. Although the consequences that disease-causing mutations have on the chloride-channel function have been studied extensively, little is known about the effects that mutations have on the regulatory function. To address this issue, we transiently expressed CFTR-bearing mutations associated with CF or its milder phenotype, congenital bilateral absence of the vas deferens, and determined whether mutant CFTR could regulate outwardly rectifying chloride channels (ORCCs). CFTR bearing a CF-associated mutation in the first nucleotide-binding domain (NBD1), DeltaF508, functioned as a chloride channel but did not regulate ORCCs. However, CFTR bearing disease-associated mutations in other domains retained both functions, regardless of the associated phenotype. Thus, a relationship between loss of CFTR regulatory function and disease severity is evident for NBD1, a region of CFTR that appears important for regulation of separate channels.

Autoimmune vasculitis preceding aspirin-induced asthma.

Two female patients have been described in whom peripheral vasculitis with cold sensitivity preceded by about 5 years typical symptoms of aspirin-induced asthma. Vasculitis was immunologically mediated and took the form of either limited cutaneous scleroderma or perniosis. Antinuclear autoantibodies of SS-B specificity were present in the serum. Challenge with aspirin provoked asthma and distinct blood circulation disturbance in the hands. It is speculated that in these patients vasculitis and asthma were causally linked, and leukotrienes mediated bronchial and vascular reactions that occurred simultaneously following aspirin administration.

[Human recombinant interferon gamma in the treatment of atopic dermatitis]. / Ludzki rekombinowany interferon gamma w leczeniu atopowego zapalenia skóry.

Atopic dermatitis (AD) is a chronic relapsing skin disease characterized by various immunologic abnormalities. We have studied the efficacy of recombinant human interferon gamma (rhINF-gamma) administered subcutaneously at a dose of 0.05 mg/m2 in ten patients with severe AD. Patients were treated for 4 weeks. They have shown marked clinical improvement starting from the third week of treatment. The efficacy of the drug varied, with erythema, dryness and lichenification being the most responsive symptoms. There was no change in serum immunoglobulin E and IgG4 levels. Whole blood eosinophil count decreased only transiently and was accompanied by a tendency to lower values of serum eosinophil cationic protein. Patient with AD showed an increased expression of a T-cell surface activation marker CD 25 as compared to healthy controls. Moreover, clinical improvement was roughly paralleled by the decrease in this T-cell activation marker. We conclude that rhINF-gamma is a novel efficacious therapeutic approach in severe AD. We suggest that its primary action might be related to the inhibition of T-cell activation.

Interferon-gamma in the treatment of atopic dermatitis: influence on T-cell activation.

Atopic dermatitis (AD) is a chronic relapsing skin disease characterized by various immunologic abnormalities. Its pathogenesis remains obscure and its treatment difficult. We have studied the efficacy of systemic recombinant human interferon-gamma (rhIFN-gamma) treatment (0.05 mg/m2 sc on 3 consecutive days, during 4 weeks) in 10 patients with severe AD. Marked clinical improvement was observed starting from the third week of treatment. Erythema, dryness, and lichenification were the most responsive symptoms. Serum immunoglobulin E and IgG4 levels did not change during treatment. Blood eosinophil count decreased only transiently at the end of the first and second series of injections (days 4 and 11; P = 0.02). Patients with AD showed an increase in CD25-positive cells (11.0% vs 4.88%; P = 0.0001) as compared to 10 age-matched healthy controls. Moreover, in parallel with clinical improvement, a distinct decrease in CD25-positive lymphocytes was observed on days 32 and 50 (P = 0.002 and P = 0.006, respectively). We suggest that in AD the beneficial effect of rhIFN-gamma might be related to the inhibition of excessive T-cell activation, perhaps of the subpopulations, producing interleukin (IL)-4 and IL-5.