Quantitative analysis of redox proteome reveals oxidation-sensitive protein thiols acting in fundamental processes of developmental hematopoiesis.

Fetal and adult hematopoietic stem and progenitor cells (HSPCs) are characterized by distinct redox homeostasis that may influence their differential cellular behavior in normal and malignant hematopoiesis. In this work, we have applied a quantitative mass spectrometry-based redox proteomic approach to comprehensively describe reversible cysteine modifications in primary mouse fetal and adult HSPCs. We defined the redox state of 4,438 cysteines in fetal and adult HSPCs and demonstrated a higher susceptibility to oxidation of protein thiols in fetal HSPCs. Our data identified ontogenic changes to oxidation state of thiols in proteins with a pronounced role in metabolism and protein homeostasis. Additional redox proteomic analysis identified oxidation changes to thiols acting in mitochondrial respiration as well as protein homeostasis to be triggered during onset of MLL-ENL leukemogenesis in fetal HSPCs. Our data has demonstrated that redox signaling contributes to the regulation of fundamental processes of developmental hematopoiesis and has pinpointed potential targetable redox-sensitive proteins in in utero-initiated MLL-rearranged leukemia.

Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations.

BACKGROUND: Thoracic aortic aneurysms and dissections (TAAD) are silent but possibly lethal condition with up to 40 % of cases being hereditary. Genetic background is heterogeneous. Recently next-generation sequencing enabled efficient and cost-effective examination of gene panels. Aim of the study was to define the diagnostic yield of NGS in the 51 TAAD patients and to look for genotype-phenotype correlations within families of the patients with TAAD. METHODS: 51 unrelated TAAD patients were examined by either whole exome sequencing or TruSight One sequencing panel. We analyzed rare variants in 10 established thoracic aortic aneurysms-associated genes. Whenever possible, we looked for co-segregation in the families. Kaplan-Meier survival curve was constructed to compare the event-free survival depending on genotype. Aortic events were defined as acute aortic dissection or first planned aortic surgery. RESULTS AND DISCUSSION: In 21 TAAD patients we found 22 rare variants, 6 (27.3 %) of these were previously reported, and 16 (73.7 %) were novel. Based on segregation data, functional analysis and software estimations we assumed that three of novel variants were causative, nine likely causative. Remaining four were classified as of unknown significance (2) and likely benign (2). In all, 9 (17.6 %) of 51 probands had a positive result when considering variants classified as causative only and 18 (35.3 %) if likely causative were also included. Genotype-positive probands (n = 18) showed shorter mean event free survival (41 years, CI 35-46) than reference group, i.e. those (n = 29) without any plausible variant identified (51 years, CI 45-57, p = 0.0083). This effect was also found when the 'genotype-positive' group was restricted to probands with 'likely causative' variants (p = 0.0092) which further supports pathogenicity of these variants. The mean event free survival was particularly low (37 years, CI 27-47) among the probands with defects in the TGF beta signaling (p = 0.0033 vs. the reference group). CONCLUSIONS: This study broadens the spectrum of genetic background of thoracic aneurysms and dissections and supports its potential role as a prognostic factor in the patients with the disease.

Renal artery aneurysms: presentation of five cases.

We are presenting clinical characteristics, management and follow-up of five consecutive patients with renal artery aneurysm. Renal artery aneurysms are relatively uncommon, they rarely give rise to clinical manifestations and they are usually found incidentally. However with the introduction of Doppler ultrasound, computed tomography (CT) and magnetic resonance (MR) imaging, the diagnosis of renal artery aneurysms became more frequent.

Moderate exercise training reduces arterial chemoreceptor reflex drive in mild hypertension.

The aim of our study was to check the responsiveness the chemoreceptor reflex in 28 young mildly hypertensive men (HTS), aged 18-32 years and 25 normotensive male subjects (NTS) aged 19-32 years, before and after 3-months dynamic exercise training. We tested the hypothesis that dynamic training reduces arterial chemoreceptor drive in mild hypertension. Circulatory response to 3-min hyperoxic inactivation of arterial chemoreceptors induced by 70% oxygen breathing was measured before and after training. Arterial blood pressure (BP) was recorded continuously by Finapres method, stroke volume and arm blood flow were registered by impedance reography, heart rate by ECG. Both groups were submitted to moderate 3-months dynamic exercise training. Before training the hyperoxic breathing caused in HTS a significant decrease in systolic BP by 6+/-1 mmHg p<0.01, in diastolic BP by 2+/-0.6 mmHg p<0.01, and in total peripheral vascular resistance (TPR) by 0.24+/-0.04 TPRU (p<0.01). After training hyperoxia augmented systolic BP by 2.64+/-1.9 mmHg (NS), diastolic BP by 2+/-1 mmHg p<0.05, and TPR by 0.043+/-0.05 TPRU (ANOVA). In NTS before training brief hyperoxia produced insignificant change in BP and TPR. In NTS after training hyperoxia increased systolic BP by 4.2 mm Hg+/-1.23 p<0.01 and diastolic BP by 3.1+/-0.6 mmHg p<0.01 respectively and TPR by 0.053+/-0.02 TPRU. Our results confirm earlier finding on the enhanced arterial chemoreceptor reflex drive in mild human hypertension. We conclude that normalizing arterial blood pressure in subjects with mild hypertension which occurred after 3-months dynamical exercise training is due to attenuation of the sympathoexcitatory chemoreceptor reflex drive by exercise training. The mechanism of this effect requires further study.

Effects of moderate physical training on blood pressure variability and hemodynamic pattern in mildly hypertensive subjects.

The objective of our study was to compare the cardiovascular effects of moderate exercise training in healthy young (NTS, n=18, 22.9+/-0.44 years) and in hypertensive human subjects (HTS, n=30, 23+/-1.1). The VO(2max) did not significantly differ between groups. HTS of systolic blood pressure (SBP) 148+/-3.6 mmHg and diastolic blood pressure(DBP) 88+/-2.2 mmHg, and NTS of SBP: 128.8 +/- 4 mmHg and DBP: 72 +/- 2.9 mmHg were submitted to moderate dynamic exercise training, at about 50% VO(2max) 3 times per week for one hour, over 3 months. VO(2max) was measured by Astrand's test. Arterial blood pressure was measured with Finapres technique, the stroke volume, cardiac output and arm blood flow were assessed by impedance reography. Variability of SBP and pulse interval values (PI) were estimated by computing the variance and power spectra according to FFT algorithm. After training period significant improvements in VO(2max) were observed in NTS- by 1.92 +/-0.76 and in HTS by 3+/-0.68 ml/kg/min). In HTS significantly decreased: SBP by 19 +/-2.9 mmHg, in DBP by 10.7+/-2 mmHg total peripheral resistance (TPR) by 0.28 +/-0.05 TPR units. The pretraining value of low frequency component power spectra SBP (LF(SPB)) was significantly greater in HTS, compared to NTS. PI variance was lower in HTS, compared to NTS. After physical training, in HTS PI variance increased suggesting a decrease in frequency modulated sympathetic activity and increase in vagal modulation of heart rate in mild hypertension. A major finding of the study is the significant decrease of resting low frequency component SBP power spectrum after training in HTS. The value of LF(SPB) in trained hypertensive subjects normalized to the resting level of LF(SPB) in NTS. Our findings suggest that antihypertensive hemodynamic effects of moderate dynamic physical training are associated with readjustment of the autonomic cardiovascular control system.

Correlations in the isotropic phases of chiral liquid crystals: the role of helicity modes.

The phenomenological theory of chiral liquid crystals is further developed by generalizing the model of self-consistent correlations [J. Englert, L. Longa, H. Stark, and H.-R. Trebin, Phys. Rev. Lett. 81, 1457 (1998)]. In the present approach, not only a leading helicity mode of the tensor order parameter is retained but also the remaining four modes. By considering a full fluctuating spectrum of the order parameter, the role of correlations between helicity modes in the isotropic phases is studied. Additionally, an exact form of the two-point correlation function in real space is derived and its properties are thoroughly discussed. It is shown that for chiral isotropic liquids purely chiral modes could be identified that do not exist for an ordinary liquid. Detailed results of the numerical calculations are compared with those obtained from the earlier model and these show regions where the coupling between the modes becomes important, in agreement with the available experimental data. Though the analysis up to first-order cumulant expansion does not predict a direct phase transition between the blue phase III and the isotropic phase, it is fairly easy to identify two differently correlated regions in a temperature-chirality plane. Various structural quantities, such as optical activity and specific heat, also reveal a behavior characteristic of two isotropic phases with different correlation lengths.

Outcomes of cytopathology studies presented at national pathology meetings.

The purpose of this study was to determine what factors influence the final publication status of cytopathology studies presented at national meetings. Abstracts involving cytopathology material were obtained from the following journals: Modern Pathology (volume 11, 1998), Acta Cytologica (volume 42, 1998), and the American Journal of Clinical Pathology (volumes 109 and 110, 1998). Using the National Library of Medicine Website, each abstract was searched by author and topic to determine if the study was published as a peer-reviewed article. The following parameters were evaluated: meeting where the abstract was presented, type of institution where the research was based, type of material used in the study, and application of ancillary techniques used in the study. The subsequent published articles were evaluated for journal and time to publication. Out of 257 studies presented in 1998, 85 (33%) were published in peer-reviewed journals by May 2000. The majority of papers were published in Diagnostic Cytopathology (n = 21), Acta Cytologica (n = 15), and Cancer (n = 18). The mean time for publication was 12.8 mo. The highest percentage of published studies was presented at the United States and Canadian Academy of Pathology (USCAP) meeting (50% of presented abstracts), followed by American Society of Cytopathology (ASC) (28%) and American Society of Clinical Pathologists (ASCP) (17%) meetings. Ancillary techniques were applied in 40 of 85 (47%) published studies, 27 of 85 (32%) articles focused on morphology, and 18 of 85 (21%) papers covered other topics (e.g., quality assurance (QA), cost, and role of cytology). In nonpublished studies (n = 172), special techniques were the main focus in 40%, morphology in 25%, and other topics in 35% of abstracts. The great majority (97%) of published studies were from academic institutions. Gynecological and nongynecological material were roughly equally covered in published and nonpublished studies. Only a relatively small percentage of presented studies was finalized in the form of peer-reviewed articles. Type of material and application of ancillary techniques do not significantly influence the outcome.

Synchronization induced by Langevin dynamics.

Equilibrium Langevin dynamics of one-dimensional Lennard-Jones chains is studied. It is shown that depending on the noise strength, the friction constant and the number of particles, chains can synchronize, break, or remain desynchronized. Generally the synchronization time and the maximal Lyapunov exponent are found to depend on the number of particles and the ratio of noise strength to friction constant.

Cytomorphology of small-cell (neuroendocrine) carcinoma on ThinPrep cytology as compared to conventional smears.

Small-cell (neuroendocrine) carcinoma of the female genital tract is an uncommon, aggressive neoplasm that occurs most commonly in the cervix and rarely in the vagina. Although the cytologic findings have been reported on conventional smears, the cytologic diagnosis of primary vaginal small-cell carcinoma on ThinPrep material has not been previously reported. We present a case of a 46-yr-old woman who underwent cervical/vaginal biopsies as a result of abnormal cells seen on the ThinPrep Pap Test. Small to medium-sized cells with scant cytoplasm were present singly and in loose, cohesive clusters. Nuclear molding was noted in a few cellular groups. The differential diagnosis included a high-grade squamous intraepithelial lesion, small-cell (neuroendocrine) carcinoma, endometrial adenocarcinoma, and lymphoma. Subsequent tissue biopsies with immunohistochemical staining confirmed a diagnosis of small-cell carcinoma of the vagina. The cytologic features of small-cell (neuroendocrine) carcinoma on slides prepared by the ThinPrep Pap Test are discussed and compared to those on conventional cervicovaginal smears.

[Takayasu's arteritis: underestimated cause of hypertension]. / Choroba takayasu--niedoceniana przyczyna nadcisnienia tetniczego.

UNLABELLED: Takaysu's arteritis (TA) is regarded to be a frequent cause of hypertension in Asian population. However some reports have recently informed about increasing frequency of its also in non Asian people. The aim of this study was to evaluated own experiences on diagnosis and treatment of TA as well as prevalence of TA in hypertensive patients in Caucasian population. MATERIALS AND METHODS: During last 15 years we examined 4190 hypertensive patients hospitalized in our department. Renovascular hypertension was recognized in 139 cases. The diagnosis of TA was based on angiographically proven vascular changes and its inflammatory phase on estimation increased (> 40 mm/h) sedimentation rate and immunoglobulins above normal level. The patients with acute phase of TA initially received typical immunosuppressive therapy (prednisone in monotherapy or combined with azatioprine or cyclophosphamide), followed by chronic administration of prednisone. In every case, if it was possible, we proposed angio-corrective procedure. All patients have received hypotensive and antiplatelet therapy. RESULTS: TA was recognized in 15 patients--4 men and 11 women, average age 36.3 +/- 9.8 y. The patients with TA represented 0.37% hypertensive and 10.9% cases of renovascular hypertension. Significant stenosis of renal artery and various degree of lesions in aorta and some arteries was discovered in all persons. In the observed group hypertension was effectively controlled with 2-3 hypotensive drugs, including ACE inhibitors, diuretics and Ca antagonists. The acute phase of TA was diagnosed in 11 patients and it was treated successfully (except one case) with immunosuppressive therapy. After discontinuation of the treatment (4 patients) progression of the disease was observed. In 6 patients, characterised by clinical and biochemical remission of acute phase percutaneous angioplasty renal artery was performed. A good result in long-term follow-up period was observed in 4 cases (in 2 after repeated procedure). Surgical procedure was performed in 4 cases--in 2 on carotid and in 1 on renal and the next one on coronary artery. In first 3 cases the procedures were unsuccessful (reocclusion ?). CONCLUSIONS: Our observation suggested that 1. The incidence of TA in hypertensive (especially renovascular hypertension) population is more frequent than expected. 2. Acute phase of the disease is indication to long-term the immunosuppressive therapy. 3. Angiocorrective procedure is necessary reflected in every case in period of remission of acute phase.

Primary nodal gastrinomas.

BACKGROUND: The term primary lymph node gastrinoma was first used to describe a group of patients with gastrin-producing tumors present in lymph nodes located in a well-defined anatomic region. The patients had no known primary tumors in the pancreas or gastrointestinal tract and had disease-free survival for up to 18 years. The anatomic region in question has a triangular shape that extends from the cystic and common bile ducts to the second and third portion of the duodenum and the neck and body of the pancreas. The term gastrinoma triangle was coined to identify the area; in addition, it was postulated that lymph nodes located in the gastrinoma triangle normally contained neuroendocrine cells capable of secreting gastrin and other neuropeptides. From its inception, the postulate became the subject of controversy. DESIGN: To extend previous observations, we examined the lymph nodes located in the gastrinoma triangle of 20 autopsy cases for the presence of neuroendocrine cells, as determined by immunohistochemistry, using antibodies to a panneuroendocrine substance (eg, synaptophysin) and a specific neuropeptide (eg, gastrin). Scanning for positive cells was performed by 2 observers (M.E.H. and M.C.C.). We compared the findings in these lymph nodes with lymph nodes obtained from axillary and inguinal dissections during surgical procedures. RESULTS: In all, 417 lymph nodes were studied. Five of the 20 gastrinoma triangle cases contained synaptophysin reactive cells, whereas 3 had gastrin reactive cells. None of the axillary and inguinal lymph nodes contained neuroendocrine cells. CONCLUSION: Our findings support the hypothesis of entrapment of neuroendocrine cells during development and the presence of primary nodal gastrinomas.

Identification of the asexual state of Rhizopus species on histologic tissue sections in a patient with rhinocerebral mucormycosis.

Mucormycosis is an infection caused by a group of fungi in the order Mucorales in the phylum Zygomycota. The most well-known form of this disease is rhinocerebral mucormycosis, which usually develops in diabetic or immunocompromised patients. The fungal hyphal elements are easily detected in biopsy specimens by direct or histologic examination. However, the confirmatory identification of the genus or species requires culture of the specimen. This article presents a case of rhinocerebral mucormycosis in which presumptive identification of the genus was made without microbiologic cultures and was based on the extraordinarily rare appearance of fungal sporangia and sporangiospores in histologic tissue sections. Identification of these structures allowed an early and accurate diagnosis of rhinocerebral invasive mucormycosis.

Persistent dissection of carotid artery in patients operated on for type A acute aortic dissection--carotid ultrasound follow-up.

Over a period of 5 years, 124 patients were operated on at the National Institute of Cardiology in Warsaw for acute aortic dissection, 27 of whom died. The 97 patients discharged from the hospital were included in the present analysis. The age of the patients ranged from 25 to 73 years with a mean of 50+/-10 years. Ultrasound examination of carotid arteries was performed with the patient lying on his back using a Toshiba 340A color Doppler system with a linear array probe of 7.5 MHz. Of the 97 patients examined, 15 (15%) had a dissection of at least one of the common carotid arteries (CCA). Two had Marfan syndrome. In 11 patients the dissection involved the right common carotid artery and in four it involved both the left and right common carotid arteries. The flow in the true lumen of CCA and ICA was preserved in all patients and the degree of narrowing ranged from 30 to -70%. Only one of the 15 patients with CCA dissection had an ipsilateral neurological deficit which was already present before the aortic aneurysm operation. Ultrasound follow-up was performed in all patients with the CCA dissection found on first examination. The mean duration of follow-up was 21 months. In 14 patients the degree and extent of the dissection as well as the narrowing of the true lumen was comparable, and in one patient the false channel closed spontaneously. During follow-up there were no new major neurological events despite the persistence of the CCA dissection with different degrees of narrowing of the true lumen. Doppler ultrasound examination of the carotid arteries can supply additional information about the extent of the dissection, and help to assess the flow in the persisting 'double channel' common carotid artery during the follow-up of patients.

[Accelerated and malignant hypertension--clinical observation]. / Nadcisnienie tetnicze przyspieszone i zlosliew--obserwacja kliniczna.

There were 101 (4.6%) cases of malignant and accelerated hypertension among 2195 hypertensives patients treated in Department of Hypertension of National Institute of Cardiology between 1981 and 1990. Almost 30% of these patients were diagnosed as having secondary cause of hypertension. Comparison with control group of patients with moderate or mild hypertension revealed that malignant hypertensives had a shorter history of illness, lower level of education, higher evidence of smoking and over-consumption of alcohol. The systolic and diastolic blood pressure values were significantly higher in this group. The patients with malignant hypertension had significantly higher blood concentration of urea, creatinine and uric acid. Mild anemia was also present. Severe cardiovascular complications (myocardial infarction, stroke, encephalopathy, left ventricular failure) were observed in 44% cases of malignant hypertension. Due to efficacious hypotensive treatment blood pressure decreased significantly and biochemical indicators of renal function improved. Withdrawal of characteristic for malignant hypertension changes in fundoscopy was also observed. Results of this study indicate that prompt and aggressive treatment with normalization of blood pressure results in reversal of vascular lesions and permits recovery of cerebral and renal function.

[Malignant arterial hypertension--clinical picture, prognosis, management]. / Nadcisnienie tetnicze zlosliwe--obraz kliniczny, rokowanie, leczenie.

Malignant hypertension is the most severe form of hypertension. Untreated--quickly leads to target organs damage and death. The most important things are early diagnosis and treatment, which can improve prognosis in the group of patients with malignant hypertension. Pathogenesis of malignant hypertension is not completely established, although histopathological changes are well known. The article presents recent opinions on etiopathogenesis, clinical course and treatment of malignant hypertension.

[Renovascular hypertension--clinical observations and long-term follow-up]. / Nadcisnienie naczyniowo-nerkowe--obserwacja kliniczna i odlegle wyniki leczenia.

Renovascular hypertension is one of the most common causes of secondary hypertension. Its early diagnosis is particularly important, firstly because it is one of the few potentially reversible causes of chronic renal failure. In many centers, including our own, renal angioplasty (PTA) or surgery is the treatment of choice for patients with renovascular hypertension. The aim of the study was the evaluation of the early and late results of PTA versus renovascular surgery. The diagnostic procedures and clinical course of renovascular hypertension were also analyzed. Among patients with renovascular hypertension treated in our Department during the 1981-1993 years, 89 patients (46 men, 43 women) were diagnosed and having renovascular hypertension (3% of all hypertensive patients). The average duration of hypertension in this group was 5 years. High incidence of accelerated hypertension (18%) and cardiovascular complications were observed: myocardial infarction in 20.2% of cases and stroke in 4.5%. The presence of renal failure was found in 22.5% of cases, hypokalemia in 11.2%, 38.3% of patients had changes in other arteries. Renal angioscintigraphy and captopril renal scintigraphy were performed in accordance with renal arteriography in 80% of patients. Arteriography showed unilateral renal artery stenosis in 78.7% of patients and bilateral - in 21.3%. The most common cause of renovascular hypertension in our material was atherosclerosis (65.2%). Fibromuscular dysplasia and Takayasu arteritis were diagnosed less frequently (25.8% and 9.0% respectively). Forty four patients were treated with PTA, 15 underwent surgical revascularization and 11 - unilateral nephrectomy. Early beneficial therapeutic effect (normalization or improvement of blood pressure control) was observed in 88.6% for PTA and 66.7% for surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

[Comparative studies on the effects of propranolol and acebutolol on blood pressure, serum lipids and lipoproteins in patients with primary hypertension]. / Porównawcze badania nad wplywem propranololu i acebutololu na cisnienie tetnicze oraz lipidy i lipoproteiny surowicy w nadcisnieniu tetniczym pierwotnym.

A comparative studies on the effect of propranolol and acebutolol on blood pressure, cardiac function, blood serum lipids and lipoproteins were carried out in 48 patients with the primary hypertension double-blind method was applied. Tested drugs were given for 12 weeks. It was found, that both drugs are potent and comparable hypotensive agents normalizing blood pressure in the majority of treated patients. No significant difference in the effect on heart rate and adverse reactions has been noted. Acebutolol did not change lipid metabolism parameters whereas propranolol slightly but statistically significantly increased serum triglycerides.

[Ambulatory 24-hour blood pressure monitoring in patients with resistant hypertension]. / Rejestracja 24-godzinna cisnienia tetniczego krwi u chorych z tzw. Opornym nadcisnieniem tetniczym.

The aim of the study was to assess the usefulness of 24-hour blood pressure (BP) and heart rate (HR) monitoring in patients with "resistant" hypertension. 30 patients (44.1 +/- 9.9 years) with diastolic BP 100 mm Hg or more in spite of treatment with three or more antihypertensive drugs were studied. Ambulatory recording of BP and HR was performed by means of Del Mar Avionics monitoring system 9000. Mean recording time was 21.5 hours and mean number of measurements during one recording--56.7. Mean ambulatory systolic and diastolic BP values were significantly lower than mean value of three casual measurements (146.0 +/- 24.6 vs 171.5 +/- 21.2 mm Hg for systolic and 97.2 +/- 11.3 vs 110.4 +/- 7.5 mm Hg for diastolic BP p less than 0.01) In 14 (46.6%) systolic BP and in 10 patients (33.3%) diastolic BP were normal. The patients with normal and abnormal ambulatory BP recordings did not differ in regard to age and mean clinic BP levels. However, patients with abnormal ambulatory BP recordings were more often overweight and showed a greater frequency of left ventricular hypertrophy and family history of hypertension and its complications. The results of the study show that ambulatory BP monitoring may be of value in assessing the response to antihypertensive treatment in patients with so called resistant hypertension as judged on the basis of clinic pressure.