Cone-rod dysfunction in patients with unexplained reduction in visual acuity

Electrophysiologic tests were performed in 233 patients who complained of reduced visual acuity with no satisfactory clinical explanation. The functional integrity of the retina was assessed from the light-and dark-adapted electroretinogram., Macular function and conduction in the optic nerves were estimated from the flash visual evoked potentials. Of the 233 patients 78 were grouped together on the basis of the electrophysiologic and clinical findings. They were characterized by subnormal electroretinogram responses with the cone system more affected than the rod system. The flash visual evoked potential responses were of abnormal waveform and prolonged implicit times. Most of these patients exhibited normal fundi. The reduction in visual acuity, the degree of electroretinogram deficits and the pattern of the visual evoked potential responses were similar in both eyes of each, patient, indicating a symmetric disorder. Slight deterioration of visual acuity and electrophysiologic variables were observed in 37 of the patients who were followed up over a period of up to 8 years. The electrophysiologic findings indicate that about 20% of patients complaining of unexplained reduction in visual acuity were suffering from a diffuse retinal disorder affecting the peripheral retina as well as the macular region. On the basis of electrophysiologic findings and clinical symptoms, we suggest grouping these patients under a new entity: cone-rod dysfunction.     

Internal mobility of PMMA in concentrated CDCl3 solutions, 2. 13C NMR spectra

The ¹³C NMR relaxation parameters (T₁, line widths and NOE factors) were measured and analyzed for two samples of atactic poly(methyl methacrylate) (PMMA) of molecular weight M_w 4,20·10⁴ and 1,76.10⁶ in CDCl₃ solutions in the concentration range 11 to 54% (by weight) of polymer, at 297 and 323 K. By this analysis it was found that the backbone segmental motion of PMMA is spatially isotropic in the whole measured concentration range; the motion of the α-CH₃ group may be approximated by the double reorientation model; the motion of the ester CH₃ group can be approximated by the isotropic model only at concentrations lower than 12%; in more concentrated solutions, a satisfactory approximation is obtained neither by the isotropic, nor by the double reorientation models. The reasons of this behaviour are discussed.     

Liver cell membrane alterations during hemorrhagic shock in the rat

Previous studies using the Ling-Gerard microelectrode to measure membrane potential and a muscle biopsy technique to determine water and electrolyte content have established a skeletal muscle cell membrane defect in hemorrhagic shock. The present study was undertaken to compare and contrast changes occurring on a cellular level in the liver and skeletal muscle of the rat during sustained hemorrhagic shock. The liver has been suggested as a possible primary site of organ failure during prolonged shock with a loss of normal liver processes and important hepatic metabolic functions. Thirty-four experiments were performed in rats with 11 experiments in the control group. Skeletal muscle membrane potential as well as liver cell membrane potential was measured after opening the abdomen through a midline incision. The ventral lobe of the liver was exposed and placed on a suspension apparatus to decrease respiratory interference and the liver was impaled with a Ling-Gerard microelectrode. Muscle cell resting membrane potentials were measured in exposed skeletal muscle in the leg of the animals. Biopsy samples were obtained at intervals in both the liver and skeletal muscle. Twenty-three experiments were conducted by producing hemorrhage with the withdrawal of blood over a 5- to 15-min period of time and maintaining a systolic blood pressure of 60 mm Hg for 115 ± 40 min. The distribution of water and electrolytes in intra- and extracellular space in the muscle biopsies as well as in the liver on the basis of chloride distribution was considered to be a passive phenomenon related to the resting cell membrane potential as predicted by the Nernst equation. Correction of the measured water and electrolyte content of the biopsies for residual blood was carried out with the use of chromium-51-tagged red blood cells. The control group of rats did not demonstrate any significant change in membrane potential of either muscle or liver cells during the experiment. The membrane potentials were maintained at normal levels in the muscle ?91.4 ± 2.2 mV; and in the liver at a mean of ?40.3 ± 3.3 mV. The hemorrhagic shock group of animals demonstrated significant changes. Muscle membrane potential decreased to ?80.99 ± 6.3 mV (P < 0.01) while at the same time period the liver membrane potential decreased to ?24.1 ± 4.6 mV (P < 0.001). The results of these experiments give further evidence of a cellular membrane defect in hemorrhagic shock. The liver cell membrane potential changes and accompanying water and electrolyte shifts occurred before any significant changes in the muscle tissue. The data indicate the existence of a major alteration in rat liver cell membrane function early in the shock state.     

Crypt-restricted loss and decreased protein expression of cytochrome C oxidase subunit I as potential hypothesis-driven biomarkers of colon cancer risk.

There is an increasing demand for the development of intermediate biomarkers to assess colon cancer risk. We previously determined that a live cell bioassay, which assesses apoptosis resistance in the nonneoplastic colonic mucosa, detects approximately 50% of patients with colon cancer. A hypothesis-driven biomarker that reflects apoptosis resistance in routine formalin-fixed, paraffin-embedded tissue would be easier to use. Cytochrome c oxidase is a critical enzyme that controls mitochondrial respiration and is central to apoptosis. We did an immunohistochemical study of cytochrome c oxidase subunit I expression in 46 colonic mucosal samples from 16 patients who had undergone a colonic resection. These included five patients without evidence of colonic neoplasia (three normal and two diverticulitis), three patients with tubulovillous adenomas, and eight patients with colonic adenocarcinomas. Analysis of aberrancies in expression of cytochrome c oxidase subunit I showed that, compared with nonneoplasia, the patients with neoplasia had a higher mean incidence of crypts having decreased expression (1.7 versus 22.8, P = 0.03) and a higher mean incidence having crypt-restricted loss (0.6 versus 3.2, P = 0.06). The percentage with segmented loss was low and was similar in the two groups. Combining these results, the mean % normal (i.e., with none of the three types of abnormality) was 96.7 in nonneoplasia versus only 73.2 in patients with neoplasia (P = 0.02). It should be noted that a defect in cytochrome c oxidase subunit I immunostaining was not detected in all biopsy samples from each patient for whom some abnormality was found, indicating a "patchiness" in the cytochrome c oxidase subunit I field defect. As a result of this "patchiness," the increased variability in the incidence of crypt-restricted loss of cytochrome c oxidase subunit I expression was a statistically significant feature of the neoplasia group. Crypt-restricted loss of cytochrome c oxidase subunit I has not been previously reported in colonic mucosa and is presumably the result of a crypt-restricted stem cell mutation. Decreased cytochrome c oxidase subunit I expression also significantly correlated with apoptosis resistance, a factor known to contribute to carcinogenesis. The results suggest, however, that aberrant cytochrome c oxidase subunit I expression may be a better biomarker than loss of apoptosis competence for increased colon cancer risk.     

Revisiting the role of hematopoietic stem cell transplantation in chronic lymphocytic leukemia

Since the advent of hematopoietic stem cell transplantation more than 40 years ago, numerous methods of transplantation have been developed, modified and improved upon. Although hematopoietic stem cell transplantation has been used in a variety of malignant diseases since then, its use in the treatment of chronic lymphocytic leukemia has recently started to gain interest. Patients with chronic lymphocytic leukemia are generally elderly, and because of its relatively benign course, they were not considered suitable candidates for hematopoietic stem cell transplantation. Nonetheless, there have been marked improvements in transplantation techniques, including better conditioning regimens that have decreased treatment-related morbidity and mortality. In this article, the authors review the most recent data on hematopoietic stem cell transplantation in chronic lymphocytic leukemia as well as the change in risk stratification based on newer prognostic factors and its impact on treatment decisions in chronic lymphocytic leukemia.     

Short to long term mortality of patients hospitalised with heart failure in the Czech Republic--a report from the EuroHeart Failure Survey

BACKGROUND AND AIM: The European Society of Cardiology initiated the EuroHeart Failure Survey to obtain more data about the quality of care in patients hospitalised with suspected heart failure (HF). The Czech Republic was 1 of the 24 European Society countries included in the survey. The aim of this report is to extend the original follow-up period of 12 weeks out to 4 years to assess mortality. METHODS: All admitted patients were screened according to the EuroHeart Survey Protocol, over a 6-week period in six hospitals in Pilsen, Prague and Brno in the year 2000. Annual mortality and cause of death were obtained from the Prague Institute for Health Statistical Information (UZIS Praha). RESULTS: A total of 2365 patients were screened and about 25% of all admitted patients fulfilled the criteria for HF. About 14% of patients died between admission and the 12-week follow-up, 36% of male and 42% of female patients died during the 4-year follow-up (2000-2003). Cardiovascular diseases were the main causes of death (92%). Deceased patients were significantly older, had lower haemoglobin and total plasma cholesterol level, and had renal insufficiency and higher levels of big endothelin and BNP than the survivors. Mortality risk was increased independently by positive history of previous myocardial infarction OR=2.39 (1.59-3.59), by age OR=1.03 (1.01-1.05) and by plasma creatinine level OR=1.04 (1.01-1.07). Treatment with diuretics and digoxin was associated with a higher risk of death; by contrast, a protective effect of beta-blockers and statins was found in these HF patients. CONCLUSION: Patients with HF were older and had a poor prognosis; approximately one third of the patients will die within 3 years.     

Long-term serial echocardiographic examination of late anthracycline cardiotoxicity and its prevention by dexrazoxane in paediatric patients

The authors conducted an 8-year prospective non-randomised study to determine whether dexrazoxane (ICRF-187) would reduce late anthracycline-induced cardiotoxicity in patients treated in childhood for haematological malignancy. The authors examined prospectively 75 patients (40 male/35 female) aged 2–17 years (median 6.5 years) at the time of diagnosis. The cardioprotection was given to 53 patients (26 male/17 female) and the standard protocol was used in 22 patients (14 male/8 female). The prospective echocardiographic evaluation was done before and after the chemotherapy and every year during the follow-up period. Dynamic stress echocardiography (DSE) was assessed in the final year. The clinical cardiotoxicity was not diagnosed. Higher cumulative doses of anthracycline were given in the dexrazoxane group (234±58 mg/m², median 240 mg/m² versus 203±86 mg/m², median 210 mg/m², P <0.04) and a significantly higher percentage of patients received cumulative doses >240 mg/m² of anthracycline ( P <0.05). During the follow-up period, the fractional shortening (FS) declined in the no-dexrazoxane group only in the 8th year and was significantly lower compared to the dexrazoxane group ( P <0.05). The pathological decrease in FS was present in 24% of patients; 41% in the no-dexrazoxane and 17% in the dexrazoxane groups, respectively ( P <0.05). DSE demonstrated lower rest EF and cardiac index (CI) in the no-dexrazoxane group ( P <0.05); however, neither the response of EF and CI to the stress echocardiography nor the exercise tolerance significantly differed between sub-groups. A higher number of patients in the dexrazoxane group had very good exercise tolerance (ET) >3 Watts/kg ( P <0.05) and a lower number responded with a decreased ET <2 Watts/kg ( P <0.05) compared to the no-dexrazoxane group. Conclusion:Dexrazoxane seems to reduce the risk of late subclinical cardiotoxicity. Dexrazoxane-treated patients revealed better exercise tolerance; however the haemodynamic response to the stress was no different in both sub-groups.     

The effect of mannose binding lectin gene polymorphisms on susceptibility to tuberculosis in different ethnic groups

In order to investigate the role of MBL gene polymorphisms in susceptibility to tuberculosis (TB) we genotyped 487 TB cases and 232 controls. Among African-American individuals, the frequency of B allele was lower among controls than cases (p < 0.01), but we found no differences between cases and controls of white and Hispanic ethnicity.     

Adipose tissue expression of the lipid droplet-associating proteins S3-12 and perilipin is controlled by peroxisome proliferator-activated receptor-gamma

In a systematic search for peroxisome proliferator-activated receptor-gamma (PPAR-gamma) target genes, we identified S3-12 and perilipin as novel direct PPAR-gamma target genes. Together with adipophilin and tail-interacting protein of 47 kDa, these genes are lipid droplet-associating proteins with distinct expression pattern but overlapping expression in adipose tissue. The expression of S3-12 and perilipin is tightly correlated to the expression and activation of PPAR-gamma in adipocytes, and promoter characterization revealed that the S3-12 and the perilipin promoters contain three and one evolutionarily conserved PPAR response elements, respectively. We furthermore demonstrate that the expression of S3-12 and perilipin is reduced in obese compared with lean Zucker rats, whereas the expression of adipophilin is increased. Others have shown that perilipin is an essential factor in the hormonal regulation of lipolysis of stored triglycerides within adipose tissue. The direct regulation of perilipin and S3-12 by PPAR-gamma therefore is likely to be an important mediator of the in vivo effects of prolonged treatment with PPAR-gamma activators: insulin sensitization, fatty acid trapping in adipose tissue, reduced basal adipose lipolysis, and weight gain.     

Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases

Commensal microflora (normal microflora, indigenous microbiota) consists of those micro-organisms, which are present on body surfaces covered by epithelial cells and are exposed to the external environment (gastrointestinal and respiratory tract, vagina, skin, etc.). The number of bacteria colonising mucosal and skin surfaces exceeds the number of cells forming human body. Commensal bacteria co-evolved with their hosts, however, under specific conditions they are able to overcome protective host responses and exert pathologic effects. Resident bacteria form complex ecosystems, whose diversity is enormous. The most abundant microflora is present in the distal parts of the gut; the majority of the intestinal bacteria are Gram-negative anaerobes. More than 50% of intestinal bacteria cannot be cultured by conventional microbiological techniques. Molecular biological methods help in analysing the structural and functional complexity of the microflora and in identifying its components. Resident microflora contains a number of components able to activate innate and adaptive immunity. Unlimited immune activation in response to signals from commensal bacteria could pose the risk of inflammation; immune responses to mucosal microbiota therefore require a precise regulatory control. The mucosal immune system has developed specialised regulatory, anti-inflammatory mechanisms for eliminating or tolerating non-dangerous, food and airborne antigens and commensal micro-organisms (oral, mucosal tolerance). However, at the same time the mucosal immune system must provide local defense mechanisms against environmental threats (e.g. invading pathogens). This important requirement is fulfilled by several mechanisms of mucosal immunity: strongly developed innate defense mechanisms ensuring appropriate function of the mucosal barrier, existence of unique types of lymphocytes and their products, transport of polymeric immunoglobulins through epithelial cells into secretions (sIgA) and migration and homing of cells originating from the mucosal organised tissues in mucosae and exocrine glands. The important role of commensal bacteria in development of optimally functioning mucosal immune system was demonstrated in germ-free animals (using gnotobiological techniques). Involvement of commensal microflora and its components with strong immunoactivating properties (e.g. LPS, peptidoglycans, superantigens, bacterial DNA, Hsp) in etiopathogenetic mechanism of various complex, multifactorial and multigenic diseases, including inflammatory bowel diseases, periodontal disease, rheumatoid arthritis, atherosclerosis, allergy, multiorgan failure, colon cancer has been recently suggested. Animal models of human diseases reared in defined gnotobiotic conditions are helping to elucidate the aetiology of these frequent disorders. An improved understanding of commensal bacteria-host interactions employing germ-free animal models with selective colonisation strategies combined with modern molecular techniques could bring new insights into the mechanisms of mucosal immunity and also into pathogenetic mechanisms of several infectious, inflammatory, autoimmune and neoplastic diseases. Regulation of microflora composition (e.g. by probiotics and prebiotics) offers the possibility to influence the development of mucosal and systemic immunity but it can play a role also in prevention and treatment of some diseases.