Anti-V3 loop spectrotype in HIV-infected individuals during zidovudine therapy.
In order to investigate the role played by zidovudine (ZDV) as immune modulator, particularly on B-cell response, the anti-V3 loop spectrotype in 115 sera from 26 HIV-infected individuals was evaluated, prior to and during treatment with ZDV, by isoelectric focusing and reverse blotting (IEF-RB), a technique useful for indirectly measuring the activity and the number of B-cell clones. All 18 patients showing seroreactivity by IEFRB displayed a clear oligoclonal banding pattern, with no change in the spectrotype (i.e. new bands), in sequential analysis over the course of therapy. Only minor changes in band intensity were found, without any correlation with ZDV treatment or CD4+ cell count. In addition, among the sera reactive in spectrotypic analysis, the percentage of those with p24 antigen positivity was significantly lower than those with no detectable p24 antigen (19.8% vs 80.2%, respectively, p = < 0.0001, Fisher's exact test). In conclusion, it could not be demonstrated by IEFRB that there was any effect of ZDV on the activity and the number of anti-V3 specific B-cell clones. This data is in line with previous studies showing the constancy of anti-gp120 antibody spectrotype over the long course of the disease.


[Treatment of obstructive sleep apnea syndrome].
Obstructive sleep apnea syndrome (OSAS) is a chronic disorder in which the subject experiences an abnormally large number of episodes of more or less complete and prolonged ventilatory arrest due to pharyngeal obstruction leading to fragmented sleep pattern and reduced arterial oxygen saturation. OSAS produces invalidating daytime symptoms and appears to be associated with cardiovascular complications and overmortality. Diagnosis is based on an exploration of the sleeping pattern with recording of ventilation function, arterial oxygen saturation, heart rate, and electrophysiological characteristics (polysomnography). Prevalence of a high apnea index (more than 5 per hour of sleep) associated with day-time somnolence may be as high as 3% of the population in the 30 to 60 year age range. Current treatment is mainly based on nasal continuous positive airway pressure given via the nasal route during sleep and pharyngeal surgery (uvulopalatopharyngoplasty). Surgery is reserved for subgroups of patients with anatomic abnormalities and free of contraindications for anesthesia. Continuous positive pressure is always effective in case of symptomatic apnea and has a favorable effect on several associated complications. It can be proposed for any patient with OSAS but its use is limited due to incomplete compliance (approximately 70%). It appears that patients with particularly severe disease benefit most. Thus the ANDEM experts recommend treatment for all symptomatic patients with 30 or more episodes of apnea or hypopnea per hour of sleep during night-time exploration. Below this threshold, electrophysiological recordings are required to eliminate another cause of fragmented sleep which could explain the symptomatology despite a moderately elevated apnea index. Once the treatment has been started, regular surveillance is recommended. In addition, general health and nutritional counselling (weight reduction, smoking cessation, interruption of alcohol consumption and use of sedatives) should be proposed but usually have minimal and transitory effect.


Kidney injury after sodium phosphate solution beyond the acute renal failure.
Screening colonoscopy with polipectomy reduces colonorectal cancer incidence and mortality. An adequate bowel cleansing is one of the keys to achieving best results with this technique. Oral sodium phosphate solution (OSP) had a widespread use in the 90s decade. Its efficacy was similar to polyethylene glycol (PEG) solution, but with less cost and convenient administration. Series of patients with acute renal failure due to OSP use have been reported. However, large cohorts of patients found no difference in the incidence of renal damage between these two solutions. From 2006 to 2009 we identified twelve cases of phosphate nephropathy after colonoscopy prepared with OSP. All patients were followed up to six months. All patients had received just a single dose. We analyzed 12 cases with phosphate nephropathy; three patients debuted with AKI and nine patients had chronic renal injury. Four cases were confirmed with renal biopsy. One patient with AKI needed hemodialysis at diagnosis without subsequent recovery. Two patients (both with chronic damage) fully recovered their previous renal function. The remaining patients (nine) had an average loss of estimated glomerular filtration rate of 24ml/min/1.73m(2). The use of OSP can lead to both acute and chronic renal damage. However, chronic injury was the most common pattern. Both forms of presentation imply a significant and irreversible loss of renal function. Further studies analyzing renal damage secondary to bowel cleaning should consider these two different patterns of injury.


Abdominal aortic aneurysm: pretherapy assessment with dual-slice helical CT angiography.
The purpose of this study was to evaluate dual-slice helical CT in the pretherapy assessment of abdominal aortic aneurysms. Dual-slice helical CT angiography was performed in 47 consecutive patients (mean age, 59 years) with abdominal aortic aneurysm to determine whether we could then evaluate the extent of aneurysm and see associated renal, celiac, mesenteric, and iliofemoral artery disease. Results were compared with those of digital subtraction angiography (n = 47) and surgery (n = 37). The proximal and distal extents of abdominal aortic aneurysm correlated well with surgical findings. Dual-slice helical CT showed all main (n = 102) and accessory (n = 13) renal arteries with a sensitivity of 91% and a specificity of 100% for revealing associated renal artery stenosis exceeding 50%. Sensitivity and specificity of dual-slice helical CT for revealing stenosis exceeding 75% in celiac and superior mesenteric arteries were both 100%. Three of four iliofemoral artery stenoses and two occlusions of the common iliac artery were revealed by dual-slice helical CT. Helical CT angiography with dual-slice scanning is a useful and minimally invasive technique that can provide with high accuracy all the necessary information for treatment of abdominal aortic aneurysm.


[Relationship between changes of genetic damage and development of disease in patients with arsenism caused by coal-burning].
To investigate the changes of genetic damage in patients with arsenism caused by coal-burning in 9 years. To analyze the relationship between the changes of genetic damage and disease progression and provide a basis for condition monitoring. Of 206 arsenism patients from the area with endemic arsenism in Guizhou province were tracking surveyed in February 1998 and divided into 4 groups, including suspicious, mild, moderate and severe poisoning group. Another 67 healthy residents from a neighbour township 12 km away where arsenic was not prevalent were surveyed. Over a 9-year follow-up, 131 arsenism patients and 45 controls with the complete biochemical indexes among them were selected as subjects in December 2006. Arsenic (As) concentration of urine and hair were detected by silver diethyldithiocarbamate spectrophotometry (Ag-DDC). Micronucleis (MN) and chromosome aberrations (CA) were analyzed by conventional methods. DNA single-strand breaks of peripheral blood were measured by single cell gel electrophoresis (SCGE), and the tail lengths of comet were used to measure DNA damage. Among the control, suspicious, mild, moderate and severe arsenic poisoning group, the As contents of urine and hair were respectively (34.16 ± 10.25), (52.35 ± 22.41), (62.26 ± 31.13), (71.43 ± 49.92), (78.45 ± 50.64) µg/L and (1.37 ± 0.56), (3.69 ± 1.78), (4.88 ± 3.49), (5.21 ± 3.10), (6.25 ± 4.04) µg/g in 2006, which were lower than that 9 years before (urine as contents were (36.07 ± 20.70), (73.65 ± 41.33) , (90.92 ± 82.14) , (126.55 ± 107.31) and (139.44 ± 90.90) µg/L, and hair As contents were (1.41 ± 1.18), (4.85 ± 4.20), (5.72 ± 4.07) , (6.43 ± 4.32) and (7.19 ± 4.68) µg/g, respectively, F value was 10.63, 7.72, 14.66, 11.00 respectively, all P values were < 0.05). Except for suspicious poisoning group, the differences of urine As contents in the other groups all showed significance (P < 0.05). The incidences of MN were (0.238 ± 0.130) %, (0.268 ± 0.192) %, (0.283 ± 0.157) % and (0.391 ± 0.233)%; the incidences of CA were (14.36 ± 5.44) %, (18.09 ± 6.49) %, (19.38 ± 5.63)% and (19.83 ± 5.84) %; the tail lengths of comet were (29.88 ± 13.81) , (29.84 ± 12.80) , (34.50 ± 9.88) and (41.58 ± 12.98) µm respectively in 2006 for all poisoning groups; which were higher than that 9 years before(the incidences of MN were (0.163 ± 0.051) %, (0.186 ± 0.117) %, (0.196 ± 0.104) % and (0.273 ± 0.142) %; the incidences of CA were (13.18 ± 5.17)%, (14.48 ± 6.61)%, (15.67 ± 8.49) % and (16.90 ± 8.38) %; the tail lengths of comet were (15.07 ± 12.93) , (19.57 ± 8.80) , (27.03 ± 10.77) and (34.71 ± 14.95) µm) , except for the incidences of MN and CA in suspicious poisoning group and of MN in mild poisoning group , the differences of the three indexes in the other groups were significant (P < 0.05) . The state of illness of arsenic poisoning patients aggravated 9 years later. With the increase of urine and hair As contents and the development of arsenism, the incidences of MN, CA and the tail lengths of comet of all poisoning groups increased. There were positive correlations among them (r values were respectively 0.212, 0.316, 0.232, 0.263, 0.321, 0.654 and 0.760) (P < 0.05). The exacerbation of genetic damage was related to constantly high arsenic loads. The accumulation of genetic damage and its irreversibility might be one of the important reasons of the development of arsenism and cancer.


Proliferation and apoptosis in newly diagnosed and relapsed childhood acute lymphoblastic leukemia.
Children with acute lymphoblastic leukemia (ALL) who are treated with chemotherapy have remissions in more than 95% of the cases. However, 25% of the patients relapse and show resistance to chemotherapy. In this investigation we compared 25 newly diagnosed and 25 relapsed cases of ALL with respect to proliferation and apoptosis. Using immunocytochemistry and Western blotting, we determined the expression of cyclin A protein as a measure of the proliferative activity and the pro-apoptotic and anti-apoptotic factors, Fas, Fas ligand, caspase-3 and Bcl-2. Cyclin A expression was observed in 32% of the newly diagnosed cases and in 52% of the relapsed cases. Expression of Fas was found in 58% of the newly diagnosed and in only 27% of the relapsed samples. Of the newly diagnosed ALL, 88% expressed the Fas ligand while such expression was observed in 54% of the relapsed ALL. Sixty-four percent of the newly diagnosed cases expressed caspase-3 while only 48% of the relapsed samples did so. The anti-apoptotic factor, Bcl-2, was more frequently expressed in relapsed than in newly diagnosed cases. These data indicate that relapsed ALL more frequently exhibits high proliferative activity and reduced apoptosis than does newly diagnosed ALL.


Segregation models for disomic, tetrasomic and intermediate inheritance in tetraploids: a general procedure applied to Rorippa (yellow cress) microsatellite data.
Tetraploid inheritance has two extremes: disomic in allotetraploids and tetrasomic in autotetraploids. The possibility of mixed, or intermediate, inheritance models has generally been neglected. These could well apply to newly formed hybrids or to diploidizing (auto)tetraploids. We present a simple likelihood-based approach that is able to incorporate disomic, tetrasomic, and intermediate inheritance models and estimates the double-reduction rate. Our model shows that inheritance of microsatellite markers in natural tetraploids of Rorippa amphibia and R. sylvestris is tetrasomic, confirming their autotetraploid origin. However, in F(1) hybrids inheritance was intermediate to disomic and tetrasomic inheritance. Apparently, in meiosis, chromosomes paired preferentially with the homolog from the same parental species, but not strictly so. Detected double-reduction rates were low. We tested the general applicability of our model, using published segregation data. In two cases, an intermediate inheritance model gave a better fit to the data than the tetrasomic model advocated by the authors. The existence of inheritance intermediate to disomic and tetrasomic has important implications for linkage mapping and population genetics and hence breeding programs of tetraploids. Methods that have been developed for either disomic or tetrasomic tetraploids may not be generally applicable, particularly in systems where hybridization is common.


Emergency Response System for Pollution Accidents in Chemical Industrial Parks, China.
In addition to property damage and loss of lives, environment pollution, such as water pollution and air pollution caused by accidents in chemical industrial parks (CIPs) is a significant issue in China. An emergency response system (ERS) was therefore planned to properly and proactively cope with safety incidents including fire and explosions occurring in the CIPs in this study. Using a scenario analysis, the stages of emergency response were divided into three levels, after introducing the domino effect, and fundamental requirements of ERS design were confirmed. The framework of ERS was composed mainly of a monitoring system, an emergency command center, an action system, and a supporting system. On this basis, six main emergency rescue steps containing alarm receipt, emergency evaluation, launched corresponding emergency plans, emergency rescue actions, emergency recovery, and result evaluation and feedback were determined. Finally, an example from the XiaoHu Chemical Industrial Park (XHCIP) was presented to check on the integrality, reliability, and maneuverability of the ERS, and the result of the first emergency drill with this ERS indicated that the developed ERS can reduce delays, improve usage efficiency of resources, and raise emergency rescue efficiency.


Survey of cardiac pacing and implanted defibrillator practice patterns in the United States in 1997.
A survey of implanters of permanent cardiac pacemakers and ICDs in the United States during 1997 was conducted to identify present and changing patterns in indications for pacing, implantation techniques, pacing-mode selection, follow-up, and opinions regarding pacing and ICD related issues. This report is an update from 1993 of surveys performed every 4 years for the International Cardiac Pacing and Electrophysiology Society (ICPES). Questionnaires were sent to implanting physicians who were members of the North American Society of Pacing and Electrophysiology (NASPE), and who might, therefore, be expected to be more conversant than others with the state of the art. Four major manufacturers also provided estimates of the numbers of pacemakers and ICDs implanted in the United States from 1994 through 1997. In 1997, approximately 182,000 new rhythm management devices, including 153,000 primary pacing systems and 29,000 ICDs, were implanted, an increase of 24% for pacemakers and 90% for ICDs since 1994. In 1997, pacemaker implantations were performed by about 8,600 physicians working in 3,300 hospitals and 1,000 independent "surgi-centers." From 1994 to 1997, sales in the United States of dual chamber pacemakers rose from 58% to 69% of the total, and adaptive rate systems from 74% to 90%. ICD sales increased by about 29% per year from 18,700 to 35,000 units. This study disclosed significant differences among implanter subcategories and between present and earlier practices, and it provided useful insights into trends in pacemaker and defibrillator practice. Future surveys would be facilitated if a standardized implant registry like that used in Europe were established in the United States.


The effect of breathing exercises combined with manual therapy on muscle tension dysphonia in traditional singers: a blinded randomized controlled trial.
Muscle tension dysphonia (MTD) is common in traditional singers and can lead to serious complications, but there is inconclusive evidence about how MTD should be treated in singers as professional voice users. This study was conducted to investigate the effects of breathing exercises combined with manual therapy versus breathing exercises and manual therapy on voice quality in traditional singers suffering from MTD. In this blinded randomized clinical trial, 60 patients with MTD were randomly allocated to four groups: (1) breathing exercises, (2) manual therapy, (3) combined intervention (CI) and (4) control. Patients received treatments for 13 sessions, once per week. Treatment effects were assessed in terms of primary outcome measures: (1) breathing performance, measured by maximum phonation time (MPT) and (2) laryngeal function, measured by Stroboscopy Evaluation Rating Form (SERF). Secondary outcome measure was patient's self-perceived voice handicap, measured by Persian version of Singing Voice Handicap Index (SVHIp). All outcome variables were measured before and after treatment. The between group comparisons on MPT and SVHIp score were investigated using analysis of covariance (ANCOVA). The Kruskal-Wallis non-parametric test was used for between group comparisons of SERF items. Three treatment groups had improved regarding breathing performance, laryngeal function and voice handicap over the time (P < 0.01). The improvements achieved in all outcomes were significantly greater in the CI group than those of the breathing exercises, manual therapy and control groups. This randomized controlled trial showed that the combination of breathing exercises and manual therapy significantly improved the laryngeal function, breathing performance and voice handicap in traditional singers suffering from MTD. IRCT2015102524686N1.


Chiasmal syndrome.
Chiasmal syndrome is the constellation of signs and symptoms that are associated with lesions of the optic chiasm. Pituitary adenoma is its single most common cause. A MEDLINE search of the biomedical literature was conducted to uncover papers on topics related to chiasmal syndrome published since 1989. The MEDLINE search retrieved a total of 163 citations. Each citation was screened for relevance. Copies of each relevant paper were obtained and their references were examined for any publications that the original search may have missed and for older publications that continue to be of importance. This review article discusses the etiology, diagnosis, and management of chiasmal syndrome.


Motility of the terminal ileum and ileocecal sphincter in healthy humans.
Factors controlling the transit of contents between the ileum and cecum should be important determinants of intestinal function; however, the dynamics of the ileocecal region remain largely unexplored in healthy humans. Accordingly, prolonged recordings of intraluminal pressure were obtained from the distal ileum, across the ileocecal sphincter, and from the proximal colon of healthy adults. In one set of studies, 16 subjects each contributed 6 h of basal, fasting recordings; in 2 of the 16, postprandial patterns were also recorded. In a second set, 6 fasting subjects were studied for a total of 120 h. Less than 10% of interdigestive cycles (migrating motor complexes) reached the ileocecal sphincter. The remainder faded out and merged into an active, apparently random pattern of pressure waves that became more intense closer to the sphincter. Discrete, short bursts of phasic pressures migrated rapidly for long distances in the distal ileum and a unique peristaltic wave also migrated rapidly, though infrequently, through the region. Tonic pressures were recorded across the ileocecal sphincter but were present only during the passage of phasic pressure waves; basal tone was minimal. We believe these are the first prolonged observations of motility from the ileocecal sphincter of healthy humans. These descriptions provide insights into and a basis for further studies of a largely unexplored area of the human bowel.


Modeling Short-Term Maximum Individual Exposure from Airborne Hazardous Releases in Urban Environments. Part I: Validation of a Deterministic Model with Field Experimental Data.
The release of airborne hazardous substances in the atmosphere has a direct effect on human health as, during the inhalation, an amount of concentration is inserted through the respiratory system into the human body, which can cause serious or even irreparable damage in health. One of the key problems in such cases is the prediction of the maximum individual exposure. Current state of the art methods, which are based on the concentration cumulative distribution function and require the knowledge of the concentration variance and the intermittency factor, have limitations. Recently, authors proposed a deterministic approach relating maximum individual exposure to parameters such as the fluctuation intensity and the concentration integral time scale. The purpose of the first part of this study is to validate the deterministic approach with the extensive dataset of the MUST (Mock Urban Setting Test) field experiment. This dataset includes 81 trials, which practically cover various atmospheric conditions and stability classes and contains in total 4004 non-zero concentration sensor data with time resolutions of 0.01-0.02 s. The results strengthen the usefulness of the deterministic model in predicting short-term maximum individual exposure. Another important output is the estimation of the methodology uncertainty involved.


Distinct pathoclinical clusters among patients with uncontrolled type 2 diabetes: results from a prospective study in rural India.
Inadequate glycemic control among patients with type 2 diabetes mellitus (T2DM) poses an enormous challenge. Whether this uncontrolled T2DM population is a heterogenous mix of disease subtypes remains unknown. Identification of these subtypes would result in a customized T2DM management protocol thereby paving the way toward personalized therapy. Electronic health records of 339 patients with uncontrolled T2DM patients followed up for a median period of 14 months were analyzed using Uniform Manifold Approximation and Projection followed by density-based spatial clustering of applications with noise. Baseline clinical features and final diagnoses with drug combinations were selected in the analysis. A 30 min oral glucose tolerance test was next performed for assessing the underlying insulin resistance and β cell dysfunction. Three major clusters were identified. The first cluster characterized by recent onset T2DM had moderately preserved β cell function. The second cluster with a longer duration of T2DM and associated hypertension showed the best glycemic control with dual antidiabetic therapy. The third cluster with the longest history of T2DM and no history of hypertension had the worst glycemic control in spite of the highest percentage of patients on triple therapy (34.58%) and quadruple therapy (8.41%). Uncontrolled T2DM comprises a heterogeneous population with respect to disease duration, presence of co-morbidities and β cell function without significant difference in insulin resistance. Stratifying them on the basis of pathoclinical features is the first step toward a personalized management in T2DM.


Osteoclastogenesis during infective exacerbations in patients with cystic fibrosis.
Adults with cystic fibrosis (CF) are at increased risk of developing osteoporosis. During infective exacerbations, increased production of proinflammatory cytokines and markers of bone resorption have been reported. The aim of this study is to investigate the growth and proliferation of potential osteoclast precursor cells before, during, and after intravenous antibiotic treatment of infective exacerbations in patients with CF. Hematopoietic precursor cell growth was examined using colony formation assays using Methocult culture medium. Circulating potential osteoclast precursors were identified using four-color flow cytometry by CD14, CD33, CD34, and CD45 expression. At the start of an infective exacerbation increases in hematopoietic precursor colony formation (15.42 colonies/10(5) cells plated, p = 0.025), proliferation (28.5%, p < 0.001), and the numbers of circulating potential osteoclast precursors (6.5%, p < 0.001) were seen in comparison with baseline levels. These increases declined after treatment with intravenous antibiotics to a level close to baseline. The results demonstrate an increase in the production of potential osteoclast precursors in the peripheral blood during CF infective exacerbations. This may result in increased bone resorption and contribute to bone loss in patients with CF.


The John Charnley Award. Inhibition of wear debris mediated osteolysis in a canine total hip arthroplasty model.
In this study the efficacy of an oral bisphosphonate therapy to inhibit wear debris mediated bone resorption was evaluated in a canine total hip replacement model. Adult canines were randomized to three groups (n = 8 each) with a right uncemented total hip replacement performed on each animal. Group I (control) received no particulate debris. In Groups II and III, a mixture of 1 x 10(9) particles were introduced into the proximal femoral gap intraoperatively. The particle mixture consisted of fabricated ultra high molecular weight polyethylene (mean 2.3 microns, 90% by number), titanium alloy (mean 3.1 microns, 5%), and cobalt chrome alloy (mean 0.8 micron, 5%). Group III canines additionally received oral drug therapy (5 mg once a day, alendronate sodium) which was begun on postoperative Day 7 and continued until the time of sacrifice. Postoperatively, all animals were allowed 24 weeks of full ambulation before euthanasia. Radiographs obtained preoperatively, postoperatively, and at time of sacrifice were evaluated for periprosthetic osteolysis. Interfacial tissues were examined histologically and placed in organ culture and the supernatants were assayed for prostaglandin E2 and interleukin-1. One animal receiving debris (Group II) suffered a periprosthetic fracture and was sacrificed from the study. Radiographically, one of eight Group I (control) and six of seven canines from Group II (debris) had periprosthetic radiolucencies with endosteal scalloping develop. In contrast, only one of eight animals from Group III (debris + alendronate) had periprosthetic radiolucencies develop. Whereas tissues from control animals were mostly fibrous and acellular, tissues from both experimental groups had significant macrophage infiltration. Levels of prostaglandin E2 and interleukin-1 were elevated significantly in periprosthetic tissues from both experimental groups compared with controls. Continuous administration of alendronate effectively inhibited bone lysis for the 24-week duration of the study. This is consistent with the literature indicating that alendronate is incorporated in the mineralizing matrix making it refractory to osteoclastic resorption. This report has significant clinical implications for controlling the most common cause of implant failure.


[A retrospective study of ruptured abdominal aortic aneurysms--association with respiratory function and leukocytic granular elastase].
Fifty-two cases of abdominal aortic aneurysms including common iliac aneurysms operated on during July, 1981 and December, 1989 have been studied. They were divided into the following three of elective operation (n = 34), impending rupture (n = 5), and ruptured (n = 13) groups. Cases with abdominal operations without aneurysms were randomly selected as the control group (n = 12). Overall operative mortality was 9.6%, consisted of 30.8% of the ruptured, 20.0% of the impending rupture and 0% of the elective operation groups. Respiratory functions including FEV1.0%, V75, V50, V25 and V25/Ht were significantly lowered in the ruptured group. PaO2 of the ruptured group was also significantly lowered in comparison with both the control and the elective operation groups. Leukocytic granular elastase, playing a role of destruction of the elastin component in the pulmonary alveoli and the aortic media, was increased in the patients with ruptured aortic aneurysms, though the difference was not significant. The data suggested the possibility of aneurysm rupture in case with elevated leukocytic granular elastase. Surgery for abdominal aortic aneurysm, even in cases with decreased pulmonary function, should be considered aggressively to elimination of ominous result of aneurysm rupture.


Circulating CD95-ligand as a potential prognostic marker for recurrence in patients with synchronous colorectal liver metastases.
To assess whether circulating soluble CD95 ligand (sCD95L) levels are associated with recurrence-free survival (RFS) in patients with synchronous colorectal liver metastases. Blood samples were obtained from 62 patients with synchronous colorectal liver metastases before and after liver surgery. Serum sCD95L levels were determined using enzyme-linked immunosorbent assay (ELISA). Cox regression analysis was performed to determine the correlation between sCD95L levels and RFS and overall survival (OS). Median follow-up was 33 months. High pre-operative sCD95L levels were associated with poor RFS and OS in univariable (p=0.019 and p=0.020) and multivariable analyses (p=0.020 and p=0.003). Preoperatives CD95L is a potential prognostic factor for RFS and OS of patients undergoing surgery for synchronous colorectal liver metastases. Low preoperatives CD95L levels may help identify a subgroup of patients with synchronous liver metastases that are likely to benefit from liver surgery.


Moving Beyond 'Therapy' and 'Enhancement' in the Ethics of Gene Editing.
Since the advent of recombinant DNA technology, expectations (and trepidations) about the potential for altering genes and controlling our biology at the fundamental level have been sky high. These expectations have gone largely unfulfilled. But though the dream (or nightmare) of being able to control our biology is still far off, gene editing research has made enormous strides toward potential clinical use. This paper argues that when it comes to determining permissible uses of gene editing in one important medical context-germline intervention in reproductive medicine-issues about enhancement and eugenics are, for the foreseeable future, a red herring. Current translational goals for gene editing research involve a different kind of editing than would be required to achieve manipulation of complex traits such as intelligence, and there are more pressing (and unresolved) questions that need attention if clinical use of gene editing in reproductive medicine ever becomes a possibility.


Treatment of late-life depression: a role of non-invasive brain stimulation techniques.
Late-life depression (LLD) is a frequent complication of the ageing process, occurring in up to 5% of community-dwelling elderly and in a higher proportion of subjects with coexistent medical illnesses. Its presence has been consistently associated with cognitive impairment, greater disability and increased mortality. Approximately half of patients with LLD have evidence of subcortical ischaemic damage in prefrontal circuits revealed by MRI. This might constitute the biological substrate of the cardinal symptoms of depression and of executive dysfunction. An important proportion of patients with LLD do not achieve remission of their depressive symptoms in spite of adequate pharmacological and psychotherapeutic treatment. In addition, a group of LLD patients progress to further impairment and disability in the form of a dementing disorder. There is an imperative need to develop new treatment strategies for LLD. Non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are safe and efficacious interventions that might be used in combination with other therapeutic options to improve treatment outcomes. However, there are still questions regarding the optimal way in which rTMS and dTCS should be delivered as well as to the way in which we may identify the subjects who will benefit the most from these interventions.


5-Fluoro-2'-deoxyuridine induction of the fragile site on Xq28 associated with X linked mental retardation.
5-Fluoro-2'-deoxyuridine (FUdR) was found to be highly effective in inducing the heritable fragile site on Xq28 associated with mental retardation. Lymphocytes from two affected males manifested the fragile site in 30 to 40% of the mitoses when grown in the presence of FUdR. This observation suggests that depletion of the dTMP pool via thymidylate synthetase inhibition is responsible for the expression of the heritable fragile site on Xq28.


Corrosion Resistance of Waterborne Epoxy Resin Coating Cross-Linked by Modified Tetrabutyl Titanate.
The development of waterborne coating is essentially important for environmental protection, and cross-linking agent is of great significance for ensuring corrosion resistance of the coating. In this work, tetrabutyl titanate was modified by ethylene glycol and tris(2-hydroxyethyl) amine and used for the solidification of waterborne acrylic-epoxy resin. Fourier-transform infrared spectroscopy (FTIR) analysis revealed that the agent reacted with OH groups first to cross-link the resin preliminarily, and then, when the amount of agent was further increased, the amino groups opened epoxide rings resulting in a secondary cross-link. Field emission scanning electron microscope (FESEM) observation and electrochemical impedance spectroscopy (EIS) test found that, when the cross-linking agent was used at 6%, the coating remains intact and kept an impedance of as high as 108 Ωcm2 even after being immersed in NaCl solution for 30 days. Copper-accelerated acetic acid-salt spray (CASS) test confirmed that the coating containing 6% cross-linking agent provided the best protection for the carbon steel substrate.


Regulation of skeletal muscle blood flow during contractions.
Skeletal muscle blood flow increases nearly 20-fold during exercise. Despite experimental work in this area for more than a century, the physiological mechanisms responsible for the regulation of skeletal muscle blood flow during contractions remain relatively unknown. Historically, experiments have focused on identifying chemical factors associated with increased tissue metabolism that also act as vasodilators. However, functional vasodilation cannot be attributed to changes in the local concentration of any single metabolic factor. The rapid increase in muscle blood flow during the initial moments of exercise led others to consider a role for neural mechanisms in the development of functional hyperemia. However, a specific neural pathway has not been identified. Mechanical factors, such as vascular compression and increases in perfusion pressure, also affect vascular resistance and skeletal muscle blood flow. Yet the specific manner in which these mechanical factors interact during muscle contractions is not well understood. The recent determination that arterial feed vessels, upstream from the active tissue and microcirculation, also dilate during muscle contractions has led to the consideration that the vessels are primarily responsible for the regulation of bulk flow to the tissue. Since these vessels are anatomically separated from the active tissue, more complex, indirect regulatory mechanisms must be explored. It is also likely that the specific factors responsible for functional vasodilation and increased muscle blood during exercise differ between muscle fiber types and relative contraction intensities. Consideration of these factors may lead to a better understanding of the regulation of muscle blood flow.


Selective effects of nerve growth factor on spatial recent memory as assessed by a delayed nonmatching-to-position task in the water maze.
Nerve growth factor (NGF) ameliorates age-related deficits in certain types of memory in rats. Although the effects of NGF on reference memory are well documented, the influence of NGF on recent memory is less well understood. The issue of recent memory is of primary importance in the design of therapies for cognitive disorders, because this type of memory is impaired in elderly humans and is severely affected early in the course of Alzheimer's disease (AD). The present study was designed to evaluate the efforts of NGF on recent memory in a task that used escape from water as the motivating stimulus and used the same design as forced-choice recognition tasks given to humans. Fischer-344 rats, 4 months old (4MO) or 23 months old (23MO), were pretested in a new spatial recent memory task designed for the Morris water maze, a delayed nonmatching-to-position task, and infused intraventricularly with recombinant human NGF or vehicle. After 2 weeks of NGF infusion, no substantial changes in behavior were observed in either age group. However, NGF treatment extended over 4 weeks improved considerably the choice accuracy of 23MO rats to a level similar to the performance of 4MO rats. These results, together with our previous work (Markowska et al., 1994), indicate that the effects of NGF on spatial recent memory are more intense than on spatial reference memory. NGF suppressed the body weight gain in 4MO rats but did not affect 23MO rats. In 23MO rats, NGF mildly counteracted age-related deficits in inhibitory avoidance, but did not have an effect in young rats.


Isolation of genomic and cDNA clones encoding bovine poly(A) binding protein II.
cDNA clones for bovine poly(A) binding protein II (PAB II) were isolated. Their sequence predicts a protein of 32.8 kDa, revising earlier estimates of molecular mass. The protein contains one putative RNA-binding domain of the RNP type, an acidic N-terminal and a basic C-terminal domain. Analyses of authentic PAB II were in good agreement with all predictions from the cDNA sequence except that a number of arginine residues appeared to be post-translationally modified. Poly(A) binding protein II expressed in Escherichia coli was active in poly(A) binding and reconstitution of processive polyadenylation, including poly(A) tail length control. The cDNA clones showed a number of potential PAB II binding sites in the 3' untranslated sequence. Bovine poly(A)+RNA contained two mRNAs hybridizing to a PAB II-specific probe. Analysis of a genomic clone revealed six introns in the coding sequence. The revised molecular mass led to a demonstration of PAB II oligomer formation and a reinterpretation of earlier data concerning the protein's binding to poly(A).


Alternating d(GA)n DNA sequences form antiparallel stranded homoduplexes stabilized by the formation of G.A base pairs.
Alternating d(GA)n DNA sequences form antiparallel stranded homoduplexes which are stabilized by the formation of G.A pairs. Three base pairings are known to occur between adenine and guanine: AH+ (anti).G(syn), A(anti).G(anti) and A(syn).G(anti). Protonation of the adenine residues is not involved in the stabilization of this structure, since it is observed at any pH value from 8.3 to 4.5; at pH < or = 4.0 antiparallel stranded d(GA.GA) DNA is destabilized. The results reported in this paper strongly suggest that antiparallel stranded d(GA.GA) homoduplexes are stabilized by the formation of alternating A(anti).G(anti) and G(anti).A(syn) pairs. In this structure, all guanine residues are in the anti conformation with their N7 position freely accessible to DMS methylation. On the other hand, adenines in one strand adopt the anti conformation, with their N7 position also free for reaction, while those of the opposite strand are in the syn conformation, with their N7 position hydrogen bonded to the guanine N1 group of the opposite strand. A regular right-handed helix can be generated using alternating G(anti).A(syn) and A(anti).G(anti) pairs.


A New Approach to Overcome Insulin Resistance in Patients with Impaired Glucose Tolerance: The Results of a Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial of Efficacy and Safety of Subetta.
Impaired glucose tolerance (IGT) is a common carbohydrate metabolism disorder world-wide. To evaluate the efficacy and safety of 12-week Subetta therapy in correcting 2-h plasma glucose in patients with IGT, a multicenter, double-blind, placebo-controlled, randomized clinical trial was performed. Derived by technological treatment of antibodies to insulin receptor β-subunit and endothelial NO synthase, Subetta increases the sensitivity of insulin receptors by activating the insulin signaling pathway. Oral glucose tolerance test (OGTT), fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) were examined at screening, after 4 and 12 weeks. In Per Protocol population, 2-h plasma glucose in the Subetta group decreased by 2.05 ± 2.11 mmol/L (versus 0.56 ± 2.55 mmol/L in the Placebo group) after 12 weeks. The difference between the two groups was 1.49 ± 2.33 mmol/L (p < 0.0001). After 12 weeks, 65.2% of patients had 2-h plasma glucose <7.8 mmol/L. FPG remained almost unchanged. HbA1c tended to decrease. The number of adverse events did not differ in both groups. Subetta treatment is beneficial for patients with IGT; it also prevents progression of carbohydrate metabolism disorders.


Clopidogrel hypersensitivity: a novel multi-day outpatient oral desensitization regimen.
Clopidogrel hypersensitivity has posed a problem for the acute treatment and long-term care of a particular patient population with coronary artery disease and stent placement. Patients with clopidogrel hypersensitivity have had an increased risk of hypersensitivity reactions, including anaphylaxis, if they ingest clopidogrel without undergoing an oral desensitization procedure. The previously published desensitization protocols have either been performed in the intensive care unit, requiring significant cost and healthcare utilization, or have required a full-day outpatient commitment on behalf of the patient. To determine whether a multi-day outpatient oral clopidogrel desensitization protocol is effective and safe for patients with clopidogrel hypersensitivity. We retrospectively assessed the efficacy of a 10-dose outpatient multi-day clopidogrel desensitization protocol performed in a university allergy-immunology center from April 2006 to October 2008 in patients with clopidogrel hypersensitivity. Patients were desensitized over 2-3 half-day clinical visits and were able to go home between desensitization sessions. A preliminary cost analysis was performed using the average of actual costs for the outpatient clopidogrel desensitization procedure and was compared with the average cost for an inpatient oral desensitization completed at our institution. Eight patients with coronary artery disease, cardiac stent placement, and clopidogrel hypersensitivity underwent an outpatient multi-day oral clopidogrel desensitization procedure. All patients were successfully desensitized with the multi-day protocol without complications. No patient had recurrence of allergic reaction 3 months after the procedure. A preliminary cost analysis demonstrated a lower cost for the outpatient compared to the inpatient oral clopidogrel desensitization protocol. This outpatient 10-dose multi-day clopidogrel desensitization protocol is a safe and effective novel approach for the treatment of clopidogrel hypersensitivity in patients with coronary artery disease and cardiac stent placement. In addition to safety and efficacy, this protocol offers the patient the convenience of avoiding hospital admission or full-day time commitments.


Validation of a European Spanish-version of the Self-Evaluation of Negative Symptoms (SNS) in patients with schizophrenia.
Negative symptoms can be grouped into five domains: apathy/avolition, anhedonia, asociality, alogia, and affective flattening. There are few validate self-rated measures that assess these five dimensions. Therefore, this study aimed to validate the Self-Evaluation of Negative Symptoms (SNS) in Spanish patients with schizophrenia. Cross-sectional, validation study in 104 outpatients with schizophrenia evaluated using the Spanish version of the following scales: Clinical Assessment Interview for Negative Symptoms (CAINS), Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale for Schizophrenia (CGI-SCH), Personal and Social Performance (PSP), Motivation and Pleasure Scale - Self-Report (MAP-SR), 36-item Short-Form Health Survey (SF-36) and the Self-Evaluation of Negative Symptoms (SNS). Internal consistency (Cronbach's alpha) was 0.915. Convergent validity: The Pearson correlation coefficient between MAP-SR and SNS Total scores was 0.660 (p<0.001). For PANSS-N, the correlation was 0.437 (p<0.005) and with the CAINS-Total was 0.478 (p<0.005). Divergent validity: The Pearson correlation coefficient between SNS and PSP was r=-0.372 (p≤0.001), and with SF-36 Physical and Mental Summary Component scores were r=-0.213 (p=0.066) and r=-0.144 (p=0.219), respectively. Discriminant validity: SNS Total scores were significantly statistically different according to the severity of the negative symptomatology rated by the CGI-SCH negative scale (p<0.001). The SNS is a reliable and valid instrument to self-rate the five domains of negative symptoms in patients with schizophrenia and seems to be appropriate for use in everyday clinical practice as a complementary measure to the evaluation performed by the clinician.


Vancomycin induced DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) in a patient with tricuspid endocarditis.
A 57-year-old man presented for an elective pacemaker upgrade, complicated by the discovery of device infection. He had a background of complex congenital heart disease, including replacement of heart valves, and was treated for presumed infective endocarditis that was later confirmed by echocardiography. Antibiotic treatment, with intravenous vancomycin, was given as per the tissue sample sensitivities. On day 24 of treatment he deteriorated clinically, with the evolution of recurrent fever, epigastric pain, diarrhoea, widespread pruritic rash, lymphadenopathy and severe hypoxia over the subsequent 7-10 days. Blood tests revealed development of a marked eosinophilia, transaminitis and rising inflammatory markers. Further radiological imaging was non-diagnostic. On the basis of these clinical and biochemical features a diagnosis of drug reaction with eosinophilia and systemic symptoms syndrome was made. This led to the cessation of vancomycin, the offending agent and the referral for specialist immunology advice. He was subsequently treated with oral prednisolone and made a full recovery.


Magnolol induces apoptosis in MCF-7 human breast cancer cells through G2/M phase arrest and caspase-independent pathway.
Magnolol, a small-molecule hydroxylated biphenol, isolated from the root and stem bark of Magnolia officinalis, has been shown to possess antiproliferative effect on various cancer cell lines. In the current study, we found that magnolol potently inhibited proliferation and induced apoptosis in MCF-7 human breast cancer cells. Further mechanistic studies revealed that induction of apoptosis is associated with cell cycle arrest at G2/M phase, increased generation of reactive oxygen species (ROS), reduced mitochondrial membrane potential (MMP), release of cytochrome c (Cyto c) and apoptosis inducing factor (AIF) from mitochondria to cytosol, upregulation of Bax, p21 and p53, and down-regulation of Bcl-2, cyclin B1 and cyclin-dependent kinase 1 (CDK1). Our findings indicated that magnolol induced apoptosis in MCF-7 cells via the intrinsic pathway with release of AIF from mitochondrial and G2/M phase arrest pathway. Therefore, magnolol might be a potential lead compound in the therapy of breast cancer.


Cardiovascular Health Is Associated With Physical Function Among Older Community Dwelling Men and Women.
Age related decline in physical function is a significant concern affecting the quality of life of older individuals. We examined the associations between baseline overall cardiovascular health (CVH), its components, and physical function in 906 men and women from the InCHIANTI cohort. Physical function was assessed using the Short Performance Physical Battery and poor physical function was defined as an Short Performance Physical Battery score less than 10. Overall CVH score, ranging from 0 to 12 in the cohort, was operationalized using adherence to ideal levels for health behaviors including smoking status, physical activity, body mass index, and diet quality; and health factors including blood pressure, plasma cholesterol, fasting blood glucose, with higher scores indicating better CVH. Mean age at baseline was 74 (SD = 6.7) years and 55% were women. At baseline and over 9 years, as compared to the lowest tertile of overall CVH score, the highest tertile was associated with a 69% (p < .001) and 63% (p < .001), respectively, lower risk of poor physical function. Among the CVH components, adherence to ideal levels of health behaviors was more strongly and consistently associated with lower odds of poor physical function than health factors. Better overall CVH was protective against poor physical function in community-dwelling men and women aged 65 years and older. Improving CVH may be instrumental in the prevention of poor physical function in older adults.


[Histochemical and ultrastructural observations of limb muscle in spontaneous diabetic mice].
Spontaneous non-obese diabetic (NOD) mice were used to study the morphological change of muscle fibers in diabetes mellitus. The gastrocnemius and soleus muscles were removed from the NOD mice suffering from diabetes mellitus for 1, 3, 6 or 9 weeks. Muscle fibers were observed electronmicroscopically and histochemically, by staining with Sudan black B. Single fiber atrophy was noted in white fibers at an early stage of the illness. At the age of 6 and 9 weeks, white fibers showed extensive damage, characterized by the atrophy and wide separation of myofibrils, irregularity and thinness of myofilaments and massive glycogen deposition. The damage in the myofibril itself, however, was less pronounced in red and intermediate fibers, and those fibers had more abnormal mitochondria and a decreased affinity for sudan pigment. Morphological changes were varied in the three types of fibers. It is concluded that diabetes mellitus had different effects on each three types of muscle fibers neurogenically and metabolically.


Optical manipulation and transport of microparticles on silicon nitride microring-resonator-based add-drop devices.
We demonstrate optical manipulation and transport of 1 microm sized polystyrene particles on silicon nitride microring-resonator-based add-drop devices in an integrated optofluidic chip. By tuning the input laser wavelength and upon certain resonance quality factors, we observe microparticles (i) transported to the throughput port, (ii) routed to the microring and trapped in round trips, and (iii) transported to the drop port. We investigate the microparticle velocity at various laser wavelengths and in various spatial regions of the devices with different resonance quality factors. Such a device can act as a particle add-drop filter for "particle circuits" in lab-on-a-chip applications.


Studies on histopathological changes in the gill, liver and kidney of Channa punctatus (Bloch) exposed to Alachlor.
Freshwater fish, Channa punctatus was exposed to sublethal concentration of a chloroacetanilide herbicide alachlor technical grade and lasso 50% EC for a period of 10 days. The histopathological changes in the gill include: necrosis, vacuolar degeneration, fusion and atrophy of primary and secondary gill lamellae. The tissue damages like degeneration of cytoplasm in hepatocytes, atrophy formation of vacuoles, rupture in blood vessels and disposition of hepatic cords are the histopathological changes observed in the liver. The changes in the kidney include: necrosis, swelling of renal tubules, cellular hypertrophy and granular cytoplasm.


Development of an oral exposure mouse model to predict drug-induced hypersensitivity reactions by using reporter antigens.
The capability of certain drugs to cause immune-mediated drug hypersensitivity reactions in susceptible individuals has initiated a search for pre-clinical screening tools to identify immunosensitizing drugs. Since most drugs are taken orally, hazard assessment of their immunosensitizing potential should include oral exposure models. In this study, the predictive value of the reporter antigen (RA) approach was investigated in combination with oral or intraperitoneal (ip) exposure to a selection of allergenic drugs, i.e., D-penicillamine (D-Pen), Diclofenac (DF), or Nevirapine (Nevi). The RA trinitrophenyl-Ovalbumin (TNP-OVA) was used to assess the capacity of the drugs to stimulate systemic immune responses to a bystander antigen, whereas the RA TNP-Ficoll was used to indicate whether the drugs were able to induce specific anamnestic T-cell responses. TNP-OVA was injected (ip) in C3H/HeOuJ mice that were subsequently exposed (orally or ip) to one of the drugs via different exposure protocols. All three model drugs used resulted in delayed type hypersensitivity reactions to TNP-OVA after ip and oral exposure. In addition, TNP-specific serum antibody levels were increased after ip exposure to Nevi, and after both oral and ip exposure to D-Pen and DF. These data indicate that the present drugs are able to stimulate immune responses to bystander antigens. Responses to TNP-Ficoll were measured in the popliteal lymph node of BALB/c mice three weeks after they received a single oral dose of D-Pen or DF. Results of this approach show that orally pre-treated mice responded with enhanced responses (TNP-specific IgG1 and IFN-gamma production) to sub-optimal doses of D-Pen or DF in a drug-specific manner. Data with TNP-Ficoll indicate that these drugs stimulate systemic formation of specific T cells. Together, the RA-approach allows assessment of systemic sensitization upon oral and/or ip exposure to the selected drugs. To further evaluate the utility of these models, more drugs, including non-allergenic drugs and those that require metabolic conversion to become allergenic need to be studied in the present models.


Fractal Analysis Method for the Complexity of Cell Cluster Staining on Breast FNAB.
Because of the increased precision of ultrasound breast cancer screening, early cancer cases with no clear mass or extraction of microcysts on imaging have recently increased, and improvement of the accuracy of breast fine-needle aspiration biopsy (FNAB) cytology is needed. The objective of this study was to investigate the usefulness of cluster gray image-fractal analysis evaluating the darkness of clusters, cluster unevenness, and complexity of hyperchromicity (cluster density) of deep-stained cell clusters, known as hyperchromatic crowded cell groups (HCG), on FNAB as a cytology assistance system for breast FNAB. One hundred clusters collected from 10 patients with fibroadenoma (FA), 90 clusters from 9 patients with ductal carcinoma in situ (DCIS), and 122 clusters from 11 patients with invasive breast carcinoma of no special type (IBC-NST) were used. (1) Cluster size classification: clusters were classified into small, middle, and large clusters (small cluster: smaller than 40 × 102 μm2; large cluster: 100 × 102 μm2 or larger; middle cluster: intermediate), and their frequency was calculated. (2) Cluster gray image-fractal analysis: (a) the darkness of clusters (luminance), (b) cluster unevenness (complexity), and (c) complexity of cluster density (roundness-corrected fractal value) were assessed. For statistical analysis, the multiple comparison Steel-Dwass test was used, with a significance level of p < 0.05. (1) Cluster size classification: in FA, small, middle, and large clusters appeared at a similar frequency, and the frequency (30%) of large clusters was significantly higher than that in other diseases. In IBC-NST, many small clusters (61%) appeared and their frequency was significantly higher than that in other diseases, whereas the frequency of large clusters was significantly lower. (2) Cluster gray image-fractal analysis: in IBC-NST, the luminance of small clusters was low (dark), the cluster unevenness was high, and the complexity of cluster density was high, whereas the luminance of large clusters was high (bright), the cluster unevenness was high, and complexity of cluster density was high compared with those in FA. Cluster gray image-fractal analysis evaluating the darkness of clusters, cluster unevenness, and complexity of cluster density in breast FNAB HCG is a useful cytology assistance system for breast FNA.


MicroRNA-204 modulates colorectal cancer cell sensitivity in response to 5-fluorouracil-based treatment by targeting high mobility group protein A2.
MicroRNAs (miRNAs) are a conserved class of ∼22 nucleotide RNAs that playing important roles in various biological processes including chemoresistance. Recently, many studies have revealed that miR-204 is significantly attenuated in colorectal cancer (CRC), suggesting that this miRNA may have a function in CRC. However, whether miR-204 modulates chemosensitivity to 5-fluorouracil (5-Fu) in colorectal cancer is still unclear. In our present study, we discuss this possibility and the potential mechanism exerting this effect. We identified high mobility group protein A2 (HMGA2) as a novel direct target of miR-204 and showed that miR-204 expression was decreased while HMGA2 expression was increased in CRC cell lines. Additionally, both MiR-204 overexpression and HMGA2 inhibition attenuated cell proliferation, whereas forced expression of HMGA2 partly restored the inhibitory effect of miR-204 on HCT116 and SW480 cells. Moreover, the miR-204/HMGA2 axis modulated the resistance of tumor cells to 5-Fu in HCT-116 and SW480 colon cancer cells via activation of the PI3K/AKT pathway. These results demonstrate that the miR-204/HMGA2 axis could play a vital role in the 5-Fu resistance of colon cancer cells. Taken together, our present study elucidated that miR-204 upregulated 5-Fu chemosensitivity via the downregulation of HMGA2 in colorectal cancer and provided significant insight into the mechanism of 5-Fu resistance in colorectal cancer patients. More importantly, our present study suggested that miR-204 has potential as a therapeutic strategy for 5-Fu-resistant colorectal cancer.


[Diabetic ketoacidosis (169 episodes in 131 patients in the course of 10 years)].
Diabetic patient material--presenting hyperglycaemic ketoacidotic episode--observed in Gyula and Szekszárd County Hospitals in period 1980-89, was reviewed by authors. 131 patients were admitted with 169 ketoacidotic episodes (among them 23 patients had 62 recurrences). The mean age of patients were 49.4 years (14-84 years), duration of diabetes 9.5 years (from one month to 45 years). The common cause of diabetic ketoacidosis was respiratory (26 per cent) and enteral (35.5 per cent) infection. The consciousness of patients had shown close correlation with the increase of blood sugar and urea nitrogen level as well as with the decreasing of the pH value of capillary blood. The first step of the therapy was the parenteral fluid intake with isotonic solution (in the first hour the average 1351 ml). In 18 patients fast-acting insulin (Novo Actrapid MC) was given by constant infusion, in the remaining cases intravenous or intramuscular low doses of the same insulin were administered. The importance of early potassium replacement, and the dangers of forced and rapid correction of acidosis is emphasized. Lethality related to episodes was 10 per cent, related to the patients 12.9 per cent. The number of ketoacidotic cases did not decrease parallel with the improvement of therapeutic possibilities, as it was experienced by their earlier evaluations. The importance of the prevention of acute metabolic disorders is outlined might be resulted from increasing the efficacy of patients education and better knowledge of GP's, as well.


Antiarrhythmics in atrial fibrillation.
Atrial fibrillation (AF) is a common arrhthymia that exists in both the acute and chronic form. As the molecular basis of arrhythmogenesis is further elucidated, the discovery of novel antiarrhythmic agents, which can be tailored to individual patients and the particular subtype of AF, while minimizing potential side effects, will become possible.


Effect of energy density in the diet and milking frequency on hepatic long chain fatty acid oxidation in early lactating dairy cows.
The objective of this study was to examine the effects of diet energy density (high versus low) and increased milk yield, induced by increased milking frequency (two versus three times daily), on the hepatic status of triacylglycerol (TAG) and glycogen content and hepatic long chain fatty acid (LCFA) oxidation capacity in early lactation in a 2 x 2 factorial design. Forty multiparous Danish-Holstein dairy cows were used from 8 weeks before to 8 weeks after calving. Liver biopsies and blood samples were taken in weeks -2, 2, and 7 from calving. The cows fed the high energy density diet, compared with the cows fed the low energy density diet, had an 18 and 28% higher milk production and net energy intake, respectively. Milk yield was increased by 10% when the cows were milked three times compared with twice daily. Complete (CO2 production) and incomplete (ketone body production) LCFA oxidation capacity in the liver were 35 and 32% higher, respectively, and liver TAG content was 48% lower for the cows fed the high energy density diet compared with the low energy density diet. Overall there was no effect of milking frequency on liver parameters. However, a significant interaction between diet and milking frequency showed that the cows milked three times daily and fed the low energy density diet had the lowest liver LCFA oxidation (CO2 and ketone body) capacity. Furthermore, these cows had the numerically highest liver TAG content. The results for liver LCFA metabolism are discussed in relation to the plasma concentration of metabolites and insulin. In conclusion, cows in early lactation given a high energy density diet will, in general, have a lower risk of high TAG infiltration in the liver.


[Study for searching equilibrium point in dentulous hemimandibulectomy patients].
Occlusal registration for prosthodontic rehabilitation in dentulous hemimandibulectomy patient has various difficulties due to mandibular instability. The purpose of this study was to find the occlusal contact position for remaining dentition to stabilize the hemiresected mandible during clenching. Three hemimandibulectomized subjects without surgical bony construction were selected and custom-made Gothic-arch typed apparatus was fabricated. Mandibular movements during clenching were recorded with jaw movement tracking device with six degrees of freedom. The results were as follows: 1. The direction of the mandibular rotation around each coordinate axis in 3-dimensional space during clenching was constant in each subject, regardless of stylus position. 2. The most stable points on the hemimandibules during clenching did not necessarily correspond to the mid-portion of the remaining dentition of the mandible. 3. When referred to the maxillary arch, the point was lined up within the distal half of the second premolar and the mesial third of the first molar in mid-sagittal plane along the long axis of the remaining dentition. 4. Rotational axis during clenching existed on the horizontal plane. 5. It was assumed that the most stable point of the mandible in a hemimandibulectomy patient may be useful in interocclusal registration in clinical dental practice.


Interictal Fast Ripples Are Associated With the Seizure-Generating Lesion in Patients With Dual Pathology.
Rationale: Patients with dual pathology have two potentially epileptogenic lesions: One in the hippocampus and one in the neocortex. If epilepsy surgery is considered, stereotactic electroencephalography (SEEG) may reveal which of the lesions is seizure-generating, but frequently, some uncertainty remains. We aimed to investigate whether interictal high-frequency oscillations (HFOs), which are a promising biomarker of epileptogenicity, are associated with the primary focus. Methods: We retrospectively analyzed 16 patients with dual pathology. They were grouped according to their seizure-generating lesion, as suggested by ictal SEEG. An automated detector was applied to identify interictal epileptic spikes, ripples (80-250 Hz), ripples co-occurring with spikes (IES-ripples) and fast ripples (250-500 Hz). We computed a ratio R to obtain an indicator of whether rates were higher in the hippocampal lesion (R close to 1), higher in the neocortical lesion (R close to -1), or more or less similar (R close to 0). Results: Spike and HFO rates were higher in the hippocampal than in the neocortical lesion (p < 0.001), particularly in seizure onset zone channels. Seizures originated exclusively in the hippocampus in 5 patients (group 1), in both lesions in 7 patients (group 2), and exclusively in the neocortex in 4 patients (group 3). We found a significant correlation between the patients' primary focus and the ratio Rfast ripples, i.e., the proportion of interictal fast ripples detected in this lesion (p < 0.05). No such correlation was observed for interictal epileptic spikes (p = 0.69), ripples (p = 0.60), and IES-ripples (p = 0.54). In retrospect, interictal fast ripples would have correctly "predicted" the primary focus in 69% of our patients (p < 0.01). Conclusions: We report a correlation between interictal fast ripple rate and the primary focus, which was not found for epileptic spikes. Fast ripple analysis could provide helpful information for generating a hypothesis on seizure-generating networks, especially in cases with few or no recorded seizures.


[250 years of English psychiatry].
The history of British psychiatry is considered from five main viewpoints: clinical practice, the institutional basis, the legislative basis, lay perspectives of-mental disorder, and European influences. Its philosophical basis can be traced back to the work of the seventeenth-century philosophers. Thomas Hobbes and John Locke. In Scotland, both 'philosophy of mind' and new clinical methods flourished during its Enlightenment; the concept of 'neurosis' was developed by William Cullen. Around 1800, James Prichard's concept of 'moral insanity' became the foundation of modern work on personality disorder and psychopathy. The psychotic illness of King George III, beginning in 1788, led to greater public sympathy for the mentally ill. Attitudes since then have varied, with 'antipsychiatry' becoming very influential in the 1960s. By the mid-eighteenth century, specialised institutions for the mentally ill existed in a number of cities, there were also units attached to charitable general hospitals, but none of these continued after about 1830. The neglect of patients in private madhouses, prisons, and poorhouses led to increasing concern by Parliament, which resulted in the development of public asylums throughout the country. Severe legal restrictions on their activities were modified in 1930 and completely reformed in 1959. From the mid-nineteenth century, French and German influences became increasingly strong, but British universities played no active part in psychiatry until the 1950s. Psycho-analysis did not develop strongly in Britain, where the main contribution was through translation and biography, but some leading analysts came as refugees in the 1930s-as did other psychiatrists from central Europe. Another important influence was that of Adolf Meyer at the Institute of Psychiatry, London, particularly through Sir Aubrey Lewis; physical treatment methods also came to Britain from Europe. In the second half of this century, the most important British developments have been in social psychiatry therapeutic communities, day hospitals, comprehensive district services, psychogeriatrics, etc. Academic psychiatry has also become strong since the 1960s.


Effects of calcium entry blockers on calcium fluxes in a vascular smooth muscle cell line.
A smooth muscle cell line was used for studies on the activity of the voltage-sensitive calcium channel (VSCC). Upon exposure to a depolarizing solution or to a calcium channel activator, an increase in 45Ca2+ uptake was observed. Calcium entry blockers inhibited the uptake with potencies very similar to those observed in relaxing depolarization-induced constriction of aortic rings. The two enantiomers of the dihydropyridine PN 200-110 showed about a 300-fold potency difference in blocking 45Ca2+ uptake.


A microwave and quantum chemical study of cyclopropaneselenol.
The microwave spectrum of cyclopropaneselenol, C 3H 5SeH, has been investigated in the 21.9-80 GHz frequency range. The microwave spectra of the ground vibrational state of five isotopologues of cyclopropaneselenol (C 3H 5 (82)SeH, C 3H 5 (80)SeH, C 3H 5 (78)SeH, C 3H 5 (77)SeH, and C 3H 5 (76)SeH) of one conformer, as well as the spectra of two vibrationally excited states of each of the C 3H 5 (80)SeH and C 3H 5 (78)SeH isotopologues of this rotamer, have been assigned. The H-C-Se-H chain of atoms is synclinal in this conformer, and there is no indication of further rotameric forms in the microwave spectrum. The b-type transitions of the ground vibrational state of the more abundant species C 3H 5 (80)SeH and C 3H 5 (78)SeH were split into two components, which is assumed to arise from tunneling of the proton of the selenol group between two equivalent synclinal potential wells. The tunneling frequencies were 0.693(55) MHz for C 3H 5 (80)SeH and 0.608(71) MHz for C 3H 5 (78)SeH. The microwave study has been augmented by high-level density functional and ab initio quantum chemical calculations, which indicate that the H-C-Se-H dihedral angle is approximately 75 degrees from synperiplanar (0 degrees).


Evaluating qualitative assays using sensitivity and specificity.
Sensitivity and specificity are two important indices of performance of qualitative assays. Evaluating these indices usually requires one to identify the true disease state of each subject involved in a study. This implies that a perfect test, a "gold standard," is needed to test each subject. However, a gold standard test cannot always be performed on all subjects, whether because of cost or adverse effect on a subject's welfare. In these situations, a common practice is to apply both a currently used assay and an investigational assay to the same specimen. If the testing results are discordant, a gold standard test is applied. This approach has been criticized by many and, in fact, the statistics based on this approach usually overestimate sensitivity and specificity. This paper proposes two alternative methods to estimate sensitivity and specificity. Simulation results show that these methods perform better than the commonly used existing ones. This paper proposes new acceptance criteria and designs to specific topics for the evaluation of blood related assays as well. To evaluate a qualitative assay related to blood specimens, one must also perform studies of storage conditions, interfering substances, and other related factors, in order to establish the equivalency of the assay under standard and various other conditions. To conduct these studies, true negative blood donor specimens are used as a sample from a nondiseased population; and blood donor specimens with spiked analyte are used to represent a sample from a diseased population. Currently, the target-spiking ranges and sample sizes are determined subjectively. This paper presents new acceptance criteria on acceptable conditions and objective standards for selecting the target-spiking range and sample size.


[Developments in surgical gynecology].
This farewell lecture presents an overview of the development of operative gynecology on the basis of oncological surgery, removal of the uterus with or without pelvic floor reconstruction as well as corrective surgery of the uterovaginal canal. Without doubt the significance of endoscopic surgery, especially involving the adnexa and the cavum uteri, has increased. Uterus extirpation should remain in the domain of the vaginal approach. An experienced 'vaginalist' has has hardly any need for parasocpic assistance which should influence the renaissa lance of the vaginal method. Emphasis should be put on vaginal reconstruction of the affected pelvic floor in the course of incontinence surgery. Thanks to new diagnostic means malformations of the uterus can be detected more frequently, and it appears essential to develop and improve these methods further if one is to prevent laparoscopic polypragmatism. The author's opinion about the insufficient surgical experience and training in medical specialist education will be discussed.


Effects of IL-1 molecules on growth patterns of 3-MCA-induced cell lines: an interplay between immunogenicity and invasive potential.
The balance between inflammation and immunity is cardinal for the outcome of the malignant process. Local attenuated inflammatory responses mediated by innate cells may provide accessory signals for the development of acquired immunity against malignant cells. In contrast, excessive inflammatory responses accompany tumorigenesis and tumor invasiveness, by the induction of immunosuppression. In the present study, we have assessed the role of tumor cell-derived IL-1 in determining the invasive versus immunostimulatory potential of tumor cells. For this purpose, we have used 3-MCA-induced fibrosarcoma cell lines from IL-1 knockout (KO) versus control mice. Cell lines with no IL-1 failed to establish tumors in intact mice, while lines obtained from control mice were invasive and induced a potent angiogenic response. In contrast, cell lines from IL-1KO mice were more immunogenic. SDF-1 and IL-6, each induced by IL-1, were the two major cytokines whose levels differed in cell lines with or without IL-1. We could not detect differences in cell surface markers related to immunogenicity, such as MHC Class I, co-stimulatory, or adhesion molecules between both types of cells. However, more T-cells were observed at the inoculation site of tumor cells devoid of IL-1 and more pronounced parameters related to anti-tumor immunity were observed in the spleen (IL-12 and IFNgamma) of these mice, compared to mice bearing tumors derived from control mice, where host-derived IL-1 is present. In addition, injection of tumor cells devoid of IL-1, which failed to grow in mice, induced an anti-tumor cell immune memory, while in mice injected with tumor cells from control mice; no immune memory could be detected. From the results, it seems that IL-1 is a crucial factor in determining the balance between immunity and inflammation in tumor-bearing mice. This suggests that manipulation of IL-1 could be useful in anti-tumor therapy, by reducing invasiveness and promoting immunity against the malignant cells.


The ARRONAX project.
A new high-energy and high-intensity cyclotron, ARRONAX, has been set into operation in 2010. ARRONAX can accelerate both negative ions (H- and D-) and positive ions (He++ and HH+). Protons can be accelerated from 30 MeV up to 70 MeV with a maximum beam intensity of 2 × 375 μAe whereas He++ can be accelerated at 68 MeV with a maximum beam current of 70 μAe. The main fields of application of ARRONAX are radionuclide production for nuclear medicine and irradiation of inert or living materials for radiolysis and radiobiology studies. A large part of the beam time will be used to produce radionuclides for targeted radionuclide therapy (copper-67, scandium-47 and astatine-211) as well as for PET imaging (scandium-44, copper-64, strontium-82 for rubidium-82 generators and germanium-68 for gallium-68 generators). Since the beginning of the project a particular interest has been devoted to alpha-radionuclide therapy using complex ligands like antibodies and astatine-211 has been selected as a radionuclide of choice for such type of applications. Associated with appropriate carriers, all these radionuclides will respond to a maximum of unmet clinical needs.


Neutrophil to Lymphocyte Ratio as a Predictive Marker of Vestibular Schwannoma Growth.
To examine the predictive value of neutrophil to lymphocyte ratio (NLR) for vestibular schwannoma (VS) growth. Retrospective case-control study. Tertiary, referral center. Patients with sporadic VS and available NLR obtained within 1 year from the diagnosis were divided into two groups with growing or non-growing tumor. Patients with known conditions affecting NLR were excluded. NLR and tumor growth as determined by linear measurements on serial magnetic resonance imaging. VS growth, demographic factors, and NLR were compared using multi-variant logistic regression and Receiver Operating Characteristic (ROC) curve analysis. A total of 161 patients fulfilled the inclusion criteria, 79 with growing VS (men:women ratio = 43:36, mean age, 61.8 years) and 82 with non-growing tumors (men:women ratio = 37:45, mean age, 64.9 years). Mean NLR for the group with growing VS was 3.34 (SD [standard deviation] = 1.5) and 2.31 (SD = 0.76) for the group with non-growing VS (p = 0.001; 0.03 when adjusted for all parameters). The optimal cut-off point was NLR = 3.05 with positive predictive value 83.8% and 100% for NLR greater than 5.3. ROC analysis of the adjusted data for age, sex, and side, gave an area under the curve of 0.768, indicating NLR as a good independent predictive marker. Interestingly, the size of tumor was statistically significantly higher for the growing VS group (p = 0.001). Despite the low specificity of low NLR, our results indicate high NLR as a good predictive marker for VS growth. Confirmation by prospective studies will have a significant impact on patients' management.


Effect of student vulnerability on perceptions of teacher-student sexual involvement.
This study explored whether the vulnerability of an adolescent student affected perceptions of teacher sexual misconduct. Respondents (150 male and 150 female undergraduates) read scenarios depicting teacher sexual misconduct varied by respondent gender, gender dyad (male teacher-female student and female teacher-male student), and three levels of student vulnerability. The vulnerability of the student was found to have little impact on perceptions. On most variables, interactions emerged between respondent gender and gender dyad. Specifically, male respondents viewed the female teacher-male student dyad less negatively than the male teacher-female student dyad. Female respondents generally did not make distinctions based on gender dyad.


Canal-centering ability of two rotary file systems.
The ability of two nickel-titanium rotary file systems to maintain the original path of the canal were compared by using a new split-mold design (the Endodontic Cube). The mesial roots of 10 mandibular first- and second-molar teeth with separate canals from orifice to foramen were divided into two groups based on canal curvature and morphology. Working lengths for each canal were determined 1.0 mm short of where the file tip was visible on the external surface of the root. The teeth were embedded in composite resin by using the Endodontic Cube as a mold and sectioned into five pieces. ProFile Ni-Ti.06 taper Series 29 and ProFile GT rotary instrumentation techniques were randomly assigned to one of the canals and used in a crown-down fashion to a 0.217 ProFile and a 0.06 GT master apical file, respectively. Digital photographs were made of the middle three sections and software features of Adobe Photoshop were used to measure the movement of the canal centers by superimposing the images of the instrumented and uninstrumented canals. Data were analyzed using ANOVA. Both systems remained centered within the canal with minimal deviation from the original canal path. The largest mean movement was less than 0.15 mm. The Endodontic Cube was an effective tool for studying and comparing instrumentation techniques.


Photosynthesis in trees: organization of chlorophyll and photosynthetic unit size in isolated gymnosperm chloroplasts.
Chloroplasts have been isolated in high yield from several gymnosperms and from two deciduous trees. The organization of chlorophyll in the chloroplasts of these woody species is basically similar to that in angiosperm crop plants and green algae. The tree chloroplasts contain two chlorophyll proteins, the P700-chlorophyll a-protein and the major light-harvesting chlorophyll a/b-protein, the size, spectral characteristics, and function of which are the same as the equivalent complexes previously isolated from other classes of green plants. All the gymnosperms have chlorophyll/P700 ratios (photosynthetic unit sizes) 1.6 to 3.8 times larger than that typically found in crop plants; the deciduous trees have units of intermediary size. The presence of fewer but larger photosynthetic units in the woody species can partially account for their lower photosynthetic rate and explains why their photosynthetic processes saturate at lower light intensities. Chloroplasts of shade needles have large units containing a greater proportion of the light-harvesting chlorophyll a/b-protein than those of sun needles.


Antibacterial Activity of Lumbricus Rubellus Earthworm Extract Against Porphyromonas Gingivalis as the Bacterial Cause of Periodontitis.
The purpose of this study was to determine the antibacterial activity of Lumbricus rubellus earthworms through inhibitory zone diameter to the growth of the bacterium Phorphyromonas gingivalis as the cause of periodontitis. This was an experimental study with randomised posttest-only control group design. The study was conducted at the Microbiology Research Center laboratory at the Faculty of Dentistry, Airlangga University, Indonesia. The study was conducted in vitro, the sample size was calculated using the Federer formula as many as four agar plates containing bacteria Phorphyromonas gingivalis, with each plate given five different treatments: control (ethanol), Lumbricus rubellus earthworm extract (ECT) with concentrations of 50%, 25%, 12.5%, and 6.25% respectively. The data in the form of inhibition zone diameter (measured in millimetres) obtained were tested using One-Way ANOVA. The mean diameter of the inhibitory zone extract of Lumbricus rubellus earthworm on the growth of Phorphyromonas gingivalis bacteria in the treatment group had significant differences (p < 0.05). The mean inhibition zones between controls and the ECT treatment group (ECT 50%, ECT 25%, ECT 12.5%) were statistically different (p < 0.05), in contrast with ECT 6.25% (p > 0.05) which did not show significant difference with the control group (p > 0.05). Lumbricus rubellus earthworm extract with a concentration of 50% has the largest diameter of the inhibitory zone on the growth of the Phorphyromonas gingivalis bacteria. The 6.25% earthworm extract showed no antibacterial activity against the growth of Phorphyromonas gingivalis bacteria.


Viewing the proteome from oligopeptides and prediction of protein function.
Our research activity of making the lexicon of relatively short oligopeptides has been one of the first steps to view the world of proteome from the perspective of oligopeptides. We propose a new method for the prediction of protein function, especially GeneOntology terms (GO terms), based on statistical characteristics of oligopeptides as an application of the lexicon. In the lexicon, a known function of a protein is inherited to its oligopeptides, and the correspondence between oligopeptides and the function is calculated in the whole proteins. In our method, unknown functions of proteins are predicted by means of the correspondence automatically. We measured the prediction performance using the 28,520 whole human proteins registered in RefSeq for several GO terms by recall-precision graphs. The GO terms include 'membrane', 'nucleus', 'ATP binding', 'hydorolase activity', 'GTP binding', 'intracellular signaling cascade' and 'ubiquitin cycle'. In most cases, it scores 70% recall with 80% precision. The prediction for ATP binding and GTP binding results in quite high performance: it scores 80% recall with 80% precision. Even in the worst case (ubiquitin cycle), it scores 62.6% recall with 80% precision. These results suggest that the proposed method is quite efficient for predicting GO terms.


Intracerebral HIV-1 glycoprotein 120 produces sickness behavior and pituitary-adrenal activation in rats: role of prostaglandins.
HIV infection is associated with profound neurobehavioral and neuroendocrine impairments. Previous studies demonstrated that HIV causes neuropathological alterations indirectly, via shedding of glycoprotein 120 (gp120) within the brain. To extend these findings, we examined the neurobehavioral and neuroendocrine effects of central administration of gp120, as well as the role of brain prostaglandins in mediating these effects. Intracerebroventricular (i.c.v.) injection of gp120 in rats produced a marked sickness behavior syndrome, consisting of reduced exploratory behavior, suppressed consumption of food and saccharin solution, and reduced body weight. Gp120 also induced a significant febrile response and increased serum levels of ACTH and corticosterone. Following i.c.v. gp120 administration, the ex vivo production of PGE2 by the hypothalamus, frontal cortex, and hippocampus was significantly elevated, and indomethacin, a prostaglandin synthesis inhibitor, attenuated this elevation. Pre-treatment with indomethacin reduced the fever and adrenocortical activation induced by gp120 administration, but not its behavioral effects. These findings indicate that gp120 may be responsible for some of the behavioral and endocrine abnormalities seen in HIV-infected patients. Prostaglandins are important mediators of the physiological, but not the behavioral effects of brain gp120.


Epigenetic downregulation of STAT6 increases HIF-1α expression via mTOR/S6K/S6, leading to enhanced hypoxic viability of glioma cells.
Multifunctional signal transducer and activator of transcription (STAT) proteins play important roles in cancer. Here, we have shown that STAT6 is epigenetically silenced in some cases of malignant glioblastoma, which facilitates cancer cell survival in a hypoxic microenvironment. This downregulation results from hypermethylation of CpG islands within the STAT6 promoter by DNA methyltransferases. STAT6 interacts with Rheb under hypoxia and inhibits mTOR/S6K/S6 signaling, in turn, inducing increased HIF-1α translation. STAT6 silencing and consequent tumor-promoting effects are additionally observed in glioma stem-like cells (GSC). Despite recent advances in cancer treatment, survival rates have shown little improvement. This is particularly true in the case of glioma, where multimodal treatment and precision medicine is needed. Our study supports the application of epigenetic restoration of STAT6 with the aid of DNA methyltransferase inhibitors, such as 5-aza-2-deoxycytidine, for treatment of STAT6-silenced gliomas.


Critical materialism: science, technology, and environmental sustainability.
There are widely divergent views on how science and technology are connected to environmental problems. A view commonly held among natural scientists and policy makers is that environmental problems are primarily technical problems that can be solved via the development and implementation of technological innovations. This technologically optimistic view tends to ignore power relationships in society and the political-economic order that drives environmental degradation. An opposed view, common among postmodernist and poststructuralist scholars, is that the emergence of the scientific worldview is one of the fundamental causes of human oppression. This postmodernist view rejects scientific epistemology and often is associated with an anti-realist stance, which ultimately serves to deny the reality of environmental problems, thus (unintentionally) abetting right-wing efforts to scuttle environmental protection. We argue that both the technologically optimistic and the postmodernist views are misguided, and both undermine our ability to address environmental crises. We advocate the adoption of a critical materialist stance, which recognizes the importance of natural science for helping us to understand the world while also recognizing the social embeddedness of the scientific establishment and the need to challenge the manipulation of science by the elite.


Multinucleated giant cell reaction in lower lip squamous cell carcinoma: a clinical, morphological, and immunohistochemical study.
Multinucleated giant cell (MGC) reactions have been identified in several malignancies, but their frequency and significance in lower lip squamous cell carcinoma (SCC) are not established. This study evaluated the MGC reactions and their association with clinicopathological parameters in lower lip SCCs. The polarization profile of these cells (M1 or M2 macrophages) was also assessed. The presence and distribution of MGC reactions in high-power fields (400×) were evaluated in hematoxylin/eosin-stained histological sections of 91 lower lip SCCs. The histopathological grade of malignancy was evaluated using two grading systems (World Health Organization [WHO] and Malignancy Grading of the Deep Invasive Margins). The histiocytic nature (CD68) and polarization profile (M1-HLA-DR+ or M2-CD163+) of MGCs were evaluated by immunohistochemistry. Multinucleated giant cell reaction was identified in 36 (39.6%) cases, and its frequency was 3.3 times higher in well/moderately differentiated tumors than in poorly differentiated tumors (WHO grading system) (P = 0.006). For Malignancy Grading of the Deep Invasive Margins, the frequency was 2.03 times higher in highly/moderately keratinized tumors than in tumors with minimal/no keratinization (P = 0.012). No significant associations were observed between the presence/distribution of MGCs and clinical parameters (tumor size, lymph node metastasis, distant metastasis, and clinical stage) (P > 0.05). All MGCs were positive for CD68 and there was a predominance of HLA-DR+ over CD163+ MGCs (P = 0.031). Multinucleated giant cell reactions may not be involved in tumor progression in lower lip SCCs. In this microenvironment, MGCs tend to exhibit a predominantly M1 phenotype and may represent a foreign body reaction to SCC keratin pearls.


Hemorheological disorders during ischemic brain infarcts in patients with and without diabetes mellitus.
The aim of the present study was the comparative analysis of the role of specific hemorheological derangements in the pathogenesis of ischemic brain infarcts with and without diabetes mellitus. Blood plasma viscosity, as well as red blood cells (RBC) aggregability were quantitatively investigated in all patients during the study. Both of the above mentioned indices of hemorheological disorders were significantly higher in the patients with brain infarcts and diabetes mellitus as compared to the control and the group of ischemic brain infarcts without diabetes. During the ischemic stroke, blood plasma viscosity was increased by a mean of 9.2 per cent in the first and by a mean of 17.6 per cent in the second group of patients. As to the erythrocyte aggregability index, it was changed considerably more - by a mean of 113.8 per cent during stroke without diabetes, while in the diabetic patients the RBC aggregability index was found to be increased by a mean of 147.3 per cent. Ischemic brain infarcts in patients with diabetes mellitus were associated with a significant increase of the patients' blood rheological disorders in all the investigated cases.


Role of endogenous prostaglandins in somatostatin-induced inhibition of gastrointestinal hormone secretion.
Endogenous prostaglandins have been reported to be essential for the inhibitory effect of somatostatin on acid secretion. From these results it could be suggested that the effect of somatostatin on the secretion of gastroentero-pancreatic hormones may also be medulated by prostaglandins. This hypothesis was investigated in man and in the rat. Somatostatin-induced inhibition of postprandial gastrin, cholecystokinin, pancreatic polypeptide, and insulin release was not influenced by indomethacin pretreatment in healthy subjects. Using the isolated perfused rat stomach preparation, inhibition of acetylcholine-stimulated gastrin secretion by somatostatin was found to be unchanged by indomethacin treatment. It is concluded that endogenous prostaglandins are unlikely to be indispensable for the inhibitory effect of somatostatin on gastroentero-pancreatic endocrine cells.


Unique posttranslational modifications of chitin-binding lectins of Entamoeba invadens cyst walls.
Entamoeba histolytica, which causes amebic dysentery and liver abscesses, is spread via chitin-walled cysts. The most abundant protein in the cyst wall of Entamoeba invadens, a model for amebic encystation, is a lectin called EiJacob1. EiJacob1 has five tandemly arrayed, six-Cys chitin-binding domains separated by low-complexity Ser- and Thr-rich spacers. E. histolytica also has numerous predicted Jessie lectins and chitinases, which contain a single, N-terminal eight-Cys chitin-binding domain. We hypothesized that E. invadens cyst walls are composed entirely of proteins with six-Cys or eight-Cys chitin-binding domains and that some of these proteins contain sugars. E. invadens genomic sequences predicted seven Jacob lectins, five Jessie lectins, and three chitinases. Reverse transcription-PCR analysis showed that mRNAs encoding Jacobs, Jessies, and chitinases are increased during E. invadens encystation, while mass spectrometry showed that the cyst wall is composed of an approximately 30:70 mix of Jacob lectins (cross-linking proteins) and Jessie and chitinase lectins (possible enzymes). Three Jacob lectins were cleaved prior to Lys at conserved sites (e.g., TPSVDK) in the Ser- and Thr-rich spacers between chitin-binding domains. A model peptide was cleaved at the same site by papain and E. invadens Cys proteases, suggesting that the latter cleave Jacob lectins in vivo. Some Jacob lectins had O-phosphodiester-linked carbohydrates, which were one to seven hexoses long and had deoxysugars at reducing ends. We concluded that the major protein components of the E. invadens cyst wall all contain chitin-binding domains (chitinases, Jessie lectins, and Jacob lectins) and that the Jacob lectins are differentially modified by site-specific Cys proteases and O-phosphodiester-linked glycans.


Identification of vasospasm biomarkers for cerebral hemorrhage via bio-informatics analysis.
The incidence of cerebral hemorrhage has rapidly increased over time, and vascular dysfunction has a significant influence on the pathogenesis and outcome of these patients. This is also the case for vasospasm in cerebral hemorrhage, but there is no method to assess this. We conducted this study to find molecular biomarkers of vasospasm in cerebral hemorrhage patients. Raw data of GSE37924 was downloaded from the Gene Expression Omnibus (GEO) database, including 66 samples with cerebral vasospasm and 62 samples without cerebral vasospasm. Differentially expressed genes (DEGs) between samples with cerebral vasospasm and those without cerebral vasospasm were analyzed using the limma package in R software. To determine the functions of DEGs, we conducted functional enrichment analysis of DEGs through the clusterProfiler package in R. The protein-protein interaction (PPI) network of DEGs was constructed through STRING (https://string-db.org/) and generated via Cytoscape software. To understand the correlation between DEGs and immune-related genes, immune-related cerebral vasospasm genes were obtained via intersecting immune-related genes and cerebral vasospasm DEGs. We also compared the infiltration of 28 immune cells between cases with cerebral vasospasm and those without cerebral vasospasm. Finally, we constructed a model to perform the validation experiments. Of the DEGs, there were 24 upregulated and 21 downregulated genes in the vasospasm samples compared to the no-vasospasm samples. Functional enrichment analysis showed that these genes play key roles in several biological processes and signaling pathways such as the bone morphogenetic protein (BMP) signaling pathway, cellular response to BMP stimulus, natural killer cell chemotaxis, negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway, MHC protein complex binding, and receptor ligand activity, among others. CCL4, HLA-DQA1, IGF2, NTS, and so on were the significant immune-related genes. Furthermore, the immune cell infiltration results showed that there were differences between patients with vasospasm and those without vasospasm. Finally, we found that CCL4 had significantly higher expression in patients with vasospasm than those without vasospasm. CCL4 is an important regulator of vascular dysfunction in cerebral hemorrhage.


Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia and LDL-C of 160 mg/dl or Higher.
Even with statins and other lipid-lowering therapy (LLT), many patients with heterozygous familial hypercholesterolemia (heFH) continue to have elevated low-density lipoprotein cholesterol (LDL-C) levels. ODYSSEY HIGH FH (NCT01617655) assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 monoclonal antibody, versus placebo in patients with heFH and LDL-C ≥ 160 mg/dl despite maximally tolerated statin ± other LLT. Patients were randomized to subcutaneous alirocumab 150 mg or placebo every 2 weeks (Q2W) for 78 weeks. The primary endpoint was percent change in LDL-C from baseline to week 24. Mean baseline LDL-C levels were 196.3 mg/dl in the alirocumab (n = 71) and 201.0 mg/dl in the placebo groups (n = 35). Significant mean (standard error [SE]) reductions in LDL-C from baseline to week 24 were observed with alirocumab (-45.7 [3.5] %) versus placebo (-6.6 [4.9] %), a difference of -39.1 (6.0) % (P < 0.0001). Absolute mean (SE) LDL-C levels were reduced from baseline by 90.8 (6.7) mg/dl with alirocumab at week 24, with reductions maintained to week 78. Treatment-emergent adverse events were generally comparable between groups. Injection-site reactions were more frequent in the alirocumab group (8.3 %) versus placebo (5.7 %); most were mild in severity and did not result in study medication discontinuation. In patients with heFH and very high LDL-C baseline levels despite maximally tolerated statin ± other LLT, alirocumab 150 mg Q2W demonstrated significant reductions in LDL-C levels with 41 % of patients achieving predefined LDL-C goals. Alirocumab was generally well tolerated.