A comparative analysis of coordinated neuronal activity in the thalamic ventrobasal complex of rats and cats.
There are substantial differences in the incidence of inhibitory neurons in the ventrobasal complex of rat and cat thalamus. This marked dissimilarity in neuronal composition suggests that there should be corresponding differences in the orchestration of neural activity in these regions during cutaneous stimulation. To explore this possibility, we conducted a cross-correlation analysis of neuronal activity in the ventroposterolateral (VPL) nucleus of anesthetized rats and cats. Pairs of neurons representing hairy skin were recorded simultaneously with one or two electrodes during air jet stimulation of multiple sites throughout the receptive fields. Cross-correlation histograms indicated that correlated activity among adjacent neurons occurred in three distinct patterns. In one pattern, classified as narrow-unimodal, the discharge of one neuron preceded a discharge in the partner neuron over a narrow interval of time (< 5 ms). Narrow-bimodal patterns were characterized by responses in which the temporal order of discharges from the two neurons was variable, but the interspike intervals were always < 5 ms. In wide-unimodal patterns, the discharge of one neuron was correlated with subsequent discharges in the partner neuron over a wide interval of time (> 5 ms). In rat VPL, two-thirds of the 58 neuron pairs showing correlated responses were characterized by narrow-unimodal responses and nearly one-third of the neuron pairs displayed narrow-bimodal patterns. Only one pair of rat VPL neurons were characterized by a wide-unimodal pattern of coordination. By comparison, half of the 61 adjacent neuron pairs with coordinated responses in cat VPL were characterized by narrow-unimodal patterns. Slightly more than one-third of the correlated neuron pairs had narrow-bimodal patterns, while the remainder (13%) were classified as wide-unimodal responses. Pairs of neurons separated by 340-405 microns discharged synchronously in a pattern that was similar to the temporal relationship expressed in the narrow-bimodal patterns found among adjacent neurons. In both species, the wide-unimodal patterns had the strongest coordinated responses as measured by the correlation coefficient. Although inhibitory relationships did not appear in correlation histograms that had been corrected for stimulus coordination, cross-correlation analysis of the raw spike trains revealed brief (10-40 ms) periods of inhibition that were associated with cat VPL neurons exhibiting wide-unimodal coordination patterns. In rat VPL, most inhibition involved longer (30-60 ms) periods of inhibitory oscillations appearing amidst a much larger rhythmic pattern. These results suggest that correlation patterns transpiring over narrow (< 5 ms) time intervals represent the coordination of activity among neighboring thalamocortical relay neurons.(ABSTRACT TRUNCATED AT 400 WORDS)


Azolla pinnata, Aspergillus terreus, and Eisenia fetida for fasterrecycling of nutrients from wheat straw.
A vast amount of surplus wheat straw/stubble (a carbon-rich bioresource) is wasted every year by burning. Harmful gases and residue matter released due to burning cause harmful effects on the environment and human health. Therefore, there is a strong need to recycle this bioresource in a sustainable manner. In the present study, wheat straw (W) was spiked with cattle dung (C), Azolla pinnata (A), and Aspergillus terreus (F) to make eight different treatments (1 kg each), viz. W (1 kg), WC (666 g + 334 g), WA (980 g + 20 g), WF (980 g + 20 ml), WCF (666 g + 314 g + 20 ml), WCA (666 g + 314 g + 20 g), WFA (960 g+ 20 ml + 20 g), and WCFA(666 g + 294 g + 20 ml + 20 g), and subjected to vermicomposting (Vcom) and aerobic composting (Acom). A comparison was made for the time required for degradation and nutrient profile of the products. The fastest recycling of wheat straw/stubble (120 days) was observed in WCA and WCFA, but the nutrient quality of WCA was better (N 18.67, P 3.88, K 38.84 g/kg). In the Acom group, longer time was required for degradation of various mixtures, but in this group also, WCA was degraded first of all (138 days) and yielded a product with the best nutrient quality (N 14.77, P 2.56, K 28.80 g/kg). Maximum growth of E. fetida and maximum number of hatchlings were observed in WCA while the highest cocoon production was observed in WCFA. It was observed that azolla enhanced conversion of wheat straw into a nutrient-rich product for agronomic use. Thus its use will reduce the amount of cattle dung in the mixture and the bulk to be handled by the farmers for ecosafe disposal of surplus straw/stubble. Therefore, this technology can be adopted as an alternative to burning.


Impact of body mass index on clinical and cost outcomes after radical cystectomy.
To evaluate the effect of body mass index (BMI, kg/m(2)) on the cost and clinical variables after radical cystectomy (RC), as studies show that obesity might adversely affect the outcomes after RC. The charts of patients who had RC from January 2004 to March 2007 were reviewed retrospectively. Complete cost and clinical information was available for 99 patients; the patient and tumour characteristics and peri-operative outcomes were recorded. Detailed cost information (room and board, laboratory, pharmacy, radiology, operating room, surgical supply, anaesthesia, and recovery room) was obtained from hospital billing. Patients were stratified and compared in three groups of BMI, i.e. normal weight (<25), overweight (25-<30) and obese (> or =30). The mean age of the patients was 66 years; 27% were normal weight, 38% were overweight and 34% were obese. Of obese patients, 24% had an Eastern Cooperative Oncology Group performance score of 0, vs none and 2.6% in the normal and overweight groups, respectively (P = 0.001). Those of normal weight had the highest overall and major complication rates (P = 0.57 and 0.28, respectively). Obese patients had insignificantly higher transfusion rates (P = 0.28). The direct cost was higher in normal weight ($14,314) than overweight ($13,808) and obese ($13,666) patients (P = 0.47). Higher room and board cost in normal-weight patients was the only significant cost difference (P = 0.008). BMI was not associated with increased costs of cystectomy. The absence of differences in cost-related and clinical outcomes might be attributable to variable comorbidity among groups and the experience of a high-volume surgeon and staff at a tertiary-care referral centre that routinely cares for obese patients.


Molecular characterization of porphyrias in Italy: a diagnostic flow-chart.
The porphyrias are disorders associated with inherited or acquired enzyme deficiencies in the heme biosynthetic pathway. The differential diagnosis is often difficult since the phenotype is very similar in some forms and the biochemical tests are not commonly available. Here we provide an update on the molecular diagnosis of porphyrias in Italy and a flow-chart to facilitate the identification of mutations in heme biosynthetic genes. The molecular analysis has allowed us to identify the molecular defect underlying the disease in 66 probands with different porphyrias [acute intermittent porphyria (AIP), variegate porphyria (VP), porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP)]. No Italian patients with defects in coproporphyrinogen oxidise (CPOX) gene, responsible for hereditary coproporphyria (HCP), have been detected. The molecular characterization has been extended to 115 relatives with the identification of 55 asymptomatic mutation carriers and 60 normal subjects. We have so far identified 50 different mutations among 4 genes associated with the most common porphyrias showing a high molecular heterogeneity: 22 in the hydroxymethylbilane synthase (HMBS) gene (AIP), 7 in the protoporphyrinogen oxidase (PPOX) gene (VP), 16 in the uroporphyrinogen decarboxylase (UROD) gene (PCT) and 5 in the ferrochelatase (FECH) gene (EPP). Among the 50 molecular defects, 29 seem to be restricted to the Italian population.


[Pioglitazone hydrochloride a instrumental analytical perspective by Raman spectroscopy and HPLC].
The thiazolidinediones (pioglitazone) increases the action of insulin and produces the glycemic control in the patients with type 2 diabetes mellitus. Also, the pharmacological effect may be affected by the purity and pioglitazone plasma concentration. Therefore, the instrumental techniques offer a tool for characterization, identification and/or quantification of the pioglitazone; Raman spectroscopy offers several advantages due to its easy application methodology and structural analysis and the HPLC technique is the gold standard vs. other qualitative and quantitative techniques. The aim of this work is to develop and validate analytical techniques for the characterization of pioglitazone hydrochloride by Raman spectroscopy and quantitative analysis in human plasma by HPLC. The pioglitazone hydrochloride was analyzed by Raman spectroscopy with a 678 mW power and 3 integration time seconds. The analytical method for quantification by HPLC was validated with the guidelines of the NOM-177SSAl-1998. The Raman technique allowed us to elucidate the functional groups of the pioglitazone hydrochloride and the HPLC technique was linear, accurate, precise, specific and sensitive in the range of 30 to 2000 ng/mL under the chromatographic conditions specified. The structure analysis by Raman spectroscopy allowed us a complete characterization of the functional groups of pioglitazone hydrochloride effectively and non-destructively. Likewise, the analytical technique for the pioglitazone hydrochloride quantification by HPLC was linear, accurate, precise and sensitive in the range of 30 to 2000 ng/mL under the guidelines.


Simulation of pyrite oxidation in fresh mine tailings under near-neutral conditions.
Sulphidic residual products from ore processing may produce acid rock drainage, when exposed to oxygen and water. Predictions of the magnitude of ARD and sulphide oxidation rates are of great importance in mine planning because they can be used to minimize or eliminate ARD and the associated economic and environmental costs. To address the lack of field data of sulphide oxidation rate in fresh sulphide-rich tailings under near-neutral conditions, determination and simulation of the rate was performed in pilot-scale at Kristineberg, northern Sweden. The quality of the drainage water was monitored, along with oxygen and carbon dioxide concentrations. The chemical composition of the solid tailings was also determined. The field data were compared to predictions from simulations of pyrite oxidation using a 1-D numerical model. The simulations' estimates of the amount of Fe and S released over a seven year period (52 kg and 178 kg, respectively) were in reasonably good agreement with those obtained by analysing the tailings (34 kg and 155 kg, respectively). The discrepancy is probably due to the formation of secondary precipitates such as iron hydroxides and gypsum; which are not accounted for in the model. The observed mass transport of Fe and S (0.05 and 1.0 kg per year, respectively) was much lower than expected on the basis of the simulations and the core data. Neutralization reactions involving carbonates in the tailings result in a near-neutral pH at all depths except at the oxidation front (pH < 5), indicating that the dissolution of carbonates was too slow for the acid to be neutralized, which instead neutralized deeper down in the tailings. This was also indicated by the reduced abundance of solid Ca at greater depths and the high levels of carbon dioxide both of which are consistent with the dissolution of carbonates. It could be concluded that the near-neutral pH in the tailings has no decreasing effect on the rate of sulphide oxidation, but does reduce the concentrations of dissolved elements in the drainage water due to the formation of secondary minerals. This means that sulphide oxidation rates may be underestimated if determined from drainage alone.


Laryngeal penetration and aspiration during swallowing after the treatment of advanced oropharyngeal cancer.
To determine whether laryngeal penetration and aspiration in oropharyngeal cancer survivors differ by treatment group. Cross-sectional study of patients with stage III or IV oropharyngeal squamous cell carcinoma who were at least 12 months removed from combined modality therapy and clinically free of disease. Potential subjects were stratified by tumor site and tumor T stage to achieve a similar comparison between chemoradiotherapy (n = 10) and surgery/radiotherapy (n = 11) groups. Validated instruments used to evaluate swallowing included the Penetration-Aspiration Scale and the M. D. Anderson Dysphagia Inventory. Patients with oropharyngeal cancer treated with chemoradiotherapy demonstrated greater airway protection according to Penetration-Aspiration Scale scores than those treated with surgery and radiotherapy on 5-mL (P = .02), 10-mL (P = .04), and 20-mL (P = .04) liquid barium swallows. Also, the oropharyngeal chemoradiotherapy group had better self-perceived swallowing ability than the surgery-radiotherapy group on the basis of the M. D. Anderson Dysphagia Inventory (P = .02). The present study suggests that patients with oropharyngeal cancer who successfully complete chemoradiotherapy protocols without surgical salvage retain greater airway protection during swallowing and better swallowing-related quality of life than patients treated with primary surgery and radiotherapy.


Are Prerequisite Courses Barriers to Pharmacy Admission or the Keys to Student Success?
The variability and complexity of course prerequisites across colleges and schools of pharmacy can result in barriers to admission. While prerequisites play an important role in the admissions process and assuring student preparation, requiring excessive prerequisites can create unnecessary challenges for applicants. Prospective students may choose not to apply to a particular pharmacy school or even enter the profession because they cannot complete all course prerequisites in time to apply. Extraneous prerequisites can also contribute to the cost of education and educational indebtedness, which can more adversely affect minority and disadvantaged students. Pharmacy programs should carefully examine their course prerequisite requirements and consider new ways to measure preparedness to attract a diverse and competent pool of applicants to the profession while also being more competitive with other health professions programs.


The significance of pneumatosis intestinalis or bowel perforation in patients with gynecologic malignancies.
The objectives of this study were to evaluate the clinical significance and outcome of pneumatosis intestinalis or bowel perforation in patients with gynecologic malignancies. A retrospective review of all gynecologic oncology patients at our institution from 1996 to the present was performed to identify computed tomography examinations showing pneumatosis, free air, or the presence of portal venous gas. Admission symptoms, laboratory testing, radiographic and operative findings, and overall survival were evaluated. At the discretion of the attending gynecologic oncologist, patients were managed either surgically or conservatively. Statistical analysis was performed with Fisher's exact test. Twenty-eight patients met study criteria. Thirteen patients were excluded as a result of radiographic free air immediately following surgery, thus leaving 15 patients for analysis. Sixty percent (n = 9) of patients were managed surgically while 40% (n = 6) were managed conservatively. Pain and tenderness at presentation prompted surgical intervention in a statistically significant number of patients (P = 0.04). No other sign or symptom was significant. Of the 6 patients managed conservatively, 3 (50%) died within 1 week of diagnosis. Survival for the others was 2, 4, and 6 months. Of the 9 patients managed surgically 6 (67%) patients died, 4 within 2 weeks of surgery and the remainder at 2 and 12 months postoperatively. The 3 patients who survived all had surgical intervention and none had radiographic or pathologic evidence of cancer at the time of presentation (P = 0.01). Overall mortality at 6 months was 73% (11/15). Surgical management was associated with prolonged ICU care, mechanical ventilation, and sepsis. Pneumatosis intestinalis and bowel perforation carry a grave prognosis for patients with gynecologic malignancies. These data suggest that patients explored for radiographic evidence of pneumatosis or perforation with preoperative evidence of active malignancy do not survive the immediate postoperative period. The balance between quality and quantity of life must be considered when weighing the options for the management of this condition.


Alpha-synuclein inclusions in Alzheimer and Lewy body diseases.
Alpha-synuclein has assumed particular neuropathological interest in the light both of its identification as a non-beta-amyloid plaque constituent in Alzheimer disease (AD), and the recent association between dominant inheritance of Parkinson disease (PD) and 2 missense mutations at positions 30 and 53 of the synuclein protein. We report a systematic study of alpha-synuclein, tau, and ubiquitin immunoreactivity in representative neurodegenerative disorders of late life. The alpha-synuclein association with Lewy bodies is variable, peripheral, and is not stable with respect to proteases or acid treatment, whereas there is no association with Pick bodies. Stable patterns of immunoreactivity included neurites and a novel inclusion body. Although there is an overlap between the presence of Lewy bodies and stable alpha-synuclein immunoreactivity, this is seen only in the presence of concomitant neuropathological features of AD. The novel alpha-synuclein inclusion body identified in pyramidal cells of the medial temporal lobe in particular was found in AD and in the Lewy body variant of AD, and was associated neither with ubiquitin nor tau protein. The inclusion is therefore neither a Lewy body nor a PHF-core body, but may be confused with the Lewy body, particularly in the Lewy body variant of AD. Abnormal processing of alpha-synuclein leading to its deposition in the form of proteolytically stable deposits is a particular feature of the intermediate stages of AD.


Opposing roles for dopamine and serotonin in the modulation of human spatial working memory functions.
Neurocognitive research has focused on monoaminergic influences over broad behavior patterns. For example, dopamine (DA) generally facilitates informational transfer within limbic and cortical networks to promote reward-seeking behavior. Specifically, DA activity in prefrontal cortex modulates the ability for nonhuman primates and humans to perform spatial working memory tasks. Serotonin (5HT) constrains the activity of DA, resulting in an opposing relationship between DA and 5HT with respect to emotional and motor behaviors. A role for 5HT in constraining prefrontally guided spatial working memory (WM) processes in humans has not been empirically demonstrated but is a logical avenue for study if these principles of neurotransmitter activity hold within cortical networks. In this study, normal humans completed a visuospatial WM task under pharmacological challenge with (i) bromocriptine, a DA agonist and (ii) fenfluramine, a serotonin agonist, in a double-blind, repeated-measures, placebo-controlled design. Findings indicate that bromocriptine facilitated spatial delayed, but not immediate, memory performance. Fenfluramine resulted in impaired delayed spatial memory. These effects were not due to nonspecific arousal, attentional, sensorimotor or perceptual changes. These findings suggest that monoaminergic neurotransmitters (DA and 5HT) may interact within cortical networks to modulate the expression of specific cognitive behaviors, particularly effortful processes associated with goal-directed activity.


Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE).
Gender accounts for important differences in the incidence and prevalence of a variety of age-related diseases. Considering people of far advanced age, demographic data document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories during aging. In the present investigation, we report data from a nationwide study on Italian centenarians (a total of 1162 subjects), and from two studies on centenarians living in two distinct zones of Italy, i.e., the island of Sardinia (a total of 222 subjects) and the Mantova province (Northern Italy) (a total of 43 subjects). The female/male ratio was about 2:1 in Sardinia, 4:1 in the whole of Italy, and about 7:1 in the Mantova province. Thus, a complex interaction of environmental, historical and genetic factors, differently characterizing the various parts of Italy, likely plays an important role in determining the gender-specific probability of achieving longevity. Gender differences in the health status of centenarians are also reported, and an innovative score method to classify long-lived people in different health categories, according to clinical and functional parameters, is proposed. Our data indicate that not only is this selected group of people, as a whole, highly heterogeneous, but also that a marked gender difference exists, since male centenarians are less heterogeneous and more healthy than female centenarians. Immunological factors regarding the age-related increase in pro-inflammatory status, and the frequency of HLA ancestral haplotypes also show gender differences that likely contribute to the different strategies that men and women seem to follow to achieve longevity. Concerning the different impact of genetic factors on the probability of reaching the extreme limits of the human life-span, emerging evidence (regarding mtDNA haplogroups, Thyrosine Hydroxilase, and IL-6 genes) suggests that female longevity is less dependent on genetics than male longevity, and that female centenarians likely exploited a healthier life-style and more favorable environmental conditions, owing to gender-specific cultural and anthropological characteristics of the Italian society in the last 100 years.


A new phenotypic manifestation of familial adenomatous polyposis.
Familial adenomatous polyposis (FAP) is an autosomal dominant disease with hundreds of colorectal adenomas in teenagers and progression to colorectal cancer if colectomy is not performed. We investigated the association of two phenotypic manifestations-oral mucosal vascular density (OMVD) and oral mucosal reflectance (OMR)--with FAP and patients with multiple colorectal adenomas. Thirty-three patients with FAP from 29 unrelated pedigrees with APC gene mutation, 5 with multiple adenomas and no known gene mutations, and 50 population controls were evaluated for the two different manifestations utilizing a photographic/spectrophotometric system capturing images and reflectance at various wavelengths. Statistical analysis was performed with student t test and test performance characteristics were calculated. There were no significant differences in demographic variables between the FAP and control group. A significant difference in OMVD between FAP patients and controls was noted, P < 0.001. The sensitivity and specificity of oral mucosal vascular density for FAP was 91 and 90%, respectively. No association between this phenotypic manifestation and age or gender was found. All 5 patient with multiple polyps were positive for OMVD and the value was significantly higher than controls, P = 0.002. No significant difference was noted in OMR between the two patient groups and controls. OMVD is a new phenotypic manifestation in patients with FAP and also may identify those with multiple adenomas without known gene mutation.


Does HLA Class II haplotype play a role in adult acute disseminated encephalomyelitis? Preliminary findings from a Southern Italy hospital-based study.
Acute Disseminated Encephalomyelitis (ADEM) is an acute, multifocal, monophasic, inflammatory demyelinating disease of the central nervous system that affects predominantly children. Aim of the study was to evaluate the distribution of Human Leukocyte Antigen (HLA) class II haplotype in adult ADEM patients, in order to better characterize this rare clinical entity. Six patients (3 males and 3 females; median age 50 years) with ADEM were retrospectively studied in our Neurology Unit; 29 healthy subjects (8 males and 21 females, mean age 43.4±14.3) were the control group. All the study subjects were molecularly typed for HLA class II haplotype. The frequencies of HLA-DRB1*16 (17% vs 3% in control group; Py=0.02) and HLA-DQB1*05 (42% against 24% in the control group; Py=0.010), as well as the association HLA-DRB1*16/HLA-DQB1*05 were significantly increased in ADEM population compared to the control group. The frequencies of allelic association between 13-04 (P < 0.01) and homozygosis 14 (P < 0.05) alleles at HLA-DRB1* locus and 05-02 (P < 0.05) alleles at HLA-DQB* locus also were increased in ADEM patients. Our preliminary data provide further evidence that the HLA-DR/DQ haplotypes may be involved in susceptibility to immunomediate demyelinating diseases of central nervous system in the Caucasian population.


Cell lines as an investigational tool for the study of biology of small cell lung cancer.
Tumors, whether they be of clonal or polyclonal origin, are dynamic processes, constantly undergoing alterations, both in vivo and in vitro. However, in many if not most tumors, certain properties are relatively stable. There must be selective advantages for tumor populations to maintain these properties. A careful comparison of the properties of tumors and their cell lines, and correlating these data with the clinical history of the tumor is essential. From such studies we conclude that cell lines are suitable models to study the biology of SCLC and many important contributions would have been impossible without a large comprehensive panel of cell lines. These lines may be suitable for the selection of the best in vitro regimen to treat individual patients from whom the lines were derived, a hypothesis currently being tested in our Branch. Finally, in vitro studies already (and will continue to) suggest newer, more rational approaches to tumor control.


Apparent diffusion coefficient by diffusion-weighted magnetic resonance imaging as a sole biomarker for staging and prognosis of gastric cancer.
To investigate the role of apparent diffusion coefficient (ADC) from diffusion-weighted magnetic resonance imaging (DW-MRI) when applied to the 7th TNM classification in the staging and prognosis of gastric cancer (GC). Between October 2009 and May 2014, a total of 89 patients with non-metastatic, biopsy proven GC underwent 1.5T DW-MRI, and then treated with radical surgery. Tumor ADC was measured retrospectively and compared with final histology following the 7th TNM staging (local invasion, nodal involvement and according to the different groups - stage I, II and III). Kaplan-Meier curves were also generated. The follow-up period is updated to May 2016. Median follow-up period was 33 months and 45/89 (51%) deaths from GC were observed. ADC was significantly different both for local invasion and nodal involvement (P<0.001). Considering final histology as the reference standard, a preoperative ADC cut-off of 1.80×10-3 mm2/s could distinguish between stages I and II and an ADC value of ≤1.36×10-3 mm2/s was associated with stage III (P<0.001). Kaplan-Meier curves demonstrated that the survival rates for the three prognostic groups were significantly different according to final histology and ADC cut-offs (P<0.001). ADC is different according to local invasion, nodal involvement and the 7th TNM stage groups for GC, representing a potential, additional prognostic biomarker. The addition of DW-MRI could aid in the staging and risk stratification of GC.


Topic Discovery on Farsi, English, French, and Arabic Tweets Related to COVID-19 Using Text Mining Techniques.
Social networks are a good source for monitoring public health during the outbreak of COVID-19, these networks play an important role in identifying useful information. This study aims to draw a comparison of the public's reaction in Twitter among the countries of West Asia (a.k.a Middle East) and North Africa in order to make an understanding of their response regarding the same global threat. 766,630 tweets in four languages (Arabic, English French, and Farsi) tweeted in March 2020, were investigated. The results indicate that the only common theme among all languages is "government responsibilities (political)" which indicates the importance of this subject for all nations. Although nations react similarly in some aspects, they respond differently in others and therefore, policy localization is a vital step in confronting problems such as COVID-19 pandemic.


The protective potentials of 4-chloro-3, 5-xylenol (Dettol) against Mansonian schistosomiasis.
Laboratory tests were conducted to determine the prophylactic effectiveness of 4-chloro-3, 5-xylenol (Dettol) against mammalian schistosomiasis. The findings showed that this antiseptic was capable of protecting the albino mice against Mansonian schistosomiasis and of acting as an effective miracidicide, cercaricide and molluscicide.


Immunocytochemical diagnosis of lymphoma from urine sediment.
Cytologic studies were done on the urine sediment of a patient with an indolent lymphoma of 20 years' duration. The patient had localized disease in his groins and developed marked swelling in his penis and scrotum and pedal edema shortly after radiotherapy was instituted to the inguinal areas. The urine specimen obtained after chemotherapy showed many large mononucleated malignant cells. These cells were extremely fragile and were best demonstrated by supravital staining of wet preparations. Although morphologic examination could not confidently indicate the origin of these malignant cells, cytochemical and immunocytochemical studies showed them to be monoclonal B lymphocytes. This study suggests that, even under unusually difficult circumstances, a combined cytologic, cytochemical and immunocytochemical approach can be successfully applied for cytodiagnosis.


Two additional principles for determining which species to monitor.
Monitoring to detect population declines is widespread, but also costly. There is, consequently, a need to optimize monitoring to maximize cost-effectiveness. Here we develop a quantitative decision analysis framework for how to optimally allocate resources for monitoring among species. By keeping the framework simple, we analytically establish two new principles about which species are optimal to monitor for detecting declines: (1) those that lie on the boundary between species being allocated resources for conservation action and species that are not and (2) those with the greatest uncertainty in whether they are declining. These two principles are in addition to other factors that are also important in monitoring decisions, such as complementarity. We demonstrate the efficacy of these principles when other factors are not present, and show how the two principles can be combined. This analysis demonstrates that the most cost-effective species to monitor are ones where the information gained from monitoring is most likely to change the allocation of funds for action, not necessarily the most vulnerable or endangered. We suggest these results are general and apply to all ecological monitoring, not just of biological species: monitoring and information are only valuable when they are likely to change how people act.


Causes and consequences of failed adaptation to biological invasions: the role of ecological constraints.
Biological invasions are a major challenge to native communities and have the potential to exert strong selection on native populations. As a result, native taxa may adapt to the presence of invaders through increased competitive ability, increased antipredator defences or altered morphologies that may limit encounters with toxic prey. Yet, in some cases, species may fail to adapt to biological invasions. Many challenges to adaptation arise because biological invasions occur in complex species-rich communities in spatially and temporally variable environments. Here, we review these 'ecological' constraints on adaptation, focusing on the complications that arise from the need to simultaneously adapt to multiple biotic agents and from temporal and spatial variation in both selection and demography. Throughout, we illustrate cases where these constraints might be especially important in native populations faced with biological invasions. Our goal was to highlight additional complexities empiricists should consider when studying adaptation to biological invasions and to begin to identify conditions when adaptation may fail to be an effective response to invasion.


Subclinical hypothyroidism as a risk factor for the development of cardiovascular disease in obese adolescents with nonalcoholic fatty liver disease.
No data are available on the relationship between subclinical hypothyroidism and risk factors for the development of cardiovascular disease in obese adolescents with nonalcoholic fatty liver disease (NAFLD). This study aimed to determine whether an association exists between subclinical hypothyroidism and risk factors for the development of cardiovascular disease in obese adolescents with NAFLD. The study enrolled 111 obese adolescents and 42 lean subjects. The obese subjects were divided into two subgroups based on the presence or absence of fatty liver with high transaminases: a NAFLD group and a non-NAFLD group. Subclinical hypothyroidism was defined as a thyroid-stimulating hormone (TSH) level higher than 4 mIU/l and a normal free-thyroxine level (0.6-1.8 ng/dl). Insulin resistance was calculated by the homeostasis model assessment (HOMA-IR). Left ventricular mass (LVM), LVM index measurements, carotid intima media thickness (IMT), and HOMA-IR values were higher in the NAFLD obese group with TSH levels higher than 4 mIU/l than in the NAFLD obese group with TSH levels lower than 4 mIU/l. Elevated TSH values in the NAFLD obese group were positively correlated with most of the metabolic and cardiovascular risk parameters such as total cholesterol (r = 0.606, p = 0.001), triglycerides (r = 0.476, p = 0.016), low-density lipoprotein cholesterol (r = 0.461, p = 0.004), insulin (r = 0.607, p = 0.001), HOMA-IR (r = 0.596, p = 0.002), carotid IMT (r = 0.894, p < 0.0001), and LVM (r = 0.563, p = 0.003). The findings demonstrated that the obese adolescents with NAFLD and subclinical hypothyroidism had a more adverse cardiovascular risk profile and a higher carotid IMT and LVM.


Acute vitamin D3 toxicosis in horses: case reports and experimental studies of the comparative toxicity of vitamins D2 and D3.
Acute vitamin D toxicosis was diagnosed in 2 horses fed a grain ration containing 1,102,311 IU of cholecalciferol (vitamin D3)/kg (500,000 IU/lb) for about 30 days. Horse 1 died acutely with extensive mineralization of cardiovascular and other soft tissues. Horse 2, which had severe clinical signs and clinicopathologic changes of toxicosis, was treated with nonsteroidal antiinflammatory drugs and recovered in about 6 months. In an experimental study, the toxicity of ergocalciferol (vitamin D2) and cholecalciferol was compared in 2 horses (No. 3 and 4) given the respective vitamins at a daily dosage of 33,000 IU/kg of initial (day 0) body weight for 30 days. Except for slight loss in body weight (8%) during the 1st few days of treatment, horse 3 remained clinically normal. Horse 4 developed limb stiffness and tachycardia, became anorectic, weak, and recumbent, lost 29% of body weight, and had polydipsia and polyuria. Horses 2, 3, and 4 developed persistent hyperphosphatemia. Horse 2 remained normocalcemic whereas horses 3 and 4 became hypercalcemic by day 28. In horse 3, serum vitamin D2 metabolite concentrations on days 0, 1, 14, and 26 were: vitamin D2 (ng/ml) = less than 5.0, 5.7, 71.4, and 188.0; 25-hydroxy-vitamin D2 (ng/ml) = less than 5.0, less than 5.0, 43.1, and 117.5; and 1,25-dihydroxy-vitamin D (pg/ml) = 19.7, 23.2, 25.0, and 45.7, respectively. In horse 4, serum vitamin D3 metabolite concentrations on the same days were: vitamin D3 (ng/ml) = less than 5.0, 110.0, 1,049.0, and 887.0; 25-hydroxy-vitamin D3 (ng/ml) = less than 5.0, 18.9, 201.0 and 182.0; and 1,25-dihydroxy-vitamin D (pg/ml) = 21.5, 18.9, 25.2, and 21.6, respectively. Urine of horses 2 and 4 became acidic (pH 6). Horses 2, 3, and 4 became hyposthenuric, but the decrease in urine specific gravity (sp gr) in horse 3 occurred only after 3 weeks of treatment and was only moderate (sp gr, 1.018 to 1.021) and nonprogressive. Hyposthenuria was evident in horse 4 on day 4 (sp gr, 1.028), and was progressive and marked (sp gr, days 28 to 32: 1.006 to 1.009). Urine sp gr of horse 2 ranged from 1.002 to 1.007. Fractures were demonstrated radiographically and histologically in the costochondral junctions of horses 3 and 4. Mineralization of cardiovascular and other soft tissues developed in horses 3 and 4, with lesions being more severe and having a wider tissue distribution in horse 4.


Tunable control of polyproline helix (PPII) structure via aromatic electronic effects: an electronic switch of polyproline helix.
Aromatic rings exhibit defined interactions via the unique aromatic π face. Aromatic amino acids interact favorably with proline residues via both the hydrophobic effect and aromatic-proline interactions, C-H/π interactions between the aromatic π face and proline ring C-H bonds. The canonical aromatic amino acids Trp, Tyr, and Phe strongly disfavor a polyproline helix (PPII) when they are present in proline-rich sequences because of the large populations of cis amide bonds induced by favorable aromatic-proline interactions (aromatic-cis-proline and proline-cis-proline-aromatic interactions). We demonstrate the ability to tune polyproline helix conformation and cis-trans isomerism in proline-rich sequences using aromatic electronic effects. Electron-rich aromatic residues strongly disfavor polyproline helix and exhibit large populations of cis amide bonds, while electron-poor aromatic residues exhibit small populations of cis amide bonds and favor polyproline helix. 4-Aminophenylalanine is a pH-dependent electronic switch of polyproline helix, with cis amide bonds favored as the electron-donating amine, but trans amide bonds and polyproline helix preferred as the electron-withdrawing ammonium. Peptides with block proline-aromatic PPXPPXPPXPP sequences exhibited electronically switchable pH-dependent structures. Electron-poor aromatic amino acids provide special capabilities to integrate aromatic residues into polyproline helices and to serve as the basis of aromatic electronic switches to change structure.


Epithelioma cuniculatum plantare.
Epithelioma cuniculatum plantare is a tumor of epithelial origin occurring on the plantar aspect of the foot. It is an uncommon, locally aggressive neoplasm, not limited to this area, and in other body sites is referred to as verrucous carcinoma. The history and treatment of a patient with plantar verrucous carcinoma is presented; a survey of the literature reflects difficulty in establishing an early diagnosis. This, however, can be facilitated when the gross appearance and a history of prior surgical attempts to excise the lesion are known to the surgeon and the pathologist, and the surgical specimen ideally encompasses the deeper portions of the lesion.


Role of plasma membrane transporters in muscle metabolism.
Muscle plays a major role in metabolism. Thus it is a major glucose-utilizing tissue in the absorptive state, and changes in muscle insulin-stimulated glucose uptake alter whole-body glucose disposal. In some conditions, muscle preferentially uses lipid substrates, such as fatty acids or ketone bodies. Furthermore, muscle is the main reservoir of amino acids and protein. The activity of many different plasma membrane transporters, such as glucose carriers and transporters of carnitine, creatine and amino acids, play a crucial role in muscle metabolism by catalysing the influx or the efflux of substrates across the cell surface. In some cases, the membrane transport process is subjected to intense regulatory control and may become a potential pharmacological target, as is the case with the glucose transporter GLUT4. The goal of this review is the molecular characterization of muscle membrane transporter proteins, as well as the analysis of their possible regulatory role.


Fiber fuse effect in hollow optical fibers.
We examined nonlinear fiber fuse effect (FFE) in hollow optical fibers (HOFs) that consist of a central air hole surrounded by a high-index ring core and silica cladding. In contrast to conventional solid-core fibers, the HOF with a hole diameter of 4 μm showed high threshold power of 4 W, and resulted in unique tadpole-like voids in periodic arrays after the FFE. As the hole diameter increased to 6 μm, plasma propagation was suppressed within the distance of 1 mm inside of the HOF. Detailed comparisons were made in terms of threshold power, void formation, and penetration length.


In silico analysis of HLA-1 and HLA-2 recognition of a designed recombinant human papillomavirus vaccine based on L1 protein HPV subtype 45.
Human leukocyte antigen (HLA) can bind and present the processed antigenic peptide derived from the vaccine to the T cell receptor, and this capability is crucial in determining the effectivity of the vaccine to terminate virus-infected cells, activate macrophages, and induce B cells to produce antibodies. A recombinant vaccine candidate based on protein L1 HPV45 was designed and analysed whether it is recognisable by T cells through the binding of their epitopes to HLAs. The study consisted of two parts: part one was the analysis of the L1 recombinant protein binding to HLA-1 and 2 epitopes, whereas part two was the distribution analysis of HPV-linked HLA allele. HLA allele sets found at high frequency in the general population and in specific Indonesian population were listed for the binding analysis of the recombinant L1 HPV45 protein. In part one, immunoepitope servers from IEDB were used to predict the binding of the designed proteins to HLA alleles. The prediction method for MHC-I binding prediction was the NetMHCpan EL 4.1 whilst for MHC-II binding prediction was the Consensus approach. Antigenicity analysis for each peptide was conducted using VaxiJen 2.0 with the threshold 1.0 to select the highly antigenic peptides, and positions of these epitopes in the secondary and tertiary structure of the recombinant protein were also predicted. The percent population coverage of the alleles capable of binding to these epitopes worldwide was also estimated. In part two, the worldwide distribution and frequency of HPV-related HLA-1 and 2 were studied. Two highly antigenic peptides (EEYDLQFIF and KLKFWTVDLK) were recognised by high-frequency HLA-1 alleles in both, the general and Western Javanese. In addition to these two epitopes, a few more peptides are also recognised by the high-frequency Western Javanese HLA-1 alleles, which are not in Weiskopf's list of high-frequency HLA-1 alleles in the general population. Analysis of the highly antigenic epitopes binding to HLA-DRB1 alleles in general (YIKGTSANM) and Western Javanese (LRRRPTIGP) populations showed that these peptide cores associate to HLA-DRB1*04, albeit the different sub-types, due to the presence of different allele in each population group. Analysis of the epitopes and the positive binding alleles showed on average 25.65% population coverage. The recombinant vaccine candidate based on protein L1 HPV45 is presumed to contain highly antigenic peptides that can bind to high-frequency HLA-1 and 2 alleles present in general and Western Javanese populations. It was expected that the protein is capable of eliciting T cell-mediated responses in both populations; however, in vitro study is needed to prove the protectiveness of the designed recombinant protein.


Comparison of the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depressive disorder.
Only two-thirds of depressive patients respond to antidepressant treatment. In recent years, addition of an atypical antipsychotic drug to ongoing treatment with an antidepressant has been considered effective and well-tolerated. In the present study, we compared the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depression. Twenty-four patients who met the DSM-IV criteria for major depressive disorder who did not at least two different classes of antidepressants were enrolled in the study. Nine were male and thirteen were female, and their ages ranged from 28 to 66 (mean±SD=39±12) years. Patients were prescribed paroxetine (n=11) or sertraline (n=13) for 4weeks. Then, those whose scores on the 17-item Hamilton Rating Scale for Depression (HAMD17) decreased below 50% received adjunctive therapy of aripiprazole for 4weeks. Although the use of either combination treatment decreased the HAMD17 scores compared to the respective monotherapy, there was no significant difference in HAMD17 scores between the paroxetine plus aripiprazole group and sertraline plus aripiprazole group. Aripiprazole augmentation therapy with paroxetine or sertraline was equally effective and tolerated in patients with refractory major depressive order.


Recent advances in the biosynthesis of penicillins, cephalosporins and clavams and its regulation.
The beta-lactam antibiotics have been serving mankind for over 70 years. Despite this old age, they continue to provide health to the world population by virtue of industrial production and discoveries of new secondary metabolite molecules with useful activities. Sales of these remarkable compounds have reached over $20 billion dollars per year. They include penicillins, cephalosporins, cefoxitin, monobactams, clavulanic acid and carbapenems. Strain improvement of the penicillin-producing species of Penicillium has been truly remarkable, with present strains producing about 100,000 times more penicillin that the original Penicillium notatum of Alexander Fleming. A tremendous amount of information has been gathered on the biosynthetic enzymes involved, the pathways of biosynthesis of beta-lactams as well as their regulation, and the genomics and proteomics of the producing organisms. Modern aspects of the processes are discussed in the present review including genetics, molecular biology, metabolic engineering, genomics and proteomics.


Comment on "Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring".
Tyzio et al. (Reports, 7 February 2014, p. 675) reported that bumetanide restored the impaired oxytocin-mediated γ-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery in animal models of autism, ameliorating some autistic-like characteristics in the offspring. However, standard practices in the study of these models, such as the use of sex-dimorphic or males-only analyses and implementation of tests measuring social behavior, are lacking to definitely associate their findings to autism.


Neuronal degeneration in the basal ganglia and loss of pallido-subthalamic synapses in mice with targeted disruption of the Huntington's disease gene.
Huntington's disease (HD) is a progressive neurodegenerative disorder associated with CAG repeat expansion within a novel gene (IT15). We have previously created a targeted disruption in exon 5 of Hdh (Hdhex5), the murine homologue of the HD gene. Homozygotes for the Hdhex5 mutation exhibit embryolethality before embryonic day 8.5, while heterozygotes survive to adulthood and display increased motor activity and cognitive deficits. Detailed morphometric and stereological analyses of the basal ganglia in adult heterozygous mice were performed by light and electron microscopy. Morphometric analyses demonstrated a significant loss of neurons from both the globus pallidus (29%) and the subthalamic nucleus (51%), with a normal complement of neurons in the caudate-putamen and substantia nigra. The ultrastructural appearance of sporadic degenerating neurons in these regions indicated apoptosis. The highest frequency of apoptotic neurons was observed in the globus pallidus and subthalamic nucleus. Stereological analyses in the subthalamic nucleus revealed a significant decrease in the numerical density of symmetric synapses (43%), suggesting a relatively selective loss of inhibitory pallido-subthalamic afferents. Immunohistochemistry using antibodies against enkephalin and substance-P was unremarkable in heterozygotes, indicating a normal complement of enkephalin-immunoreactive striatopallidal afferents and substance-P-immunoreactive striatopeduncular and striatonigral afferents in these animals. These findings show that loss of an intact huntingtin protein is associated with significant morphological alterations in the basal ganglia of adult mice, indicating an important role for this protein during development of the central nervous system.


Multi response biomarker approach in the crab Carcinus aestuarii experimentally exposed to benzo a pyrene, polychlorobiphenyls and methyl mercury.
The aim of this study was to test a multi response biomarker approach for evaluating toxicological risk due to some of the main contaminants in the Mediterranean benzo a pyrene, polychlorobiphenyls and methyl mercury, using the Mediterranean crab Carcinus aestuarii as bioindicator organism. Forty crabs were injected with different doses of these contaminants. Several molecular, biochemical and genotoxic biomarkers were tested in different tissues and biological materials. The main conclusions were: 1 hepatopancreas, gills, haemolymph and excreta seem to be useful for biomarker studies in this species; 2 several biochemical, molecular and genotoxic biomarkers were found suitable for testing in these tissues; 3 several biomarkers were found suitable for evaluating chemical stress due to different Mediterranean contaminants.


Weather conditions and cerebrospinal meningitis in Benin (Gulf of Guinea, West Africa).
Over a 28-year period cerebrospinal meningitis, in sporadic as well as epidemic situations, mainly affected the Beninese territory from November to March, April or sometimes May. On the average, the acme occurred in February-March. A regression analysis confirmed that 14 to 34.5% of the temporal variability of the disease was due to the northern trade wind (harmattan) and a low absolute humidity in the northern areas, which constitute the main epidemiological pole of the country. On the contrary, cerebrospinal meningitis and climate turned out to be fully independent one from the other in the southernmost areas, where the harmattan is seldom experienced although the meningitis belt is at the present time spreading southwards. But the case-fatality ratio was especially high in the coastal region and during the off season, i.e. when endemic meningitis predominantly affected small children aged under one year. In any way, the climate-meningitis relationship proved to be weaker than is sometimes assumed, perhaps because this relationship is partly overshadowed by both anthropic effects (vaccination campaigns) and latency before disease outbreak.


Detection of Plasmodium vivax using Automated Hematology Analyzer in the Korean Army.
This study aimed to evaluate whether our equation model developed from the Sysmex hematology analyzer can discriminate patients with Plasmodium vivax (P. vivax) infection from those with acute febrile illness (AFI) and healthy controls. Besides, we compared our model with the previously studied models. A total of 312 blood samples were collected from the P. vivax, AFI, and healthy control groups. All samples were tested for routine complete blood count conducted by using a Sysmex XE-2100 or XE-5000 analyzer. We compared the reportable and research parameters generated from the Sysmex analyzer among the three groups. The selected parameters that showed a significant difference between the P. vivax and the other group were included in the logistic regression analysis to develop our model (N-OIpv model). Moreover, we analyzed the CBC data according to the previous models, such as the presence of abnormal blue coded events in the WBC/BASO scattergram called the observer-interpretation (OIpv) model, and the previous equation model (N-OD1pv model) developed by Campuzano-Zuluaga et al. Results: The N-OIpv model, which consists of three parameters, such as mean cell volume, plateletcrit, and Lymph-X, showed the best performance for detection of malaria (97.4% accuracy). Also, this model can increase the sensitivity by about 11.9% to 18.1% compared with the OIpv and N-OD1pv models, respectively. We concluded that the N-OIpv model using the Sysmex hematology analyzer is a useful diagnostic tool in the routine laboratory workup for malaria.


The implications of changing patterns in oral health for the general practice of dentistry.
Recent reports from several developed countries have shown reductions in caries prevalence, especially amongst children. As a result of these changes, dental practice surveys show that dentists now work fewer hours at the chairside and see fewer patients. There has been a decline in the time patients have to wait for appointments. There is anxiety amongst general dental practitioners that their income is reducing. The school dental service in the developed countries would be the first casualty of the caries-free society, and the reduction in demand for the services of school dental nurses has led to the closure of some training institutions. If the caries decline persists, the volume of restorative work will fall and there will be a shift of emphasis to periodontal care and geriatric dentistry. A change of attitude to the utilization of dental auxiliaries is predicted. In the developing countries, a restorative strategy is no answer to the increasing prevalence of dental caries, as most developing countries cannot afford the armamentarium required or its maintenance. The use of dental auxiliaries, especially dental hygienists, may not cope with the worsening picture of oral disease. It is proposed that volunteers recruited from the urban and rural areas be trained as lay health advisors. The prospects for the dentist in most developing countries are those of excessive work load, high cost of dental services and the continued neglect of preventive dental care.


BRIPPED scan for evaluation of ED patients with shortness of breath.
The BRIPPED scan is an ultrasound evaluation of pulmonary B-lines, right ventricle size, inferior vena cava collapsibility, pleural and pericardial effusion, pneumothorax, left ventricle ejection fraction, and lower extremity deep venous thrombosis. The primary goal was to evaluate the effect of the BRIPPED scan on the physician's list of differential diagnoses for patients presenting with shortness of breath. This prospective randomized control trial was performed on patients presenting to the emergency department with shortness of breath. Primary data analysis was performed using an ordinal quasi-symmetry model to compare the magnitude of change in the differential diagnoses between 2 groups. Secondary outcome measures included changes in physician orders or interventions, time to disposition, time to perform the BRIPPED scan, and the interrater reliability of the interpretation of the scan. A total of 104 patients and 24 physicians were enrolled in this study. Fifty-two patients were randomly assigned to each cohort. Among the BRIPPED cohort, there was significant movement of likelihood for several etiologies of shortness of breath on the physician differential. There was no significance in the change of differential diagnosis between the BRIPPED and control cohorts. The average (SD) time to perform the scan was 5.7 (1.3) minutes (95% confidence interval, 5.4-6 minutes). The BRIPPED scan is a rapid ultrasound evaluation of shortness of breath in the emergency department. BRIPPED influenced physician differential diagnoses to the same degree as laboratory and radiographic testing. BRIPPED did not alter the final diagnosis in this patient population.


Ninhydrin sweat test: a simple method for detecting antibodies neutralizing botulinum toxin type A.
Approximately 5% of patients with cervical dystonia receiving repeated botulinum neurotoxin A (BoNT/A) injections develop secondary loss of treatment benefit. Currently available tests to directly detect neutralizing BoNT/A antibodies (BoNT/A-AB) are either expensive or time consuming. To establish a simple, clinically useful test for antibody detection, we adapted the ninhydrin sweat test (NST). Eighteen dystonic patients with secondary nonresponse and clinically suspected BoNT/A-AB formation were tested for BoNT/A-AB in the mouse diaphragm test (MDT). In addition, the size of the anhidrotic area was determined by the NST 21 days after an intradermal dose of 10 U Dysport into the hypothenar region of the left palm. In nine patients, positive BoNT-AB titers were found in the MDT. There was a significant correlation between the BoNT/A-AB titers and the anhidrotic area (Spearman's rho = -0.9, P < 0.0001). Both tests provided comparably good results with respect to qualitative antibody detection. In the clinical situation of secondary nonresponse to BoNT/A therapy, the economical NST may be a helpful tool to detect neutralizing BoNT/A-AB.


The impact of progesterone receptor expression on prognosis of patients with rapidly proliferating, hormone receptor-positive early breast cancer: a post hoc analysis of the IBIS 3 trial.
In the Italian Breast Cancer Intergroup Studies (IBIS) 3 phase III trial, we compared cyclophosphamide, methotrexate, 5-fluorouracil (CMF) alone to sequential epirubicin/CMF regimens in patients with rapidly proliferating early breast cancer (RPEBC). We performed a post hoc analysis in the subgroup of patients with hormone-receptor-positive RPEBC on the prognostic role of progesterone receptor (PgR) status. RPEBC was defined by thymidine labeling index (TLI) >3% or grade 3 or S-phase >10% or Ki67 >20%. We analyzed 466 patients with hormone-receptor-positive RPEBC receiving sequential epirubicin/CMF regimens followed by tamoxifen, and for whom the status of ER and PgR was available. Considering both cut-off values of 10% and 20%, PgR expression was significantly associated with age, menopausal status, and ER expression; HER2 status was associated with PgR status only at a cutoff value of 20% PgR. Upon univariate analysis, tumor size, nodal status, and PgR were significantly associated with disease-free survival (DFS) and overall survival (OS), while age class and local treatment type were associated only with DFS. Patients with PgR <20% showed lower 5- and 10-year DFS [hazard ratio (HR) = 1.48; 95%CI: 1.01-2.18; p = 0.044] and OS (HR = 1.85; 95%CI: 1.08-3.19, p = 0.025) rates compared with patients with PgR ⩾20%. Upon multivariate analysis, only tumor size, nodal status, and PgR were independent prognostic factors. Our results highlight the independent prognostic relevance of PgR expression in patients with hormone-receptor-positive RPEBC treated with adjuvant chemotherapy and endocrine therapy, where the definition of prognostic subgroups is still a major need.


Process inhibition due to organic acids in fed-batch composting of food waste--influence of starting culture.
Inhibition of the degradation during low pH conditions has been observed in fed-batch composting systems. To analyse this phenomenon, fed-batch composting of food waste with different amounts of starting culture was examined in laboratory reactor experiments. Changes in temperature, carbon dioxide evolution, pH, solids, ash and short chain organic acids were measured. In reactors with a daily feed rate of 24% or less of the starting culture, thermophilic temperatures occurred and the pH and carbon dioxide evolution were high and stable after a starting period of 4-5 days. In reactors with a daily feed rate of 48% or more of the starting culture the composting process failed, as the pH dropped below 6 and remained there and the temperature and carbon dioxide evolution were low. It was concluded that the use of adequate amounts of starting culture consisting of active compost can efficiently prevent low pH conditions and process inhibition in fed-batch composting of food waste.


Role of glutathione modulation in acrylonitrile-induced gastric DNA damage in rats.
Acrylonitrile (VCN) or its reactive metabolites irreversibly interact with gastric DNA in vivo and cause DNA damage. The effect of glutathione (GSH) modulation on VCN-induced genotoxicity and unscheduled DNA repair synthesis (UDRS) in DNA of gastric mucosal tissues was investigated. VCN-induced UDRS was determined: in control rats, rats with depleted gastric GSH contents, and rats treated with sulfhydryl compounds. A single oral dose (23 mg/kg) of VCN induced a time- and dose-dependent increase in gastric UDRS and decrease in GSH levels. While maximal UDRS in gastric mucosa was observed 2 h following oral administration of 23 mg/kg VCN, maximal GSH depletion (50% of control) was detected 4 h following treatment. Increasing the VCN dose to 46 mg/kg caused a further decrease in gastric GSH level (27% of control), while UDRS was elevated. Inhibition of VCN oxidation by treatment of the animals with the cytochrome P450 inhibitor, SKF 525-A, prior to VCN administration caused 65% reduction in VCN-induced UDRS. Treatment of rats with the GSH depletor diethylmaleate (DEM) prior to VCN administration caused 167% increase in UDRS in gastric mucosal tissues. Treatment of the animals with the sulfhydryl compounds, cysteine and penicillamine, prior to VCN administration protected against VCN-induced UDRS. The results demonstrated an inverse and highly significant correlation between gastric GSH levels and VCN-induced UDRS (r = -0.873, P < 0.0001). In conclusion, our study indicates that VCN bioactivation and the homeostasis of gastric GSH may play a major, role in the initial processes underlying VCN-induced gastric carcinogenesis.


Total adrenalectomy versus subtotal adrenalectomy for bilateral pheochromocytoma: meta-analysis.
Bilateral pheochromocytomas are rare and often heritable. Total adrenalectomy leads to a definitive oncological cure, with subsequent definitive hypocortisolism. Subtotal adrenalectomy is a possible alternative. The aim of this study was to assess the effects of total adrenalectomy and subtotal adrenalectomy on bilateral pheochromocytoma in terms of post-surgical rate of recurrence, metastatic disease, and steroid dependence. Systematic searches in the bibliographic databases PubMed, Embase, and Europe PMC were performed for 1945 to 1 June 2023. PRISMA guidelines were followed and the PICO strategy was applied to English-language studies comparing subtotal adrenalectomy with total adrenalectomy. A random-effects model was used to assess the different outcomes for studies with high heterogeneity. The Newcastle-Ottawa scale and the Risk Of Bias In Non-randomized Studies of Interventions ('ROBINS-I') tool were used to assess quality and risk of bias. From a total of 12 909 studies, 1202 patients (from 10 retrospective studies) were eligible for the meta-analysis. In six studies, including 1176 patients, the recurrence rate after subtotal adrenalectomy and total adrenalectomy was 14.1 versus 2.6 per cent respectively (OR 4.91, 95 per cent c.i. 1.30 to 18.54; P = 0.020; I2 72 per cent). In nine studies, including 1124 patients, the rate of post-surgical steroid dependence was 93.3 versus 11.6 per cent after total adrenalectomy and subtotal adrenalectomy respectively (OR 0.003, 95 per cent c.i. 0.0003 to 0.03; P < 0.00001; I2 66 per cent). Based on two studies, including 719 patients, no differences were evident regarding the occurrence of post-surgery metastatic disease. Subtotal adrenalectomy leads to less post-surgical primary adrenal insufficiency, but leads to a higher postoperative recurrence rate. Future prospective randomized studies, with clear eligibility criteria, are needed to confirm these results.


Increased c-Jun expression and reduced GATA2 expression promote aberrant monocytic differentiation induced by activating PTPN11 mutants.
Juvenile myelomonocytic leukemia (JMML) is characterized by myelomonocytic cell overproduction and commonly bears activating mutations in PTPN11. Murine hematopoietic progenitors expressing activating Shp2 undergo myelomonocytic differentiation, despite being subjected to conditions that normally support only mast cells. Evaluation of hematopoietic-specific transcription factor expression indicates reduced GATA2 and elevated c-Jun in mutant Shp2-expressing progenitors. We hypothesized that mutant Shp2-induced Ras hyperactivation promotes c-Jun phosphorylation and constitutive c-Jun expression, permitting, as a coactivator of PU.1, excessive monocytic differentiation and reduced GATA2. Hematopoietic progenitors expressing activating Shp2 demonstrate enhanced macrophage CFU (CFU-M) compared to that of wild-type Shp2-expressing cells. Treatment with the JNK inhibitor SP600125 or cotransduction with GATA2 normalizes activating Shp2-generated CFU-M. However, cotransduction of DeltaGATA2 (lacking the C-terminal zinc finger, needed to bind PU.1) fails to normalize CFU-M. NIH 3T3 cells expressing Shp2E76K produce higher levels of luciferase expression directed by the macrophage colony-stimulating factor receptor (MCSFR) promoter, which utilizes c-Jun as a coactivator of PU.1. Coimmunoprecipitation demonstrates increased c-Jun-PU.1 complexes in mutant Shp2-expressing hematopoietic progenitors, while chromatin immunoprecipitation demonstrates increased c-Jun binding to the c-Jun promoter and an increased c-Jun-PU.1 complex at the Mcsfr promoter. Furthermore, JMML progenitors express higher levels of c-JUN than healthy controls, substantiating the disease relevance of these mechanistic findings.


Effects of lung volume and fatigue on evoked diaphragmatic phonomyogram in normal subjects.
A diaphragmatic phonomyogram (PMG) evoked by maximal phrenic nerve stimulation at end expiratory lung volume (FRC) has been previously described as a good index of changes in diaphragmatic contractility with fatigue. A study was undertaken to assess whether this conclusion could be extended to different lung volumes. Diaphragmatic compound motor action potentials (CMAPs) were recorded on each side of the chest by the means of surface electrodes placed over the eight intercostal spaces in five healthy subjects. Diaphragmatic PMGs from both sides were recorded with condenser microphones fixed to the skin close to the CMAP recording electrodes. Oesophageal and gastric balloon tipped catheters were employed to measure transdiaphragmatic pressure twitches (TwPDI) which served as the standard measure of changes in diaphragmatic contractility. PMG and TwPDI responses were compared at different lung volumes over inspiratory capacity both before and after fatiguing inspiratory resistive loading. No consistent relationship was found in different subjects or on different days in the same subject between PMG and lung volume or between PMG and TwPDI. However, the PMG:CMAP ratio from both sides at any given lung volume decreased after fatigue in roughly the same proportion as the TwPDI. These results show that, although PMG can detect changes in diaphragmatic contractility caused by fatigue in normal subjects, lung volume changes need to be controlled and each subject should serve as his or her own control.


Dysfunction of chromatin assembly factor 1 induces shortening of telomeres and loss of 45S rDNA in Arabidopsis thaliana.
Chromatin Assembly Factor 1 (CAF1) is a three-subunit H3/H4 histone chaperone responsible for replication-dependent nucleosome assembly. It is composed of CAC 1-3 in yeast; p155, p60, and p48 in humans; and FASCIATA1 (FAS1), FAS2, and MULTICOPY SUPPRESSOR OF IRA1 in Arabidopsis thaliana. We report that disruption of CAF1 function by fas mutations in Arabidopsis results in telomere shortening and loss of 45S rDNA, while other repetitive sequences (5S rDNA, centromeric 180-bp repeat, CACTA, and Athila) are unaffected. Substantial telomere shortening occurs immediately after the loss of functional CAF1 and slows down at telomeres shortened to median lengths around 1 to 1.5 kb. The 45S rDNA loss is progressive, leaving 10 to 15% of the original number of repeats in the 5th generation of mutants affecting CAF1, but the level of the 45S rRNA transcripts is not altered in these mutants. Increasing severity of the fas phenotype is accompanied by accumulation of anaphase bridges, reduced viability, and plant sterility. Our results show that appropriate replication-dependent chromatin assembly is specifically required for stable maintenance of telomeres and 45S rDNA.


Oral disopyramide after admission to hospital with suspected acute myocardial infarction. U. K. Rythmodan Multicentre Study Group.
A multi-centre double-blind randomized study is reported in which the effect on mortality of oral disopyramide (300 mg loading dose, then 100 mg qds) was compared with placebo in 1985 patients entering hospital with suspected acute myocardial infarction. Treatment was commenced with 24 hr of onset of symptoms (mean time to first dose 9 hr) and continued until discharge from hospital or 14 days, whichever came first. Nine-hundred and ninety-five patients were allocated to disopyramide and 990 to placebo. The overall mortality, calculated on an intention-to-treat basis, was 7.2% for the disopyramide and 5.6% for the placebo patients. Among those patients with proven infarction mortality was 9.5% of 687 on disopyramide and 7.4% of 716 on placebo. These differences are not statistically significant. Patients with cardiac failure or hypotension at entry did not fare worse on disopyramide, but those with a conduction defect did. Reinfarction was not significantly influenced by disopyramide. The prophylactic use of disopyramide in patients with suspected acute myocardial infarction does not reduce mortality or the incidence of early reinfarction.


Effectiveness of Yoga Intervention in Reducing Felt Stigma in Adults With Epilepsy: A Randomized Controlled Trial.
Persons with epilepsy are afflicted with comorbidities such as stigma, anxiety, and depression which have a significant impact on their quality of life. These comorbidities remain largely unaddressed in resource-limited countries. This randomized controlled trial (RCT) aimed to investigate whether yoga and psychoeducation were effective in reducing felt stigma (primary outcome), neuropsychiatric outcomes, and seizure frequency, as compared with sham yoga and psychoeducation in persons with epilepsy. This was an assessor-blinded, sham yoga-controlled RCT. Patients clinically diagnosed with epilepsy, aged 18-60 years, and scoring higher than the cutoff score for felt stigma as measured by the Kilifi Stigma Scale (KSS) in our population were randomly assigned to receive either yoga therapy plus psychoeducation (intervention) or sham yoga therapy plus psychoeducation (comparator) for a duration of 3 months. The primary outcome was a significant decrease in felt stigma as compared with the comparator arm as measured by the KSS. Primary and secondary outcomes (seizure frequency, quality of life, anxiety, depression, mindfulness, trait rumination, cognitive impairment, emotion regulation) were assessed at baseline, 3 months, and 6 months. Parametric/nonparametric analysis of covariance and the χ2 test were used to compare the 2 arms. A total of 160 patients were enrolled in the trial. At the end of the follow-up period (6 months), the intervention arm reported significant reduction in felt stigma as compared with the control arm (Cohen's d = 0.23, 95% CI -0.08 to 0.55, p = 0.006). Significantly higher odds of >50% seizure reduction (odds ratio [OR] 4.11, 95% CI 1.34-14.69, p = 0.01) and complete seizure remission (OR 7.4, 95% CI 1.75-55.89, p = 0.005) were also observed in the intervention group. The intervention group showed significant improvement in symptoms of anxiety, cognitive impairment, mindfulness, and quality of life relative to the control group at the end of follow-up period (p < 0.05). Yoga can alleviate the burden of epilepsy and improve the overall quality of life in epilepsy by reducing perceived stigma. Clinical Trials Registry of India (CTRI/2017/04/008385). This study provides Class I evidence that yoga reduces felt stigma in adult patients with epilepsy.


Supplemental description of Myxobolus squamalis (Myxozoa).
Myxobolus squamalis is a myxozoan skin parasite first reported from rainbow trout (Oncorhynchus mykiss). Identification of the parasite based on myxospore morphology is unreliable because M. squamalis is similar to several other myxobolids that share host species and geographic ranges. The only ssrRNA gene sequence available for M. squamalis is from Chinook salmon, Oncorhynchus tschawytscha, but these data are not linked with any information on spore morphology. Here we provide a supplemental description of M. squamalis from its type host, O. mykiss, using myxospore morphology, morphometry, and ssrRNA gene sequence data. Our ssrRNA sequence data were only 78% similar to the GenBank M. squamalis sequence from Chinook salmon, which raises the possibility of misidentification. We suggest that Chinook salmon are not a host of the parasite, as no infections were found in current stocks or in >30 yr of historical data from hatchery fish held in waters that harbored M. squamalis in rainbow trout, and we could find no well-identified report of M. squamalis from Chinook salmon. Our complementary morphological and molecular data sets will facilitate unambiguous future identification of M. squamalis.


Polymorphism in endothelial connexin40 enhances sensitivity to intraluminal pressure and increases arterial stiffness.
To determine whether impairment of endothelial connexin40 (Cx40), an effect that can occur in hypertension and aging, contributes to the arterial dysfunction and stiffening in these conditions. A new transgenic mouse strain, expressing a mutant Cx40, (Cx40T202S), specifically in the vascular endothelium, has been developed and characterized. This mutation produces nonfunctional hemichannels, whereas gap junctions containing the mutant are electrically, but not chemically, patent. Mesenteric resistance arteries from Cx40T202S mice showed increased sensitivity of the myogenic response to intraluminal pressure in vitro, compared with wild-type mice, whereas transgenic mice overexpressing native Cx40 (Cx40Tg) showed reduced sensitivity. In control and Cx40Tg mice, the sensitivity to pressure of myogenic constriction was modulated by both NO and endothelium-derived hyperpolarization; however, the endothelium-derived hyperpolarization component was absent in Cx40T202S arteries. Analysis of passive mechanical properties revealed that arterial stiffness was enhanced in vessels from Cx40T202S mice, but not in wild-type or Cx40Tg mice. Introduction of a mutant form of Cx40 in the endogenous endothelial Cx40 population prevents endothelium-derived hyperpolarization activation during myogenic constriction, enhancing sensitivity to intraluminal pressure and increasing arterial stiffness. We conclude that genetic polymorphisms in endothelial Cx40 can contribute to the pathogenesis of arterial disease.


Integrated Analysis of Expression and Prognostic Values of Acyl-CoA Dehydrogenase short-chain in Colorectal Cancer.
Background: Acyl-CoA dehydrogenase short-chain (ACADS) is a crucial enzyme in the fatty acid metabolism pathway located in mitochondria. However, the expression level and prognostic value of ACADS in colorectal cancer (CRC) remain unclear. Methods: The mRNA and protein expression data of ACADS was obtained from The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Oncomine. Prognostic values of ACADS were calculated using Kaplan-Meier survival analysis. Correlations between ACADS and immune infiltration were estimated using TIMER, CIBERSORT, EPIC, quanTIseq, and xCell. The UALCAN and MEXPRESS databases were utilized for Methylation analysis. The co-expression analysis based on mRNA expression and interaction network of ACADS were performed via several online tools. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on ACADS co-expressed genes were performed using the Metascape. Results: The expression analysis demonstrated that ACADS was down-regulated in CRC tissues compared with paired normal tissue. Expression of ACADS was found to be significantly associated with clinical cancer stages and the consensus molecular subgroups (CMS) constituent ratio in CRC patients. Besides, lower ACADS expression was found to predict poor prognosis and be significantly associated with common immune checkpoint genes and MMR genes in CRC. ACADS expression levels were positively related to B cells, CD4+ T cells, CD8+ T cells, M1 macrophages, neutrophils, and Tregs, while negatively correlated with M0 macrophages, M2 macrophages. The methylation level of ACADS in normal tissues was significantly higher than that in tumor tissues, and several methylation sites were identified. The enrichment analysis suggested the co-expressed genes mainly enriched in cell mitochondrial metabolism. Conclusions: The present study provided multilevel evidences for expression of ACADS in CRC and the function of ACADS in prognostic prediction, immune infiltration, and methylation. ACADS might have the potential as the novel biomarker and therapeutic target in CRC patients.


Probing a Continuous Polar Defect: A Reaction Coordinate for Pore Formation in Lipid Membranes.
Various biophysical processes involve the formation of aqueous pores over lipid membranes, including processes of membrane fusion, antimicrobial peptide activity, lipid flip-flop, and membrane permeation. Reliable and efficient free-energy calculations of pore formation using molecular dynamics simulations remained challenging due to the lack of good reaction coordinates (RCs) for pore formation. We present a new RC for pore formation that probes the formation and rupture of a continuous polar defect over the membrane. Potential of mean force (PMF) calculations along the new RC rapidly converge and exhibit no hysteresis between pore-opening and pore-closing pathways, in contrast to calculations based on previous RCs. We show that restraints along the new RC may restrain the system tightly to the transition state of pore formation, rationalizing the absence of hysteresis. We observe that the PMF of pore formation in a tension-free membrane of dimyristoylphosphatidylcholine (DMPC) reveals a free-energy barrier for pore nucleation, confirming a long-hypothesized metastable prepore state. We test the influence of the lipid force field, the cutoff distance used for Lennard-Jones interactions, and the lateral membrane size on the free energies of pore formation. In contrast to PMF calculations based on previous RCs, we find that such parameters have a relatively small influence on the free energies of pore nucleation. However, the metastability of the open pore in DMPC may depend on such parameters. The RC has been implemented into an extension of the GROMACS simulation software. The new RC allows for reliable and computationally efficient free-energy calculations of pore formation in lipid membranes.


Relationship between the daily rhythms of locomotor activity and body temperature in eight mammalian species.
The relationship between the daily rhythms of locomotor activity and body temperature was studied by telemetry in four nocturnal and four diurnal mammalian species. The results showed that the two rhythms are very closely synchronized, as they 1) ascend past the daily mean at the same time, 2) reach the daily acrophase at the same time, and 3) are best correlated at time lags approaching zero. The rhythms of nocturnal animals crossed the daily mean at the transition between the light and dark phases of the light-dark cycle and reached their acrophases during the dark phase, whereas the rhythms of diurnal animals crossed the daily mean at the transition between the dark and light phases and reached their acrophases during the light phase. Despite the close synchrony of the two rhythms, the results indicate that the temperature rhythm is not a byproduct of the activity rhythm, as body temperature during the active phase of the daily cycle was higher than body temperature during the inactive phase in all species irrespective of the activity level prevailing during each phase.


Frequent cytolytic T-cell responses to peptide MAGE-A10(254-262) in melanoma.
MAGE genes encode tumor-specific shared antigens that are among the most interesting candidates for cancer vaccines. Despite extensive studies, however, CD8+ T-cell responses to MAGE-derived epitopes have been detected only occasionally in cancer patients, even after vaccination. In contrast with these findings, we report here that HLA-A2 melanoma patients respond frequently to the recently identified peptide MAGE-A10(254-262). Indeed, as assessed by staining with fluorescent HLA-A2/peptide MAGE-A10(254-262) tetramers, CD8+ T cells directed against this peptide were readily detectable in a large proportion of HLA-A2+ melanoma patients. These results provide new insight into the immunogenicity of MAGE antigens and underline the potential usefulness of MAGE-A10 peptide-based cancer vaccines.


Conformational properties of oxazole-amino acids: effect of the intramolecular N-H···N hydrogen bond.
Oxazole ring occurs in numerous natural peptides, but conformational properties of the amino acid residue containing the oxazole ring in place of the C-terminal amide bond are poorly recognized. A series of model compounds constituted by the oxazole-amino acids occurring in nature, that is, oxazole-alanine (L-Ala-Ozl), oxazole-dehydroalanine (ΔAla-Ozl), and oxazole-dehydrobutyrine ((Z)-ΔAbu-Ozl), was investigated using theoretical calculations supported by FTIR and NMR spectra and single-crystal X-ray diffraction. It was found that the main feature of the studied oxazole-amino acids is the stable conformation β2 with the torsion angles φ and ψ of -150°, -10° for L-Ala-Ozl, -180°, 0° for ΔAla-Ozl, and -120°, 0° for (Z)-ΔAbu-Ozl, respectively. The conformation β2 is stabilized by the intramolecular N-H···N hydrogen bond and predominates in the low polar environment. In the case of the oxazole-dehydroamino acids, the π-electron conjugation that is spread on the oxazole ring and C(α)═C(β) double bond is an additional stabilizing interaction. The tendency to adopt the conformation β2 clearly decreases with increasing the polarity of environment, but still the oxazole-dehydroamino acids are considered to be more rigid and resistant to conformational changes.


Minimally invasive approaches in severe panfacial fractures.
Minimally invasive approaches to severe panfacial fractures are being used increasingly to reduce surgical trauma and the related complications. In this study, it was aimed to determine the ideal surgical approaches in severe panfacial fractures. Sixteen patients with severe panfacial fractures were included in this study. Minimally invasive approaches were used for Le Fort III fracture in six patients, for Le Fort II fracture in four patients, and for bilateral maxillary and orbital floor fractures in six patients. We used subciliary, intraoral vestibular, lateral eyebrow incisions to reach orbital, maxillary, zygomaticomaxillary buttress, and nasoethmoidal fractures, respectively. All fractures were repaired with miniplates and screws. No hematoma, wound infections or other complications were observed. Minimally invasive approaches in severe panfacial fractures are considered suitable and effective in terms of aesthetic results.


The metabolic syndrome and antioxidant concentrations: findings from the Third National Health and Nutrition Examination Survey.
Oxidative stress may play a role in the pathophysiology of diabetes and cardiovascular disease, but little is known about antioxidant status among individuals with the metabolic syndrome who are at high risk for developing these conditions. Using data from the Third National Health and Nutrition Examination Survey (1988-1994), we compared circulating concentrations of vitamins A, C, and E; retinyl esters; five carotenoids; and selenium in 8,808 U.S. adults aged > or = 20 years with and without the metabolic syndrome. After adjusting for age, sex, race or ethnicity, education, smoking status, cotinine concentration, physical activity, fruit and vegetable intake, and vitamin or mineral use, participants with the metabolic syndrome had significantly lower concentrations of retinyl esters, vitamin C, and carotenoids, except lycopene. With additional adjustment for serum lipid concentrations, vitamin E concentrations were significantly lower in participants with the metabolic syndrome than those without the syndrome. Retinol concentrations were similar between the two groups. After excluding participants with diabetes, the results were very similar. Consumption of fruits and vegetables was also lower among people with the metabolic syndrome. Adults with the metabolic syndrome have suboptimal concentrations of several antioxidants, which may partially explain their increased risk for diabetes and cardiovascular disease.


Serine synthesis pathway upregulated by E-cadherin is essential for the proliferation and metastasis of breast cancers.
The loss of E-cadherin (E-cad), an epithelial cell adhesion molecule, has been implicated in the epithelial-mesenchymal transition (EMT), promoting invasion and migration of cancer cells and, consequently, metastasis. However, recent studies have demonstrated that E-cad supports the survival and proliferation of metastatic cancer cells, suggesting that our understanding of E-cad in metastasis is far from comprehensive. Here, we report that E-cad upregulates the de novo serine synthesis pathway (SSP) in breast cancer cells. The SSP provides metabolic precursors for biosynthesis and resistance to oxidative stress, critically beneficial for E-cad-positive breast cancer cells to achieve faster tumor growth and more metastases. Inhibition of PHGDH, a rate- limiting enzyme in the SSP, significantly and specifically hampered the proliferation of E-cad- positive breast cancer cells and rendered them vulnerable to oxidative stress, inhibiting their metastatic potential. Our findings reveal that E-cad adhesion molecule significantly reprograms cellular metabolism, promoting tumor growth and metastasis of breast cancers.


Stoichiometry of ozonation of environmentally relevant olefins in saturated hydrocarbon solvents.
The double bond-to-ozone reaction stoichiometry was quantified for ozonation of several environmentally relevant unsaturated fatty acids and monoterpenes in saturated hydrocarbon solvents. Olefins with initial concentrations from 30 microM to 3mM were injected in a solvent (n-hexadecane, nonane, or cyclohexane) while an ozone-oxygen mixture was slowly bubbled through the solution. The number of ozone molecules consumed by the injection was quantified in the outgoing flow, and the expected 1:1 double bond-to-ozone reaction stoichiometry was observed only under subambient temperature conditions (T < 250 K). At room temperature, the effective number of double bonds oxidized by each ozone molecule increased to 2-5, with a higher degree of oxidation occurring at lower initial olefin concentrations. The observed enhancement in the stoichiometry is consistent with a competition between direct ozonation and free radical initiated oxidation of double bonds, with free radicals being produced by slow reactions between dissolved ozone and solvent molecules.


Molecular cloning of cDNA for CENP-B, the major human centromere autoantigen.
We have isolated a series of overlapping cDNA clones for approximately 95% of the mRNA that encodes CENP-B, the 80-kD human centromere autoantigen recognized by patients with anticentromere antibodies. The cloned sequences encode a polypeptide with an apparent molecular mass appropriate for CENP-B. This polypeptide and CENP-B share three non-overlapping epitopes. The first two are defined by monoclonal antibodies elicited by injection of cloned fusion protein. Epitope 1 corresponds to a major antigenic site recognized by the anticentromere autoantibody used to obtain the original clone. Epitope 2 is a novel one not recognized by the autoantibody. These epitopes were shown to be distinct both by competitive binding experiments and by their presence or absence on different subcloned portions of the fusion protein. The third independent epitope, recognized by a subset of anticentromere-positive patient sera, maps to a region substantially closer to the amino terminus of the fusion protein. DNA and RNA blot analyses indicate that CENP-B is unrelated to CENP-C, a 140-kD centromere antigen also recognized by these antisera. CENP-B is the product of a 2.9-kb mRNA that is encoded by a single genetic locus. This mRNA is far too short to encode a polypeptide the size of CENP-C. The carboxy terminus of CENP-B contains two long domains comprised almost entirely of glutamic and aspartic acid residues. These domains may be responsible for anomalous migration of CENP-B on SDS-polyacrylamide gels, since the true molecular mass of CENP-B is approximately 65 kD, 15 kD less than the apparent molecular mass deduced from gel electrophoresis. Quite unexpectedly, immunofluorescence analysis using antibodies specific for CENP-B reveals that the levels of antigen vary widely between chromosomes.


The Role of Personal Identity on Positive and Negative Symptoms in Psychosis: A Study Using the Repertory Grid Technique.
People with psychosis experience disruptions in personal identity that affect positive and negative symptoms, but the complexity of these phenomena needs to be addressed in an in-depth manner. Using the Personal Construct Theory, we examined whether distinct dimensions of personal identity, as measured with the Repertory Grid Technique along with other cognitive factors, might influence psychotic symptomatology. Eighty-five outpatients with schizophrenia-spectrum disorders completed a repertory grid, an observed-rated interview of psychotic symptoms, and measures of cognitive insight, depressive symptoms, neurocognition, and theory of mind. Structural equation models revealed that interpersonal dichotomous thinking directly affected positive symptoms. Self-discrepancies influenced positive symptoms by mediation of depressive symptoms. Interpersonal cognitive differentiation and interpersonal cognitive richness mediated the impact of self-reflectivity and neurocognitive deficits in negative symptomatology. This study is the first of its kind to examine the structure of personal identity in relation to positive and negative symptoms of psychosis. Results suggest interventions targeted to improving interpersonal dichotomous thinking, self-discrepancies, interpersonal cognitive differentiation, and interpersonal cognitive richness may be useful in improving psychotic symptoms.


"We can't get along without each other": Qualitative interviews with physicians about device industry representatives, conflict of interest and patient safety.
Physician relationships with device industry representatives have not been previously assessed. This study explored interactions with device industry representatives among physicians who use implantable cardiovascular and orthopedic devices to identify whether conflict of interest (COI) is a concern and how it is managed. A descriptive qualitative approach was used. Physicians who implant orthopedic and cardiovascular devices were identified in publicly available directories and web sites, and interviewed about their relationships with device industry representatives. Sampling was concurrent with data collection and analysis. Data were analyzed and discussed using constant comparative technique by all members of the research team. Twenty-two physicians (10 cardiovascular, 12 orthopedic) were interviewed. Ten distinct representative roles were identified: purchasing, training, trouble-shooting, supplying devices, assisting with device assembly and insertion, supporting operating room staff, mitigating liability, conveying information about recalls, and providing direct and indirect financial support. Participants recognized the potential for COI but representatives were present for the majority of implantations. Participants revealed a tension between physicians and representatives that was characterized as "symbiotic", but required physicians to be vigilant about COI and patient safety, particularly because representatives varied regarding disclosure of device defects. They described a concurrent tension between hospitals, whose policies and business practices were focused on cost-control, and physicians who were required to comply with those policies and use particular devices despite concerns about their safety and effectiveness. Given the potential for COI and threats to patient safety, further research is needed to establish the clinical implications of the role of, and relationship with device industry representatives; and whether and how hospitals do and should govern interaction with representatives, or support their staff in this regard.


Recurrence of dysembryoplastic neuroepithelial tumor following resection.
Dysembryoplastic neuroepithelial tumor (DNT) is an increasingly recognized surgically curable tumor that characteristically presents with seizures in children. We report a case of a patient who underwent resection of a histologically proven DNT at 6 years of age. The resection was thought to be total at the time of surgery, and this impression was confirmed on postoperative imaging. Following the initial resection, the patient underwent surveillance imaging at regular intervals. Six years following the initial surgery, surveillance imaging demonstrated an enlarging area of signal abnormality at the site of the prior resection. The patient underwent a second resection with pathological confirmation of DNT recurrence. Although recurrence of DNT following resection is rare, this case suggests that surveillance imaging may have a role in patients with DNT, even following resections that are thought to be complete.


CMR-Derived Extracellular Volume Fraction as a Marker for Myocardial Fibrosis: The Importance of Coexisting Myocardial Inflammation.
The aim of the present study was to evaluate whether extracellular volume fraction (ECV) can reliably inform on the extent of diffuse fibrosis in the simultaneous presence of myocardial inflammation, which has not been verified to date. Diffuse myocardial fibrosis is associated with unfavorable outcome in patients with cardiomyopathy, and is of prognostic relevance. Assessment of ECV bears promise for being a noninvasive surrogate parameter, but it may be altered by other pathologies. In this prospective study, 107 consecutive patients with clinical suspicion of inflammatory cardiomyopathy were included. All patients underwent left ventricular (LV) endomyocardial biopsy (EMB) and cardiac magnetic resonance imaging on a 1.5-T scanner. T1 mapping was obtained with the modified Look-Locker inversion recovery sequence, and ECV was calculated. Myocardial inflammation was present in 66 patients. Patients with and without inflammation were of similar age and had comparable LV ejection fraction (37 ± 17% vs. 36 ± 18%; p = 0.9) and symptom duration (median 14 days [interquartile range: 5 to 36 days] vs. median 14 days [interquartile range: 7 to 30 days]; p = 0.73). Although LV collagen volume percentage was comparable between groups (inflammation 12.3 ± 17.8% vs. noninflammation 11.4 ± 7.9%; p = 0.577), ECV was significantly higher in patients with inflammation (0.37 ± 0.06%) than in those without inflammation (0.33 ± 0.08%; p = 0.02). Importantly, ECV adequately estimated the degree of LV fibrosis percentage only in patients without inflammation (r = 0.72; p < 0.0001) and not in those with inflammation (r = 0.24; p = 0.06). These findings prove the theoretical concept of ECV as an estimate for diffuse myocardial fibrosis, but only in the absence of significant myocardial inflammation. Assuming that various degrees of myocardial inflammation and fibrosis coexist in such a scenario, the measured ECV will reflect a sum of these different pathologies but will not inform solely on the extent of diffuse fibrosis.


A chondroitin sulfate based injectable hydrogel for delivery of stem cells in cartilage regeneration.
Chondroitin sulfate (CS), as a popular material for cartilage tissue engineering scaffolds, has been extensively studied and reported for its safety and excellent biocompatibility. However, the rapid degradation of pure CS scaffolds has brought a challenge to regenerate neo-tissue similar to natural articular cartilage effectively. Meanwhile, the poly(ethene glycol) (PEG) -based biopolymer is frequently applied as a structural constituent material because of its remarkable mechanical properties, long-lasting in vivo stability, and hypo-immunity. Here, we report that the combination of CS and hyperbranched multifunctional PEG copolymer (HB-PEG) could synergistically promote cartilage repair. The thiol functionalised CS (CS-SH)/HB-PEG hydrogel scaffolds were fabricated via thiol-ene reaction, which exhibits rapid gelation, excellent mechanical properties and prolonged degradation properties. We found that rat adipose-derived mesenchymal stem cells presented great cell viability and improved chondrogenesis in CS-SH/HB-PEG hydrogels. Moreover, the injectable hydrogel scaffolds reduced stem cell inflammatory response, consistent with the well-documented anti-inflammatory activities of CS.


The electronic structure of capped and uncapped CdS nanoparticles.
The electronic structure of spherical Cd(m),S(n) nanoparticles having zinc-blende symmetry and the diameters of up to around 3 nm has been studied by Hartree-Fock theory to find out the effect of the cluster size on the optical energy gap between HOMO and LUMO. The effect of encapsulation on the electronic structure has been also investigated for CdS4 and Cd13S4 clusters embedded in SiO2 matrix and sodalite cage by Hartree-Fock theory. It was found that the energy gap of CdS nanoparticles can be regulated by both the cluster size and the interface provided by the SiO2 matrix and sodalite cage. The energy gap between HOMO and LUMO has been found to be increased to upper boundary of the visible spectra when CdS4 and Cd13S4 clusters have been embedded in either SiO2 matrix or sodalite cage.