Antiobesity activities of indole-3-carbinol in high-fat-diet-induced obese mice.
This study investigated the effects of indole-3-carbinol (I3C), a cruciferous vegetable derivative, on obesity and its associated factors in high-fat-diet-induced obese (DIO) mice. Eighteen male C57BL/6 mice were randomly assigned to one of three groups: basal, high fat (HF), and HF + 5 mg/kg of I3C intraperitoneally (HFI). After 12 wk of treatment, obesity-associated factors, including body weight, organ weight, serum concentrations of glucose, triacylglycerol, insulin, and adipokines, and macrophage accumulation and lipid metabolism-associated factors in epididymal adipose tissue were measured. Body weight and epididymal adipose tissue weight were greater (P < 0.01), and adipocytes were larger in the HF group than in the basal and HFI groups. Compared with the HF group, the HFI group had improved glucose tolerance, a higher serum adiponectin concentration, lower serum glucose, triacylglycerol, insulin, and leptin concentrations, and less F4/80 expression in epididymal adipose tissue (P < 0.001). Furthermore, I3C treatment decreased acetyl coenzyme A carboxylase mRNA expression (P < 0.05) and increased peroxisome proliferator-activated receptor-γ protein expression (P < 0.05) in epididymal adipose tissue of DIO mice. The I3C treatment decreased body weight and fat accumulation and infiltrated macrophages in epididymal adipose tissue of DIO mice, and these reductions were associated with improved glucose tolerance and with modulated expression of adipokines and lipogenic-associated gene products, including acetyl coenzyme A carboxylase and peroxisome proliferator-activated receptor-γ.


[Characterisation of microbial growth and role of the foot tendinous-synovial formation in pathogenesis of diabetic gangrene of the lower extremity].
The paper is based on the analysis of results of treatment of 74 patients with diabetes mellitus complicated by pyo-necrotic injuries of the foot. In all patients, microbiological procedures were done besides general clinical studies. The material for microbiological assays was the purulent exudation taken from the deeper portions of the wound immediately after lancing the pathological focus. The microbial content was studied separately in fragments of the tendon from its distal (adjacent to the wound) and proximal (every other 6 to 7 cm within the confines of the intact common integument) ends. In the wound, it came up to 6.45 +/- 0.16 lg/ml and 5.2 +/- 0.31 lg/ml (P < 0.05), in the distal end it was 5.93 +/- 0.19 lg/ã and 4.81 +/- 0.24 lg/ã (P < 0.005) for aerobs and anaerobs respectively. In the proximal end of tendons 6-7 cm from the primary pathological focus, aerob gradient was 2.8 +/- 0.19 lg/ã, that for representatives of anaerobic microbes being 1.71 +/- 0.161 lg/ã (P < 0.001). In one third of patients the anaerobic microflora gradient was not found out.


Association of Cardiovascular Health Score With Early- and Later-Onset Diabetes and With Subsequent Vascular Complications of Diabetes.
BACKGROUND Little attention has been paid to how well the American Heart Association's cardiovascular health (CVH) score predicts early-onset diabetes in young adults. We investigated the association of CVH score with early- and later-onset diabetes and with subsequent complications of diabetes. METHODS AND RESULTS Our sample included 4547 Black and White adults in the CARDIA (Coronary Artery Risk Development in Young Adults) study without diabetes at baseline (1985-1986; aged 18-30 years) with complete data on the CVH score at baseline, including smoking, body mass index, physical activity, diet quality, total cholesterol, blood pressure, and fasting blood glucose. Incident diabetes was determined based on fasting glucose, 2-hour postload glucose, hemoglobin A1c, or self-reported medication use throughout 8 visits for 30 years. Multinomial logistic regression was used to assess the association between CVH score and diabetes onset at age <40 years (early onset) versus age ≥40 years (later onset). Secondary analyses assessed the association between CVH score and risk of complications (coronary artery calcium, clinical cardiovascular disease, kidney function markers, diabetic retinopathy, and diabetic neuropathy) among a subsample with diabetes. We identified 116 early- and 502 later-onset incident diabetes cases. Each 1-point higher CVH score was associated with lower odds of developing early-onset (odds ratio [OR], 0.64 [95% CI, 0.58-0.71]) and later-onset diabetes (OR, 0.78 [95% CI, 0.74-0.83]). Lower estimates of diabetic complications were observed per 1-point higher CVH score: 19% for coronary artery calcification≥100, 18% for cardiovascular disease, and 14% for diabetic neuropathy. CONCLUSIONS Higher CVH score in young adulthood was associated with lower early- and later-onset diabetes as well as diabetic complications.


Evolution towards simplicity in bacterial small heat shock protein system.
Evolution can tinker with multi-protein machines and replace them with simpler single-protein systems performing equivalent functions in an equally efficient manner. It is unclear how, on a molecular level, such simplification can arise. With ancestral reconstruction and biochemical analysis, we have traced the evolution of bacterial small heat shock proteins (sHsp), which help to refold proteins from aggregates using either two proteins with different functions (IbpA and IbpB) or a secondarily single sHsp that performs both functions in an equally efficient way. Secondarily single sHsp evolved from IbpA, an ancestor specialized in strong substrate binding. Evolution of an intermolecular binding site drove the alteration of substrate binding properties, as well as the formation of higher-order oligomers. Upon two mutations in the α-crystallin domain, secondarily single sHsp interacts with aggregated substrates less tightly. Paradoxically, less efficient binding positively influences the ability of sHsp to stimulate substrate refolding, since the dissociation of sHps from aggregates is required to initiate Hsp70-Hsp100-dependent substrate refolding. After the loss of a partner, IbpA took over its role in facilitating the sHsp dissociation from an aggregate by weakening the interaction with the substrate, which became beneficial for the refolding process. We show that the same two amino acids introduced in modern-day systems define whether the IbpA acts as a single sHsp or obligatorily cooperates with an IbpB partner. Our discoveries illuminate how one sequence has evolved to encode functions previously performed by two distinct proteins.


Human chorionic somatommamotropin (HCS) and pregnancy. Its relation with insulin.
Plasma HCS levels have been measured in normal and pathological pregnant women. In the normal group HCS levels increased from 6--8 weeks till 33-34 weeks and then felt significantly. HCS pattern in prediabetic and chemical diabetic pregnant women was similar to the normal group. However HCS levels in chemical diabetics were significantly higher during the first two trimesters. HCS levels increased in twin pregnancy, diminished in cases of eclampsia, hypertension, fetal growth retardation, mole and blighted ovum, and disappeared after intrauterine death. Nothing could be deduced from the obese and Rh-isoimmunization groups. It is confirmed the value of HCS determination as an index of placental maturation. Also, insulin/HCS ratio may be of some aid in the study of carbohydrate intolerance in pregnancy.


Case-control study of severe pre-eclampsia of early onset.
Twenty four women with severe pre-eclampsia diagnosed before 34 weeks' gestation were compared with 48 randomly selected controls matched for age and parity. Subjects were studied in the puerperium using a questionnaire, clinical examination, and review of case records. A history of infertility, headaches (particularly migraine), pre-eclampsia in a previous pregnancy, or a raised serum alpha-fetoprotein concentration at the time of screening for neural tube defect in the index pregnancy were all identified as significant risk factors in the pre-eclamptic women. Maternal age, a history of chronic hypertension or renal disease, or excessive maternal weight were not significantly associated with pre-eclampsia. Almost all the infants of pre-eclamptic women showed retarded growth: 18 were below the 10th centile and only one weighed more than the 25th centile. Four babies died. These observations indicate that pre-eclampsia of early onset may differ from the late onset disease not only in its very high perinatal morbidity and mortality but in its distinctive maternal risk factors.


HNK-1-Reactive oligosaccharide, sulfate-O-3GlcAbeta1-4Xylbeta1-MU, synthesized by cultured human colorectal cancer cells.
Human colorectal cancer cells were incubated with medium containing 4-methylumbelliferyl-beta-D-xyloside (Xyl-MU). The cells synthesized Xyl-MU-derivatives which were detected in the culture medium by gel-filtration high-performance liquid chromatography. These included a Xyl-MU-induced glycosaminoglycan and its biosynthetic intermediates, Galbeta1-4Xylbeta1-MU and Galbeta1-3Galbeta1-4Xylbeta1-MU, and other Xyl-MU-induced oligosaccharides, not related to Xyl-MU-induced glycosaminoglycan, were also synthesized. One of these oligosaccharides, sulfate-O-3GlcAbeta1-4Xylbeta1-MU, reacted with HNK-1, a mouse monoclonal antibody raised against human natural killer cells. Human neural cells and skin fibroblasts have also been reported to synthesize HNK-1-reactive sugar chains. Since HNK-1-reactive sugar chains are known to be involved in cell adhesion in the nervous system, the present results suggest that epithelium-derived colorectal cancer cells might also be able to utilize them in cell adhesion.


Type 2-depleted fungal laccase.
Although copper is quantitatively removed from fungal laccase (Polyporus versicolor) by extended dialysis against high concentrations of cyanide, we have been unable to reconstitute the protein by addition of Cu(I) ions. However, two new methods for reversibly removing the type 2 Cu centre have been developed. The visible absorption at 610 nm, which is attributable to type 1 Cu, is unaffected by the procedure, but the absorbance of the type 3 Cu at 330 nm is decreased by 60 +/- 10%. The decrease is due, at least in part, to partial reduction of the binuclear type 3 centre, although there may be some change in the molar absorptivity of the oxidized chromophore as well. The change in the c.d. spectrum that occurs at approx. 350 nm may be explained in the same way, but it may also reflect the loss of a signal due to the type 2 Cu. Upon removal of the type 2 Cu an absorbance increase appears at approx. 435 nm, and it is assigned to the semi-reduced form of the type 3 pair. In the e.p.r. spectrum of the type 2-depleted enzyme the type 1 Cu signal exhibits well-resolved ligand hyperfine splitting, which can be simulated on the basis of contributions from two N and two H nuclei (AH congruent to AN congruent to 25 MHz). The H atoms are assumed to be attached to the beta-carbon of the covalently bonded cysteine ligand. A signal from a semi-reduced form(s) of the type 3 site can also be resolved in the spectrum of the type 2-depleted enzyme, and on the basis of the second integral of the e.p.r. spectrum 40% of the type 3 pairs are believed to be in a partially reduced state. The semi-reduced type 3 site is remarkably stable and is not readily oxidized by H2O2 or IrCl6(2-) or reduced by Fe(CN)6(4-). Intramolecular electron transfer is apparently quite slow in at least some forms of the type 2-depleted enzyme, and this may explain why the activity is at best 5% of that of the native enzyme. Full activity returns when type 2 copper is restored.


Divergent density feedback control of migratory predator recovery following sex-biased perturbations.
Uncertainty in risks posed by emerging stressors such as synthetic hormones impedes conservation efforts for threatened vertebrate populations. Synthetic hormones often induce sex-biased perturbations in exposed animals by disrupting gonad development and early life-history stage transitions, potentially diminishing per capita reproductive output of depleted populations and, in turn, being manifest as Allee effects. We use a spatially explicit biophysical model to evaluate how sex-biased perturbation in life-history traits of individuals (maternal investment in egg production and male-skewed sex allocation in offspring) modulates density feedback control of year-class strength and recovery trajectories of a long-lived, migratory fish-shovelnose sturgeon (Scaphirhynchus platorynchus)-under spatially and temporally dynamic synthetic androgen exposure and habitat conditions. Simulations show that reduced efficiency of maternal investment in gonad development prolonged maturation time, increased the probability of skipped spawning, and, in turn, shrunk spawner abundance, weakening year-class strength. However, positive density feedback disappeared (no Allee effect) once the exposure ceased. By contrast, responses to the demographic perturbation manifested as strong positive density feedback; an abrupt shift in year-class strength and spawner abundance followed after more than two decades owing to persistent negative population growth (a strong Allee effect), reaching an alternative state without any sign of recovery. When combined with the energetic perturbation, positive density feedback of the demographic perturbation was dampened as extended maturation time reduced the frequency of producing male-biased offspring, allowing the population to maintain positive growth rate (a weak Allee effect) and gradually recover. The emergent patterns in long-term population projections illustrate that sex-biased perturbation in life-history traits can interactively regulate the strength of density feedback in depleted populations such as Scaphirhynchus sturgeon to further diminish reproductive capacity and abundance, posing increasingly greater conservation challenges in chemically altered riverscapes.


[Dynamics of the efferent regulation of muscle contraction. Analysis of transition processes: frequency of efferent stimulation--muscle length].
Transition processes of the length changes were studied in the ankle extensors of anesthetized cats. The processes were evoked under isotonical conditions by step changes in frequency of distribution stimulation of the efferents supplying these muscles. The system dynamics was essentially nonlinear because the time constants of the processes were dependent on amplitudes and sign of the input signal. The time constants abruptly decreased when the sign of the length changes alternated from minus to plus and continuously decreased when amplitude of the transition process rose in the absolute value. The time constants for the transition processes were 1.15 +/- 0.09 s for soleus shortening and 0.40 +/- 0.07 s for its lengthening. The same parameters in fast muscles were 0.51 +/- 0.085 for shortening and 0.21 +/- 0.04 s for lengthening. These time constants are very close to the parameters of the transition processes: external load-muscles length. The observed properties of the muscles are discussed for their functional significance.


Prevention of local recurrence after surgical debulking of nodal and subcutaneous melanoma deposits by hypofractionated radiation.
Local recurrence (LR) after surgical debulking of nodal or subcutaneous melanoma deposits defeats the purpose of operation and may worsen prognosis if the procedure was performed for stage III disease. To decrease LR rates in this setting, we extended the previously described role of hypofractionated radiation for melanoma deposits of the neck to all situations where the patient was felt to be at high risk for postoperative relapse after resection of bulky disease. Hypofractionated external beam radiation was administered in 6-Gy doses for 5 fractions (total dose 30 Gy, given over a median of 15 elapsed days) to 42 resected melanoma deposit sites in 41 patients. Stages of the 41 patients at the time of treatment were: 22 stage III and 19 stage IV. All patients had complete gross resection of disease at the radiation site before radiation. Mean time between operation and initiation of radiation was 4 weeks. The 42 sites of treatment included 27 neck, 9 axilla, 3 groin, and 3 subcutaneous deposits. There were no treatment-related deaths; side effects were minimal and self-limited. Transient erythema, desquamation, fibrosis, telangiectasias, and mucositis, parotiditis, and xerostomia (for head and neck radiation) were reported, but no patient required interruption of therapy for these events. Of the 42 treated sites, only 2 recurred in the treatment field (one neck, one axilla) during the mean follow-up time of 22.4 months, for a treatment failure rate of 4.8%. This represents improved local control compared with patients treated with surgery alone at our institution and with published recurrence rates. The addition of hypofractionated radiation therapy after resection of nodal and subcutaneous melanoma deposits at a variety of sites is a rapid and well-tolerated method of providing excellent local control.


[Role of S-100 protein in the function of brain cell nuclei].
Data on physico-chemical properties and functional role of protein S-100 have been generalized. An analysis of literary data permits making a conclusion that the protein interaction with Ca2+ ions plays great part in its action mechanisms. Data are presented on the properties of the family of Ca-binding proteins similar to protein S-100 as to their structure. Peculiar attention is paid to the analysis of this protein function in the cellular nucleus, changing the degree of proteins phosphorylation and RNA synthesis.


Nano-phase separation and structural ordering in silica-rich mixed network former glasses.
We investigate the structure, phase separation, glass transition, and crystallization in a mixed network former glass series, i.e., B2O3-Al2O3-SiO2-P2O5 glasses with varying SiO2/B2O3 molar ratio. All the studied glasses exhibit two separate glassy phases: droplet phase (G1) with the size of 50-100 nm and matrix phase (G2), corresponding to a lower calorimetric glass transition temperature (Tg1) and a higher one (Tg2), respectively. Both Tg values decrease linearly with the substitution of B2O3 for SiO2, but the magnitude of the decrease is larger for Tg1. Based on nuclear magnetic resonance and Raman spectroscopy results, we infer that the G1 phase is rich in boroxol rings, while the G2 phase mainly involves the B-O-Si network. Both phases contain BPO4- and AlPO4-like units. Ordered domains occur in G2 upon isothermal and dynamic heating, driven by the structural heterogeneity in the as-prepared glasses. The structural ordering lowers the activation energy of crystal growth, thus promoting partial crystallization of G2. These findings are useful for understanding glass formation and phase separation in mixed network former oxide systems, and for tailoring their properties.


The discovery of Burkitt's lymphoma.
An account is given of the steps that led to the recognition of the tumor that became known as Burkitt's lymphoma. This is followed by a description of the methods employed in the subsequent epidemiologic studies, the manner in which successive hypotheses of etiology were erected and demolished, and the discovery by Epstein and his colleagues of the Epstein-Barr virus. The impact that this tumor has had on aspects of cancer research is considered.


miR-196, an Emerging Cancer Biomarker for Digestive Tract Cancers.
Over the past decade, the emergence of microRNA (miRNA) research has firmly established this molecular family as a key component in cells. MiRNAs, which function as negative gene regulators, participate in multiple biological processes and maintain homeostasis in cells. The dysregulation of miRNA may contribute to numerous human disorders, including cancer. Recently, miR-196 was found to be aberrantly expressed in a wide range of malignant diseases, which suggests that it plays important roles in carcinogenesis. Here, we summarize the current knowledge concerning miR-196 family in cancers. This review includes miR-196 gene structure and aberrant expression in various cancers, and current understanding of numerous functions and regulatory targets of miR-196 in specific cancers. Since miR-196 are consistently found over-expressed in digestive tract cancer tissues, we also reviewed the clinical significance and potential applications of miR-196 in these cancers. We highlight that miR-196 may serve as an emerging cancer biomarker for digestive tract cancers.


Sex-specific associative learning cues and inclusive fitness benefits in the Seychelles warbler.
In cooperative breeding vertebrates, indirect fitness benefits would be maximized by subordinates that accurately assess their relatedness to group offspring and preferentially help more closely related kin. In the Seychelles warbler (Acrocephalus sechellensis), we found a positive relationship between subordinate-nestling kinship (determined using microsatellite marker genotypes) and provisioning rates, but only for female subordinates. Female subordinates that helped were significantly more related to the nestlings than were nonhelpers, and the decision to help appears to be based on associative learning cues. High levels of female infidelity means that subordinates cannot trust their legitimacy through the male line, consequently they appear to use the continued presence of the primary female, but not the primary male, as a reliable cue to determine when to feed nestlings. By using effective discrimination, female subordinates are able to maximize the indirect benefits gained within a cooperative breeding system otherwise driven primarily by direct breeding benefits.


Development and application of a radioimmunoassay for tetracycline.
Antiserum against tetracycline was produced in rabbits immunized with a tetracycline hapten conjugated to bovine serum albumin. The antiserum was used to develop a radioimmunoassay for tetracycline. As little was 1 ng of tetracycline can be detected in one sample. The antitetracycline antiserum showed a considerable degree of specificity since it cross-reacted only with chlortetracycline (70%). However, its cross-reactivity with oxytetracycline, doxycycline, demeclocycline, methacycline and rolitetracycline was only negligible. The radioimmunoassay of tetracycline was used to measure the systemic bioavailability of orally administered tetracycline (25 mg/kg) to a group of mongrel dogs. Detectable levels of tetracycline were exhibited within 30 min and maximum plasma concentrations of the drug occurred within 3 to 4 hr after dose administration.


Cystic fibrosis microbiology: Advances in antimicrobial therapy.
Much of the improvement in the survival of individuals with cystic fibrosis (CF) is due to advancements in antimicrobial treatments. New aerosolized antibiotic formulations have recently been introduced (such as inhaled aztreonam), and others are in development (inhaled levofloxacin and liposomal amikacin). Licensed dry powder formulations include tobramycin inhalation powder and dry powder colistimethate (available in Europe). Although inhaled antibiotics have the advantage of being able to deliver high intrapulmonary concentrations of drug, antimicrobial resistance can still develop and is a concern in CF. Antimicrobial resistance might be mitigated by using non-antibiotic treatments, antibiotic adjuvants, which have activity against bacteria. Examples include agents such as gallium, antimicrobial peptides and anti-biofilm compounds such as alginate oligosaccharides (OligoG) and garlic. Vaccination strategies and antibody therapy (IgY) against Pseudomonas aeruginosa have also been attempted to prevent initial infection with this organism in CF. Although aggressive and long-term use of antibiotics has been crucial in slowing lung function decline and improving survival in people with CF, it has added a significant burden of care and associated toxicities in these individuals. Careful surveillance and the use of preventative strategies for antibiotic related toxicity (such as nephrotoxicity and ototoxicity) are essential. Continued development of effective antimicrobial agents that can function in the conditions encountered in the CF lung, such as against bacterial biofilm growth and under anaerobic conditions, is needed.


Correlates of life satisfaction among older people in China: an examination of two cultural variables.
This article examines the relationships between the two cultural variables of having mianzi in social interactions and Chinese cultural beliefs of adversity and life satisfaction among older people in a coastal city in mainland China. The mediating effect of having mianzi in social interactions on the relationship between Chinese cultural beliefs of adversity and life satisfaction is also examined. The study applies a non-probability sampling and adopts a face-to-face interview approach using a questionnaire composed of close-ended questions. A total of 532 valid questionnaires are obtained. Multiple regression analysis is used to test the hypotheses. Findings indicate that the two cultural variables are associated significantly with life satisfaction, while controlling for socio-demographic variables. The variable of Chinese cultural beliefs of adversity is also indirectly associated with life satisfaction through its effect on having mianzi in social interactions. Older people with higher endorsement of positive Chinese cultural beliefs of adversity and higher degree of having mianzi in social interactions tend to have higher life satisfaction. Professionals working with older people should be sensitive to cultural variables that exert impacts on older people's life satisfaction.


cAMP/PKA-CREB-BDNF signaling pathway in hippocampus mediates cyclooxygenase 2-induced learning/memory deficits of rats subjected to chronic unpredictable mild stress.
To investigate the mechanism of cyclooxygenase 2 (COX2) in learning and memory impairments in rats subjected to chronic unpredictable mild stress (CUMS), meloxicam was used intragastrically to inhibit the activity of cyclooxygenase 2. Moreover, cyclooxygenase 2 over-expressing or RNA interfere lentivirus was injected intraventricularly to increase or decrease the enzyme's expression, respectively. The body weights and sucrose consumption were used to analyze depressive behaviors, while the Morris water maze and step-down-type passive avoidance tests were carried out to evaluate the learning-memory functions. The levels of inflammatory cytokines were measured to estimate inflammation and the contents of cyclic adenosine monophosphate (cAMP) were used to measure the levels of the second messenger. Changes in cyclooxygenase 2 mRNA levels were analyzed using reverse transcription polymerase chain reaction. Moreover, the expression of cyclooxygenase 2, brain-derived neurotrophic factor (BDNF), prostaglandins receptor 3 (EP3), protein kinase A (PKA), cAMP response element binding protein (CREB), and phosphorylated CREB were estimated using immunohistochemical staining or western blotting. The results showed that CUMS led to significant depressive-like behaviors and learning and memory dysfunctions. Also, the cAMP levels decreased significantly, while levels of inflammatory cytokines and prostaglandins E2 increased significantly. The expressions of PKA, BDNF, phosphorylated CREB/CREB declined and cyclooxygenase 2 was increased. Meloxicam and cyclooxygenase 2 RNA interfere lentivirus reversed the changes caused by CUMS while cyclooxygenase 2-overexpressing lentivirus worsened these abnormalities. The findings also showed that CUMS increased cyclooxygenase 2 expression, which can cause learning and memory impairments, mainly through activating the hippocampal neuronal cAMP/PKA-CREB-BDNF signaling pathways.


[Pathology of soft tissue sarcomas: 238 cases of the childhood tumor registry].
Until April 1981 malignant soft tissue sarcomas were registered from 238 patients. Rhabdomyosarcoma was the most common tumor (115/238 = 48.3%). The embryonal subtype was predominantly seen among the rhabdomyosarcomas (83/115 = 72.2%). Rhabdomyosarcomas were localized most frequently in the head and neck area (40/115 = 34.8%), followed by genitourinary system (15/115), pelvis soft tissue (12), abdomen (10) and extremities (10). Non-rhabdomyosarcomatous soft tissue sarcomas (123/238 = 51.7%) were synovial sarcomas (20 = 8.4%), fibrosarcomas including spindle cell sarcoma (17 = 7.4%), leiomyosarcomas (12 = 5.0%), malignant tumors of the vascular system (11 = 4.6%) and neurofibrosarcomas (9 = 3.8%). Other types of sarcoma were extremely rare. 42 (17.6%) of all soft tissue sarcomas could not be classified histogenetically. Rhabdomyosarcomas could be diagnosed much more accurately (105/115 = 91.3%), compared to all other soft tissue sarcomas (99/121 = 81.8%). At present, the most difficult diagnostic problems remain with the tumors of connective tissue, in particular with fibrosarcomas and with the differential diagnosis of juvenile fibrosarcomas versus juvenile fibromatoses.


Nitrogen fixation by floating diatom mats: a source of new nitrogen to oligotrophic ocean waters.
Nitrogen fixation, apparently by bacterial endosymbionts, is associated with intertwining chains of two species of the diatom Rhizosolenia. In situ fixation rates were enhanced by incubation in the dark, whereas concurrent shipboard experiments either underestimated or did not detect nitrogen fixation. This is the first example of nitrogen fixation associated with a bacteria-diatom symbiosis in the pelagic zone, and it indicates that these systems may contribute a significant amount of "new" nitrogen to oligotrophic waters.


Emotional Intelligence and Burnout in Surgical Residents: A 5-Year Study.
We sought to characterize the interactions of burnout with internal and external factors over the past 5 years for surgery residents at our institution. We hypothesized that burnout levels would be consistent among years, inversely related to emotional intelligence (EI) and job resources, and directly related to disruptive behaviors. General surgery residents at a single institution were invited to complete a survey each year from 2015 to 2019 that included a combination of the 22-item Maslach-Burnout Inventory, 30-item trait EI questionnaire, as well as focused questions assessing disruptive behaviors (8 items), job resources (8 items), and demographic characteristics. Burnout was defined as scoring high in depersonalization (≥ 10 points) or emotional exhaustion (≥ 27 points). Student's t tests and Wilcoxon tests were used to compare continuous variables; chi-square and Fisher's exact tests were used to compare categorical variables, as appropriate. Spearman's rho was used to calculate correlation. A logistic regression and separate linear regression model were constructed to assess relation of variables to burnout. The general surgery residency program at the University of Alabama at Birmingham, Birmingham, Alabama, a large tertiary care academic center. An average of 47 surveys were completed each year, for a total of 236 (response rate 81%). One hundred seventeen (58.5%) met criteria for burnout. Burnout rates each year ranged from 68% to 53%, with the lowest value occurring in 2019. Incidence of burnout was lowest among the postgraduate year (PGY) 1 class and highest among the PGY5 class (38% versus 64%, p = 0.02). Individuals without burnout had higher scores for EI overall (5.7 versus 5.3, p < 0.001) as well as in each of its 4 subcomponents (p < 0.001). Individuals who were subjected to disruptive behaviors, particularly others taking credit for work and public humiliation, were more likely to experience burnout (p = 0.02). Those with burnout also had significantly lower scores in each of the 4 domains of the Job Resources model (p < 0.01). On multivariate logistic regression, increasing PGY level remained a significant predictor of burnout risk. Each of the sub-domains of EI and jobs resources inversely corelated with burnout, while disruptive behaviors directly correlated with burnout. ON subsequent multivariable linear regression, resident well-being and professional development remained independent predictors of lower burnout scores. Burnout is prevalent among trainees at our institution, but a trend toward improvement has been shown over 5 years. Burnout rates increase each year of surgical training beyond PGY2. Factors that mitigate burnout include resident well-being and professional development. Disruptive behaviors lead to increase burnout rates.


In experimental diabetes the decrease in the eye of lens carnitine levels is an early important and selective event.
Carnitine is present in the eye tissues of the rabbit and the highest concentration is found in the lens. In streptozotocin-diabetic rats, the carnitine loss of the lens is an initial and important event. At 8 days after the induction of diabetes, the carnitine content in the rat lens was reduced by 63% compared to control. The loss of lens carnitine continued at 15 and 45 days after the induction. Total carnitine level in the serum was diminished by 15 days, and the reduction in percentage term was much lower in comparison to the loss of lens carnitine. In the rabbit after alloxan-diabetes induction, there is an extensive loss of carnitine in the lens: -85% after 4 months. The carnitine levels in the other eye tissues seem substantially unaffected. The loss of lens carnitine was present even with an inconsistent hyperglycaemia. No difference was found in serum carnitine levels between controls and alloxan-treated rabbits. The role of carnitine in lens is still unclear, but its loss may be related to the appearance of cataract. A derivative of carnitine, acetylcarnitine, might prevent the processes involved in the formation of cataracts by a pharmacological action, as has been shown for aspirin.


Can Geriatric Psychiatry Patients Complete Symptoms Self-Reports Using Tablets? A Randomized Study.
With our aging population and limited number of geriatric psychiatrists, innovations must be made in order to meet the growing demands for geriatric psychiatry services. Emerging technologies could greatly improve access to care and systematic data collection. This randomized study compared completion rates and time to completion (primary outcomes) when using iPad technology vs. traditional paper forms to complete self-report psychiatric symptoms. Geriatric psychiatry outpatients (n = 72) and adult psychiatry inpatients (n = 50) were recruited to complete the Brief Symptom Inventory (BSI-53), the Activities of Daily Living (ADL), and Patient Health Questionnaire (PHQ-9) questionnaires. Geriatric psychiatry outpatients completed the iPad and paper questionnaires at similar rates (91.7% vs. 97.2%, Fisher's Exact p = .61). In two-way ANOVA, including patients aged ≥ 60 (n = 85), outpatient status (F(1,81) = 4.48, p = .037) and iPad format (F (1,81) = 8.96, p = .04) were associated with a shorter time to completion. The effect of questionnaire formats was especially prominent in the inpatient group on time to completion. Older adults with mental illness demonstrate a similar ability to complete self-report questionnaires whether iPads or paper forms. iPad questionnaires may even require less time to complete in geriatric psychiatry inpatients. Patients also found iPad questionnaires to be easy to use and read. Tablets could potentially be used for psychiatric symptom assessment for clinical, research, and population health purposes.


Future challenges and treatment of Staphylococcus aureus bacteremia with emphasis on MRSA.
Staphylococcus aureus bacteremia (SAB) is an urgent medical problem due to its growing frequency and its poor associated outcome. As healthcare delivery increasingly involves invasive procedures and implantable devices, the number of patients at risk for SAB and its complications is likely to grow. Compounding this problem is the growing prevalence of methicillin-resistant S. aureus (MRSA) and the dwindling efficacy of vancomycin, long the treatment of choice for this pathogen. Despite the recent availability of several new antibiotics for S. aureus, new strategies for treatment and prevention are required for this serious, common cause of human infection.


Perioperative nasal and paranasal sinus considerations in transsphenoidal surgery for pituitary disease.
Endoscopic endonasal skull base surgery has emerged as the treatment modality of choice for a range of skull base lesions, particularly pituitary adenomas. However, navigation and manipulation of the nasal corridor and paranasal sinuses requires that surgeons are aware of effective techniques to maximize patient outcomes and avoid sinonasal morbidity postoperatively. This paper is a narrative review aimed to provide an updated and consolidated report on the perioperative management of the nasal corridor and paranasal sinuses in the setting of endoscopic skull base surgery for pituitary disease. Anatomic variants and common surgical techniques are discussed. Post-operative complications are evaluated in detail. Understanding the structural implications of the endonasal approach to the sphenoid is crucial to optimization of the surgical outcomes. We propose guidelines for perioperative management of endoscopic endonasal skull base surgery for pituitary diseases. Standardized treatment algorithms can improve patient satisfaction, and increase the comparability and the quality of reported information across research studies.


[Congenital hydrocephalus--an analysis of the course of pregnancy, prenatal studies and labor].
An analysis of the pool of our patients revealed few disturbances during pregnancy. In two cases the malformations were possibly due to drugs. Prenatal sonographic diagnostics were performed in one-third of the cases or documented: in 60% of the investigated cases a hydrocephalus was found, this being only 20% of the whole pool. The major part of the births were performed by Caesarean section, mainly because of a prolongation of the birth directly or indirectly due to the large circumference of the head. The hereditary trait of associated malformations and malformations of the central nervous system was frequent. Therefore, we advocate a better prenatal work-up and a birth by planned Caesarean section.


Ramlibacter humi sp. nov., isolated from tropical forest soil.
A Gram-stain-negative, aerobic and non-motile strain, designated 18x22-1T, was isolated from a forest soil sample collected from Limushan Nature Reserve in Hainan Province, PR China. Growth occurred at 15-37 °C and pH 6.0-8.0 without NaCl. The 16S rRNA gene sequence analyses showed that strain 18x22-1T was closely related to Ramlibacter tataouinensis DSM 14655T (98.5 %), followed by Ramlibacter henchirensis DSM 14656T (97.9 %) and other Ramlibacter species and formed a stable cluster with R. tataouinensis DSM 14655T, R. henchirensis DSM 14656T, Ramlibacter solisilvae JCM 19319T and Ramlibacter rhizophilus CCTCC AB 2015357T. Results of chemotaxonomic analyses showed that ubiquinone-8 (Q-8) was the major respiratory quinone, and the major fatty acids (>10 % of the total amounts) were C16 : 0 and C17 : 0cyclo. The major polar lipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, two unidentified aminopholipids and four unidentified phospholipids. The draft genome sequence was 4.47 Mb long with a G+C content of 68.9 mol%. The average nucleotide identity and digital DNA-DNA hybridization values between strain 18x22-1T and four closely related type strains were in the range of 79.3-82.3 % and 21.9-25.1 %, respectively. The results of phenotypic, phylogenetic and chemotaxonomic analyses supported that strain 18x22-1T represents a novel species of the genus Ramlibacter, for which the name Ramlibacterhumi sp. nov. is proposed. The type strain is 18x22-1T (=GDMCC 1.1584T=KCTC 52922T).


In Vivo Imaging of Bioluminescent Mycobacterium ulcerans: A Tool to Refine the Murine Buruli Ulcer Tail Model.
Buruli ulcer (BU) is a neglected tropical disease caused by infection with Mycobacterium ulcerans. Unclear transmission, no available vaccine, and suboptimal treatment regimens hamper the control of this disease. Carefully designed preclinical research is needed to address these shortcomings. In vivo imaging (IVIS®, Perkin Elmer, Waltham, MA) of infection is an emerging tool that permits monitoring of disease progression and reduces the need to using large numbers of mice at different time-points during the experiment, as individual mice can be imaged at multiple time-points. We aimed to further describe the use of in vivo imaging (IVIS) in BU. We studied the detection of M. ulcerans in experimentally infected BALB/c mouse tails and the subsequent histopathology and immune response in this pilot study. IVIS-monitoring was performed weekly in ten infected BALB/c mice to measure light emitted as a proxy for bacterial load. Nine of 10 (90%) BALB/c mice infected subcutaneously with 3.3 × 105 M. ulcerans JKD8049 (containing pMV306 hsp16+luxG13) exhibited light emission from the site of infection, indicating M. ulcerans growth in vivo, whereas only five of 10 (50%) animals developed clinical signs of the disease. Specific antibody titers were detected within 2 weeks of the infection. Interferon (IFN)-γ and interleukin (IL)-10 were elevated in animals with pathology. Histopathology revealed clusters of acid-fast bacilli in the subcutaneous tissue, with macrophage infiltration and granuloma formation resembling human BU. Our study successfully showed the utility of M. ulcerans IVIS monitoring and lays a foundation for further research.


Clinical predictors of worsening heart failure during withdrawal from digoxin therapy.
Previous work provides limited information concerning predictors of clinical deterioration after digoxin withdrawal. We investigated the association between selected baseline clinical characteristics and symptomatic deterioration in two similarly designed trials: Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) and Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE). Cox proportional-hazards analysis found the following independent predictors of worsening during follow-up in the combined PROVED and RADIANCE patients: heart failure score, left ventricular ejection fraction, cardiothoracic ratio, use of an angiotensin-converting enzyme inhibitor, use of digoxin, and age. When these factors, except for digoxin use, were tested in the subgroup of patients withdrawn from digoxin, they all were significant independent predictors of worsening heart failure. In contrast, only use of angiotensin-converting enzyme inhibitor predicted deterioration in patients who continued digoxin. Patients with more congestive symptoms, worse ventricular function, greater cardiac enlargement, or who were not taking an angiotensin-converting enzyme inhibitor were significantly more likely to worsen early after digoxin discontinuation than patients without these characteristics.


The prevalence and associated factors of depression among medical students of Saudi Arabia: A systematic review.
The main purpose of our review study was to estimate depression prevalence among Saudi Arabian medical students according to the published articles and try to reveal the main associated factors. A systematic search was performed through PubMed/Medline and Google Scholar databases. A review of 18 studies published between January 2010 and March 2019 was composed of the following selection of necessary articles approved by PICO (population, intervention, control, and outcomes) criteria. The prevalence of depression among medical students of Saudi Arabia ranged from 30.9% to 77.6% with a mean prevalence of 51.5%. Depression severity was evaluated by various questionnaires, so we summarized the extracted data and revealed that medical students tend to have moderate to severe depression to a greater extent than mild depressive symptoms (33.27% vs 29.9%). The findings of this review suggest a high incidence of depression among medical students and the influence of associate sociodemographic factors. Females are considered to be at a higher risk of depression. First-year medical students are the most susceptible to develop depressive symptoms. Smoking is strongly associated with depression severity. Marital status, eating habits, usage of stimulants, and sleep disturbances are within significant findings of our review study.


Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer.
At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer. Notably, Met is over expressed in up to 80% of invasive pancreatic cancers but not in normal ductal cells correlating with poor overall patient survival and increased recurrence rates following surgical resection. However the functional role of Met signaling in pancreatic cancer remains poorly understood. Here we used RNA interference to directly examine the pathobiological importance of increased Met signaling for pancreatic cancer. We show that Met knockdown in pancreatic tumor cells results in decreased cell survival, cell invasion, and migration on collagen I in vitro. Using an orthotopic model for pancreatic cancer, we provide in vivo evidence that Met knockdown reduced tumor burden correlating with decreased cell survival and tumor angiogenesis, with minimal effect on cell growth. Notably, we report that Met signaling regulates the secretion of the pro-angiogenic chemokine interleukin-8/CXCL8. Our data showing that the interleukin-8 receptors CXCR1 and CXCR2 are not expressed on pancreatic tumor cells, suggests a paracrine mechanism by which Met signaling regulates interleukin-8 secretion to remodel the tumor microenvironment, a novel finding that could have important clinical implications for improving the effectiveness of treatments for pancreatic cancer.


Human p32: a coactivator for Epstein-Barr virus nuclear antigen-1-mediated transcriptional activation and possible role in viral latent cycle DNA replication.
The Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1) is required for the maintenance of the viral chromosome in latently infected, proliferating cells and plays a role in latent cycle DNA replication. EBNA-1 also functions as a positive and negative regulator of EBV gene expression. We have investigated the interaction of EBNA-1 with p32, a host mitochondrial protein that associates with EBNA-1 in EBV-positive Burkitt's lymphoma cells. Using a chromatin immunoprecipitation assay, we found that a fraction of p32 localizes to the viral latent cycle origin of DNA replication oriP in vivo. p32 binds EBNA-1 independently of other proteins or DNA. EBNA-1 variants lacking one of two p32 binding elements did not interact stably with p32 in cultured cells and were defective for both transcriptional activation of a reporter gene linked to oriP FR and replication and/or maintenance of a plasmid bearing oriP. These results support a role for p32 in transcriptional activation by EBNA-1 and suggest that p32 plays a role in EBV latent cycle DNA replication.


Systemic Inflammation in Cachexia - Is Tumor Cytokine Expression Profile the Culprit?
Cachexia affects about 80% of gastrointestinal cancer patients. This multifactorial syndrome resulting in involuntary and continuous weight loss is accompanied by systemic inflammation and immune cell infiltration in various tissues. Understanding the interactions among tumor, immune cells, and peripheral tissues could help attenuating systemic inflammation. Therefore, we investigated inflammation in the subcutaneous adipose tissue and in the tumor, in weight stable and cachectic cancer patients with same diagnosis, in order to establish correlations between tumor microenvironment and secretory pattern with adipose tissue and systemic inflammation. Infiltrating monocyte phenotypes of subcutaneous and tumor vascular-stromal fraction were identified by flow cytometry. Gene and protein expression of inflammatory and chemotactic factors was measured with qRT-PCR and Multiplex Magpix(®) system, respectively. Subcutaneous vascular-stromal fraction exhibited no differences in regard to macrophage subtypes, while in the tumor, the percentage of M2 macrophages was decreased in the cachectic patients, in comparison to weight-stable counterparts. CCL3, CCL4, and IL-1β expression was higher in the adipose tissue and tumor tissue in the cachectic group. In both tissues, chemotactic factors were positively correlated with IL-1β. Furthermore, positive correlations were found for the content of chemoattractants and cytokines in the tumor and adipose tissue. The results strongly suggest that the crosstalk between the tumor and peripheral tissues is more pronounced in cachectic patients, compared to weight-stable patients with the same tumor diagnosis.


Discrimination of cell types in mixed cortical culture using calcium imaging: a comparison to immunocytochemical labeling.
Neuronal-glial interactions in the central nervous system are important for both normal function and response to pathological states. Differences in calcium processing between these cell types may be exploited to allow dynamic differentiation using calcium-imaging protocols without the need to fix and immunostain the study population. Mixed rat primary cortical cultures were grown on coverslips, incubated for 30 min in 2 microM fluo-3 AM and mounted in a devised, low volume imaging chamber. Calcium influx was measured over the duration of a 50s exposure to 30 microM glutamate in all cells. Cells were then fixed in situ, and immunostained for NeuN and GFAP. Direct comparison between live calcium dynamics and cell type markers were made. Over the duration of the glutamate exposure, those cells that subsequently stained for NeuN exhibited a sustained increase in intracellular calcium, whereas GFAP positive and non-staining cells exhibited a decline over the duration of the glutamate exposure. We found that examining the average calcium fluorescence over the last 10s of glutamate exposure allowed the identification of cells as neuronal if the average was >85% of the maximal calcium change, or non-neuronal if the average was <85% of the maximal calcium change. This technique compares very favourably to the established technique of immunocytochemical labeling for the identification of cell types; both techniques agreed in their classification of cells as neuronal or non-neuronal 96.83% of the time. However, this technique cannot reliably distinguish between non-neuronal cell types.


Edge detection in ultrasound imagery using the instantaneous coefficient of variation.
The instantaneous coefficient of variation (ICOV) edge detector, based on normalized gradient and Laplacian operators, has been proposed for edge detection in ultrasound images. In this paper, the edge detection and localization performance of the ICOV-squared (ICOVS) detector are examined. First, a simplified version of the ICOVS detector, the normalized gradient magnitude squared, is scrutinized in order to reveal the statistical performance of edge detection and localization in speckled ultrasound imagery. Both the probability of detection and the probability of false alarm are evaluated for the detector. Edge localization is characterized by the position of the peak and the 3-dB width of the detector response. Then, the speckle-edge response of the ICOVS as applied to a realistic edge model is studied. Through theoretical analysis, we reveal the compensatory effects of the normalized Laplacian operator in the ICOV edge detector for edge-localization error. An ICOV-based edge-detection algorithm is implemented in which the ICOV detector is embedded in a diffusion coefficient in an anisotropic diffusion process. Experiments with real ultrasound images have shown that the proposed algorithm is effective in extracting edges in the presence of speckle. Quantitatively, the ICOVS provides a lower localization error, and qualitatively, a dramatic improvement in edge-detection performance over an existing edge-detection method for speckled imagery.


HPV-16 E6 promotes cell growth of esophageal cancer via downregulation of miR-125b and activation of Wnt/β-catenin signaling pathway.
High-risk human papillomavirus (HPV) is a possible cause of esophageal cancer. However, the molecular pathogenesis of HPV-infected esophageal cancer remains unclear. The expression levels of some microRNAs including miR-125b have been negatively correlated with HPV infection, and miR-125b downregulation is associated with tumorigenesis. In addition, Wnt/β-catenin signaling pathway has been suggested to play an important role in esophageal cancer (EC). We examined miR-125b and Wnt/β-catenin signaling pathway in HPV-16 E6 promoted tumor progression in EC. HPV-16 E6 transfection decreased markedly the expression levels of miR-125b and promoted the colony formation in the Eca 109 and Kyse 150 cell lines, and restoration of miR-125b expression level antagonized the increased colony formation in HPV-16 E6 transfected cell lines. We also demonstrated that overexpression of E6 upregulated the Wnt/β-catenin signaling activity via modulating the multiple regulators including TLE1, GSK3β, and sFRP4. Overexpression of miR-125b restored the expression levels of these proteins. Expression of miR-125b was lower in HPV-16 E6 positive esophageal cancer tissues, and was negatively correlated with E6 mRNA levels. Our results indicate that HPV-16 E6 promotes tumorigenesis in EC via down-regulation of miR-125b, and this underlying mechanism may be involved in the activation of the Wnt/β-catenin signaling pathway.


Outbreak of lymphocytic choriomeningitis virus infections in medical center personnel.
An outbreak of lymphocytic choriomeningitis (LCM) virus infections occurred in Medical Center personnel at the University of Rochester in 1972-1973. A total of 48 infections was discovered, 31 in staff of the radiation therapy area, 12 in the staff of the Vivarium facility, and 5 in other individuals who worked in the Medical Center. Twenty-one of the infections were associated with recent febrile illness with myalgia. Epidemiologic and virologic studies indicated that the source of the infection was Syrian hamsters which were used in tumor research; the tumor cell lines themselves were shown to be contaminated with LCM virus and probably represented the original source of contamination of the Rochester facility. Infection occurred not only through direct contact with infected animals but also from mere presence in the room where the animals were held. This outbreak emphasizes the need for restricting access to animal quarters and for surveillance of hamsters and tumor cell lines and indicate the necessity of separating animal facilities from patient-care facilities.


Membrane transport of natural folates and antifolate compounds in murine L1210 leukemia cells: role of carrier- and receptor-mediated transport systems.
L1210-B73 cells, variants of L1210 cells grown in medium containing nanomolar concentrations of folates, express a membrane associated folate binding protein (mFBP) in addition to the classical reduced folate/methotrexate carrier (RF/MTX-carrier) present in L1210 cells grown in standard high folate medium (G. Jansen et al., Cancer Res., 49: 1959-1963, 1989). In this study we used L1210-B73 and L1210 cells as a model system to study the affinity of the RF/MTX-carrier and the mFBP for the natural folate compounds folic acid and 5-formyltetrahydrofolate (5-CHO-THF), as well as a number of antifolate compounds. Furthermore we studied the contribution of the RF/MTX-carrier and the mFBP in membrane transport of these (anti)folates, and finally we analyzed the role of the mFBP and RF/MTX-carrier in the cytotoxic effects of the antifolates. The antifolates used were either inhibitors of dihydrofolate reductase, including methotrexate (MTX) and 10-ethyl-10-deazaaminopterin (10-EdAM), or two folate-based inhibitors of thymidylate synthase, N10-propargyl-5,8-dideazafolic acid (CB3717) and 2-deamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI-198,583). The affinity of the RF/MTX-carrier for natural and antifolate compounds declined in the order 10-EdAM greater than or equal to ICI-198,583 greater than or equal to 5-CHO-THF greater than MTX much greater than CB3717 much greater than folic acid. The mFBP exhibited a high binding affinity for CB3717 and ICI-198,583 but a poor binding affinity for MTX and 10-EdAM. Binding affinities of the mFBP decreased in the order CB3717 greater than or equal to folic acid = ICI-198,583 greater than or equal to 5-CHO-THF much greater than MTX = 10-EdAM. Over 24 h, at 25 nM, [3H]folic acid uptake in L1210-B73 cells was found to proceed for more than 98% via the mFBP. Uptake of [3H]-5-CHO-THF, at 50 nM extracellular concentration, occurred via both the mFBP (81%) and the RF/MTX-carrier (19%). With respect to antifolates, the mFBP in L1210-B73 cells contributed for less than 30% in the uptake of [3H]MTX but was the predominant route (92%) in the uptake of [3H]ICI-198,583. Results from affinity and membrane transport observations were consistent with growth inhibition studies on L1210-B73 cells demonstrating that the mFBP played only a minor role in the cytotoxic effects of MTX or 10-EdAM. On the other hand, L1210-B73 cells were significantly more sensitive to CB3717 (220-fold) and ICI-198,583 (10-fold) than parental L1210 cells.(ABSTRACT TRUNCATED AT 400 WORDS)


Choline acetyltransferase and the nicotinic acetylcholine receptor AChRα7 in experimental myositis.
It is not known to what extent a non-neuronal cholinergic system is involved in myositis (muscle inflammation) evoked by marked muscle overuse. Therefore, in the present study, a recently established rabbit myositis model was used and the expression patterns of ChAT and nicotinic acetylcholine receptor AChRα7 (α7nAChR) were evaluated. Immunohistochemistry and in situ hybridization were used. The model leads to myositis including occurrence of muscle fiber necrosis. It was found that the infiltrating white blood cells as well the walls of small blood vessels exhibited immunoreactivity for both ChAT and α7nAChR. There was also pronounced immunoreactivity for these in the white blood cells that had coalesced within the necrotic muscle fibers. The findings show that there is a presence of a non-neuronal cholinergic system in the situation of muscle inflammation. Cholinergic effects may be highly involved in the inflammation-modifying events that occur in muscle overuse.


Comprehensive single-cell analysis demonstrates radiotherapy-induced infiltration of macrophages expressing immunosuppressive genes into tumor in esophageal squamous cell carcinoma.
Radiotherapy (RT) combined with immunotherapy is promising; however, the immune response signature in the clinical setting after RT remains unclear. Here, by integrative spatial and single-cell analyses using multiplex immunostaining (CODEX), spatial transcriptome (VISIUM), and single-cell RNA sequencing, we substantiated the infiltration of immune cells into tumors with dynamic changes in immunostimulatory and immunosuppressive gene expression after RT. In addition, our comprehensive analysis uncovered time- and cell type-dependent alterations in the gene expression profile after RT. Furthermore, myeloid cells showed prominent up-regulation of immune response-associated genes after RT. Notably, a subset of infiltrating tumor-associated myeloid cells showing PD-L1 positivity exhibited significant up-regulation of immunostimulatory (HMGB1 and ISG15), immunosuppressive (SIRPA and IDO1), and protumor genes (CXCL8, CCL3, IL-6, and IL-1AB), which can be targets of immunotherapy in combination with PD-L1. These datasets will provide information on the RT-induced gene signature to seek an appropriate target for personalized immunotherapy combined with RT and guide the timing of combination therapy.


The effects of vitamin C on DDP-induced anemia in rats.
The aim of this study was to investigate the effects of vitamin C on cisplatin (DDP)-induced anemia and explore its possible mechanisms in rats. Adult male Sprague-Dawley rats were randomly divided into six groups: control, vitamin C 50, vitamin C 100, DDP, DDP plus vitamin C 50 and DDP plus vitamin C 100-treated groups. DDP was intravenous injected as a single dose and vitamin C was administered by gavage. Serum erythropoietin (Epo), hemoglobin (Hb) and blood urea nitrogen (BUN) concentration were measured 4 and 14 days after DDP treatment. The changes of renal tissue were examined by light microscope. Administration of DDP to rats induced anemia and nephrotoxicity, characterized with a significant decrease in serum Epo and Hb and increase in BUN concentrations. Pathological examination revealed that DDP caused significant renal damage in rats. Vitamin C administration produced amelioration in biochemical indices of anemia and nephrotoxicity and in histological change when compared to group DDP alone; concurrent administration of vitamin C at doses of 100 mg/kg being more effective. Results from this study indicate that the novel natural antioxidant vitamin C might have protective effect against DDP-induced anemia in rats.


Providing Better-Matched Donors for HLA Mismatched Compatible Pairs Through Kidney Paired Donation.
Participation of compatible pairs (CP) in kidney paired donation (KPD) could be attractive to CPs who have a high degree of HLA mismatch, if the CP recipient will gain a better HLA match. Because KPD programs were not designed to help CP, it is important to define allocation metrics that enable CP to receive a better-matched kidney, without disadvantage to incompatible pairs (ICP). Simulations using 46 ICPs and 11 fully HLA-mismatched CPs were undertaken using the Australian KPD matching algorithm. Allocations were preformed adding 1 CP at a time or all 11 CPs at once, and with and without exclusion of unacceptable antigens selected to give a virtual calculated panel-reactive antibody ranging 70% to 80% to improve HLA matching in CP recipients. On average, most CP recipients could be matched and had a lower eplet mismatch (EpMM) with the matched donor (57 ± 15) than with their own donor (78 ± 19, P < 0.02). However, only recipients who had an EpMM to own donor greater than 65 achieved a significant reduction in the EpMM with the matched donor. The gain in EpMM was larger when CPs were listed with unacceptable antigens. Furthermore, inclusion of 1 CP at a time increased matching in ICP by up to 33%, and inclusion of all 11 CPs at once increased ICP matching by 50%. Compatible pair participation in KPD can increase match rates in ICP and can provide a better immunological profile in CP recipients who have a high EpMM to their own donor when using allocation based on virtual crossmatch.


An experimental study and a randomized, double-blind, placebo-controlled clinical trial to evaluate the antisecretory activity of Lactobacillus acidophilus strain LB against nonrotavirus diarrhea.
Previous studies have shown that selected strains of Lactobacillus have the capacity to antagonize rotavirus-induced diarrhea. However, only a few reports have documented their efficacy against nonrotavirus diarrhea. This study involved an experimental investigation and a clinical trial of the antisecretory activity of Lactobacillus acidophilus strain LB in the context of nonrotavirus diarrhea. The activity of a culture of L. acidophilus LB or of the lyophilized, heat-killed L. acidophilus LB bacteria plus their spent culture medium was tested in inhibiting the formation of fluid-formed domes in cultured human intestinal Caco-2/TC7 cell monolayers infected with diarrheagenic, diffusely adhering Afa/Dr Escherichia coli C1845 bacteria. A randomized, double-blind, placebo-controlled clinical trial of male or female children who were 10 months of age and presented with nonrotavirus, well-established diarrhea was conducted to evaluate the therapeutic efficacy of a pharmaceutical preparation that contains 10 billion heat-killed L. acidophilus LB plus 160 mg of spent culture medium. Infection of the cells with C1845 bacteria that were treated with L. acidophilus LB culture or the lyophilized, heat-killed L. acidophilus LB bacteria plus their culture medium produced a dosage-dependent decrease in the number of fluid-formed domes as compared with cells that were infected with untreated C1845 bacteria. The clinical results show that in selected and controlled homogeneous groups of children with well-established, nonrotavirus diarrhea, adding lyophilized, heat-killed L. acidophilus LB bacteria plus their culture medium to a solution of oral rehydration solution shortened by 1 day the recovery time (ie, the time until the first normal stool was passed) as compared with children who received placebo oral rehydration solution. Heat-killed L. acidophilus LB plus its culture medium antagonizes the C1845-induced increase in paracellular permeability in intestinal Caco-2/TC7 cells and produces a clinically significant benefit in the management of children with nonrotavirus, well-established diarrhea.


Distal femoral fixation: a biomechanical comparison of trigen retrograde intramedullary (i.m.) nail, dynamic condylar screw (DCS), and locking compression plate (LCP) condylar plate.
The purpose of this study was to establish if there are biomechanical differences between implants in stiffness of construct, microdisplacement, and fatigue failure in a supracondylar femoral fracture model. A retrograde intramedullary (i.m.) nail, dynamic condylar screw (DCS), and locked condylar plate (LCP) were tested using 33-cm long synthetic femurs. A standardized supracondylar medial segmental defect was created in the distal femur bone models. A gap away from the distal joint axis and parallel to the knee axis was created for axial testing of the specimens (Arbeitsgemeinschaft fur Osteosynthesefragen [AO] type 33-A) and a T-fracture (33-C) was created for the fatigue testing of the specimens. Peak displacements were measured, and analysis was done to determine construct stiffness and gap micromotion in axial loading. Cyclic loading was performed for fatigue testing. It was observed that there were statistically significant differences in micromotion across the fracture gap and overall stiffness of various implant constructs. The stiffness of the i.m. nail, DCS, and LCP were 1,106, 750, and 625 N/mm, respectively. The average total micromotion across the fracture gap for the i.m. nail, DCS, and LCP were 1.96, 10.55, and 17.74 mm, respectively. In fatigue testing, the i.m. nail distal screws failed at 9,000 cycles, the DCS did not fail (80,000 cycles completed), and the LCP failed at 19,000 and 23,500 cycles. When considering micromotion and construct stiffness, the i.m. nail had statistically significant higher stiffness and significantly lower micromotion across the fracture gap with axial compression. Hence, the i.m. nail tested had the greatest stability for type 33-A fractures. However, the nail demonstrated the least amount of resistance to fatigue failure with type 33-C fractures, whereas the DCS did not fail with testing in any pattern.


Gene expression patterns associated with neurological disease in human HIV infection.
The pathogenesis and nosology of HIV-associated neurological disease (HAND) remain incompletely understood. Here, to provide new insight into the molecular events leading to neurocognitive impairments (NCI) in HIV infection, we analyzed pathway dysregulations in gene expression profiles of HIV-infected patients with or without NCI and HIV encephalitis (HIVE) and control subjects. The Gene Set Enrichment Analysis (GSEA) algorithm was used for pathway analyses in conjunction with the Molecular Signatures Database collection of canonical pathways (MSigDb). We analyzed pathway dysregulations in gene expression profiles of patients from the National NeuroAIDS Tissue Consortium (NNTC), which consists of samples from 3 different brain regions, including white matter, basal ganglia and frontal cortex of HIV-infected and control patients. While HIVE is characterized by widespread, uncontrolled inflammation and tissue damage, substantial gene expression evidence of induction of interferon (IFN), cytokines and tissue injury is apparent in all brain regions studied, even in the absence of NCI. Various degrees of white matter changes were present in all HIV-infected subjects and were the primary manifestation in patients with NCI in the absence of HIVE. In particular, NCI in patients without HIVE in the NNTC sample is associated with white matter expression of chemokines, cytokines and β-defensins, without significant activation of IFN. Altogether, the results identified distinct pathways differentially regulated over the course of neurological disease in HIV infection and provide a new perspective on the dynamics of pathogenic processes in the course of HIV neurological disease in humans. These results also demonstrate the power of the systems biology analyses and indicate that the establishment of larger human gene expression profile datasets will have the potential to provide novel mechanistic insight into the pathogenesis of neurological disease in HIV infection and identify better therapeutic targets for NCI.


Paging Dr. Google: The Effect of Online Health Information on Trust in Pediatricians' Diagnoses.
This study investigates how parental trust in physician diagnoses and likelihood of seeking a second opinion (SO) are affected by Internet sources. In an anonymous survey, 1374 parents of minors viewed a vignette describing their child's symptoms followed by Internet results that either supported or contradicted the pediatrician's diagnosis (Dx). A control group did not view any Internet results. After learning the Dx, participants rated trust in the Dx and likelihood of seeking a SO on a 7-point Likert-type scale. Participants who viewed contradicting results were less likely to trust the Dx ( P < .001) and more likely to seek a SO than the control ( P < .001). Participants who viewed supporting results were more likely to trust the Dx ( P < .001) and less likely to seek a SO than the control ( P < .001). Physicians must be aware of the influence the Internet may have on patients' trust.


Endoplasmic reticulum stress regulates glutathione metabolism and activities of glutathione related enzymes in Arabidopsis.
Stress conditions generate an extra load on protein folding machinery in the endoplasmic reticulum (ER) and if the ER cannot overcome this load, unfolded proteins accumulate in the ER lumen, causing ER stress. ER lumen localised protein disulfide isomerase (PDI) catalyses the generation of disulfide bonds in conjugation with ER oxidoreductase1 (ERO1) during protein folding. Mismatched disulfide bonds are reduced by the conversion of GSH to GSSG. Under prolonged ER stress, GSH pool is oxidised and H2O2 is produced via increased activity of PDI-ERO1. However, it is not known how glutathione metabolism is regulated under ER stress in plants. So, in this study, ER stress was induced with tunicamycin (0.15, 0.3, 0.45μg mL-1 Tm) in Arabidopsis thaliana (L.) Heynh. Glutathione content was increased by ER stress, which was accompanied by induction of glutathione biosynthesis genes (GSH1, GSH2). Also, the apoplastic glutathione degradation pathway (GGT1) was induced. Further, the activities of glutathione reductase (GR), dehydroascorbate reductase (DHAR), glutathione peroxidase (GPX) and glutathione S-transferase (GST) were increased under ER stress. Results also showed that chloroplastic GPX genes were specifically downregulated with ER stress. This is the first report on regulation of glutathione metabolism and glutathione related enzymes in response to ER stress in plants.


Transactivation of prothymosin alpha and c-myc promoters by human papillomavirus type 16 E6 protein.
The human papillomavirus type 16 E6 protein exerts a transforming activity through inactivation of tumor suppressor p53. Recently E6 has been shown to have additional transforming activities independent of p53. E6 is able to transactivate or repress several specific viral promoters. However, underlying molecular mechanisms and cellular target genes for the activity are not well understood. Using a differential hybridization technique, we identified the prothymosin alpha gene as a cellular target of E6 transactivation. E6 was able to transactivate the prothymosin alpha promoter in H358 cells lacking p53 and in C33A cells harboring a mutant p53 allele. Disruption of the E-box in intron 1 of the prothymosin alpha promoter abolished the responsiveness to E6. Then we determined if E6 up-regulates the expression of Myc, by which the prothymosin alpha promoter is transactivated through the E-box. We found that E6 is also able to transactivate the c-myc promoter in H358 cells and in C33A cells. These results suggest that E6 is able to transactivate the c-myc promoter independently of p53, and that the prothymosin alpha promoter is subsequently transactivated by Myc.


Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study.
To investigate whether age at onset of epilepsy, type of epilepsy, family history of psychosis, or family history of epilepsy affect the risk of schizophrenia or schizophrenia-like psychosis among patients with epilepsy. Comparison of population based data. Danish longitudinal registers. The cohort comprised 2.27 million people. Epilepsy, psychosis, personal birth data. We found an increased risk of schizophrenia (relative risk 2.48, 95% confidence interval 2.20 to 2.80) and schizophrenia-like psychosis (2.93, 2.69 to 3.20) in people with a history of epilepsy. The effect of epilepsy was the same in men and in women and increased with age. Family history of psychosis and a family history of epilepsy were significant risk factors for schizophrenia and schizophrenia-like psychosis, and the effect of epilepsy, both in cases and families, was greater among people with no family history of psychosis. In addition, the increased risk for schizophrenia or schizophrenia-like psychosis did not differ by type of epilepsy but increased with increasing number of admissions to hospital and, particularly, was significantly greater for people first admitted for epilepsy at later ages. There is a strong association between epilepsy and schizophrenia or schizophrenia-like psychosis. The two conditions may share common genetic or environmental causes.


The Performance of SARS-CoV-2 Serology Testing in the Diagnosis of COVID-19.
COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) has been a reference test for diagnosing a disease since the very beginning of the pandemic. COVID-19 serology tests have also been developed and used to estimate the prevalence of individuals who have already been infected. We aimed to evaluate the performance of serology tests for the diagnosis of patients who had been referred to medical centers with acute symptoms. In this cross-sectional study, 80 individuals suspected of COVID-19 who had been referred to Imam Khomeini Hospital Complex, Tehran, Iran, were examined. Upper respiratory tract specimens for RT-PCR and blood samples for COVID-19 IgM and IgG antibody level tests were collected and the results were compared. The overall proportion in agreement, the agreement between positive results, and the agreement between negative results when comparing RT-PCR and IgM serology test were 40% (kappa = -0.006, P = 0.9), 32%, and 66.6%, respectively, and when comparing RT-PCR and IgG serology test were 46% (kappa = -0.006, P = 0.94), 43.5%, and 55.5%, respectively. The absence of a gold standard method for the diagnosis of COVID-19 makes it very challenging to determine the true sensitivity and specificity of different methods. The study results revealed no agreement between the two methods; so the RT-PCR test for upper respiratory tract specimen cannot be replaced with COVID-19 serology test for the diagnosis of patients with acute symptoms.


Association of Src family tyrosine kinase Lyn with ganglioside GD3 in rat brain. Possible regulation of Lyn by glycosphingolipid in caveolae-like domains.
Association of gangliosides with specific proteins in the central nervous system was examined by co-immunoprecipitation with anti-ganglioside antibody. Protein kinase activity was detected in precipitates with monoclonal antibody to ganglioside GD3 (R24) from membranal fraction of rat brain. Using in vitro kinase assay, several phosphorylated proteins of 40, 53, 56, and 80 kDa were isolated by gel electrophoresis. Of these proteins, the proteins of 53 and 56 kDa (p53/56) were identified as two isoforms of Src family tyrosine kinase Lyn, based on co-migration during gel electrophoresis, comparative peptide mapping, and sequential immunoprecipitation with anti-Lyn antibody. The identification was confirmed using a cDNA expression system in Chinese hamster ovary (CHO) cells, which express solely ganglioside GM3, the enzymatic substrate of GD3 synthase. In co-transfection with GD3 synthase and Lyn expression plasmids, R24 immunoprecipitated Lyn and anti-Lyn antibody immunoprecipitated GD3. R24 treatment of rat primary cerebellar cultures induced Lyn activation and rapid tyrosine phosphorylation of several substrates including mitogen-activated protein kinases. Furthermore, sucrose density gradient analysis showed that Lyn of cerebellum and CHO transfectants were detected in a low density light-scattering band, i.e. the caveolae membrane fraction. R24 immunoprecipitated caveolin from Triton X-100 extract of CHO transfectants. These observations suggest that GD3 may regulate Lyn in a caveolae-like domain on brain cell membranes.


Exploratory data from complete genomes of familial alzheimer disease age-at-onset outliers.
Identifying genes that modify the age at onset (AAO) of Alzheimer disease and targeting them pharmacologically represent a potential treatment strategy. In this exploratory study, we sequenced the complete genomes of six individuals with familial Alzheimer disease due to the autosomal dominant mutation p.Glu280Ala in PSEN1 (MIM# 104311; NM_000021.3:c.839A>C). The disease and its AAO are highly heritable, motivating our search for genetic variants that modulate AAO. The median AAO of dementia in carriers of the mutant allele is 49 years. Extreme phenotypic outliers for AAO in this genetically isolated population with limited environmental variance are likely to harbor onset modifying genetic variants. A narrow distribution of AAO in this kindred suggests large effect sizes of genetic determinants of AAO in these outliers. Identity by descent (IBD) analysis and a combination of bioinformatics filters have suggested several candidate variants for AAO modifiers. Future work and replication studies on these variants may provide mechanistic insights into the etiopathology of Alzheimer disease.


Augmenting selective serotonin reuptake inhibitors with clomipramine in obsessive-compulsive disorder: benefits and risks.
A small body of literature suggests that clomipramine may usefully augment selective serotonin reuptake inhibitor (SSRI) treatment in obsessive-compulsive disorder (OCD) patients who do not respond to SSRI monotherapy. The combination, however, is associated with the risk of clinically significant drug interactions. Clomipramine can raise the blood levels and hence the adverse effects of most SSRIs, and many SSRIs can raise the blood levels and hence the adverse effects of clomipramine. The latter situation is more important because certain dose-dependent adverse effects of clomipramine, such as seizures, can be life-threatening. This article presents an evidence-based discussion of the pharmacodynamic and pharmacokinetic adverse effects of the SSRI-clomipramine combination along with suggestions for dosing and monitoring when the combination is used in OCD.


[Partial ureterectomy in a case of intrinsic-type ureteral endometriosis].
We report a case of intrinsic-type ureteral endometriosis in a 28-year-old woman. She visited our hospital, complaining of lower abdominal pain. Drip infusion pyelography (DIP) showed left hydronephrosis, and left retrograde pyelography revealed a filling defect of the left pelvic ureter. Biopsy under ureteroscopy showed chronic ureteritis. It was difficult to exclude a malignant tumor, and we performed left partial ureterectomy and uretero-ureterostomy. The pathological examination showed endometrial tissue in the submucosal and muscle layer, and we diagnosed it as intrinsic-type ureteral endometriosis judging from the findings of the ureteroscopy and the operation. After the operation, drip infusion pyelography showed the improvement of the left hydronephrosis and ureteral passage, and the right ovarian endometriosis was found by gynecologists. She received hormonal therapy with the luteinizing hormone releasing hormone agonist for about half a year, but the right ovarian endometriosis remained unchanged. This is the ninth case in the Japanese literature reported as intrinsic-type ureteral endometriosis.


Examining the Impact of Race on Motivational Interviewing Implementation and Outcomes with HIV+ Heavy Drinking Men Who Have Sex with Men.
Motivational interviewing (MI)-based interventions focus on changing behavior through building client motivation. It is unknown how racial mismatch between clients and providers may impact MI implementation and subsequent behavior. We used a mixed methods approach to examine differences in Motivational Interviewing Skill Code (MISC) coded sessions and post-session outcomes between a sample of HIV-positive cisgender men who have sex with men (MSM) participants of an MI-based intervention to reduce heavy drinking who identified as persons of color (POC; n = 19) and a matched sample of White participants (n = 19). We used quantitative methods to analyze how providers implemented the intervention (i.e., MISC codes) and post-session drinking. We used qualitative analyses of session transcripts to examine content not captured by MISC coding. Quantitative analyses showed that providers asked fewer open-ended questions and had a lower ratio of complex reflections to simple reflections when working with POC participants, but no significant differences were observed in drinking post-intervention between participants. Qualitative analyses revealed that participants discussed how racial and sexual orientation discrimination impacted their drinking. Allowing clients to share their experiences and to explore individually meaningful reasons for behavioral change may be more important than strict adherence to MI techniques.


Advanced Boundary Electrode Modeling for tES and Parallel tES/EEG.
This paper explores advanced electrode modeling in the context of separate and parallel transcranial electrical stimulation (tES) and electroencephalography (EEG) measurements. We focus on boundary condition-based approaches that do not necessitate adding auxiliary elements, e.g., sponges, to the computational domain. In particular, we investigate the complete electrode model (CEM) which incorporates a detailed description of the skin-electrode interface including its contact surface, impedance, and normal current distribution. The CEM can be applied for both tES and EEG electrodes which are advantageous when a parallel system is used. In comparison to the CEM, we test two important reduced approaches: the gap model (GAP) and the point electrode model (PEM). We aim to find out the differences of these approaches for a realistic numerical setting based on the stimulation of the auditory cortex. The results obtained suggest, among other things, that GAP and GAP/PEM are sufficiently accurate for the practical application of tES and parallel tES/EEG, respectively. Differences between CEM and GAP were observed mainly in the skin compartment, where only CEM explains the heating effects characteristic to tES.


Nootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPK.
AMP-activated protein kinase (AMPK) is a serine/threonine kinase that is implicated in the control of energy metabolism and is considered to be a molecular target for the suppression of obesity and the treatment of metabolic syndrome. Here, we identified and characterized nootkatone, a constituent of grapefruit, as a naturally occurring AMPK activator. Nootkatone induced an increase in AMPKalpha1 and -alpha2 activity along with an increase in the AMP/ATP ratio and an increase the phosphorylation of AMPKalpha and the downstream target acetyl-CoA carboxylase (ACC), in C(2)C(12) cells. Nootkatone-induced activation of AMPK was possibly mediated both by LKB1 and Ca(2+)/calmodulin-dependent protein kinase kinase. Nootkatone also upregulated PPARgamma coactivator-1alpha in C(2)C(12) cells and C57BL/6J mouse muscle. In addition, administration of nootkatone (200 mg/kg body wt) significantly enhanced AMPK activity, accompanied by LKB1, AMPK, and ACC phosphorylation in the liver and muscle of mice. Whole body energy expenditure evaluated by indirect calorimetry was also increased by nootkatone administration. Long-term intake of diets containing 0.1% to 0.3% (wt/wt) nootkatone significantly reduced high-fat and high-sucrose diet-induced body weight gain, abdominal fat accumulation, and the development of hyperglycemia, hyperinsulinemia, and hyperleptinemia in C57BL/6J mice. Furthermore, endurance capacity, evaluated as swimming time to exhaustion in BALB/c mice, was 21% longer in mice fed 0.2% nootkatone than in control mice. These findings indicate that long-term intake of nootkatone is beneficial toward preventing obesity and improving physical performance and that these effects are due, at least in part, to enhanced energy metabolism through AMPK activation in skeletal muscle and liver.


Laser in situ keratomileusis with Alcon CustomCornea.
To report the 3-month results of our first cases of laser in situ keratomileusis (LASIK) with Alcon's CustomCornea. Wavefront analysis was performed using the LADARWave aberrometer and ablation was performed with the LADARVision4000 system. Thirty-one eyes of 17 patients were analyzed prospectively, at 1 and 3 months after CustomCornea surgery. Psychophysical tests were performed, including high and low contrast acuity, and contrast sensitivity under scotopic and photopic conditions. In addition, psychometric testing was performed using a subjective vision questionnaire. Mean spherical equivalent refraction improved from a baseline -3.05 +/- 1.92 D to +0.02 +/- 0.28 D at 3 months (28 eyes). At 3 months, 46.4% (13 eyes) had uncorrected visual acuity of 20/16, 92.7% (26 eyes) had 20/20, and 100% (28 eyes) had 20/25 uncorrected visual acuity. Three months after CustomCornea surgery, there was a statistically significant improvement in contrast sensitivity under both scotopic and photopic conditions, and a statistically significant increase in third and fourth order aberrations. There was a statistically significant improvement in visual quality as measured by the subjective vision index, increasing from a preoperative mean 66.62 to 87.63 at 3 months after surgery. CustomCornea was an improvement over conventional LASIK as measured by most psychophysical and psychometric parameters. The relationship between higher order aberrations and other psychophysical and psychometric measurements needs more analysis.


Postoperative objective outcomes for upright, supine, and bipositional reflux disease following laparoscopic nissen fundoplication.
Traditionally, patients with gastroesophageal reflux disease fall into 3 categories based on 24-hour pH testing and the clinical occurrence of their acid exposure. Patients with upright reflux are believed to do worse following surgery compared with supine or bipositional reflux patients. We assessed objective postoperative outcomes for patients with upright, supine, and bipositional reflux following laparoscopic Nissen fundoplication to determine if there is a category of refluxing patient who should be counseled against antireflux surgery. Retrospective analysis of prospectively collected data. Esophageal physiology laboratory at a tertiary care teaching hospital. A total of 225 patients (supine, 45; upright, 92; bipositional, 88) with preoperative and postoperative 24-hour pH measurements, manometry results, and standardized symptom assessment forms were included in the study. A Nissen fundoplication was performed based on 24-hour pH and manometry result. Esophageal manometry was performed with a water-perfused system, and 24-hour pH was measured with a digital capture device. Preoperative and postoperative symptom correlation, 24-hour pH, and manometric variables. There was a significant difference in preoperative symptom correlation between groups. Patients with bipositional reflux disease have significantly worst reflux disease (percentage of time with a pH <4, total number of reflux episodes, longest reflux episode, and Johnson-DeMeester score) and the weakest preoperative lower esophageal sphincter pressure. Postoperative symptom correlation was low among all 3 groups. There was no significant difference in postoperative 24-hour pH or manometry among groups. Success following surgery was achieved in 73.3% with supine reflux, 80.4% with upright reflux, and 75.0% with bipositional reflux. Patients with bipositional reflux have the most severe disease. Supine, upright, and bipositional reflux patients perform equally well following laparoscopic fundoplication as defined by objective outcome criteria.


Three-dimensional neuroanatomic images in CT-guided stereotaxic neurosurgery.
A technique is described for three-dimensional reconstruction of human diencephalic structures based on information contained in a widely used stereotaxic brain atlas. Various methods of graphically representing the obtained diencephalic volumes are discussed and examples are given. The anatomic information contained in the computerized atlas can be implemented with computed tomography performed under stereotaxic conditions. Volume data provided by the tomograms are used for three-dimensional "stretching" of the volumes presented in the atlas. Improved accuracy in identifying "invisible" diencephalic targets in functional stereotaxic neurosurgery is expected to result from this new technique.


Impartiality and disability discrimination.
Cost-effectiveness analysis is the standard analytical tool for evaluating the aggregate health benefits of treatments and health programs. According to a common objection, however, its use may lead to unfair discrimination against people with disabilities. Since the disability discrimination objection is seldom articulated in a precise way, I first provide a formulation that avoids some implausible implications. Then I turn to the standard defense of cost-effectiveness analysis and argue that it does not succeed. But this does not settle the question of whether the use of cost-effectiveness analysis leads to unfair discrimination. Rather, it shows that the controversy should be approached in a different way. Thus, I conclude by outlining an alternative strategy for answering the question.


Hurricane prediction: progress and problem areas.
The subjective approach to hurricane prediction of yesteryear has given way to the automation of many facets of prediction, leaving the forecaster with more time to reason dynamically in making the final adjustments to the official track derived from a hierarchy of computer-generated guidances. The most important task immediately ahead is to develop and apply better diagnostic procedures to help the forecaster identify the guidance sources which are most likely to contain the truth, and to help assure that his final decision will either succeed or fail safely. The ultimate prediction method for both hurricane development and movement will probably need to simulate not only the circulation of the hurricane but the interaction of the cloud clusters in its vortex with the largescale environment. Assuming that this can be effectively done, the most important further handicap will be the problem of describing the initial conditions. The development of a model which will dependably simulate the behavior of the three hurricanes in ten that turn out to be bad actors will not likely become operational in the near future. The most troubling problem in applying such a model-and it would have to be tested for years over a range of many storm types and conditions before becoming fully operational-is that the more complex the model is the more inscrutable the results are and the more difficult it becomes to identify the condition in which computational failure is probable. It would appear, therefore, that engineering approache to prediction and diagnostic procedures of evaluation will dominate the methodology of hurricane forecasting for a number of years to come.


Patients' perspectives on the effect of the COVID-19 pandemic on access to cancer care and social contacts in Sweden and the UK: a cross-sectional study.
We aimed to determine whether there was a difference in access to cancer-related healthcare between people living in Sweden and the United Kingdom (UK) during the COVID-19 pandemic. We also describe how the pandemic affected social contact of patients undergoing treatment. This cross-sectional study used survey data collected through the War on Cancer mobile phone application between September 5, 2020, and January 6, 2021. We included individuals with cancer diagnoses living in Sweden or the UK. The association between difficulty accessing cancer-related healthcare and country was examined using logistic regression. Frequencies were used to describe the effect of the pandemic on social contact. Of 491 individuals included in the study, 183 were living in the UK and 308 in Sweden. Living in the UK was associated with greater difficulty accessing cancer-related healthcare (n = 99/183, 54.1%) than living in Sweden (n = 100/308, 32.5%) (odds ratio 2.12, 95% CI 1.39-3.23, p < 0.001). The pandemic affected social contact for almost all patients (n = 218/238, 91.6%) undergoing treatment. This study highlights the differential impact that the pandemic may have had on patients' access to cancer-related care in the UK and Sweden. In both countries, the pandemic overwhelmingly affected social contact of individuals undergoing cancer treatment. New ways must be found to improve access to cancer-related care and reduce social isolation for patients with cancer during a pandemic.


Specific proteolysis of the kinase protein kinase C-related kinase 2 by caspase-3 during apoptosis. Identification by a novel, small pool expression cloning strategy.
The caspase family of proteases plays a critical role in the execution of apoptosis. However, efforts to decipher the molecular mechanisms by which caspases induce cell death have been greatly hindered by the lack of systematic and broadly applicable strategies to identify their substrates. Here we describe a novel expression cloning strategy to rapidly isolate cDNAs encoding caspase substrates that are cleaved during apoptosis. Small cDNA pools (approximately 100 clones each) are transcribed/translated in vitro in the presence of [35S]methionine; these labeled protein pools are then incubated with cytosolic extracts from control and apoptotic cells. cDNA pools encoding proteins that are specifically cleaved by the apoptotic extract and whose cleavage is prevented by the caspase inhibitor acetyl-Tyr-Val-Ala-Asp chloromethylketone are subdivided and retested until a single cDNA is isolated. Using this approach, we isolated a partial cDNA encoding protein kinase C-related kinase 2 (PRK2), a serine-threonine kinase, and demonstrate that full-length human PRK2 is proteolyzed by caspase-3 at Asp117 and Asp700 in vitro. In addition, PRK2 is cleaved rapidly during Fas- and staurosporine-induced apoptosis in vivo by caspase-3 or a closely related caspase. Both of the major apoptotic cleavage sites of PRK2 in vivo lie within its regulatory domain, suggesting that its activity may be deregulated by proteolysis.


Regulatory patterns in molecular interaction networks.
Understanding design principles of molecular interaction networks is an important goal of molecular systems biology. Some insights have been gained into features of their network topology through the discovery of graph theoretic patterns that constrain network dynamics. This paper contributes to the identification of patterns in the mechanisms that govern network dynamics. The control of nodes in gene regulatory, signaling, and metabolic networks is governed by a variety of biochemical mechanisms, with inputs from other network nodes that act additively or synergistically. This paper focuses on a certain type of logical rule that appears frequently as a regulatory pattern. Within the context of the multistate discrete model paradigm, a rule type is introduced that reduces to the concept of nested canalyzing function in the Boolean network case. It is shown that networks that employ this type of multivalued logic exhibit more robust dynamics than random networks, with few attractors and short limit cycles. It is also shown that the majority of regulatory functions in many published models of gene regulatory and signaling networks are nested canalyzing.