Rap1b association with the platelet cytoskeleton occurs in the absence of glycoproteins IIb/IIIa.
Platelet membrane glycoproteins (GP) IIb/IIa and rap1b, a 21 kDa GTP binding protein, associate with the triton-insoluble, activation-dependent platelet cytoskeleton with similar rates and divalent cation requirement. To examine the possibility that GPIIb/IIIa was required for rap1b association with the cytoskeleton, experiments were performed to determine if the two proteins were linked under various conditions. Chromatography of lysates from resting platelets on Sephacryl S-300 showed that GPIIb/IIIa and rap1b were well separated and distinct proteins. Immunoprecipitation of GPIIb/IIIa from lysates of resting platelets did not produce rap1b or other low molecular weight GTP binding proteins and immunoprecipitation of rap1b from lysates of resting platelets did not produce GPIIb/IIIa. Finally, rap1b was associated with the activation-dependent cytoskeleton of platelets from a patient with Glanzmann's thrombasthenia who lacks surface expressed glycoproteins IIb and IIIa. Based on these findings, we conclude that no association between GPIIb/IIIa and raplb is found in resting platelets and that rap1b association with the activation-dependent cytoskeleton is at least partly independent of GPIIb/IIIa.


Meeting Report: The Fourth Artificial Pancreas Workshop: Testing and Adoption of Current and Emerging Technologies.
On July 6 and 7, 2016 the Fourth Artificial Pancreas Workshop: Testing and Adoption of Current and Emerging Technologies was held on the National Institutes of Health (NIH) Campus at the Lister Hill Auditorium. The meeting was sponsored by a group of governmental organizations and NGOs, listed in Appendix A. This was a very timely meeting as the artificial pancreas appears to be growing from academic studies to commercial projects. The first artificial pancreas may be marketed within 12 months and a few may be approved within 24 months. The NIH, the FDA, the JDRF, Helmsley Trust, Diabetes Technology Society, and other agencies, funders, and organizations have been strongly supportive of advancing artificial pancreas technology and usability, and thus the proceedings from this conference should be of exceptional interest to the diabetes technology community.


Study of Quantitative Trait Loci (QTLs) Associated with Allelopathic Trait in Rice.
In rice there are few genetic studies reported for allelopathy traits, which signify the ability of plants to inhibit or stimulate growth of other plants in the environment, by exuding chemicals. QTL analysis for allelopathic traits were conducted with 98 F8 RILs developed from the cross between the high allelopathic parents of 'Sathi' and non-allelopathic parents of 'Nong-an'. The performance of allelopathic traits were evaluated with inhibition rate on root length, shoot length, total length, root weight, shoot weight, and total weight of lettuce as a receiver plant. With 785 polymorphic DNA markers, we constructed a linkage map showing a total of 2489.75 cM genetic length and 3.17 cM of average genetic distance between each adjacent marker. QTL analysis detected on QTL regions on chromosome 8 responsible for the inhibition of shoot length and inhibition of total length. The qISL-8 explained 20.38% of the phenotypic variation for the inhibition on the shoot length. The qITL-8 explained 14.93% of the phenotypic variation for the inhibition on total length. The physical distance of the detected QTL region was 194 Kbp where 31 genes are located.


Identification and Validation of a Metabolism-Related Prognostic Signature Associated with M2 Macrophage Infiltration in Gastric Cancer.
High levels of M2 macrophage infiltration invariably contribute to poor cancer prognosis and can be manipulated by metabolic reprogramming in the tumor microenvironment. However, the metabolism-related genes (MRGs) affecting M2 macrophage infiltration and their clinical implications are not fully understood. In this study, we identified 173 MRGs associated with M2 macrophage infiltration in cases of gastric cancer (GC) using the TCGA and GEO databases. Twelve MRGs were eventually adopted as the prognostic signature to develop a risk model. In the high-risk group, the patients showed poorer survival outcomes than patients in the low-risk group. Additionally, the patients in the high-risk group were less sensitive to certain drugs, such as 5-Fluorouracil, Oxaliplatin, and Cisplatin. Risk scores were positively correlated with the infiltration of multiple immune cells, including CD8+ T cells and M2 macrophages. Furthermore, a difference was observed in the expression and distribution between the 12 signature genes in the tumor microenvironment through single-cell sequencing analysis. In vitro experiments proved that the M2 polarization of macrophages was suppressed by Sorcin-knockdown GC cells, thereby hindering the proliferation and migration of GC cells. These findings provide a valuable prognostic signature for evaluating clinical outcomes and corresponding treatment options and identifying potential targets for GC treatment.


Immune tolerance and control of CNS autoimmunity: from animal models to MS patients.
Multiple sclerosis (MS) is a chronic inflammatory disease resulting in demyelination and axonal loss within the CNS. An autoimmune reaction directed against myelin antigens contributes to the disease process. As the CNS has long been considered an immune privileged site, how such an immune response can develop locally has remained enigmatic. Recent data, mostly based on the study of animal models for MS, have shown that the CNS is in fact more permissive to the development of immune responses than previously thought. This observation is counterbalanced by the fact that immune tolerance to myelin antigens can be induced outside the CNS. This review focuses on the mechanisms preventing CNS autoimmunity, which act in three separate tissues. In the thymus, expression of CNS autoantigens promotes partial protection, notably through elimination of autoreactive T cells. In the secondary lymphoid organs, the remaining autoreactive T cells are kept under control by the naturally occurring regulatory T cells of the CD4(+)Foxp3(+) phenotype. In the CNS, multiple mechanisms including the local activation of regulatory T cells further limit autoimmunity. A better understanding of the induction of regulatory T cells, of their mechanisms of action, and of approaches to manipulate them in vivo may offer new therapeutic opportunities for MS patients.


Attract-and-kill as a new strategy for the management of the potato tuber moths Phthorimaea operculella (Zeller) and Symmetrischema tangolias (Gyen) in potato: evaluation of its efficacy under potato field and storage conditions.
Attract-and-kill composed of pure sex pheromones of the potato tuber moths Phthorimaea operculella (Zeller) and Symmetrischema tangolias (Gyen) and the insecticide cyfluthrin resulted in 100% mortality of males under controlled laboratory conditions. The aim of the present study was to investigate the efficacy of this strategy in different potato agroecologies as well as under simulated potato storage conditions. Attract-and-kill was highly effective at reducing male flight activity and significantly reduced daily moth catches in pheromone-baited water traps (by 51.8-99.9%) in comparison with untreated plots. This largely depended on the field size, the attract-and-kill droplet size and the density applied per hectare. Highest efficacy, which was independent of pest density, was achieved when attract-and-kill was applied on larger potato fields using a droplet density of 2500 source points ha(-1) at a droplet size of 100 µL. Consequently, pest infestation on vegetative plant parts as well as on tubers was significantly reduced (by up to 90%) in comparison with untreated controls. Under simulated storage conditions with a high number of females and males released periodically, an efficacy of 84.1 and 87.2% was achieved in reducing tuber infestation by P. operculella and S. tangolias respectively. Attract-and-kill is very effective in controlling the two potato tuber moth species under both field and storage conditions; it is a new, attractive and (for storage conditions) low-cost method that can be easily integrated in potato pest management programmes, especially in small-scale agricultural systems of the tropics and subtropics.


Paediatric obesity research in early childhood and the primary care setting: the TARGet Kids! research network.
Primary paediatric health care is the foundation for preventative child health. In light of the recent obesity epidemic, paediatricians find themselves at the frontline of identification and management of childhood obesity. However, it is well recognized that evidence based approaches to obesity prevention and subsequent translation of this evidence into practice are critically needed. This paper explores the role of primary care in obesity prevention and introduces a novel application and development of a primary care research network in Canada--TARGet Kids!--to develop and translate an evidence-base on effective screening and prevention of childhood obesity.


Distinctive Cytoskeletal Organization in Erythrocytes of the Cold-Seep Vesicomyid Clam, Calyptogena kilmeri.
Erythrocytes have long served as model cells, useful for analyzing cytoskeletal structure and function. In non-mammalian vertebrates, erythrocytes are typically highly flattened, nucleated ellipsoids in which a marginal band (MB) of microtubules interacts with the membrane skeleton (MS) to generate and maintain cell shape. Though relatively rare, erythrocytes also occur in representatives of many invertebrate phyla, including the arcid and vesicomyid molluscs, but the structure and function of these cells are not well understood. Previous work has shown arcid erythrocytes to be highly flattened ellipsoids containing the MB-MS cytoskeletal system, similar to vertebrates but with an additional interesting feature: a functional centriole-containing centrosome associated with each MB. In the present study we have examined, for the first time, erythrocyte morphology and cytoskeletal structure in a vesicomyid. Using Calyptogena kilmeri, the dominant invertebrate at many Pacific cold seeps, we have found that the erythrocytes are only slightly flattened and do not contain MBs. Rather, their cytoskeletons display a peripheral centriole-containing centrosome with radiating fibers, a distinctive type of organization not observed previously in mature erythrocytes from any species.


Rapid canine distalization using distraction of the periodontal ligament: a preliminary clinical validation of the original technique.
The process of rapid canine distalization through the distraction of the periodontal ligament is similar to the process in the midpalatal suture during rapid palatal expansion. Rapid canine distalization can be achieved in three weeks with this technique. The aim of this research was to evaluate the effects of rapid canine distalization on dentoalveolar tissues during the rapid distalization of canine teeth with semirigid, individual tooth-borne distractors. The study was carried out on 43 canine teeth in 18 (seven male and 11 female) patients who required first premolar extractions. The mean age of the patients was 16.7 years. The second premolars and first molars were used as anchor units. Orthodontic models, cephalometric and panoramic radiographs, and standard photographs of all the patients were taken before treatment and after the consolidation period. Periapical radiographies of the canines and anchor units were obtained once a week during the distalization period. The distractors were activated 0.25 mm three times a day, and the canines were distalized efficiently an average of three weeks. The within-group differences were evaluated with the Wilcoxon test. The maxillary canines were distalized an average of 5.76 mm with 11.47 degrees distal tipping. The maxillary first molars moved mesially 0.56 mm and extruded 0.64 mm. The maxillary incisors showed 1.44 degrees of palatal tipping. The mean distal movement of the mandibular canines was 3.5 mm with 7.16 degrees distal tipping. Anchorage loss was not observed in the mandibular first molars.


Bio-Orthogonal Mediated Nucleic Acid Transfection of Cells via Cell Surface Engineering.
The efficient delivery of foreign nucleic acids (transfection) into cells is a critical tool for fundamental biomedical research and a pillar of several biotechnology industries. There are currently three main strategies for transfection including reagent, instrument, and viral based methods. Each technology has significantly advanced cell transfection; however, reagent based methods have captured the majority of the transfection market due to their relatively low cost and ease of use. This general method relies on the efficient packaging of a reagent with nucleic acids to form a stable complex that is subsequently associated and delivered to cells via nonspecific electrostatic targeting. Reagent transfection methods generally use various polyamine cationic type molecules to condense with negatively charged nucleic acids into a highly positively charged complex, which is subsequently delivered to negatively charged cells in culture for association, internalization, release, and expression. Although this appears to be a straightforward procedure, there are several major issues including toxicity, low efficiency, sorting of viable transfected from nontransfected cells, and limited scope of transfectable cell types. Herein, we report a new strategy (SnapFect) for nucleic acid transfection to cells that does not rely on electrostatic interactions but instead uses an integrated approach combining bio-orthogonal liposome fusion, click chemistry, and cell surface engineering. We show that a target cell population is rapidly and efficiently engineered to present a bio-orthogonal functional group on its cell surface through nanoparticle liposome delivery and fusion. A complementary bio-orthogonal nucleic acid complex is then formed and delivered to which chemoselective click chemistry induced transfection occurs to the primed cell. This new strategy requires minimal time, steps, and reagents and leads to superior transfection results for a broad range of cell types. Moreover the transfection is efficient with high cell viability and does not require a postsorting step to separate transfected from nontransfected cells in the cell population. We also show for the first time a precision transfection strategy where a single cell type in a coculture is target transfected via bio-orthogonal click chemistry.


[Sigmund Freud and the origin of countertransference's concept].
The aim of this paper is to contextualize and analyze historically the birth and early development of the concept of countertransference, introduce by Freud in 1909. In order to do so, will be considered scientific publications, the epistolary and the historical information about the personal relationship between Freud and his students, and among them and some of their patients.


Understanding Gender-Based Perception During Pregnancy: A Qualitative Study.
Gender-based perceptions about maternal health care during pregnancy draw attention to the existence of gender inequity in maternal health care. This study aimed to understand the gender-based perception of gender roles and norms, gender relations, social support, and psychosocial variation in maternal health care during pregnancy. A qualitative study was conducted in three rural districts of Jimma, Ethiopia. Participants were purposefully chosen from the community groups, including male and female health development armies, religious leaders, health extension workers, midwifery nurses, and primary health care unit directors. The data was gathered through in-depth interviews and focus group discussions. The actual data was collected by men and women qualitative study experts. Atlas ti Ver 9 was used for the analysis. The data was initially coded then changed to a sub-category and at last converted to a category. Four categories emerged: Gender-based roles and norms, psychosocial variation, social support, and gender relations. The informants described men's and women's independent and shared roles improve maternal health care service usage during pregnancy. Once the women became pregnant, men undertook a variety of demanding duties to enhance maternity service consumption. Gender relations and shared decision-making were essential in facilitating maternal healthcare utilization during pregnancy and beyond. This study revealed that maternal health care should not be limited to women alone. Men's and women's prior maternal health experiences, in addition to their knowledge and beliefs, have significantly impacted the utilization of maternal healthcare services during pregnancy. Policymakers and academics should consider men's essential contribution to maternal health care during pregnancy. However, in order to increase their intention to use maternal health care services, it is necessary to clearly identify the interests of women in which men should be involved.


Medical costs of osteoporosis in the Iranian elderly patients.
Background: In the coming years and near future, Iran will experience a main demographic transition resulting in an aging phenomenon and increased number of people over 65 years. Aging leads to increased medical expenditures associated with chronic diseases such as osteoporosis. This study aimed to investigate the patient-specific hospitalization costs of osteoporosis treatment in elderly patients. Methods: A retrospective cost analysis of hospitalization arising from osteoporosis conducted on all the elderly patients (adults aged 65 years and above) in a teaching hospital in Tehran through examining hospital admissions during 2017. The elderly patients consisted of 295 with a length of stay ≥ 24 hours. Cost analysis was performed using a bottom-up micro-costing approach and payer perspective (patient and insurer); and the result was statistically significant (p≤0.05). Nonparametric tests, including Mann-Whitney and Kruskal-Wallis tests, were used to investigate the relationship between affecting variables. Hospital training was considered as a control variable. The data were analyzed using SPSS 11 software Results: The mean age of the patients was 71.3 years; of the patients, 79% were female and 21% male. The overall crude prevalence of osteoporosis was 80% among people ≥ 65 years and 85% among patients who experienced relevant surgeries. The average cost of hospitalization was $3794.13. Also, 3 main areas of hospital costs were identified: consumables (57.70%), hoteling (17.24%), and surgical services (15.76%). The prevalence of osteoporosis was 4 times higher in women compared with men. Moreover, there were significant differences between the variables affecting hospital costs, such as gender, length of stay, diagnosis, intensive care unit services, and surgery (p<0.05). Conclusion: Age-associated diseases such as osteoporosis increase the health care costs. The dominant cost drivers in this study were the consumables, hoteling, and surgical services, respectively. Policymakers and health care planners should consider such variables as gender, previous surgeries in the patients' records, length of stay, and intensive care unit services as driving factors and determinants of hospital costs for older seniors with osteoporosis.


Phloem loading and unloading of Cowpea mosaic virus in Vigna unguiculata.
Within their host plants, viruses spread from the initially infected cell through plasmodesmata to neighbouring cells (cell-to-cell movement), until reaching the phloem for rapid invasion of the younger plant parts (long-distance or vascular movement). Cowpea mosaic virus (CPMV) moves from cell-to-cell as mature virions via tubules constructed of the viral movement protein (MP). The mechanism of vascular movement, however, is not well understood. The characteristics of vascular movement of CPMV in Vigna unguiculata (cowpea) were examined using GFP-expressing recombinant viruses. It was established that CPMV was loaded into both major and minor veins of the inoculated primary leaf, but was unloaded exclusively from major veins, preferably class III, in cowpea trifoliate leaves. Phloem loading and unloading of CPMV was scrutinized at the cellular level in sections of loading and unloading veins. At both loading and unloading sites it was shown that the virus established infection in all vascular cell types with the exception of companion cells (CC) and sieve elements (SE). Furthermore tubular structures, indicative of virion movement, were never found in plasmodesmata connecting phloem parenchyma cells and CC or CC and SE. In cowpea, SE are symplasmically connected only to the CC and these results therefore suggest that CPMV employs a mechanism for phloem loading and unloading that is different from the typical tubule-guided cell-to-cell movement in other cell types.


Cystic granulosa cell tumor of the ovary--a case report.
A case of cystic granulosa cell tumor of ovary in a 32 year old woman is described. The patient presented with abdominal mass without any signs and symptoms of hyperestrinism and virilization. Ultrasonographically and grossly a diagnosis of benign cystadenoma was considered. Histopathology confirmed the diagnosis of cystic granulasa cell tumor.


The impact of fertilization on ammonia-oxidizing bacteria and comammox Nitrospira communities and the subsequent effect on N2O emission and maize yield in a semi-arid region.
The control of nitrous oxide (N2O) emissions through nitrification and the optimization of maize yield are important in agricultural systems. However, within the semi-arid region, the impact of fertilization on the function of nitrification communities and its connection with N2O emissions in the rhizosphere soil is still unclear. Our study investigates the influence of fertilization treatments on the communities of ammonia-oxidizing bacteria (AOB) and the complete ammonia oxidizers of the Nitrospira known as comammox (CAOB) in a maize agroecosystem. Nitrous oxide production, potential nitrification activity (PNA), maize yield, and nitrogen use efficiency (NUE) were determined for the same samples. The fertilizer treatments included a control group without fertilization (NA), inorganic fertilizer (CF), organic fertilizer (SM), combined inorganic and organic fertilizer (SC), and maize straw (MS). The SC treatment indicated a lower cumulative N2O emission than the CF treatment in the 2020 and 2021 cropping seasons. The AOB community under the CF, MS, and SM treatments was predominantly composed of Nitrosospira cluster 3b, while the SC treatment was associated with the comammox Nitrospira clade A.1 lineage, related to key species such as Ca. Nitrospira inopinata and Ca. Nitrospira nitrificans. Network analysis demonstrated a positive potential for competitive interaction between hub taxonomy and distinct keystone taxa among AOB and comammox Nitrospira nitrifiers. The structural equation model further revealed a significant positive association between AOB nitrifiers and N2O emission, PNA, soil pH, SOC, NO3--N, and DON under organic fertilization. The keystone taxa in the comammox Nitrospira nitrifier and network Module II exhibited a positive correlation with maize productivity and NUE, likely due to their functional activities stimulated by the SC treatment. It is noteworthy that the AOB community played a more significant role in driving nitrification compared to the composition of comammox Nitrospira. Collectively, combined inorganic and organic fertilizer (SC) treatment exhibits high potential for reducing N2O emissions, enhancing maize productivity, increasing NUE, and increasing the sustainability of the nitrogen dynamics of maize agroecosystems in the semi-arid Loess Plateau.


Manipulating Coherence of Near-Field Thermal Radiation in Time-Modulated Systems.
We show that the spatial coherence of thermal radiation can be manipulated in time-modulated photonic systems supporting surface polaritons. We develop a fluctuational electrodynamics formalism for such systems to calculate the cross-spectral density tensor of the emitted thermal electromagnetic fields in the near-field regime. Our calculations indicate that, due to time-modulation, spatial coherence can be transferred between different frequencies, and correlations between different frequency components become possible. All these effects are unique to time-modulated systems. We also show that the decay rate of optical emitters can be controlled in the proximity of such time-modulated structure. Our findings open a promising avenue toward coherence control in thermal radiation, dynamical thermal imaging, manipulating energy transfer among thermal or optical emitters, efficient near-field radiative cooling, and engineering spontaneous emission rates of molecules.


Neurocognitive performance and symptom profiles of Spanish-speaking Hispanic athletes on the ImPACT test.
This study documented baseline neurocognitive performance of 23,815 athletes on the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) test. Specifically, 9,733 Hispanic, Spanish-speaking athletes who completed the ImPACT test in English and 2,087 Hispanic, Spanish-speaking athletes who completed the test in Spanish were compared with 11,955 English-speaking athletes who completed the test in English. Athletes were assigned to age groups (13-15, 16-18). Results revealed a significant effect of language group (p < .001; partial η(2) = 0.06) and age (p < .001; partial η(2) = 0.01) on test performance. Younger athletes performed more poorly than older athletes, and Spanish-speaking athletes completing the test in Spanish scored more poorly than Spanish-speaking and English-speaking athletes completing the test in English, on all Composite scores and Total Symptom scores. Spanish-speaking athletes completing the test in English also performed more poorly than English-speaking athletes completing the test in English on three Composite scores. These differences in performance and reported symptoms highlight the need for caution in interpreting ImPACT test data for Hispanic Americans.


Effects of trimester-specific and total gestational weight gain on children's anthropometrics.
Gestational weight gain (GWG) has been shown to be a risk factor for overweight in offspring.Aim of this study was to quantify the contributions of trimester-specific and total GWG on offspring's BMI and waist circumference (WC). This is of interest for the design of interventions targeted at women showing a high GWG in early pregnancy. In a retrospective cohort study data on GWG (total and by trimester, exposure), a number of potential confounders, and children's BMI z-scores and WC (outcomes) were analyzed using structural equation models to disentangle the trimester-specific direct effects of GWG and indirect effects mediated via total GWG. 7313 mother child pairs with a children's mean age of 5.81 years were analyzed. Total effects (indirect + direct) of GWG (kg/week) on children's BMI z-score and WC (cm) were observed in all trimesters, most prominently in the second. The longitudinal effect of GWG is a composite of trimester-specific direct effects (on BMI: 0.105, 0.255, 0.002, on WC: 0.538, 1.64, 0.308) and total GWG (on BMI 0.608, on WC: 1.03) at the end of pregnancy. Both trimester-specific priming and total GWG explained offspring's anthropometrics. The results indicate, that reversal from additional weight gain attained early in pregnancy resulting in normal total GWG at the end of pregnancy might still contribute to a substantial reduction of offspring's BMI and WC.


Revisiting Anti-tuberculosis Activity of Pyrazinamide in Mice.
The mechanism of action of pyrazinamide, a key sterilizing drug in the treatment of tuberculosis, remains elusive; pyrazinamide is a pro-drug that requires activation by a bacterial-encoded enzyme, and its activity is most apparent on non-replicating Mycobacterium tuberculosis. Recently, it has been suggested that pyrazinamide might exert also some host-directed effect in addition to its antimicrobial activity. To address this possibility, three sequential experiments were conducted in immune-competent BALB/c and in immune-deficient, athymic nude mice. In the first experiment, BALB/c mice infected with M. bovis, which is naturally resistant to pyrazinamide because it is unable to activate the drug, were treated with standard drug regimens with and without pyrazinamide to specifically detect a host-directed effect. As no effect was observed, pyrazinamide activity was compared in M. tuberculosis-infected BALB/c and nude mice to determine whether the effect of pyrazinamide would be reduced in the immune deficient mice. As pyrazinamide did not appear to have any affect in the nude mice, a third experiment was performed in which rifampin was replaced with rifapentine (a similar drug with a longer half-life) to permanently suppress mycobacterial growth. In these experimental conditions, the antimicrobial effect of pyrazinamide was clear. Therefore, the results of our studies rule out a significant host-directed effect of pyrazinamide in the TB infected host.


Onion skin technique for open surgical replacement of aortic arch following primary endoprothesic thoracic aorta treatment.
Endovascular aortic replacement (EVAR) techniques have become the first choice option for many aortic diseases in patients in whom standard open surgery was contraindicated or with high surgical risk. A secondary open surgical treatment, following a primary EVAR procedure, could, however, be challenging depending on the type, the extension and the position of primary endoprosthesis. Here, we describe an original and easy technique capable of simplifying a secondary aortic arch replacement following EVAR treatment of the descending thoracic aorta. The basic concept of such techniques is similar to that of the conventional 'elephant trunk' technique and is based on an inverted straight tube graft inserted into the endoprosthesis and anastomized using a multi-layer double suture with external strip felt of Dacron.


Intraventricular and brachial artery thrombosis in nephrotic syndrome.
A 23-year-old Saudi female presented with nephrotic syndrome. On renal biopsy she had primary focal and segmental glomerulosclerosis which was resistant to steroids. Two years later she presented with absent left arm pulses and on investigation a diagnosis of left ventricular thrombosis and thromboembolism of left brachial artery was made. Low antithrombin III, high fibrinogen levels and diuretic therapy were the possible causative factors for hypercoagulable state. On anticoagulation therapy initiated with heparin and continued with warfarin for 8 weeks there was complete dissolution of intraventricular and improvement of left brachial artery thrombosis. An early diagnosis and treatment of this potentially serious complication of nephrotic syndrome are stressed.


Parallel or serial activation of word forms in speech production? Neurolinguistic evidence from an aphasic patient.
We report the oral picture naming performance of the German aphasic MW who presented with frequent meaning related word substitutions (e.g. tiger ==> lion) and word finding blockings (omissions) while his phonological capacities at the single word level were nearly preserved. Targets were controlled for their 'semantic competitiveness', that is, whether there exist closely meaning related lexical competitors or not. Semantic errors were far more numerous with the highly competitive targets than with the low competitive ones. However, omissions were more frequent with the low competitive items so that the sum of the semantic errors and of the omissions was comparable in both conditions. This inverse and compensatory relationship suggests that both error types are not mutually independent. The found pattern is at odds with serial psycholinguistic theories which locate word selection (and misselection) and word form access (and blockings) at different and serially connected stages of word production but supports theories which allow for a parallel architecture in lexical activation and selection involving the word form level.


Physicians underutilize topical retinoids in the management of acne vulgaris: analysis of U.S. National Practice Data.
Topical retinoids are effective in the treatment of acne, yet no current guidelines existed in the literature until recently recommending their use as an integral part of mild to moderate acne treatment. To assess whether underutilization of topical retinoids occurs in clinical practice. Weighted data on representative office visits with acne vulgaris diagnoses were analyzed using the National Ambulatory Medical Care Survey (NAMCS), from 1990 to 1999. Of the 54.2 million acne vulgaris visits, retinoids were prescribed at 35.3% visits. Dermatologists prescribed significantly more retinoids than non-dermatologists (39.4%' versus 23%). Dermatology visit was a significant predictor of topical retinoid prescription (RR: 2.27,95% CI: 1.63-3.17). Data suggest that prescribing retinoids for acne has been increasing over the past decade, primarily among dermatologists. There is a major difference between suggested treatment guidelines for acne and actual practice in the community. There is distinct under-utilization of topical retinoids for treatment of acne vulgaris by dermatologists and non-dermatologists.


Effects of 5-fluorouracil, adriamycin and irinotecan on HSC-39, a human scirrhous gastric cancer cell line.
Therapies for patients with scirrhous gastric cancer remain ineffective. Current treatments for gastric cancer based on systemic therapy, such as the combination of S-1 with cisplatin or docetaxel, show good clinical response rates. S-1 plus cisplatin is the standard treatment for HER2-negative advanced scirrhous gastric cancer in Japan. In spite of recent advances in the treatment of gastric cancer, a standard chemotherapy regimen is yet to be established for scirrhous gastric cancer. To develop new therapeutic approaches based on characteristic biological features of cancer cells, we examined the mechanisms underlying the cytotoxicity of anticancer drugs and reactive oxygen species (ROS) toward a human scirrhous cancer cell line, HSC-39, in vitro. Anticancer drugs such as 5-fluorouracil (5-FU), adriamycin (ADR) and irinotecan (CPT-11), as well as ROS, were previously shown to have important cytotoxic effects on these tumor cells. We demonstrated that 5-FU effectively induced apoptosis in HSC-39 cells in a dose‑dependent manner, while ADR and CPT-11 induced necrosis and/or aponecrosis. 5-FU effectively inhibited WST-1 decrease in the MTT viability assay, even at low doses where little LDH release was observed, while ADR and CPT-11 only inhibited WST-1 decrease at high doses where LDH release was induced. Moreover, HSC-39 cells showed high sensitivity to H2O2 and NOC-18, but less sensitivity to other ROS, suggesting a link between cell damage and membrane permeability changes induced by H2O2 and NOC-18 or related oxygen radical species such as OH· or ·O2. These results suggest that combination treatment of chemotherapeutics with a fluoropyrimidine such as 5-FU is effective chemotherapy for scirrhous gastric cancer.


Development and Psychometric Testing of the Caregiver Communication Competence Scale in Patients With Dementia.
Appropriate communication skills are essential for understanding patient needs, particularly those of patients with dementia. Assessing health care providers' competence in communicating with patients with dementia is critical for planning a communication education program. However, no formally established scale can be used. The purpose of the current study was to develop a valid and reliable instrument for determining the communication competence of health care providers with patients with dementia. Through use of a literature review and previous clinical experience, an initial 28-item scale was developed to assess the frequency of use of each item by health care providers. Fourteen items were extracted and three factors were distinguished. Results indicated that the internal consistency reliability of the 14-item scale was 0.84. Favorable convergent and discriminant validities were reached. The communication competence scale provides administrators or educators with a useful tool for assessing communication competence of health care providers when interacting with patients with dementia so a suitable education program can be planned and implemented.


Comparison of contrast-enhanced SPACE and CISS in evaluating cavernous sinus invasion by pituitary macroadenomas on 3-T magnetic resonance.
SPACE (sampling perfection with application-optimized contrasts by using different flip angle evolutions) and CISS (constructive interference in steady state) are 3-dimensional sequences that can increase the signal intensity of cavernous sinus. The purpose of this study was to determine whether contrast-enhanced (CE) SPACE and CE CISS can well demonstrate cavernous sinus invasion (CSI) by pituitary macroadenoma and which one performed better. In 56 cavernous sinuses from 28 patients with pituitary macroadenoma, CSI grades and image quality were assessed by using CE SPACE and CISS. The assessment results were compared with Knops' classification on T1-weighted images. The interreader agreement of assessment results were analyzed with k statistics. Qualitative analyses were compared using the Wilcoxon signed-ranks test. Two radiologists were in substantial agreement of CSI evaluation on both CE SPACE (k = 0.87) and CE CISS (k = 0.83). The evaluation results on CE SPACE (k = 0.76) were more coincident with Knops' classification than CE CISS (k = 0.71). Identification of CSI worked well with either CE SPACE or CE CISS, but CE SPACE performed better (mean, 3.48 ± 0.61 vs 3.28 ± 0.80; P < 0.05). Contrast-enhanced SPACE had significantly higher image scores than CE CISS in description of the relationship between pituitary adenoma and internal carotid artery (mean, 3.26 ± 0.93 vs 2.96 ± 1.01; P < 0.05). Contrast-enhanced CISS demonstrated more susceptibility artifacts (10.7% vs 0%; P < 0.05) and vessel flow artifacts (53.6% vs 0%; P < 0.05). There was no significant difference regarding contrast enhancement of pituitary adenoma and cavernous sinus (mean, 3.07 ± 1.12 vs 3.04 ± 0.96; P > 0.05). Contrast-enhanced SPACE is superior than CE CISS for identification of CSI by pituitary macroadenoma.


Attenuation of petroleum hydrocarbons by weathering: a case study.
Possible alterations in the distribution and composition of total petroleum hydrocarbon (TPH), polycyclic aromatic hydrocarbons (PAHs), and benzene, toluene, ethyl benzene, and xylene isomers (BTEX) in the released oil at Idu-Ekpeye in Niger Delta (Nigeria) were studied within two seasonal variations of two months and six months, with a view to assessing the level of attenuation of these hydrocarbons in impacted soils. Although there were significant contaminations in the kerosene range (n-C10-n-C14) two months after, especially of the n-C12 and n-C13 fractions, the complete disappearance of the n-C8 to n-C23 hydrocarbons, including the acyclic isoprenoids (pristane and phytane), and the reduced amounts of PAHs, and BTEX, six months after, provided substantial evidence of attenuation as indicated in the reduction in total hydrocarbon content (THC) from 61.17 to 42.86%. Soil physicochemical properties such as pH, moisture content, heavy metal, TOC, and TOM, all provided corroborative evidence of hydrocarbon attenuation. The pristane/phytane ratio of the spill samples suggests that the spilled oil was genetically oxic.


Prison homosexuality and its effect on post-prison sexual behavior.
Although there has grown up to a considerable literature on sex experiences in prison, little has been written on the post-prison behavioral patterns of those who, voluntarily or involuntarily, become initiated into homosexuality while incarcerated. In the light of the considerable number of prisoners and ex-prisoners in the original Kinsey sample, it is possible that the Institute for Sex Research might have in its files material that would shed light on this problem. To date, nothing has been forthcoming. In one of the few references to the subject, Kirkham (1972, p. 42) suggests that sexual experiences in prison may have permanent effects on the lives of some of the participants: "Can such men return to conventional heterosexual lives after release, or has the experience of being forced into acts of passive homosexuality been so traumatic as to preclude the resumption of sexual relations with members of the opposite sex?" In a search for an answer to his question, the present paper studies ex-prisoners whose initiation into homosexuality occurred during prison.


A NMR-compatible and reduced gravity simulation based (NRG) bioreactor for on-line monitoring cell culture metabolism.
We developed a NMR-compatible microgravity-based bioreactor (NRG[R]) that offers the advantage of an analytical non-invasive approach associated to the effects of an optimized suspension culture. The simulated microgravity conditions reached in the bioreactor are analogous to those of commercial apparatus like the Rotating Wall Vessel (RWV) system. The faster proliferation of endothelial cells cultured in the NRG bioreactor (doubling time : 28 +/- 1.7 vs. 43 +/- 5.6 h of the control grown in RWV) are attributed to different oxygenation conditions and medium wash out.


Heart transplantation. Four years' experience with conventional immunosuppression.
This article describes four years' experience with heart transplantation using conventional immunosuppression. Twenty of 32 patients are alive. The one-year survival rates were 75% (1979), 67% (1980), and 75% (1981). Actuarial survival rates for operative survivors were 70% at one year, 60% at two years, and 51% at three years. Patients in the 50- to 55-year age group have survived as well as younger recipients. Rejection resulted in six deaths, infection in three, donor heart failure in two, and multiple organ failure in one. There were 1.5 acute rejections per patient and one infection per patient in the first three posttransplant months. Postoperative hospital stay averaged 62 days and cost a total of $58,351.


Simulation of transient thermal stress in gypsum-bonded investment.
The aim of this study was to clarify the effect of heating rate on the development of both transient and residual stresses in investment molds. Solid, cylindrical, gypsum-based molds were modeled and theoretical calculations made of temperature distributions with a constant heating rate. These calculations used experimental thermal diffusivity data obtained with a laser flash method. The simulations calculated transient thermal stresses during heating and at the end of heating for two surface conditions: an unrestricted surface, and a surface restricted by a casting ring. The simulation model developed nonuniform strains and stresses at casting temperature; tangential stress was compressive at the surface and tensile at the mid-point for the unrestricted surface model. The surface restricted model developed compressive tangential stresses throughout the mold at the casting temperature. This resulted in significant thermal strain differences compared to the magnitudes of expansion of the mold due to heating.


Modern approaches to understanding stress and disease susceptibility: A review with special emphasis on respiratory disease.
Studies in animals and humans link both physical and psychological stress with an increased incidence and severity of respiratory infections. For this manuscript we define stress as the physiological responses an individual undergoes while adjusting to a continually changing environment. It is known that stressors of various types (psychological/physical) can alter the physiological levels of certain hormones, chemokines and cytokines. These alterations send information to the central nervous system to take necessary action which then sends messages to appropriate organs/tissues/cells to respond. These messages can either activate or suppress the immune system as needed and failure to compensate for this by the body can lead to serious health-related problems. Little is known how stress affects disease susceptibility, yet understanding this mechanism is important for developing effective treatments, and for improving health and food quality. The current review focuses on (a) the effects of psychological stressors in humans and animals, (b) various methodologies employed to understand stress responses and their outcomes, and (c) the current status of the attempts to correlate stress and disease with respiratory disease as model system. The methodologies included in this review span traditional epidemiological, behavioral and immunological studies to current high throughput genomic, proteomic, metabolomic/metabonomic approaches. With the advent of various newer omics and bioinformatics methodologies we postulate that it will become feasible to understand the mechanisms through which stress can influence disease onset. Although the literature in this area is limited because of the infancy of this research area, the objective of this review is to illustrate the power of new approaches to address complex biological questions. These new approaches will also aid in our understanding how these processes are related to the dynamics and kinetics of changes in expression of multiple genes at various levels.


Proximal femoral nail antirotation internal fixation in treating intertrochanteric femoral fractures of elderly subjects.
This study compared the effect of dynamic hip screw (DHS) and proximal femoral nail anti-rotation (PFNA) in the treatment of intertrochanteric femoral fractures of elderly subjects and evaluated the effect of PFNA internal fixation. Two hundred and sixteen elderly patients with intertrochanteric femoral fracture who received treatment in Binzhou Medical University Hospital, Shandong, China were selected. They were divided into a PFNA group which adopted PFNA for internal fixation and a DHS group which adopted DHS for internal fixation, 108 cases in each group. The physical condition of the patients in the two groups were recorded on admittance. The fracture was typed according to Evans-Jensen classification criteria. Patients were followed up after surgery to evaluate the postoperative recovery and Harris score of hip joint function. Except for the length of hospital stay, the length of incision, interoperative blood loss, volume of drainage and duration of operation of the PFNA group were all superior to those of the DHS group (P less than 0.05); the incidence of postoperative complications of the PFNA group was lower than that of the DHS group (P less than 0.05); the early Harris score of the treatment was superior to that of the DHS group, and there was no remarkable difference (P>0.05). PFNA has more advantages than DHS in treating intertrochanteric femoral fracture of the elderly; hence it is worth wide application in clinical use.


Foreign body granuloma mimicking recurrent intracranial tumor: a very rare clinical entity.
Gelatin sponge, oxidized cellulose and microfibrillar collagen are used to achieve hemostasis during neurosurgical procedures. Hemostatic agents may produce clinically symptomatic, radiologically apparent mass lesions. The differential diagnosis should include the foreign body along with recurrent tumor. We present a case of intracranial hemostatic agents found in a 56-year-old male patient seven years after undergoing a craniotomy for a left posterior parietal convexity meningioma. Preoperative magnetic resonance imaging (MRI) suggested the presence of a recurrent tumor. We emphasize that although it is rare, a granuloma due to a foreign body reaction can result in a false image of tumor recurrence.


Fragile-X syndrome in east Finland: molecular approach to genetic and prenatal diagnosis.
Fragile X is the most common inherited form of mental retardation, having an incidence of one in 1,250 males. The fragile X syndrome results from amplification of the CGG repeat found in the fragile X mental retardation-1-gene (FMR-1). This CGG repeat shows length variation in normal individuals and is increased significantly in both carriers and patients. Non-retarded carriers of both sexes can be detected reliably only by direct DNA analysis of the fra(X) mutation. Here we investigate fragile X families using the intragenic probes St.B 12.3 and St.B 12.3 XX (J-L Mandel). Fragile X syndrome could be verified in 51 families of the population of 900,000 in East-Finland during 1989-92. The index cases of the syndrome were found by the help of health care personnel, 463 relatives of these families consented to be tested for the mutation of the FMR-1 gene. Ninety-three relatives with the full mutation and 127 healthy carriers with the premutation of the fragile X syndrome were diagnosed. In addition, 28 decreased males were obligate carriers. During the year 1992 prenatal diagnosis for fragile X was carried out in nine pregnancies. For understanding of the occurrence of fragile X syndrome and for better prevention of this syndrome in next generations, systematic genetic counseling and carrier screening in these families is essential.


Measurement of Sub-femtomolar Concentrations of Prostate-Specific Antigen through Single-Molecule Counting with an Upconversion-Linked Immunosorbent Assay.
Single-molecule (digital) immunoassays provide the ability to detect much lower protein concentrations than conventional immunoassays. As photon-upconversion nanoparticles (UCNPs) can be detected without optical background interference, they are excellent labels for so-called single-molecule upconversion-linked immunosorbent assays (ULISAs). We have introduced a UCNP label design based on streptavidin-PEG-neridronate and a two-step detection scheme involving a biotinylated antibody that efficiently reduces nonspecific binding on microtiter plates. In a microtiter plate immunoassay, individual sandwich immune complexes of the cancer marker prostate-specific antigen (PSA) are detected and counted by wide-field epiluminescence microscopy (digital readout). The digital detection is 16× more sensitive than the respective analogue readout and thus expands the limit of detection to the sub-femtomolar concentration range (LOD: 23 fg mL-1, 800 aM). The single molecule ULISA shows excellent correlation with an electrochemiluminescence reference method. Although the analogue readout can routinely measure PSA concentrations in human serum samples, very low concentrations have to be monitored after radical prostatectomy. Combining the digital and analogue readout covers a dynamic range of more than 3 orders of magnitude in a single experiment.


Evidence for a role of oxytocin receptors in the long-term establishment of dominance hierarchies.
Exposure to stress can affect the establishment of dominance hierarchies. In our model, a social hierarchy established by two male rats during a first encounter is not maintained 1 week later. If one of the two rats is stressed, the stressed rat becomes subordinate and the hierarchy that is formed is maintained. In this study, we investigated the changes in the expression of oxytocin (Otr) and vasopressin (V1aR) receptor genes in the medial amygdala (MeA) and the lateral septum (LS) in the hours following hierarchy establishment under both stressed and basal conditions. We found that the potentiation of a social hierarchy induced by stress is accompanied by social status- and region-specific changes in the expression of Otr mRNA in the MeA 3 h after the social encounter. At this time point, no evidence was found for the regulation of V1aR mRNA in any of the brain regions examined. Results from pharmacological experiments involving the microinfusion of a specific OTR antagonist immediately after the acquisition of a subordinate status under basal, non-stress conditions suggested a role for this receptor in the MeA on the long-term establishment of the subordinate status. Altogether, these findings highlight a role for the oxytocinergic system in the mechanisms through which stress facilitates the long-term establishment of a social hierarchy.


Searching the web: a survey on the quality of advice on postnatal sequelae of intrauterine growth restriction and the implication of developmental origins of health and disease.
Intrauterine growth restriction (IUGR) and fetal growth restriction (FGR) are pregnancy complications associated with morbidity in later life. Despite a growing body of evidence from current research on developmental origins of health and disease (DOHaD), little information is currently provided to parents on long-term metabolic, cardiovascular and neurologic consequences. As parents strongly rely on internet-based health-related information, we examined the quality of information on IUGR/FGR sequelae and DOHaD in webpages used by laypersons. Simulating non-clinicians experience, we entered the terms 'IUGR consequences' and 'FGR consequences' into Google and Yahoo search engines. The quality of the top search-hits was analyzed with regard to the certification through the Health On the Net Foundation (HON), currentness of cited references, while reliability of information and DOHaD-related consequences were assessed via the DISCERN Plus score (DPS). Overall the citation status was not up-to-date and only a few websites were HON-certified. The results of our analysis showed a dichotomy between the growing body of evidence regarding IUGR/FGR-related sequelae and lack of current guidelines, leaving parents without clear directions. Furthermore, detailed information on the concept of DOHaD is not provided. These findings emphasize the responsibility of the individual physician for providing advice on IUGR/FGR-related sequelae, monitoring and follow-up.


[The value of roentgen pictures in rheumatoid arthritis].
Rheumatoid arthritis leads to many abnormalities in radiographs as a result of irreversible destruction of cartilage or underlying bone. Radiographs of hands and feet provide the most useful information. Erosions and joint space narrowing in particular can be assessed reliably, and give a good impression of the destruction of the joints. Several validated scoring methods are available to assess the severity and progression of joint damage. Abnormalities are already present shortly after onset of the disease. About 70% of the patients develop erosive disease and in the majority of the cases erosions are present one year after onset. Patients who are rheumatoid factor positive in particular develop erosions. Damage occurs earlier and is often more severe in the joints of the feet than in joints of the hands. The early occurrence of irreversible joint destruction and the availability of treatment effective in reducing this damage necessitates early treatment of patients with RA.


Highly selective synthesis of functionalized polyhydroisoquinoline derivatives via a three-component domino reaction.
Two series of novel functionalized polyhydroisoquinoline derivatives have been synthesized via the three-component domino reaction of glutaraldehyde and malononitrile with a series of β-ketoamides under microwave irradiation conditions in the presence of a catalytic amount of Et3N (10 mol%). This reaction represents the first reported process for the facile conversion of a β-ketoamide to a hydroisoquinoline via a C-N bond cleavage reaction without the need for a multistep reaction process.


Self-Continuity Moderates the Association Between Peer Victimization and Depressed Affect.
Two longitudinal studies conducted with early adolescents (ages 10-13) examined the hypothesis that self-continuity, or the degree to which individuals feel that they remain the same person over time regardless of how their specific characteristics may change, would moderate the association between victimization and depressed affect. Both Study 1 (N = 141) and Study 2 (N = 100) provided evidence of the moderating role of self-continuity as a buffer on the effect of peer victimization. Study 2 confirmed that self-continuity had a moderating effect after controlling for academic performance, number of friends, self-esteem, self-concept clarity, hopelessness, and self-blame. Findings support self-continuity as being protective with regard to negative peer environments.


HER2 Mutations in Non-Small Cell Lung Cancer: A Herculean Effort to Hit the Target.
Over the last two decades HER2 aberrations have been thoroughly investigated as potential therapeutic targets in advanced non-small cell lung cancer, with relatively modest results. Two articles published in this issue of Cancer Discovery further expand the knowledge on therapeutic exploitation of HER2 in lung cancer, addressing a large unmet medical need.See related article by Li et al., p. 674.See related article by Tsurutani et al., p. 688.


Maffucci's syndrome: a case report.
Maffucci's syndrome is a congenital nonhereditary syndrome characterized by a combination of enchondromatosis and hemangiomatosis. It is associated with an increased risk of malignancy. We report a case of a 24-year-old woman who developed severe bone distortion due to generalized enchondromas since the age of 2 years. Physical examination showed a marked shortening of both upper and lower limbs and cutaneous hemangioma in the legs. Radiological study showed symmetric well-circumscribed radiolucent cystic lesions in the hands and severe metaphysical irregularity and a shortening of all long bones. The biopsy of the third right metacarpal showed enchondroma tissue. Histological examination of the skin specimen showed a hemangioendothelioma. The diagnosis of Maffucci's syndrome was established. Abdominal ultrasound, mammography, cerebral computed tomography (CT) scan, and cervical CT were normal.


Structural transformation of apocytochrome c induced by alternating copolymers of maleic acid and alkene.
Apocytochrome c interacts with two copolymers: poly(isobutylene-alt-maleic acid) (PIMA) and poly(1-tetradecene-alt-maleic acid) (PTMA). The interaction leads to apocytochrome c, a conformational change from random coil to alpha-helical structure. The alpha-helix content is influenced by the copolymer concentration, the length of alkyl chain of the copolymers, and pH of the medium. The electrostatic attraction between the copolymer and protein is an indispensable factor for the folding of the protein at acid pH. The hydrophobic interaction is an important factor over the entire pH range, especially when both the copolymer and protein carry negative charges at alkaline pH. The electrostatic and hydrophobic attractions between the copolymer and protein exclude water molecules, promoting the formation of hydrogen bonds within the helical structure. On the other hand, the hydrogen bonds formed between the ionized carboxyl of the copolymer and the amide of the protein partly restrain the formation of hydrogen bonds within the helical structure when the copolymer concentration is higher at pH 6.5 and 10.5.


Sphere-rod morphogenesis in Arthrobacter crystallopoietes. II. Peptides of the cell wall peptidoglycan.
Cell walls of Arthrobacter crystallopoietes grown as spheres and as rods were solubilized by treatment with the B enzyme from Chalaropsis, an N-acetylmuramidase. The neutral glycopeptides were then isolated by chromatography on ECTEOLA cellulose. The glycopeptides, consisting of disaccharide-peptide units interlinked by peptide cross-bridges, were fractionated by gel filtration on Sephadex columns into oligomers of various sizes. The size distribution ranged from monomers with no cross-bridges to polymers with a high degree of polymerization, but did not differ significantly between cell walls from cells grown as spheres or rods. Some small differences in the distribution of C- and N-terminal amino acids were found. Analyses revealed that all the peptide bridges in the glycopeptide fractions from rod cell walls were formed by one l-alanine residue. In sphere cell walls, l-alanine was also found, but, in addition, higher oligomers of the glycopeptide contained glycine in their cross-bridges. These results were confirmed by determinations of C- and N-terminal amino acids released after lysostaphin and AL-1 enzyme digestions and by Edman degradations. Models representing the structures of the sphere and rod cell walls are presented. These structures indicate that the sphere cell wall is probably a more loosely knit macromolecule than is the rod cell wall.


An Analysis of Pediatric Dentistry Residents' Productivity in the Operating Room.
To analyze productivity of pediatric dental residents (PDRs) in the operating room (OR) and to determine predictors of case length. Service-mix for OR cases completed between 2010 and 2013 were converted to relative value units (RVUs). Additional information, including patients' age, gender, American Society of Anesthesiologists (ASA) status, number of teeth, and operation time was retrieved. Analysis entailed descriptive, correlational, and multivariable techniques. Eight PDRs completed 893 OR cases. First-year residents (FYRs) completed more complex cases than second-year residents (SYRs), as determined by total RVUs and number of teeth. However, SYRs were more productive, as determined by RVUs per minute. Productivity for all PDRs increased on average by 33 percent during the program, with an average of 0.39 versus 0.59 RVUs per minute during the first versus the last quarters. Case complexity - measured in total RVUs per case - was associated with number of teeth and operation time, while patients' age and ASA status were not significantly associated with case complexity in the final regression model. Clinical productivity of PDRs increased over the two-year period, with a wide variation demonstrating a differential learning curve on different individuals. A significant association between case complexity, number of teeth, and operation time was found.


Anti-digoxin antibody in digoxin intoxication.
This study was conducted to investigate the action of anti-digoxin antibody in digoxin intoxication. Anti-digoxin antibody was raised in sheep and administered to six dogs following intravenous infusion of digoxin (0.04 or 0.16 mg/kg body weight), either as whole serum or as partially purified gamma globulin. Plasma and urine digoxin levels, both bound and free, were determined on serial samples. Myocardial samples were analysed for digoxin content. Comparisons were made with six dogs given digoxin but no antibody. The results indicate that anti-digoxin antibody is effective through inactivation of digoxin in myocardium and removal of digoxin from myocardium into plasma. Loss of digoxin in urine is not responsible for toxicity reversal.


Medullary Thyroid Cancer: Clinical Characteristics and New Insights into Therapeutic Strategies Targeting Tyrosine Kinases.
Medullary thyroid carcinoma (MTC) is a hyperplasia of thyroid C-cells, accounting for 5-10% of all thyroid cancers. MTCs may appear as sporadic or hereditary forms, and several molecules and signaling pathways have been found to function defectively in MTC cells. Tyrosine kinases are the most well-studied molecules that have abnormal function in these tumor cells. Due to their limited response, chemotherapeutic agents and radiation therapy are not effective in treating patients with advanced metastatic MTC. In the past decade, significant attention has been given to the utilization of multikinase inhibitors as targeted therapeutic agents for treating MTC patients, with the most promising results arising from the study of tyrosine kinase inhibitors, which generally bind to the ATP binding sites of these kinases. Two drugs-vandetanib and cabozantinib-are approved for the treatment of aggressive advanced MTC; however, the potential for toxicities and adverse effects of these agents on patient quality of life need to be considered against any therapeutic gain. According to recent data, it appears that inhibition of only one receptor or molecule in a pathway is not as effective as simultaneous inhibition of different pathways, indicating the need to use combination therapy. The main purpose of this review is to describe the clinical characteristics, molecular mechanisms, and current molecular and targeted therapeutic strategies active in clinical trials for advanced MTC treatment.


Cystic hamartoma of the lung: report of two cases.
Two cases of cystic pulmonary hamartoma are reported with the clinical, roentgenographic and histopathologic findings. Both patients were asymptomatic, and the lesions were discovered on routine chest roentgenography. Physical examination and laboratory data revealed no significant abnormal findings, but CT scans of the chest showed cystic change in both lesions. The histopathologic pictures of the lesions were characterized by a composition of glandular bronchiolar structures lined with ciliated cuboid epithelium and fibrous connective tissue. One case demonstrated interlacing, communicating bands and whorls of smooth spindle muscle cells with elongated nuclei and rounded blunt ends. Neither the epithelial, nor muscular fibrous tissue elements exhibited any degree of anaplasia. The two patients were followed up for 10 months and 3 years, respectively. They both showed no signs of recurrence or distant metastasis.


Increased plasma norepinephrine in young patients with essential hypertension under three sodium intakes.
Increased sympathetic nerve activity may play an important role in the pathogenesis of essential hypertension. It is well known that both dietary sodium intake and age influence the plasma norepinephrine (NE) concentration. The present study was undertaken to evaluate the effects of age on sympathetic nerve activity in patients with essential hypertension and normal control subjects under low-, regular-, and high-sodium regimens (mean 24-hour sodium excretions: 30 +/- 4, 116 +/- 7,280 +/- 15 mEq, respectively). Plasma NE and epinephrine (E) were analyzed by trihydroxyindole methods after high-performance liquid chromatography separation. Subjects were categorized by age into young (less than or equal to 40 yrs), middle-aged (40-60 years), and old (greater than or equal to 60 years) subgroups. Mean plasma NE in hypertensive patients was significantly higher (p less than 0.01) than in normal subjects on each of the sodium regimens. In normal control subjects, there was a significant positive correlation between age and plasma NE with all three sodium intakes. However, no correlation was seen in hypertensive patients on any of the sodium regimens, because in the young subgroup of hypertensive patients the mean plasma NE was significantly higher than that of normal control subjects. These results suggest that the increased sympathetic nerve activity plays an important role in the pathogenesis of essential hypertension, especially in young patients.


The human c-fos serum response factor and the yeast factors GRM/PRTF have related DNA-binding specificities.
One of the elements that mediates growth factor and serum inducibility of the human c-fos gene is a region of dyad symmetry that lies between nucleotides -320 and -299 of the human gene. A mammalian protein specifically binds to this sequence element and has been termed the serum response factor (SRF). Gel-shift analysis and competition experiments demonstrate that there is a factor in the yeast Saccharomyces cerevisiae that binds specifically to the human c-fos SRE. The methylation interference pattern of the yeast factor is identical to that of the mammalian SRF. Regulatory elements of cell-type-specific genes in yeast have homologies to the c-fos SRE and complete for binding of both the mammalian and yeast factors to the SRE. Antisera to the gene product of the MCM1 locus react with the yeast SRE-binding factor. These data suggest that this yeast protein is closely related or identical to the factors [general regulator of mating type (GRM) and pheromone/receptor transcription factor (PRTF)] that are required for the regulation of cell-type-specific genes in yeast.


[SLC25A13 gene mutations in Chinese infants with intrahepatic cholestasis and abnormal blood amino acids].
To explore whether SLC25A13 gene mutation exists and what is its mutation spectrum in mainland Chinese infants with intrahepatic cholestasis and abnormal blood amino acids. Blood amino acids were analyzed by mass chromatographic analysis in infants referred to Fudan University Children's Hospital from June 2003 to June 2007 for investigations of intrahepatic cholestasis of unknown origin. SLC25A13 gene mutations were studied in 14 children whose serum levels of citrulline and/or methionine were at least two times above the upper normal range. In patients in whom only one mutation was detected, all other exons and their neighboring sequences were then analyzed. Eight patients with SLC25A13 gene mutations, including 2 with compound heterozygous mutation 851del4/1638ins23, one with homozygous mutation 851del4/851del4, one with compound heterozygous mutation 851del4/R184X, one with homozygous mutation IVS6+1G more than A/IVS6+1G more than A, and 3 with heterozygous mutation 851del4 were found. SLC25A13 gene mutations exist in Chinese infants with intrahepatic cholestasis and abnormal blood amino acids. Their mutation spectrum is different from that in Japan. 851del4 is the most common mutation in our study. IVS6+1G more than A is a mutation that has not been reported before.


4,4'-Methylenebis{N-[(E)-quinolin-2-yl-methylidene]aniline}.
The title compound, C(33)H(24)N(4), was prepared by the reaction of a bifunctional aromatic diamine (4,4'-diamino-diphenyl-methane) and an aldehyde (quinoline-2-carboxaldhyde). The mol-ecule consists of two nearly planar (or r.m.s. deviation = 0.017 Å) 4-methyl-N-[(E)-quinolin-2-yl-methyl-idene]aniline moieties, which are linked by the methyl-ene group. The angle between the mean planes of the two benzene rings connected to the methyl-ene group is 77.86 (11)°.


The role of the clinician in the multi-omics era: are you ready?
Since Garrod's first description of alkaptonuria in 1902, and newborn screening for phenylketonuria introduced in the 1960s, P4 medicine (preventive, predictive, personalized, and participatory) has been a reality for the clinician serving patients with inherited metabolic diseases. The era of high-throughput technologies promises to accelerate its scale dramatically. Genomics, transcriptomics, epigenomics, proteomics, glycomics, metabolomics, and lipidomics offer an amazing opportunity for holistic investigation and contextual pathophysiologic understanding of inherited metabolic diseases for precise diagnosis and tailored treatment. While each of the -omics technologies is important to systems biology, some are more mature than others. Exome sequencing is emerging as a reimbursed test in clinics around the world, and untargeted metabolomics has the potential to serve as a single biochemical testing platform. The challenge lies in the integration and cautious interpretation of these big data, with translation into clinically meaningful information and/or action for our patients. A daunting but exciting task for the clinician; we provide clinical cases to illustrate the importance of his/her role as the connector between physicians, laboratory experts and researchers in the basic, computer, and clinical sciences. Open collaborations, data sharing, functional assays, and model organisms play a key role in the validation of -omics discoveries. Having all the right expertise at the table when discussing the diagnostic approach and individualized management plan according to the information yielded by -omics investigations (e.g., actionable mutations, novel therapeutic interventions), is the stepping stone of P4 medicine. Patient participation and the adjustment of the medical team's plan to his/her and the family's wishes most certainly is the capstone. Are you ready?


Regulatory dendritic cells program B cells to differentiate into CD19hiFcγIIbhi regulatory B cells through IFN-β and CD40L.
Regulatory dendritic cells (DCs) play important roles in the induction of peripheral tolerance and control of adaptive immune response. Our previous studies demonstrate that splenic stroma can drive mature DCs to proliferate and further differentiate into a unique subset of CD11b(hi)Ia(low) regulatory DCs, which could inhibit T-cell response, program generation of immunosuppressive memory CD4 T cells. However, the effect of regulatory DCs on B-cell function remains unclear. Here, we report that regulatory DCs can induce splenic B cells to differentiate into a distinct subtype of IL-10-producing regulatory B cells with unique phenotype CD19(hi)FcγIIb(hi). CD19(hi)FcγIIb(hi) B cells inhibit CD4 T-cell response via IL-10. CD19(hi)FcγIIb(hi) B cells have enhanced phagocytic capacity compared with conventional CD19(+) B cells, and FcγRIIb mediates the uptake of immune complex by CD19(hi)FcγIIb(hi) B cells. We found that regulatory DC-derived IFN-β and CD40 ligand are responsible for the differentiation of CD19(hi)FcγIIb(hi) B cells. Furthermore, an in vivo counterpart of CD19(hi)FcγIIb(hi) B cells in the spleen and lymph nodes with similar phenotype and regulatory function has been identified. Our results demonstrate a new manner for regulatory DCs to down-regulate immune response by, at least partially, programming B cells into regulatory B cells.


Oxidative Aromatization of 3,4-Dihydroquinolin-2(1 H)-ones to Quinolin-2(1 H)-ones Using Transition-Metal-Activated Persulfate Salts.
Inorganic persulfate salts were identified as efficient reagents for the oxidative aromatization of 3,4-dihydroquinolin-2(1 H)-ones through the activation of readily available transition metals, such as iron and copper. The feasible protocol conforming to the requirement of green chemistry was utilized in the preparation of the key intermediate (7-(4-chlorobutoxy)quinolin-2(1 H)-one 2) of brexpiprazole in 80% isolated yield on a 100 g scale, and different quinolin-2(1 H)-one derivatives with various functional groups were demonstrated in 52-89% yields.


Characterisation of cauliflower mosaic virus DNA sequences which encode major polyadenylated transcripts.
Cauliflower mosaic virus DNA sequences which encode two major polyadenylated RNA species, the 1.9 kb messenger RNA for the 62,000 MW virus inclusion body polypeptide and 35S RNA, were mapped using the nuclease 51 procedure. The 1.9 kb RNA has an eleven nucleotide leader sequence transcribed from alpha-strand DNA located at co-ordinate 0.72 m.u. (map units), immediately upstream of the AUG initiation codon of reading frame VI. The 3'-end of 1.9 kb RNA maps at 0.95 m.u. and is co-terminal with the 3'-end of 35S RNA, a complete transcript of the DNA alpha-strand. The 5'-end of 35S RNA maps at 0.93 m.u. and is located upstream of the discontinuity G1 (zero m.u.) in the alpha-strand and some 200 nucleotides upstream of the sequence encoding its own 3'-terminus.


Indications for Rituximab Use in an Integrated Health Care Delivery System.
Rituximab is a top-selling biologic that was first approved by the FDA in 1997 for a non-Hodgkin lymphoma orphan indication. It has since been approved for additional orphan indications, with rheumatoid arthritis as the only FDA-approved, nonorphan indication. Evidence suggests that rituximab is frequently used off-label, but information on its use over time and indications for use in the United States is limited. To assess incident rituximab use over time in an integrated health care delivery system. This was a cross-sectional, retrospective study. Data were collected from administrative databases and manual chart reviews. Patients who received their first rituximab infusion between October 1, 2009, and December 31, 2017, and who were not a part of a clinical trial were included. Indication for use (FDA-approved orphan/nonorphan, off-label) was determined. Proportions of use were assessed over time. Multivariable logistic regression modeling was performed to assess factors associated with receiving rituximab for an FDA-approved indication. A total of 1,674 patients were included. The majority (66.4%) of patients had an FDA-approved indication, with lymphoma being the most common approved indication (66.4%). The most common indication for off-label use was neurologic conditions (72.7%), predominantly demyelinating diseases. Off-label indication use increased from 1.2% in 2009 to 55.6% in 2017. Factors associated with rituximab use for an FDA-approved indication included increased age (adjusted odds ratio [AOR] = 1.05, 95% CI = 1.04-1.07) and increased burden of chronic disease (chronic disease score: AOR = 1.07, 95% CI = 1.02-1.12; Charlson Comorbidity Index score: AOR = 3.52, 95% CI = 3.03-4.10). Off-label use of rituximab grew dramatically over the course of the study. With the recent FDA approval of the rituximab biosimilar and its expected lower price, off-label use will likely continue to rise. Opportunities for cost savings and to ensure appropriate use of these medications should be evaluated. This study was funded by Kaiser Permanente. All authors except Hansen are employed by Kaiser Permanente. Hansen has nothing to disclose. Preliminary results were presented at the Mountain States Conference for Residents and Preceptors in May 2019 in Salt Lake City, UT, and at an encore presentation October 2019 at the American College of Clinical Pharmacy Annual Meeting in New York, NY.


Quantitative Phosphoproteomic Analysis Reveals Potential Regulatory Mechanisms of Early Fruit Enlargement in Pecan (Carya illinoinensis).
Pecan (Carya illinoinensis) is a popular tree nut. Its fruit development undergoes slow growth, rapid expansion, core hardening, and kernel maturation stages. However, little is known about how pecan initiates fruit development and enlargement after pollination. In this study, we performed the first large-scale identification of potential phosphorylation sites and proteins at early development of pecan fruit by a label-free phosphoproteomic quantification technique. A total of 2155 phosphosites were identified from 1953 phosphopeptides covering 1311 phosphoproteins in unpollinated pistils and fruits at 5 and 9 weeks after pollination. Of these, 699 nonredundant phosphoproteins were differentially phosphorylated (DP). Furthermore, the phosphorylation intensity of DP proteins in brassinolide (BR) and auxin signaling were analyzed, and the function of CiBZR1 was investigated. Ectopic expression of CiBZR1 resulted in BR response phenotypes with curled leaves and fruit, while enlarged seed size in Arabidopsis. Subcellular localization and transcriptional activation activity assay demonstrated that CiBZR1 distributed in both the nucleus and cytoplasm with transcriptional activity. When two phosphosites mutated, CiBZR1S201P,S205G moved to the nucleus completely, while the transcriptional activity remained unchanged. Taken together, our data reveal extensive phosphoproteins and lay a foundation to comprehensively dissect the potential post-translational regulation mechanism of early development of pecan fruit.


Molecular regulation of sucrose catabolism and sugar transport for development, defence and phloem function.
Sucrose (Suc) is the major end product of photosynthesis in mesophyll cells of most vascular plants. It is loaded into phloem of mature leaves for long-distance translocation to non-photosynthetic organs where it is unloaded for diverse uses. Clearly, Suc transport and metabolism is central to plant growth and development and the functionality of the entire vascular system. Despite vast information in the literature about the physiological roles of individual sugar metabolic enzymes and transporters, there is a lack of systematic evaluation about their molecular regulation from transcriptional to post-translational levels. Knowledge on this topic is essential for understanding and improving plant development, optimizing resource distribution and increasing crop productivity. We therefore focused our analyses on molecular control of key players in Suc metabolism and transport, including: (i) the identification of promoter elements responsive to sugars and hormones or targeted by transcription factors and microRNAs degrading transcripts of target genes; and (ii) modulation of enzyme and transporter activities through protein-protein interactions and other post-translational modifications. We have highlighted major remaining questions and discussed opportunities to exploit current understanding to gain new insights into molecular control of carbon partitioning for improving plant performance.


[Effect of moxisylyte on the lower urinary tracts (1). Effect on the isolated rabbit urethra and bladder].
Effect of moxisylyte on the lower urinary tracts was studied in comparison with those of prazosin and bunazosin in the isolated rabbit bladder and urethra. Moxisylyte dose-dependently inhibited the urethral contraction induced by phenylephrine. The IC50 value of moxisylyte was 1.01 x 10(-6) M. Prazosin and bunazosin inhibited the urethral contraction as well as moxisylyte. The IC50 values of prazosin and bunazosin were 2.88 x 10(-7) M and 1.44 x 10(-7) M, respectively. Moreover, moxisylyte and bunazosin inhibited the urethral contraction induced by KCl. The IC50 values of moxisylyte and bunazosin were 1.17 x 10(-5) M and 1.35 x 10(-4) M, respectively. The KCl/phenylephrine ratios of moxisylyte, bunazosin and prazosin were as follows: 17, 938 and 9201, respectively. Moxisylyte has a relaxant action on the urethra that is probably ascribable to its alpha 1-adrenoceptor antagonist and Ca++ antagonist actions. In the isolated bladder, moxisylyte inhibited the bladder contraction induced by KCl, with an IC50 value of 4.46 x 10(-5) M. However, moxisylyte did not affect the contractile response to acetylcholine. These results suggest that the relaxant effect of moxisylyte on the urethra is due to alpha 1-adrenoceptor antagonist and Ca++ antagonist actions. Therefore, moxisylyte is useful for the therapeutic treatment of micturitional disorder.


Clinical management of patients with invasive cervical cancer following a negative Pap smear.
Among 535 patients with invasive cervical carcinoma seen between January 1975 and June 1986, 26 were found to have developed the disease within six months (65 percent), 35 within 12 months (88 percent), 37 within 13 months (93 percent), and three developed the disease within 17 months after a negative Pap smear. Eighty-eight percent of these 40 patients were under age 40 at diagnosis. Rapidly progressive cancers are highly resistant to radiation therapy. Seven stage IB patients treated only with radiation died within nine to 29 months after initial therapy. By contrast, 15 patients treated by radical hysterectomy and four by radical hysterectomy and post-surgical radiation were alive with no evidence of disease from six to 109 months after surgery (median, 30 months). Six of nine patients with stage II to IV disease treated with radiation have died; the remaining three are alive. One patient is well 14 months after therapy, but two others have developed metastases seven and 12 months after treatment. Surprisingly, 37 of 40 patients had symptoms of pain, bleeding, and discharge at the initial diagnosis, but their physicians had a false sense of security because of a recent negative Pap smear. Early biopsy diagnosis and radical hysterectomy with bilateral pelvic lymphadenectomy is the most effective management for this cancer.


Is acetylcholinesterase a pertinent biomarker to detect exposure of pyrethroids? A study case with deltamethrin.
The possibility to use acetylcholinesterase as biomarker of exposure to deltamethrin insecticide in the honeybee, Apis mellifera were considered. Joined actions of deltamethrin and pirimicarb (carbamate), alone or in association (dual treatment), were investigated on AChE activity in surviving and dead honeybees in order to test its reliability as biomarker. All treatments induced a reduction in tissue AChE activity in dead bees. In surviving bees, deltamethrin treatment induced an important increase of AChE activity that is not abolished by pirimicarb treatment. The analysis of AChE forms revealed an increase in the soluble form in surviving and dead bees and an increase of the membrane form in surviving bees. No direct effect of deltamethrin on soluble and membrane AChE was observed in vitro. The important increase in AChE activity in response to deltamethrin, not altered by pirimicarb treatment, suggests that AChE activity could represent a robust biomarker specific to deltamethrin exposure in living bees.


The validity of acid-fast smears in the diagnosis of pulmonary tuberculosis.
The acid-fast smear remains an important tool in the diagnosis of tuberculosis. Some reports have questioned the validity of this stain in situations of low prevalence. We examined the relationship between prevalence and predictive value of sputum smears in one laboratory during periods of both low and high laboratory prevalence of Mycobacterium tuberculosis. Smears were examined by fluorescence and confirmed by Kinyoun stain. The number of samples positive for mycobacteria increased from 128 (4.3%) of 2956 during the 1975 through 1978 study period to 197 (8.4%) of 2347 during the 1979 through 1982 study period. Of 47 positive smears during the first study period, only one was a false-positive. None of 96 positive smears during the second period was a false-positive. The positive predictive value of acid-fast microscopy was 97.9% and 100% for the two periods examined. We have demonstrated in practice the small effect of a shift in prevalence on the positive predictive value of an acid-fast smear when specificity is maintained.


Measurement of children's health.
Measuring child health has become a more pressing issue in the face of high rates of survival of childhood illnesses, often with residual chronic health conditions or impairments; the growing awareness of child behavioral and mental health morbidity; the focus on the importance of assessing therapeutic interventions and outcomes; and increased awareness of the multiple ways in which child health influences later adult health conditions. There is widespread belief that the perfect all-purpose measure can be developed and that researchers have not yet succeeded in doing so. This paper addresses three kinds of challenges to the measurement of child health that hamper the development of measures and make it likely that one size will not fit all. These include a series of fundamental underlying assumptions about health and its measurement, issues unique to assessing the health of children, and unresolved controversies that relate to the lens through which to assess child health.


Appropriate use of polymerase chain reaction for detection of herpes simplex virus 2 in cerebrospinal fluid of patients at an inner-city hospital.
Polymerase chain reaction (PCR) tests that detect herpes simplex virus (HSV) DNA in cerebrospinal fluid (CSF) are increasingly used to diagnose central nervous system (CNS) infections caused by HSV. To determine proper utilization of this test at an inner-city hospital, we performed a case-control study of adult patients, with HSV detected in CSF by PCR. Retrospective review of characteristics of adult patients hospitalized between 1997 and 2000 with CSF positive for HSV was done and compared to control patients with suspected CNS infection and negative CSF PCR. CSF from 1174 patients was tested; 20 (1.7%) had HSV DNA detected, 19/20 were HSV-2 and 1 was HSV-1. The HSV-2 cases were females (74%), with a median age of 41 years, of African-American ethnicity (100%). Of the cases, 90% had acute aseptic meningitis versus 13% controls (P < .001). Recurrent meningitis occurred in 42% cases and 3% controls (P < .001). CSF parameters significantly associated with HSV-2 positivity was lymphocytic pleocytosis (median leukocyte, 475 cell/mm3, 90% lymphocytes) (P < .001). In conclusion, HSV-1 was rarely detected in CSF of patients with suspected CNS infection. HSV-2 is more frequent, predominantly in young African-American women with lymphocytic aseptic meningitis, and is often recurrent. PCR testing for HSV-2 in CSF at inner-city hospitals can be greatly reduced by the application of these parameters.


Government health expenditures and health outcomes.
This paper provides econometric evidence linking a country's per capita government health expenditures and per capita income to two health outcomes: under-five mortality and maternal mortality. Using instrumental variables techniques (GMM-H2SL), we estimate the elasticity of these outcomes with respect to government health expenditures and income while treating both variables as endogenous. Consequently, our elasticity estimates are larger in magnitude than those reported in literature, which may be biased up. The elasticity of under-five mortality with respect to government expenditures ranges from -0.25 to -0.42 with a mean value of -0.33. For maternal mortality the elasticity ranges from -0.42 to -0.52 with a mean value of -0.50. For developing countries, our results imply that while economic growth is certainly an important contributor to health outcomes, government spending on health is just as important a factor.


The effects of ethanol exposure during the brain growth spurt in rats.
The purpose of this study was to determine whether micromorphological changes occur at a low level of ethanol exposure previously shown by us to induce alterations in synaptosomal biochemistry. The results suggest that 4 g ethanol per kg body weight daily throughout the brain growth spurt causes no significant structural changes in the cerebellum, lobule IX, at the light and electron microscopic levels. Although ethanol- and isocaloric sucrose-treated groups did not differ from each other in cumulative percent body weight gain throughout the treatment period, both groups differed significantly in this parameter from isocaloric milk-treated and "handled" control groups. On the day following completion of the treatment period, brain weight in the ethanol-treated group was significantly less than that of all other groups. Further, the results indicate that isocaloric sucrose "pair feeding" is contraindicated in postnatal studies and that nutritional status is better controlled by daily gavage of neonates than by other methods currently used in ethanol studies in postnatal animals.


Two forms of death in ageing Caenorhabditis elegans.
Ageing generates senescent pathologies, some of which cause death. Interventions that delay or prevent lethal pathologies will extend lifespan. Here we identify life-limiting pathologies in Caenorhabditis elegans with a necropsy analysis of worms that have died of old age. Our results imply the presence of multiple causes of death. Specifically, we identify two classes of corpse: early deaths with a swollen pharynx (which we call 'P deaths'), and later deaths with an atrophied pharynx (termed 'p deaths'). The effects of interventions on lifespan can be broken down into changes in the frequency and/or timing of either form of death. For example, glp-1 mutation only delays p death, while eat-2 mutation reduces P death. Combining pathology and mortality analysis allows mortality profiles to be deconvolved, providing biological meaning to complex survival and mortality profiles.


The efficiency of homologous recombination and non-homologous end joining systems in repairing double-strand breaks during cell cycle progression.
This study investigated the efficiency of Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR) repair systems in rejoining DNA double-strand breaks (DSB) induced in CCD-34Lu cells by different γ-ray doses. The kinetics of DNA repair was assessed by analyzing the fluorescence decrease of γ-H2AX foci measured by SOID (Sum Of Integrated Density) parameter and counting foci number in the time-interval 0.5-24 hours after irradiation. Comparison of the two methods showed that the SOID parameter was useful in determining the amount and the persistence of DNA damage signal after exposure to high or low doses of ionizing radiation. The efficiency of DSB rejoining during the cell cycle was assessed by distinguishing G1, S, and G2 phase cells on the basis of nuclear fluorescence of the CENP-F protein. Six hours after irradiation, γ-H2AX foci resolution was higher in G2 compared to G1 cells in which both NHEJ and HR can cooperate. The rejoining of γ-H2AX foci in G2 phase cells was, moreover, decreased by RI-1, the chemical inhibitor of HR, demonstrating that homologous recombination is at work early after irradiation. The relevance of HR in DSB repair was assessed in DNA-PK-deficient M059J cells and in CCD-34Lu treated with the DNA-PKcs inhibitor, NU7026. In both conditions, the kinetics of γ-H2AX demonstrated that DSBs repair was markedly affected when NHEJ was absent or impaired, even in G2 phase cells in which HR should be at work. The recruitment of RAD51 at DSB sites was, moreover, delayed in M059J and in NU7026 treated-CCD-34Lu, with respect to DNA-PKcs proficient cells and continued for 24 hours despite the decrease in DNA repair. The impairment of NHEJ affected the efficiency of the HR system and significantly decreased cell survival after ionizing radiation, confirming that DSB rejoining is strictly dependent on the integrity of the NHEJ repair system.


Subclinical effects of smoking. Physiologic comparison of healthy middle-aged smokers and nonsmokers and interrelationships of lung function measurements.
Measurements of ventilatory function, distribution of ventilation, diffusing capacity, and lung mechanics were made on healthy middle-aged smokers and nonsmokers drawn from a randomly selected population in order to assess the effects of cigarette smoking and the interrelationships of the several indices of lung function. Although very few subjects had abnormal function, there were significant differences in most indices of function between smokers and nonsmokers. For the total group studied, there were significant correlations between various indices of function. A significant proportion of the variance in diffusing capacity and in diffusing capacity per liter of lung volume can be accounted for by an index of lung recoil which may, in turn, be related to size of terminal air spaces.


Clinical target volume localization using conventional methods (anatomy and palpation) and ultrasonography in early breast cancer post-operative external irradiation.
To evaluate the accuracy of three methods, anatomy (A), palpation (P) and ultrasounds (US) in localizing the clinical target volume (CTV) in patients (pts) with early breast cancer (EBC) undergoing breast external irradiation as part of conservation therapy. One hundred consecutive pts with EBC (T(is) 1%, T1 78%, T2 21%, N- 68%, N+ 32%), treated with conservation surgery and breast irradiation with opposed tangential portals, were prospectively analyzed. Anatomically, palpatory or ultrasound defined field borders for CTV localizations were determined in the same position thanks to the utilization of a vacuum-formed cellulose acetate immobilization cast, removed during CTV definitions. P and US CTV localizations have been found to coincide on the four margins (superior, inferior, medial, lateral) in only 1/100 pts, while no pt showed identical A and US CTV localizations. Only 31/397 (8%) field measurements with A, and 98/395 (25%) with P corresponded to US border definition. If mean and median values of each field border were considered, the CTV was generally overestimated with P appearing more accurate than A in a gross definition of the target (P < 0.01). However, a geographical miss of at least one field border of CTV occurred in 55% of pts with A and in 36% of pts with P. The most critical margin to be defined with conventional methods was the superior one: an underestimation of the cranial border of CTV with A was observed in 51% and with P in 22% of pts (22% and 8%, respectively, when an underestimation by more than 1.5 cm was considered). When pre-menopausal and peri/post-menopausal groups of pts were separately analyzed, conventional methods were highly inaccurate to define the superior border in younger pts, in which a geographical miss was noted with A in 62% and with P in 35% of cases (P < 0.05). When an underestimation of more than 1.5 cm was evaluated, these values were reduced to 33% and 12%, respectively (P = 0.02). Also, in the subgroup of pre-menopausal patients the CTV defined by palpatory reference lines appeared to be more accurate than A-method (P < 0.01). Conventional methods frequently appear inadequate to localize residual mammary gland in EBC post-operative external irradiation. This analysis evidentiates the inaccuracy of empirical CTV definition, and suggests that palpation or anatomical reference borders should be critically used and that state of art imaging methods should be included in treatment planning, particularly in pre-menopausal pts. If economical or individual variables have to be taken into account, palpation might be considered in post-menopausal women.