Breast differentiation and its implication in cancer prevention.
Sporadic breast cancer is a fatal disease most frequently diagnosed in American women from all ethnic groups, suggesting that primary prevention should be the ultimate goal for breast cancer control. We have developed a novel paradigm for breast cancer prevention arising from the well-established knowledge that an early first full-term pregnancy protects the breast against neoplastic transformation, as well as from our studies of the biological principle underlying this protection. We have shown experimentally that the first pregnancy induces the expression of a specific genomic signature in the breast that results from the completion of a cycle in this organ's differentiation driven by the reproductive process. This signature, in turn, is a biomarker associated with a possible overall lifetime decrease in breast cancer risk. We have shown in an experimental model that a short treatment with human chorionic gonadotropin, a placental hormone secreted during pregnancy, induces the same genomic signature that occurs in pregnancy, inhibiting not only the initiation but also the progression of mammary carcinomas, and stopping the development of early lesions such as intraductal proliferations and carcinoma in situ. These observations indicate that human chorionic gonadotropin given for a very short period, only until this genomic signature is acquired, has significant potential as a chemopreventive agent, protecting the normal cell from becoming malignant. This is a novel concept which challenges the current knowledge that a chemopreventive agent needs to be given for a long period of time to suppress a metabolic pathway or abrogate the function of an organ.


Regulation of B cell function by the immunosuppressive agent leflunomide.
Leflunomide is an immunosuppressive drug capable of inhibiting cellular and humoral mediated responses in vivo. The mechanism responsible for suppression of B cell antibody responses in vivo has not been identified. In this study we demonstrate that leflunomide functions to inhibit murine B cell antibody production by directly acting on the B cell. Experiments performed in vivo showed that both T cell-dependent as well as T cell-independent antigen responses were suppressed by leflunomide. Initial in vitro experiments demonstrated that leflunomide inhibited B cell antibody production by decreasing B cell proliferation. The suppression of B cell proliferation induced by a variety of stimuli that use different signal cascade components suggested that leflunomide was acting on a common component required for B cell proliferation. Kinetic studies with LPS activated B cells revealed that leflunomide retained its inhibitory activity when added as late as 24 hr after stimulation in an 88-hr assay. By analyzing the cell cycle of LPS-stimulated B cells we observed that leflunomide targets two different stages in cell cycle transition: (1) from G1 to S phase and (2) from S phase to G2/M phase. Analysis of one of the cyclin-dependent kinases, Cdk2 protein, by Western blot revealed that Cdk2 levels were decreased, in the presence of leflunomide, 48 hr after stimulation. These data further confirmed that leflunomide inhibited B cell progression through the S phase. We also present evidence that the addition of exogenous uridine reversed the antiproliferative activity of leflunomide. This indicated that leflunomide acted as a pyrimidine synthesis inhibitor, thereby inhibiting B cell proliferation and cell cycle progression.


Formalin instillation for hemorrhagic radiation proctitis.
Although formalin instillation has been proven to be an effective treatment of hemorrhagic radiation proctitis, different techniques with varying success rates have been reported. The aim of this study was to assess our experience with formalin instillation for the treatment of radiation proctitis. After Institutional Review Board approval, all patients who presented with radiation proctitis and were treated with 4% formalin instillation were identified from a prospective database. Techniques of instillation were as follows: a formalin-soaked sponge stick was applied via a proctoscope (SS) and placed at each quadrant with a mean contact of 2.5 minutes (range, 0.5-3 minutes), or the formalin solution was introduced through a proctoscope in aliquots for a total of 350 to 400 mL irrigation (IR), with a mean contact time of 30 seconds in each aliquot. The patients were divided into two groups according to the method of formalin instillation and their outcomes were compared. Between March 1995 and September 2003, 21 patients who underwent formalin treatment were identified: 17 patients were in the SS and 4 patients were in the IR group. The mean age was 74.8+/-6.4 years and 70.5+/-6.8 years and the male/female ratio was 16:1 and 3:1 in the SS and IR groups, respectively. Indications for radiation therapy were prostate cancer in 19 patients: 16 (95.1%) SS patients and 3 (75%) IR patients. Four (23.5%) patients in the SS group were receiving anticoagulants or antiplatelet medications before the procedure. The mean duration of bleeding before formalin instillation was 11.7 months (range, 2-48 months) in the SS and 10.5 months (range, 7-12 months) in the IR group. Sixteen (94.1%) patients in the SS and 4 (100%) in the IR group had previous treatments for radiation proctitis, including hydrocortisone enema, 5-aminosalicylate mesalamine, and endoscopic coagulation. Eight (47.1%) patients in the SS and 2 (50%) in the IR group received a preprocedural blood transfusion, and 1 patient in the SS group required a blood transfusion after the formalin instillation. This patient subsequently underwent restorative proctosigmoidectomy because of persistent bleeding. The mean length of the procedure was 27.1+/-10.8 minutes in the SS group and 22.5+/-6.5 minutes in the IR group. The bleeding was successfully stopped on the first attempt in 14 patients (82.4%) in the SS group and 3 (75%) in the IR group. The instillation was repeated in 1 patient (5.9%) in the SS group and in 1 (25%) in the IR group. Four patients (23.5%) in the SS group experienced rectal pain after the procedure. One patient (5.9%) developed a new onset of fecal incontinence, while another (5.9%) had anococcygeal pain accompanied by worsening of fecal incontinence. One patient (25%) in the IR group developed acute colitis consistent with formalin instillation, which was managed by intravenous antibiotics. The patients were followed for a mean of 10 months (range, 1 to 38 months). Formalin instillation is effective in controlling refractory hemorrhage secondary to radiation proctitis.


Gender Stereotypes.
There are many differences between men and women. To some extent, these are captured in the stereotypical images of these groups. Stereotypes about the way men and women think and behave are widely shared, suggesting a kernel of truth. However, stereotypical expectations not only reflect existing differences, but also impact the way men and women define themselves and are treated by others. This article reviews evidence on the nature and content of gender stereotypes and considers how these relate to gender differences in important life outcomes. Empirical studies show that gender stereotypes affect the way people attend to, interpret, and remember information about themselves and others. Considering the cognitive and motivational functions of gender stereotypes helps us understand their impact on implicit beliefs and communications about men and women. Knowledge of the literature on this subject can benefit the fair judgment of individuals in situations where gender stereotypes are likely to play a role.


Alteration of genomic responses to doxorubicin and prevention of MDR in breast cancer cells by a polymer excipient: pluronic P85.
Polymer therapeutics has emerged as a new clinical option for the treatment of human diseases. However, little is known about pharmacogenetic responses to drugs formulated with polymers. In this study, we demonstrate that a formulation containing the block copolymer Pluronic P85 and antineoplastic drug doxorubicin (Dox) prevents the development of multidrug resistance in the human breast carcinoma cell line, MCF7. Specifically, MCF7 cells cultured in the presence of Pluronic were unable to stably grow in concentrations of Dox that exceeded 10 ng of Dox/mL of culture medium. In sharp contrast, MCF7 cells cultured in the absence of the block copolymer resulted in the selection and stable growth of cells that tolerated a 1000 times higher concentration of the drug (10 000 ng of Dox/mL of culture medium). Detailed characterization of the isolated sublines demonstrated that those cells selected in the polymer-drug formulation did not show amplification of the MDR1 gene, likely resulting in their high sensitivity to the drug. Conversely, cells selected with Dox alone showed an elevated level in the expression of the MDR1 gene along with a corresponding increase in the expression level of the drug efflux transporter, Pgp, and likely contributing to the high resistance of the cells to Dox. Global analysis of the expression profiles of 20K genes by DNA microarray revealed that the use of Pluronic in combination with Dox drastically changed the direction and magnitude of the genetic response of the tumor cells to Dox and may potentially enhance therapeutic outcomes. Overall, this study reinforces the need for a thorough assessment of pharmacogenomic effects of polymer therapeutics.


Does Length, Diameter, or Bone Quality Affect Primary and Secondary Stability in Self-Tapping Dental Implants?
Implant stability is a clinically valuable measurement of the strength of implant anchorage in the bone during placement and in the post-osseointegration period. This study aimed to determine 1) the effect of implant diameter and length and bone quality on measurements of primary and secondary stability (insertion torque [IT] and implant stability quotient [ISQ]), 2) the correlation between IT and primary and secondary ISQ, and 3) differences in ISQ in the post-osseointegration period (secondary stability) compared with immediate post-placement (primary) stability. In this longitudinal clinical study, titanium self-tapping implants were inserted in edentulous patients. The implants were grouped according to 3 independent variables: length (10 and 11.5 mm), diameter (3.75 and 4.25 mm), and bone quality (Lekholm and Zarb classification) to analyze primary and secondary implant stability (outcome variables). Statistical analyses were performed using the Student t test for paired data, 1-way analysis of variance, and the Tukey procedure for multiple pairwise comparisons. Data were collected on 88 self-tapping implants inserted in 63 partially edentulous patients. IT and implant stability were affected by diameter (3.75-mm implants, 26.5-N/cm IT and 74.0 ISQ; 4.25-mm implants, 33.8-N/cm IT and 77.0 ISQ) and bone type (type 1 + 2, 34.86-N/cm IT and 77.4 ISQ; type 3, 27.09-N/cm IT and 75.6 ISQ; type 4, 20.63-N/cm IT and 70.5 ISQ; P < .01 for all comparisons). Secondary ISQ was affected by diameter only (77.41 for 3.75- vs 75.51 for 4.25-mm implants). IT correlated with primary ISQ (R = 0.56; P < .01), although no clear correlation with secondary stability was found. IT and primary ISQ in self-tapping implants differed in patients with different bone quality and implant diameter but did not differ between the 2 implant lengths compared in this study. Secondary stability was not substantially affected by any of these factors. Although IT was closely related to primary ISQ, it was unrelated to secondary ISQ. Very high primary ISQ values tended to decrease, whereas intermediate and low values tended to increase, in the transition to secondary stability.


Cancer Treatment by Using Traditional Chinese Medicine: Probing Active Compounds in Anti-multidrug Resistance During Drug Therapy.
The main challenge of cancer treatment is multidrug resistance during chemotherapy. Cancer cell can evade cell death during every round of orthodox chemotherapy drugs, consequently being resistant after several rounds of standard drug treatment. One of the regimens to address this multidrug resistance problem is by drug combination. However, synthetic drugs always have problems of strong side effects and toxicity. Natural compounds deriving from traditional Chinese medicine are known to have low toxicity and genuine promising effects in reversing multidrug resistance, either induced by orthodox chemotherapeutic or targeted therapy drugs. Numerous mechanisms including suppression of drug efflux, detoxifying systems, DNA repair systems, and anti-apoptosis pathways were responsible for such process. A range of natural compounds functioned on the suppression of apoptosis are widely reported, which include flavonoids, terpenoids, alkaloids, quinones, xanthones, saponins and polysaccharides. Here, this review summarized comprehensive data from in vitro and in vivo studies to elucidate the functional roles of natural compounds in reversing multidrug resistance during cancer therapy.


Genetic diversity of native and cultivated Ugandan Robusta coffee (Coffea canephora Pierre ex A. Froehner): Climate influences, breeding potential and diversity conservation.
Wild genetic resources and their ability to adapt to environmental change are critically important in light of the projected climate change, while constituting the foundation of agricultural sustainability. To address the expected negative effects of climate change on Robusta coffee trees (Coffea canephora), collecting missions were conducted to explore its current native distribution in Uganda over a broad climatic range. Wild material from seven forests could thus be collected. We used 19 microsatellite (SSR) markers to assess genetic diversity and structure of this material as well as material from two ex-situ collections and a feral population. The Ugandan C. canephora diversity was then positioned relative to the species' global diversity structure. Twenty-two climatic variables were used to explore variations in climatic zones across the sampled forests. Overall, Uganda's native C. canephora diversity differs from other known genetic groups of this species. In northwestern (NW) Uganda, four distinct genetic clusters were distinguished being from Zoka, Budongo, Itwara and Kibale forests A large southern-central (SC) cluster included Malabigambo, Mabira, and Kalangala forest accessions, as well as feral and cultivated accessions, suggesting similarity in genetic origin and strong gene flow between wild and cultivated compartments. We also confirmed the introduction of Congolese varieties into the SC region where most Robusta coffee production takes place. Identified populations occurred in divergent environmental conditions and 12 environmental variables significantly explained 16.3% of the total allelic variation across populations. The substantial genetic variation within and between Ugandan populations with different climatic envelopes might contain adaptive diversity to cope with climate change. The accessions that we collected have substantially enriched the diversity hosted in the Ugandan collections and thus contribute to ex situ conservation of this vital genetic resource. However, there is an urgent need to develop strategies to enhance complementary in-situ conservation of Coffea canephora in native forests in northwestern Uganda.


A highly selective ratio-metric fluorescent sensor for visualizing nitroreductase in hypoxic cells.
Herein, we have developed a novel single-molecular probe (NORP) for selective and accurate determination of NTR in living cells. It was discovered that up-regulation of endogenous NTR occurred in response to hypoxic stimulation, and there was a dependence between the NTR levels and the degree of hypoxia.


Group III and subtype 4 metabotropic glutamate receptor agonists: discovery and pathophysiological applications in Parkinson's disease.
Restoring the balance between excitatory and inhibitory circuits in the basal ganglia, following the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta, represents a major challenge to treat patients affected by Parkinson's disease (PD). The imbalanced situation in favor of excitation in the disease state may also accelerate excitotoxic processes, thereby representing a potential target for neuroprotective therapies. Reducing the excitatory action of glutamate, the major excitatory neurotransmitter in the basal ganglia, should lead to symptomatic improvement for PD patients and may promote the survival of DA neurons. Recent studies have focused on the modulatory action of metabotropic glutamate (mGlu) receptors on neurodegenerative diseases including PD. Group III mGlu receptors, including subtypes 4, 7 and 8, are largely expressed in the basal ganglia. Recent studies highlight the use of selective mGlu4 receptor positive allosteric modulators (PAMs) for the treatment of PD. Here we review the effects of newly-designed group-III orthosteric agonists on neuroprotection, neurorestoration and reduction of l-DOPA induced dyskinesia in animal models of PD. The combination of orthosteric mGlu4 receptor selective agonists with PAMs may open new avenues for the symptomatic treatment of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.


Induction of autoantibody production is limited in nonautoimmune mice.
Many individuals develop a single or a few brief episodes of autoimmunity from which they recover. Mechanisms that quell pathologic autoimmunity following such a breakdown of self-tolerance are not clearly understood. In this study, we show that in nonautoimmune mice, dsDNA-specific autoreactive B cells exist but remain inactive. This state of inactivation in dsDNA-specific B cells could be disrupted by autoreactive Th cells; in this case T cells that react with peptides from the V(H) region of anti-DNA Abs (hereafter called anti-V(H) T cells). Immunization with anti-DNA mAb, its gamma-chain or peptides derived from its V(H) region induced anti-V(H) Th cells, IgG anti-dsDNA Ab, and proteinuria. The breakdown of B cell tolerance in nonautoimmune mice, however, was short-lived: anti-DNA Ab and nephritis subsided despite subsequent immunizations. The recovery from autoimmunity temporally correlated with the appearance of T cells that inhibited anti-DNA Ab production. Such inhibitory T cells secreted TGFbeta; the inhibition of anti-DNA Ab production by these cells was partly abolished by anti-TGFbeta Ab. Even without immunization, nonautoimmune mice possess T cells that can inhibit autoantibody production. Thus, inhibitory T cells in nonautoimmune mice may normally inhibit T-dependent activation of autoreactive B cells and/or reverse such activation following stimulation by Th cells. The induction of such inhibitory T cells may play a role in protecting nonautoimmune mice from developing chronic autoimmunity.


Does ulnar variance change with age and what is the influence of training and biological characteristics in this change? A short-term longitudinal study in Portuguese artistic gymnasts.
To analyze the variability and longitudinal stress-related changes in ulnar variance (UV) in a group of immature artistic gymnasts. The relationship between UV and a group of biological and training variables was also investigated. Prospective cohort study. Portuguese Federation of Gymnastics. Twenty-five Portuguese skeletally immature gymnasts competing nationally. Skeletal age (Tanner-Whitehouse 3 method), stature, body mass and body mass index (BMI) (Seca stadiometer), fat-free mass and percentage of body fat mass (Tanita BC 418), handgrip strength (Takei dynamometer), and training data (interview). To determine UV stress-related changes over time, left UV was obtained using Hafner procedure. Ulnar variance values and biological characteristics were tested twice (at baseline and after 18 months of training). Analysis of covariance analysis presented a significant interaction between age and time effect in UV at baseline. Each category of UV reacted differently to the interaction between age and training time. Significant relationships between UV and biological and training variables (chronological and skeletal age, body mass, BMI, handgrip strength, hour per week, and years of training) were evident in at least one of the moments of data collection. The gymnasts showed significant longitudinal UV changes toward less negative UV over the training period. Nevertheless, we could not find a significant correlation between UV and the majority of the researched variables. Thus, although UV has been broadly studied, this phenomenon is complex because it depends on different intrinsic and extrinsic factors that are difficult to control, making necessary additional research on this topic. The gymnast's wrist has been associated with a high incidence of painful symptomatology and injuries, leading to the formulation of several hypotheses related to the UV ethiology. Knowledge about the possible intrinsic or extrinsic factors related to UV changes and/or different UV categories (negative, neutral, and positive), as well as their consequent specific injuries in gymnasts' wrists may contribute to a primary prevention or reduction in the occurrence, recurrence and severity of pain, functional disability, or injuries in radius-ulnocarpal joint, thereby improving gymnasts' performance.


Minimally invasive complete mesocolic excision for right colon cancer.
Complete mesocolic excision (CME) with central vascular ligation (CVL) follows the same principles as the total mesorectal excision (TME) in the rectum of following the embryological planes for right-sided cancers. The number of lymph nodes yielded increased with a resultant improvement in the oncological outcomes and by reducing local recurrence rates. Hohenberger's radical CME and CVL and the East's modified CME with D3 lymphadenectomy, which traditionally followed the embryological plane dissection for most of its intraabdominal cancer resection, have both shown to harvest significantly higher number of lymph nodes leading to a higher overall survival rate than the traditional right hemicolectomies of the West. To achieve the oncologically superior excision of the CME, awareness of the significant vascular anatomical variation will enhance the precision of the oncosurgery as well as minimize the risk of vascular complications. There has been an increasing body of evidence emerging on the safety of minimally invasive surgery (MIS); both its oncological safety as well as complication rates in the hands of expert and trained surgeons. The surgical technique of a CME right hemicolectomy is described step by step to aid standardization. There is mounting evidence that CME + CVL/ D3 improves survival in patients with colon cancer. Whilst the technical aspect of MIS is more challenging than the left, with a standardized technique and systematic teaching method, safety and benefits for patients can be achieved.


Clinical and scientific aspects of muscle-specific tyrosine kinase-related myasthenia gravis.
Antibodies to muscle-specific tyrosine kinase (MuSK) characterize up to 5% of myasthenia gravis patients. This review focuses on the differences to clinical antiacetylcholine receptor-myasthenia gravis, and on the physiology and animal studies that elucidate the role of MuSK and help explain the clinical disease. MuSK forms the core of a protein complex in the postsynaptic membrane at the neuromuscular junction. During development, MuSK tyrosine kinase signaling is vital for the formation and stabilization of the postsynaptic endplate; it is now clear that long-term homeostasis of mature neuromuscular junctions requires MuSK function. Patient MuSK-antibodies are largely of the IgG4 type and in cell culture block the assembly and activation of MuSK kinase. Active immunization and passive transfer mouse models show reduced postsynaptic acetylcholine receptors and disturbed synaptic alignment, diminished synaptic potentials and impaired muscle activation.MuSK myasthenia gravis patients display particular bulbar and respiratory muscle involvement, with a high rate of myasthenic crises. Plasma exchange and immunosuppression with corticosteroids and rituximab appear to be most effective in treating MuSK myasthenia gravis. In contrast, the cholinesterase inhibitors, such as pyridostigmine, appear less suitable for this form of myasthenia gravis. MuSK myasthenia gravis has distinct clinical and pathophysiological features.


Predictors of mortality in Middle East respiratory syndrome (MERS).
We evaluated the clinical characteristics, cytokine/chemokine concentrations, viral shedding and antibody kinetics in 30 patients with Middle East respiratory syndrome (MERS), including 6 non-survivors admitted to 3 MERS-designated hospitals. Old age, low albumin, altered mentality and high pneumonia severity index score at admission were risk factors for mortality. In addition, severe signs of inflammation at initial presentation (at hospital days 1-4), such as high inducible protein-10 (p=0.0013), monocyte chemoattractant protein-1 (p=0.0007) and interleukin 6 (p=0.0007) concentrations, and poor viral control (high viral load at hospital days 5-10, p<0.001) without adequate antibody titres (low antibody titre at hospital days 11-16, p=0.07) during the course of disease, were associated with mortality.


[MR imaging of the meninges: normal and pathological findings].
The MR appearance of normal and pathological meninges was studied in 23 patients. Amongst twelve normals, T1-weighted images demonstrated the meninges as slightly hyperintense density structures (compared with CSF) which increased in signal intensity somewhat after the administration of gadolinium-DTPA. On T2-weighted images, the subarachnoid space and meninges were isointense. In eleven patients with inflammatory disease or tumourous infiltration of the meninges, abnormal findings were evident in the unenhanced images as well as after administration of gadolinium-DTPA. Compared with CT, MR proved greatly superior in the diagnosis of meningeal abnormalities.


Oculomotor function at low temperature: antarctic versus temperate fish.
The peripheral oculomotor system can be modelled as a first order linear system (Montgomery, 1983), and hence specified by its characteristic frequency and 'd.c.' gain. These parameters can be determined by recording eye movements produced by stimulation of the abducens nerve with sinusoidally modulated pulse trains, and compare well with those independently derived from the relationship between motoneurone firing and spontaneous eye movement. Characteristic frequency and gain of the peripheral oculomotor system were determined for two species of antarctic teleost and one temperate species, to examine temperature compensation within a complete motor output pathway. Compared with low temperature function in temperate fish, the characteristic frequency is clearly temperature compensated in antarctic fish, which explains in part the observed temperature compensation of their rapid eye movement. The 'd.c.' gain of the peripheral oculomotor system is inversely related to temperature, providing an automatic compensation for possible reductions in central nervous system output and sensory gain at low temperature.


Effect of pH and 3-hydroxybutyrate on insulin binding and action in cultured human fibroblasts.
The influence of pH and 3-hydroxybutyrate on insulin binding and action has been studied in cultured human fibroblasts. When the pH of the incubation medium was decreased from 7.6 to 6.8, insulin stimulation of glycogen synthase and total glucose uptake was decreased. The decreased pH induced both an increase in the insulin concentration for half-maximal response, and a decrease in maximal responsiveness. When insulin binding was measured at lower pH, receptor affinity was decreased. The effect of 3-hydroxybutyrate on insulin binding and action was assessed at pH 7.4 and 6.9. In the presence of 3-hydroxybutyrate, insulin binding increased, but insulin action on glycogen synthase and total glucose uptake was unaffected. The data show that insulin action is impaired at lower pH. The decreased sensitivity is probably related to the decrease in insulin binding affinity at lower pH, but decreased maximal responsiveness implies that postreceptor components are also affected by lower pH. The results also suggest that 3-hydroxybutyrate induced a dissociation between binding and response, since an increase of insulin binding was not accompanied by changes in the regulation of glycogen synthase and total glucose uptake.


Zinc-based biomaterials for bone repair and regeneration: mechanism and applications.
Zinc (Zn) is one of the most important trace elements in the human body and plays a key role in various physiological processes, especially in bone metabolism. Zn-containing materials have been reported to enhance bone repair through promoting cell proliferation, osteogenic activity, angiogenesis, and inhibiting osteoclast differentiation. Therefore, Zn-based biomaterials are potential substitutes for traditional bone grafts. In this review, the specific mechanisms of bone formation promotion by Zn-based biomaterials were discussed, and recent developments in their application in bone tissue engineering were summarized. Moreover, the challenges and perspectives of Zn-based biomaterials were concluded, revealing their attractive potential and development directions in the future.


Spirituality, religion, and depression in the terminally ill.
This study examined the impact of spirituality and religiosity on depressive symptom severity in a sample of terminally ill patients with cancer and AIDS. One hundred sixty-two patients were recruited from palliative-care facilities (hospitals and specialized nursing facilities), all of whom had a life expectancy <6 months. The primary variables used in this study were the FACIT Spiritual Well-Being Scale, a religiosity index similar to those used in previous research, the Hamilton Depression Rating Scale (HDRS), the Karnofsky Performance Rating Scale, the Memorial Symptom Assessment Scale, and the Duke-UNC Functional Social Support Questionnaire. A strong negative association was observed between the FACIT Spiritual Well-Being scale and the HDRS, but no such relationship was found for religiosity, because more religious individuals had somewhat higher scores on the HDRS. Similar patterns were observed for the FACIT subscales, finding a strong negative association between the meaning and peace subscale (which corresponds to the more existential aspects of spirituality) and HDRS scores, whereas a positive, albeit nonsignificant, association was observed for the faith subscale (which corresponds more closely to religiosity). These results suggest that the beneficial aspects of religion may be primarily those that relate to spiritual well-being rather than to religious practices per se. Implications for clinical interventions and palliative-care practice are discussed.


Laboratory versus Farm: The Triumph of Laboratory Science in Belgian Agriculture at the End of the Nineteenth Century .
During the 1870s Belgium followed the path of other European countries and created its first public agricultural laboratories under the direction of Arthur Petermann, a young German agricultural scientist. Petermann had been trained in the well-established European stations of renowned chemists such as Wilhelm Henneberg and Louis Grandeau. The mission of these laboratories was to acquaint the local farming community with the new scientific approach to farming, which included the use of chemical fertilizers. The laboratory scientists hoped to achieve this through education, information dissemination, and regulating chemical fertilizers. But farmers and fertilizer traders, whose practices relied on age-old family tradition, commonsense, and mutuality, were not pleased with this interference. Therefore, the scientists had to develop strategies to establish their authority.


Improved accuracy in time-resolved diffuse reflectance spectroscopy.
Significant improvements in the accuracy of time-resolved diffuse reflectance spectroscopy are reached by using a Monte Carlo scheme for evaluation of measured photon time-of-flight distributions. The use of time-resolved diffusion theory of photon migration, being the current standard scheme for data evaluation, is shown defective. In particular, the familiar problem sometimes referred to as absorption-to-scattering coupling or crosstalk, is identified as an error related to the breakdown of the diffusion approximation. These systematic errors are investigated numerically using Monte Carlo simulations, and their influence on data evaluation of experimental recordings are accurately predicted. The proposed Monte Carlo-based data evaluation avoids these errors, and can be used for routine data evaluation. The accuracy and reproducibility of both MC and diffusion modeling are investigated experimentally using the MEDPHOT set of solid tissue-simulating phantoms, and provides convincing arguments that Monte Carlo-based evaluation is crucial in important ranges of optical properties. In contrast to diffusion-based evaluation, the Monte Carlo scheme results in optical properties consistent with phantom design. Since the MEDPHOT phantoms are used for international comparisons and performance assessment, the performed characterization is carefully reported.


CLOCK 3111T/C genetic variant influences the daily rhythm of autonomic nervous function: relevance to body weight control.
Humans carrying the genetic risk variant C at the circadian CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C have been shown to have more difficulties to achieve desired weight loss than TT carriers. We tested the hypothesis that the daily rhythm of autonomic nervous function differs in CLOCK 3111C carriers, leading to reduced effectiveness in weight control. We recruited 40 overweight/obese Caucasian women (body mass index>25), 20 carrying CLOCK 3111C (CC and TC) and 20 non-carriers with matched age and body mass index who participated in a dietary obesity treatment program of up to 30 weeks. Following the treatment, ambulatory electrocardiography was continuously monitored for up to 3.5 days when subjects underwent their normal daily activities. To assess autonomic function, heart rate variability analysis (HRV) was performed hourly to obtain mean inter-beat interval between two consecutive R waves (mean RR) and s.d. of normal-to-normal heartbeat intervals (SDNN), and two parasympathetic measures, namely, proportion of differences between adjacent NN intervals that are >50 ms (pNN50), and high-frequency (HF: 0.15-0.4 Hz) power. In the TT carriers, all tested HRV indices showed significant daily rhythms (all P-values <0.0001) with lower mean RR, SDNN, pNN50, and HF during the daytime as compared with the nighttime. The amplitudes of these rhythms except for SDNN were reduced significantly in the C carriers (mean RR: ~19.7%, P=0.001; pNN50: 58.1%, P=0.001; and HF: 41.1%, P=0.001). In addition, subjects with less weight loss during the treatment program had smaller amplitudes in the rhythms of mean RR (P<0.0001), pNN50 (P=0.007) and HF (P=0.003). Furthermore, the rhythmicity-weight loss associations were much stronger in the C carriers as compared to the TT carriers (mean RR: P=0.028, pNN50: P=0.0002; HF: P=0.015). The daily rhythm of parasympathetic modulation may play a role in the influence of the CLOCK variation on body weight control.


Balancing urgency, age and quality of life in organ allocation decisions--what would you do? A survey.
Explore public attitudes towards the trade-offs between justice and medical outcome inherent in organ allocation decisions. The US Task Force on Organ Transplantation recommended that considerations of justice, autonomy and medical outcome be part of all organ allocation decisions. Justice in this context may be modeled as a function of three types of need, related to age, clinical urgency, and quality of life. A web-based survey was conducted in which respondents were asked to choose between two hypothetical patients who differed in clinical urgency (time to death <1 year), age, pretransplant and post-transplant quality of life, and life expectancy. A pool of 1600 people were notified via email about the survey; 623 (39%) responded. Respondents preferred giving organs to younger people up to an age difference of <15.4 years (SD 18) and more clinically urgent people up to a difference in urgency of <2.54 months (SD 3). Priority varied with the quality of life of the worst-off patient and the relative status of the patients. If both had worse than average quality of life, respondents preferred the better-off patient. When both had better than average quality of life, they preferred the worse-off patient. In analysis according to age versus clinical urgency, the older the patient, the more urgency needed to receive priority. In quality of life versus clinical urgency, the better the control's quality of life, the more urgency the competing patient required. The worse the patient's post-transplant outcome, the more urgency needed to receive priority. It appears that clinical urgency is only one of many factors influencing attitudes about allocation decisions and that respondents may invoke different principles of fairness depending the relative clinical status of patients.


Influence of PET reconstruction parameters on the TrueX algorithm. A combined phantom and patient study.
With the increasing use of functional imaging in modern radiotherapy (RT) and the envisaged automated integration of PET into target definition, the need for reliable quantification of PET is growing. Reconstruction algorithms in new PET scanners employ point-spread-function (PSF) based resolution recovery, however, their impact on PET quantification still requires thorough investigation. Measurements were performed on a Siemens PET/CT using an IEC phantom filled with varying activity. Data were reconstructed using the OSEM (Gauss filter) and the PSF TrueX (Gauss and Allpass filter) algorithm with all available products of iterations (i) and subsets (ss). The recovery coeffcient (RC) and threshold defining the real sphere volume were determined for all settings and compared to the clinical standard (4i21ss). PET acquisitions of eight lung patients were reconstructed using all algorithms with 4i21ss. Volume size and tracer uptake were determined with different segmentation methods. The threshold for the TrueX was lower (up to 40%) than for the OSEM. The RC for the different algorithms and filters varied. TrueX was more sensitive to permutations of i and ss and only the RC of the OSEM stabilised with increasing number. For patient scans the difference of the volume and activity between TrueX and OSEM could be reduced by applying an adapted threshold and activity correction. The TrueX algorithm results in excellent diagnostic image quality, however, guidelines for native algorithms have to be extended for PSF based reconstruction methods. For appropriate tumour delineation, for the TrueX a lower threshold than the 42% recommended for the OSEM is necessary. These filter dependent thresholds have to be verified for different scanners prior to using them in multicenter trials.


First-year medical students' assessment of their own communication skills: a video-based, open-ended approach.
Interpersonal and communication skills are a core area of competency for medical students, residents, and practicing physicians. As reflection and self-assessment are essential components of skill-building, we examined the content of medical students' assessments of their own developing communication skills. Between 2000 and 2003, a total of 674 first-year medical students completed self-assessments of their communication skills after viewing videotapes of their interaction with simulated patients. Self-assessment forms were open-ended, providing ample space for students to write about the strengths and weaknesses they observed. Completed forms were coded by two members of the research team trained in content analysis. Students identified an average of 5.0 things that went well (range 1-15, S.D.=2.2) and 2.8 areas for improvement (range 1-9, S.D.=1.3). The most frequently observed strengths were: elicited information/covered important topics (54%); made a personal connection/established rapport (51%); was supportive/encouraging/helpful (40%); attended to conversational flow and transitions (34%); ensured patient comfort (32%). The most frequently noted weaknesses involved problems with: eliciting information/covering important topics (35%); paralanguage, particularly in terms of tone, rate, volume, and disfluencies such as "uh", "um" (32%); discussing health risks (26%); attending to conversational flow and transitions (23%); students' own comfort/organization/preparation (20%). We observed that a video-based, open-ended approach to self-assessment is feasible, practical, and informative. While the self-assessments covered a broad scope, students clearly attended to tasks and skills relevant to effective communication and relationship building. Videotaped clinical encounters allow learners to review their own behavior and make specific comments supported by tangible examples. An open-ended approach to self-assessment of communication skills can serve as one important component of a systematic education and evaluation program.


Exclusive use of acid citrate dextrose for anticoagulation during extracorporeal photopheresis in patients with contraindications to heparin: an effective protocol.
Extracorporeal photopheresis (ECP) routinely uses heparin for anticoagulation. For patients with contraindications to heparin, alternative anticoagulation using acid citrate dextrose (ACD-A) has been reported to be safe and effective. However, detailed ECP protocols that exclusively use ACD-A anticoagulation and minimize citrate toxicity have not yet been published. We report a protocol that completely replaces heparin with ACD-A for ECP, which was developed at the University of California, Los Angeles (UCLA), and our experience since its implementation. ECP was performed with the UVAR XTS photopheresis system using ACD-A and control of the rate of citrate infusion. Calcium gluconate solution was administered prophylactically and as needed for symptoms of citrate toxicity. The medical records of patients who underwent ECP using the ACD-A protocol between January 2003 and July 2006 were reviewed. The incidence and severity of citrate toxicity and the technical data for all procedures were analyzed. During this period, 94 ECP procedures were performed with ACD-A anticoagulation on five patients. All patients tolerated the procedures well without significant complications. Only minimal symptoms of citrate toxicity (grade 1) were observed in 24.5% of all procedures; symptoms resolved promptly following administration of additional calcium gluconate. In conclusion, an effective protocol for ECP using ACD-A anticoagulation exclusively in patients with contraindications to heparin employs continuous monitoring of flow rates and prophylactic administration of calcium gluconate to minimize citrate toxicity.


[Decision committees in oncology: from standard to actual cases].
Medical decision making, especially in oncology, is more and more assisted by pre-established therapeutic protocols. But applying these protocols for particular cases is sometimes difficult; then, local expertise intervenes. For solving these difficult cases, Alexis-Vautrin like other centers, organizes committees for therapeutic decisions. This paper aims to describe, from a field study, the tools for medical decision making and the difficulties of using them. These result of the analysis of decision committee for breast cancers in a center using of protocols, which the first were established twenty years ago. This analysis was carried out by a team of oncologists and ergonomists; it stresses on collective decision making as a mean for adapting rules and exchanging knowledge. Furthermore, these findings lead to discuss using of decision committee for advancement and particularization of protocols themselves.


Carbon assimilation and nitrogen in needles of fertilized and unfertilized field-grown Scots pine at natural and elevated concentrations of CO2.
Effects of elevated CO2 concentration ([CO2]) on carbon assimilation and needle biochemistry of fertilized and unfertilized 25-30-year-old Scots pine (Pinus sylvestris L.) trees were studied in a branch bag experiment set up in a naturally regenerated stand. In each tree, one branch was enclosed in a bag supplied with ambient [CO2] (360 micromol mol(-1)), a second branch was enclosed in a bag supplied with elevated [CO2] (680 micromol(-1)) and a control branch was left unbagged. The CO2 treatments were applied from April 15 to September 15, starting in 1993 for unfertilized trees and in 1994 for fertilized trees, which were treated with N in June 1994. Net photosynthesis, amount and activity of Rubisco, N, starch, C:N ratio and SLA of needles were measured during the growing season of 1995. Light-saturated net photosynthetic rates of 1-year-old and current-year shoots measured at ambient [CO2] were not affected by growth [CO2] or N fertilization. Elevated [CO2] reduced the amount and activity of Rubisco, and the relative proportion of Rubisco to soluble proteins and N in needles of unfertilized trees. Elevated [CO2] also reduced the chlorophyll concentration (fresh weight basis) of needles of unfertilized trees. Soluble protein concentration of needles was not affected by growth [CO2]. Elevated [CO2] decreased the Rubisco:chlorophyll ratio in unfertilized and fertilized trees. Starch concentration was significantly increased at elevated [CO2] only in 1-year-old needles of fertilized trees. Elevated [CO2] reduced needle N concentration on a dry weight or structural basis (dry weight minus starch) in unfertilized trees, resulting in an increase in needle C:N ratio. Fertilization had no effect on soluble protein, chlorophyll, Rubisco or N concentration of needles. The decrease in the relative proportions of Rubisco and N concentration in needles of unfertilized trees at elevated [CO2] indicates reallocation of N resources away from Rubisco to nonphotosynthetic processes in other plant parts. Acclimation occurred in a single branch exposed to high [CO2], despite the large sink of the tree. The responses of 1-year-old and current-year needles to elevation of growth [CO2] were similar.


Efficacy of different irrigation techniques in the removal of calcium hydroxide from a simulated internal root resorption cavity.
To evaluate the efficacy of six irrigation techniques to remove calcium hydroxide (CH) from a simulated internal root resorption cavity. The root canals of 100 single-rooted teeth were prepared using the ProTaper system to size F5. The roots were split longitudinally, and standardized simulated internal root resorption cavities were prepared in the two root halves. The root halves were reassembled, and CH was placed into the root canals, with the exception of five teeth that served as the negative control group. Another five teeth (the positive control group) were not subjected to the CH removal procedure. Ninety teeth were randomly divided into six experimental groups (n = 15), according to the final irrigation techniques used: conventional syringe irrigation (CSI), CanalBrush (CB), passive ultrasonic irrigation (PUI), self-adjusting file (SAF) system, EndoActivator (EA), and apical negative pressure irrigation (EndoVac system). Five millilitres of 3% NaOCl and 17% EDTA were used in all experimental groups during the CH removal procedure. The amount of remaining CH was evaluated under a stereomicroscope at 20 ×magnification, using a 4-grade scoring system. The data were statistically compared using the Kruskal-Wallis and Mann-Whitney U-tests (P < 0.05). Remnants of CH in simulated internal root resorption cavities were found in all experimental groups. SAF and PUI were superior to the other groups (P < 0.05); however, there was no significant difference between the SAF and PUI (P > 0.05). There were also no significant differences between the CSI, CB, EA and EndoVac groups (P > 0.05). None of the irrigation techniques was able to completely remove CH from a simulated internal root resorption cavity.


Haemogram and Serum Biochemical Values of Four Indigenous Species of Monkeys in South West Nigeria.
Haematological and serum biochemical values are useful guides and biomarkers in health and diseases for reaching a diagnosis, estimating disease prognosis and monitoring treatment progress, in mammals. Reference ranges for some parameters differ among species of mammals and between sexes within a species. There is dearth of information on standard reference value for blood parameters for Nigerian indigenous monkeys. Whole blood and serum samples obtained from 50 apparently healthy adult monkeys in both captivity and from the wild in southwest Nigeria were subjected to haematology and serum biochemistry to obtain preliminary reference values for haematological and serum biochemical analytes for Cercocebus sebaeus (Green monkey), Cercopithecus mona (Mona monkey), Erythrocebus patas (Patas monkey) and Papio anubis (Anubis baboon). Numerical data were summarized as mean and standard deviation and subjected to statistical analysis; Student t test and analysis of variance, to compare values of blood parameters obtained between species and gender. A p-value less than 0.05 was considered significant. The hematocrit of male animals were significantly higher than that of females (P=0.01) in all the 4 species studied but there was no significant difference in other blood parameters such as total white blood cell and the differential counts, platelet count, serum aspartate transferase, alanine transferase, alkaline phosphatase, total plasma protein, albumin, and globulin concentrations between the sexes. Generally, there was no significant difference between total white blood cell and the differential counts, hematocrit, red cell count, haemoglobin concentration, platelet count, serum aspartate transferase, alanine transferase, alkaline phosphatase, total plasma protein, albumin, and globulin concentrations among the monkey species.


[Probiotics: from the lab to the consumer].
In the last years, the field of probiotics has grown notably. However, out of the thousands of strains isolated each year in the labs around the world, very few enter in a phase of industrial development and even a lower number go to the market. In this article, the main aspects that have to be taken into account in the, usually, long and winding road that a strain must follow from isolation to the market are reviewed Results and conclusions: A probiotic microorganism has to be correctly identified at the species and strain levels. The genome sequence is the gold identification standard and provides valuable information on the safety, functionality and technological properties of a strain. The cases in which a link between a probiotic and an adverse effect has been established are scarce and have involved people with underlying pathologies. There is a wide variety of in vitro, ex vivo and animal model assays for the screening of probiotics, which provide useful information throughout the selection process; however, correctly designed clinical trials are the only way to obtain direct results on the safety and efficacy of a probiotic to the target population. Probiotic companies have the need to obtain a very high bacterial biomass in an economically viable manner while preserving the concentration of live bacteria required for exerting the expected beneficial effect until the end of the probiotic's shelf life. Finally, commercial aspects play a key role in the decision of starting an industrial development and, eventually, to place a probiotic in the market.


Impact of bioenergy feedstock carbon farming on sustainable aviation fuel viability in the United States.
Biomass-derived sustainable aviation fuel holds significant potential for decarbonizing the aviation sector. Its long-term viability depends on crop choice, longevity of soil organic carbon (SOC) sequestration, and the biomass-to-biojet fuel conversion efficiency. We explored the impact of fuel price and SOC value on viable biojet fuel production scale by integrating an agroecosystem model with a field-to-biojet fuel production process model for 1,4-dimethylcyclooctane (DMCO), a representative high-performance biojet fuel molecule, from Miscanthus, sorghum, and switchgrass. Assigning monetary value to SOC sequestration results in substantially different outcomes than an increased fuel selling price. If SOC accumulation is valued at $185/ton CO2, planting Miscanthus for conversion to DMCO would be economically cost-competitive across 66% of croplands across the continental United States (US) by 2050 if conventional jet fuel remains at $0.74/L (in 2020 US dollars). Cutting the SOC sequestration value in half reduces the viable area to 54% of cropland, and eliminating any payment for SOC shrinks the viable area to 16%. If future biojet fuel prices increase to $1.24/L-Jet A-equivalent, 48 to 58% of the total cultivated land in the United States could support a more diverse set of feedstocks including Miscanthus, sorghum, or switchgrass. Among these options, only 8-14% of the area would be suitable exclusively for Miscanthus cultivation. These findings highlight the intersection of natural solutions for carbon removal and the use of deep-rooted feedstocks for biofuels and biomanufacturing. The results underscore the need to establish clear and consistent values for SOC sequestration to enable the future bioeconomy.


Contact Sensitization to Allergens in Nail Cosmetics.
Ingredients found in the nail cosmetic industry, including but not limited to methacrylate and acrylate monomers, formaldehyde, and toluene sulfonamide-formaldehyde resin, can incite allergic contact dermatitis. An eczematous outbreak presents on areas surrounding the nail plate and may spread through contact transfer of the allergen, commonly to the face and neck. Even components that were originally deemed nonsensitizing, such as the ubiquitous cyanoacrylate adhesive family, have been found to be allergenic. They do not, however, cross-react with methacrylates and acrylates. Alternative options for individuals with allergic contact dermatitis reactions to these ingredients can be avoidance of these procedures or use of products that are "3, 4, 5 free" in which the common allergens dibutyl phthalate, toluene, and formaldehyde are absent. In cases where strengthening of the nail is the sole purpose, nail wraps or preformed nails can be applied for non-cyanoacrylate-sensitive individuals.


Prenatal bisphenol a and phthalate exposure are risk factors for male reproductive system development and cord blood sex hormone levels.
Bisphenol A (BPA) and phthalates can adversely affect the fetal development. However, observational studies on the effects of these chemicals on fetal male reproductive system are still limited. A hundred of umbilical cord blood samples were analyzed for the levels of BPA, di-2-ethylhexyl phthalate (DEHP), mono-2-ethylhexyl phthalate (MEHP), and sex hormones. After birth, male newborns underwent physical examination that included measurements of anogenital distance, stretched penile length (SPL), and penile width. BPA, DEHP and MEHP levels were detectable in ≈99% of cord blood samples. In covariate-adjusted models, cord blood BPA levels were inversely associated with SPL of newborns and positively associated with cord blood estradiol levels. In addition, there was a significant inverse relationship between cord blood DEHP levels and anogenital distance index of newborn males. Our results suggest that in utero BPA and DEHP exposure exerted adverse effects on fetal male reproductive development and cord blood estradiol levels.


Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry?
Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory. Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to smaller peptide fragments by antibody hydrolysis. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Vasoactive neuropeptides are widely distributed in the body particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, blood cells and other tissues. They have a vital role in maintaining vascular flow in organs, and in thermoregulation, memory and concentration. They are co-transmitters for acetylcholine, nitric oxide, endogenous opioids and insulin, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system to toxic assault, promotion of neural development and the maintenance of homeostasis. This paper describes a biologically plausible mechanism for the development of CFS based on loss of immunological tolerance to the vasoactive neuropeptides following infection, significant physical exercise or de novo. It is proposed that release of these substances is accompanied by a loss of tolerance either to them or their receptor binding sites in CFS. Such an occurrence would have predictably serious consequences resulting from compromised function of the key roles these substances perform. All documented symptoms of CFS are explained by vasoactive neuropeptide compromise, namely fatigue and nervous system dysfunction through impaired acetylcholine activity, myalgia through nitric oxide and endogenous opioid dysfunction, chemical sensitivity through peroxynitrite and adenosine dysfunction, and immunological disturbance through changes in immune modulation. Perverse immunological memory established against these substances or their receptors may be the reason for the protracted nature of this condition. The novel status of these substances together with their extremely small concentrations in blood and tissues means that clinical research into them is still in its infancy. A biologically plausible theory of CFS causation associated with vasoactive neuropeptide dysfunction would promote a coherent and systematic approach to research into this and other possibly associated disabling conditions.


[Changes in the phospholipid composition of rat liver chromatin during treatment with hydrocortisone].
When isolating protein components of chromatin from the rat liver phospholipids are found in the fraction of nonhistone proteins but not in that of histone. Administration of hydrocortisone to animals evokes a reliable increase of the phospholipids of hydrocortisone to animals evokes a reliable increase of the phospholipids amount in the preparations of chromatin and labile-bound nonhistone proteins. In this case the fraction of phosphatidylcholine lowers considerably with a simultaneous increase of sphingomyelin and phosphatidylethanolamine. It is supposed that phospholipid metabolism in chromatin is controlled by hormones, which may be significant for mechanisms of the genetic apparatus activation by steroid hormones.


Understanding G-Quadruplex Biology and Stability Using Single-Molecule Techniques.
The link between the chemical stability of G-quadruplex (qDNA) structures and their roles in eukaryotic genomic maintenance processes has been an area of interest now for several decades. This Review seeks to demonstrate how single-molecule force-based techniques can provide insight into the mechanical stabilities of a variety of qDNA structures as well as their ability to interconvert between different conformations under conditions of stress. Atomic force microscopy (AFM) and magnetic and optical tweezers have been the primary tools used in these investigations and have been used to examine both free and ligand-stabilized G-quadruplex structures. These studies have shown that the degree of stabilization of G-quadruplex structures has a significant effect on the ability of nuclear machinery to bypass these roadblocks on DNA strands. This Review will illustrate how various cellular components including replication protein A (RPA), Bloom syndrome protein (BLM), and Pif1 helicases are capable of unfolding qDNA. Techniques such as single-molecule fluorescence resonance energy transfer (smFRET), often in conjunction with the aforementioned force-based techniques, have proven extremely effective at elucidating the factors underpinning the mechanisms by which these proteins unwind qDNA structures. We will provide insight into how single-molecule tools have facilitated the direct visualization of qDNA roadblocks and also showcase results obtained from experiments designed to examine the ability of G-quadruplexes to limit the access of specific cellular proteins normally associated with telomeres.


Recruitment and progress of minority medical school entrants 1970-1972.
This is a report on a national study of minority group applicants and entrants to the 1970, 1971, and 1972 entering classes of U.S. medical colleges. The aim of the investigation was to further understanding of the factors involved in attempting to increase minority representation in education for the practice of medicine. Data from the Association of American Medical Colleges are used to examine characteristics of successful and unsuccessful minority applicants to medical school. Socieconomic, personal, institutiona, and geographical factors that relate to the recruitment and progress of minority students in medicine are analyzed and evaluated. Differences between Caucasian and minority group students affecting admissions, retention, and promotion are documented. The investigators also compare the projections of a 1970 AAMC task force report with actual occurrences in the national effort to expand educational opportunities in medicine for blacks and other underrepresented minority students (that is, American Indians, Mexican Americans, and mainland Puerto Ricans). This comparison shows substantial progress toward the projected figures but a need for renewed commitment if they are to be reached. Suggestions are offered for improving the recruitment and progress of minority medical school entrants by such means as the AAMC Simulated Minority Admissions Exercises and by ongoing programs at individual medical schools. The study also yielded such pertinent findings as the following: 1. Confirmation that the racial characterizations self-reported by medical school applicants have a high degree of accuracy and an increasing degree of completeness. 2. An encouraging increase in the number of black premedical students who will potentially apply for the medical school classes entering in 1976 and 1977. 3. Growth in the enrollment of low-income medical students, most of it explained by the increase in the numbers of minority group members who have been admitted in recent years. 4. More mobility among blacks than Caucasians with regard to attending medical schools in other than their region of legal residence. 5. A higher proportion of women, of older, and of married students among minority medical school matriculants than among Caucasian matriculants. 6. A slightly higher medical school retention rate for Caucasians than for students from underrepresented minority groups, possibly explained in part by the greater diversity in the socioeconomic and educational backgrounds of the latter. 7. A positive relationship for blacks between the size of undergraduate college attended and successful completion of the first year of medical school.


Time to recurrence and survival in serous ovarian tumors predicted from integrated genomic profiles.
Serous ovarian cancer (SeOvCa) is an aggressive disease with differential and often inadequate therapeutic outcome after standard treatment. The Cancer Genome Atlas (TCGA) has provided rich molecular and genetic profiles from hundreds of primary surgical samples. These profiles confirm mutations of TP53 in ~100% of patients and an extraordinarily complex profile of DNA copy number changes with considerable patient-to-patient diversity. This raises the joint challenge of exploiting all new available datasets and reducing their confounding complexity for the purpose of predicting clinical outcomes and identifying disease relevant pathway alterations. We therefore set out to use multi-data type genomic profiles (mRNA, DNA methylation, DNA copy-number alteration and microRNA) available from TCGA to identify prognostic signatures for the prediction of progression-free survival (PFS) and overall survival (OS). We implemented a multivariate Cox Lasso model and median time-to-event prediction algorithm and applied it to two datasets integrated from the four genomic data types. We (1) selected features through cross-validation; (2) generated a prognostic index for patient risk stratification; and (3) directly predicted continuous clinical outcome measures, that is, the time to recurrence and survival time. We used Kaplan-Meier p-values, hazard ratios (HR), and concordance probability estimates (CPE) to assess prediction performance, comparing separate and integrated datasets. Data integration resulted in the best PFS signature (withheld data: p-value = 0.008; HR = 2.83; CPE = 0.72). We provide a prediction tool that inputs genomic profiles of primary surgical samples and generates patient-specific predictions for the time to recurrence and survival, along with outcome risk predictions. Using integrated genomic profiles resulted in information gain for prediction of outcomes. Pathway analysis provided potential insights into functional changes affecting disease progression. The prognostic signatures, if prospectively validated, may be useful for interpreting therapeutic outcomes for clinical trials that aim to improve the therapy for SeOvCa patients.


Identification of Lactobacillus sakei genes induced during meat fermentation and their role in survival and growth.
Lactobacillus sakei is a lactic acid bacterium that is ubiquitous in the food environment and is one of the most important constituents of commercial meat starter cultures. In this study, in vivo expression technology (IVET) was applied to investigate gene expression of L. sakei 23K during meat fermentation. The IVET vector used (pEH100) contained promoterless and transcriptionally fused reporter genes mediating beta-glucuronidase activity and erythromycin resistance. A genomic library of L. sakei 23K was established, and the clones were subjected to fermentation in a raw-sausage model. Fifteen in carne-induced fusions were identified. Several genes encoded proteins which are likely to contribute to stress-related functions. One of these genes was involved in acquisition of ammonia from amino acids, and the remaining either were part of functionally unrelated pathways or encoded hypothetical proteins. The construction and use of isogenic mutants in the sausage model suggested that four genes have an impact on the performance of L. sakei during raw-sausage fermentation. Inactivation of the heat shock regulator gene ctsR resulted in increased growth, whereas knockout of the genes asnA2, LSA1065, and LSA1194 resulted in attenuated performance compared to the wild-type strain. The results of our study are the first to provide an insight into the transcriptional response of L. sakei when growing in the meat environment. In addition, this study establishes a molecular basis which allows investigation of bacterial properties that are likely to contribute to the ecological performance of the organism and to influence the final outcome of sausage fermentation.


Multi-omics analyses reveal bacteria and catalase associated with keloid disease.
The pathology of keloid and especially the roles of bacteria on it were not well understood. In this study, multi-omics analyses including microbiome, metaproteomics, metabolomic, single-cell transcriptome and cell-derived xenograft (CDX) mice model were used to explore the roles of bacteria on keloid disease. We found that the types of bacteria are significantly different between keloid and healthy skin. The 16S rRNA sequencing and metaproteomics showed that more catalase (CAT) negative bacteria, Clostridium and Roseburia existed in keloid compared with the adjacent healthy skin. In addition, protein mass spectrometry shows that CAT is one of the differentially expressed proteins (DEPs). Overexpression of CAT inhibited the proliferation, migration and invasion of keloid fibroblasts, and these characteristics were opposite when CAT was knocked down. Furthermore, the CDX model showed that Clostridium butyricum promote the growth of patient's keloid fibroblasts in BALB/c female nude mice, while CAT positive bacteria Bacillus subtilis inhibited it. Single-cell RNA sequencing verified that oxidative stress was up-regulated and CAT was down-regulated in mesenchymal-like fibroblasts of keloid. In conclusion, our findings suggest that bacteria and CAT contribute to keloid disease. A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.


Suppression of adjuvant disease in the rat by heterologous antilymphocyte globulin.
The effect of antilymphocyte globulin (ALG) on adjuvant arthritis, an immunologically induced disease in the rat, was studied. ALG was prepared from the serum of rabbits immunized against rat lymphocytes. Adjuvant arthritis was induced in rats by a single intracutaneous injection of Freund's complete adjuvant; after 9 to 12 days, all control rats developed polyarthritis. Administration of antilymphocyte globulin about the time of adjuvant injection produced marked inhibition of clinical disease. Some suppression was apparent even when ALG was started after the onset of arthritis. Rats receiving ALG remained conspicuously healthy compared to controls. Urinary findings and renal histology showed no evidence of nephritis. The results of serum corticosterone determinations made it unlikely that adrenal stimulation contributed to the actions of ALG. Antilymphocyte preparations lowered peripheral lymphocyte counts and suppressed primary antibody responses to sheep erythrocytes, but had little effect on the skin reaction to PPD, even in rats protected from arthritis. All rats given ALG developed antibodies to rabbit globulin; there was no evidence that ALG inhibited the appearance of antibodies to itself, and prior hyperimmunization of rats with rabbit globulin did not interfere with the biological activity of ALG subsequently injected. Antisera produced separately against lymph node and thymus cells had identical properties with regard to agglutination of lymphocytes and thymus cells. Administered to rats, these preparations were equally potent in lowering lymphocyte counts and suppressing both adjuvant arthritis and the primary antibody response to sheep erythrocytes. It is concluded that ALG, as used in these experiments, is a potent immunosuppressive agent without obvious toxic effects.


Coatings and surface modifications imparting antimicrobial activity to orthopedic implants.
Bacterial colonization and biofilm formation on an orthopedic implant surface is one of the worst possible outcomes of orthopedic intervention in terms of both patient prognosis and healthcare costs. Making the problem even more vexing is the fact that infections are often caused by events beyond the control of the operating surgeon and may manifest weeks to months after the initial surgery. Herein, we review the costs and consequences of implant infection as well as the methods of prevention and management. In particular, we focus on coatings and other forms of implant surface modification in a manner that imparts some antimicrobial benefit to the implant device. Such coatings can be classified generally based on their mode of action: surface adhesion prevention, bactericidal, antimicrobial-eluting, osseointegration promotion, and combinations of the above. Despite several advances in the efficacy of these antimicrobial methods, a remaining major challenge is ensuring retention of the antimicrobial activity over a period of months to years postoperation, an issue that has so far been inadequately addressed. Finally, we provide an overview of additional figures of merit that will determine whether a given antimicrobial surface modification warrants adoption for clinical use.


Using the electronic health record to connect primary care patients to evidence-based telephonic tobacco quitline services: a closed-loop demonstration project.
Few smokers receive evidence-based tobacco treatment during healthcare visits. Electronic health records (EHRs) present an opportunity to efficiently identify and refer smokers to state tobacco quitlines. The purpose of this case study is to develop and evaluate a secure, closed-loop EHR referral system linking patients visiting healthcare clinics with a state tobacco quitline. A regional health system, EHR vendor, tobacco cessation telephone quitline vendor, and university research center collaborated to modify a health system's EHR to create an eReferral system. Modifications included the following: clinic workflow adjustments, EHR prompts, and return of treatment delivery information from the quitline to the patient's EHR. A markedly higher percentage of adult tobacco users were referred to the quitline using eReferral than using the previous paper fax referral (14 vs. 0.3 %). The eReferral system increased the referral of tobacco users to quitline treatment. This case study suggests the feasibility and effectiveness of a secure, closed-loop EHR-based eReferral system.


Integrating Palliative Care to Promote Earlier Conversations and to Increase the Skill and Comfort of Nonpalliative Care Clinicians: Lessons Learned From an Interventional Field Trial.
While the uptake of palliative care in the United States is steadily improving, there continues to be a gap in which many patients are not offered care that explicitly elicits and respects their personal wishes. This is due in part to a mismatch of supply and demand; the number of seriously ill individuals far exceeds the workload capacities of palliative care specialty providers. We conducted a field trial of an intervention designed to promote the identification of seriously ill patients appropriate for a discussion of their goals of care and to advance the role of nonpalliative care clinicians by enhancing their knowledge of and comfort with primary palliative care skills. At 3 large Midwestern academic medical centers, a palliative care physician or nurse clinician embedded with a selected nonpalliative care service line or unit on a regularly scheduled basis for up to 6 months. Using agreed-upon criteria, patients were identified as being appropriate for a goals of care conversation; conversations with those patients and/or their families were then conducted with the palliative care specialist providing education, coaching, and mentoring to the nonpalliative care clinician, when possible. All of the sites increased the presence of palliative care within the selected service line or unit, and the nonpalliative care clinicians reported increased comfort and skill at conducting goals of care conversations. This intervention is a first step toward increasing patients' access to palliative care to alleviate distress and to more consistently deliver care that honors patient and family preferences.


Origin and evolution of Kinesin-like calmodulin-binding protein.
Kinesin-like calmodulin-binding protein (KCBP), a member of the Kinesin-14 family, is a C-terminal microtubule motor with three unique domains including a myosin tail homology region 4 (MyTH4), a talin-like domain, and a calmodulin-binding domain (CBD). The MyTH4 and talin-like domains (found in some myosins) are not found in other reported kinesins. A calmodulin-binding kinesin called kinesin-C (SpKinC) isolated from sea urchin (Strongylocentrotus purpuratus) is the only reported kinesin with a CBD. Analysis of the completed genomes of Homo sapiens, Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and a red alga (Cyanidioschyzon merolae 10D) did not reveal the presence of a KCBP. This prompted us to look at the origin of KCBP and its relationship to SpKinC. To address this, we isolated KCBP from a gymnosperm, Picea abies, and a green alga, Stichococcus bacillaris. In addition, database searches resulted in identification of KCBP in another green alga, Chlamydomonas reinhardtii, and several flowering plants. Gene tree analysis revealed that the motor domain of KCBPs belongs to a clade within the Kinesin-14 (C-terminal motors) family. Only land plants and green algae have a kinesin with the MyTH4 and talin-like domains of KCBP. Further, our analysis indicates that KCBP is highly conserved in green algae and land plants. SpKinC from sea urchin, which has the motor domain similar to KCBP and contains a CBD, lacks the MyTH4 and talin-like regions. Our analysis indicates that the KCBPs, SpKinC, and a subset of the kinesin-like proteins are all more closely related to one another than they are to any other kinesins, but that either KCBP gained the MyTH4 and talin-like domains or SpKinC lost them.


Prevalence of Sarcopenia in Older South African Patients Following Surgery for Fragility Fractures of the Hip.
Geriatric patients with a fragility fracture of the hip (FFH) are especially prone to sarcopenia with poor functional outcomes and quality of life. We assessed the prevalence of sarcopenia in older South African patients with FFH. Risk factors for sarcopenia were also investigated. From August 1 to November 30, 2018, all older patients with FFH were invited to participate. Sarcopenia was diagnosed based on the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2). Handgrip strength (HGS) and muscle strength were assessed. Muscle quantity was determined by dual-energy X-ray absorptiometry. Demographic information was collected, and 25-hydroxyvitamin D (25[OH]D) status was determined. Of the 100 hip fracture cases, 65 were enrolled, and 52% (34/65) were sarcopenic (women: 62%; men: 38%). HGS accurately identified sarcopenia (sensitivity and specificity: 100%). Patients >80 years of age had a prevalence of sarcopenia twice (18/21 [83%]) that of younger patients (18/44 [36%]). Women with sarcopenia were smaller than those without (weight: p < 0.001; height: p < 0.001; body mass index: p = 0.018). Low 25(OH)D was almost universally present, with median 25(OH)D levels significantly lower in the patients with sarcopenia (27 nmol/L [interquartile range {IQR}: 20-39] vs. 40 nmol/L [IQR: 29-53]). Several risk factors, including advanced age; female sex; a smaller body size, especially among women; limited physical activity; and low 25(OH)D levels, were identified. The accuracy of HGS testing in this cohort underscores EWGSOP2's recommendation that muscle strength is key to sarcopenia. Further study and follow-up are required to determine the clinical relevance of sarcopenia among FFH patients. The prevalence of sarcopenia in our FFH population is high. Sarcopenia is associated with poor patient outcomes following surgical intervention. Orthopaedic surgeons should therefore be cognizant of the presentation and associated risk of sarcopenia as our patient populations age.


Effect of Novel Pretreatment of Steam Explosion Associated with Ammonium Sulfite Process on Enzymatic Hydrolysis of Corn Straw.
Effective pretreatment process to improve enzymatic saccharification and decrease inhibitors generation is a key operation involved in the lignocellulosic bioconversion. The pretreatment of steam explosion associated with ammonium sulfite (SEAS) process was carried out to investigate the effect on enzymatic hydrolysis and fermentation production as a combinatorial pretreatment. Results showed that after pretreatment (1.0 MPa, 30 min, 20%w/w ammonium sulfite added), the phenolic inhibitors derived from lignin significantly removed (37.8%), which transformed to chemical humic acid (humic acid and fulvic acid) mostly. Sugar conversion (glucan (77.8%) and xylan (73.3%)) and ethanol concentration (40.8 g/L) of combinatorial pretreated samples were increased by 24.7% and 33.8%, respectively, compared with steam explosion (SE) pretreated samples. FT-IR and elemental analysis results indicated that the lignin structure changed and aromatization degree increased after SEAS pretreatment. In addition, the ratio of C/N decreased and compost maturity degree increased with the holding time. The effect on the growth of wheat seedlings of soluble fulvic acid solution from combinatorial pretreatment was investigated, where below 1% (w/w) concentration did contribute to growth. Therefore, one-step chemical pretreatment process could be provided for inhibitors removal, enzymatic saccharification increase, and chemical humic acid formation as well.


Predicting in-hospital mortality during cardiopulmonary resuscitation.
On the average, 10-15% of patients who undergo cardiopulmonary resuscitation (CPR) following a cardiopulmonary arrest in the hospital environment will survive to be discharged. The purpose of this study was to determine objective factors influencing patient outcome after CPR to determine who should be resuscitated and when to end CPR efforts. The records of 266 patients who underwent in-hospital CPR over a 3-year period were retrospectively analyzed with regard to age, gender, co-morbid conditions, setting of arrest, duration of resuscitation, initial pH and PO2 during resuscitation, and outcome of resuscitative efforts. Twenty-four (9%) patients survived to be discharged from hospital. Eighty-seven (33%) patients arrested in the intensive care unit, 77 (29%) on the ward, 91 (34%) in the emergency room, six (2%) in the cardiac catheterization laboratory and five (2%) in the operating room. There was no significant difference in survival based on location of arrest. Factors associated with a poor prognosis included age greater than 60, co-morbid disease (i.e. pneumonia, sepsis, renal failure, heart disease, etc.), an initial PO2 < 50 mmHg and CPR efforts extending beyond 10 min. Based on this data, guidelines regarding initiation and termination of CPR should be instituted in light of poor outcome in patients over 60 years of age with co-morbid conditions, specifically after 10 min of CPR.


Colitis cystica profunda in rhesus monkeys.
Spontaneously occurring colitis cystica profunda, characterized by the presence of non-neoplastic glands and mucin-containing cysts in the submucosa of the large intestine, was observed post mortem in 4 of 28 rhesus monkeys (Macaca mulatta) but in none of 20 squirrel monkeys (Saimiri sciuresu) necropsied during the same period of time. An analogous lesion in the stomach was present in 2 of the monkeys with the colonic condition. The submucosal glands and cysts resulted from extension of the mucosa through the muscularis mucosae, and inflammation was considered to have played a primary role in this process. The cause of the intestinal inflammation was not determined, and there was no known exposure to toxic chemicals, including pesticides and polychlorinated biphenyls. Colitis cystica profunda affecting man and other animals has been described infrequently in the literature, but the importance of differentiating it from intestinal adenocarcinoma has been emphasized.


Child undernutrition in Kenya: trend analyses from 1993 to 2008-09.
Research on trends in child undernutrition in Kenya has been hindered by the challenges of changing criteria for classifying undernutrition, and an emphasis in the literature on international comparisons of countries' situations. There has been little attention to within-country trend analyses. This paper presents child undernutrition trend analyses from 1993 to 2008-09, using the 2006 WHO criteria for undernutrition. The analyses are decomposed by child's sex and age, and by maternal education level, household Wealth Index, and province, to reveal any departures from the overall national trends. The study uses the Kenya Demographic and Health Survey data collected from women aged 15-49 years and children aged 0-35 months in 1993, 1998, 2003 and 2008-09. Logistic regression was used to test trends. The prevalence of wasting for boys and girls combined remained stable at the national level but declined significantly among girls aged 0-35 months (p < 0.05). While stunting prevalence remained stagnant generally, the trend for boys aged 0-35 months significantly decreased and that for girls aged 12-23 months significantly increased (p < 0.05). The pattern for underweight in most socio-demographic groups showed a decline. The national trends in childhood undernutrition in Kenya showed significant declines in underweight while trends in wasting and stunting were stagnant. Analyses disaggregated by demographic and socio-economic segments revealed some significant departures from these overall trends, some improving and some worsening. These findings support the importance of conducting trend analyses at detailed levels within countries, to inform the development of better-targeted childcare and feeding interventions.


Reducing cell wall feruloylation by expression of a fungal ferulic acid esterase in Festuca arundinacea modifies plant growth, leaf morphology and the turnover of cell wall arabinoxylans.
A feature of cell wall arabinoxylan in grasses is the presence of ferulic acid which upon oxidative coupling by the action of peroxidases forms diferuloyl bridges between formerly separated arabinoxylans. Ferulate cross-linking is suspected of playing various roles in different plant processes. Here we investigate the role of cell wall feruloyaltion in two major processes, that of leaf growth and the turnover of cell wall arabinoxylans on leaf senescence in tall fescue using plants in which the level of cell wall ferulates has been reduced by targeted expression of the Aspergillus niger ferulic acid esterase A (FAEA) to the apoplast or Golgi. Analysis of FAE expressing plants showed that all the lines had shorter and narrower leaves compared to control, which may be a consequence of the overall growth rate being lower and occurring earlier in FAE expressing leaves than in controls. Furthermore, the final length of epidermal cells was shorter than controls, indicating that their expansion was curtailed earlier than in control leaves. This may be due to the observations that the deposition of both ether and ester linked monomeric hydroxycinnamic acids and ferulate dimerization stopped earlier in FAE expressing leaves but at a lower level than controls, and hydroxycinnamic acid deposition started to slow down when peroxidase levels increased. It would appear therefore that one of the possible mechanisms for controlling overall leaf morphology such as leaf length and width in grasses, where leaf morphology is highly variable between species, may be the timing of hydroxycinnamic acid deposition in the expanding cell walls as they emerge from cell division into the elongation zone, controlled partially by the onset of peroxidase activity in this region.


PDX models recapitulate the genetic and epigenetic landscape of pediatric T-cell leukemia.
We compared 24 primary pediatric T-cell acute lymphoblastic leukemias (T-ALL) collected at the time of initial diagnosis and relapse from 12 patients and 24 matched patient-derived xenografts (PDXs). DNA methylation profile was preserved in PDX mice in 97.5% of the promoters (ρ = 0.99). Similarly, the genome-wide chromatin accessibility (ATAC-Seq) was preserved remarkably well (ρ = 0.96). Interestingly, both the ATAC regions, which showed a significant decrease in accessibility in PDXs and the regions hypermethylated in PDXs, were associated with immune response, which might reflect the immune deficiency of the mice and potentially the incomplete interaction between murine cytokines and human receptors. The longitudinal approach of this study allowed an observation that samples collected from patients who developed a type 1 relapse (clonal mutations maintained at relapse) preserved their genomic composition; whereas in patients who developed a type 2 relapse (subset of clonal mutations lost at relapse), the preservation of the leukemia's composition was more variable. In sum, this study underlines the remarkable genomic stability, and for the first time documents the preservation of the epigenomic landscape in T-ALL-derived PDX models.


Definition of a sequence, RYVVLPR, within laminin peptide F-9 that mediates metastatic fibrosarcoma cell adhesion and spreading.
A synthetic peptide from the inner globule of the B1 chain of laminin, termed peptide F-9 (RYVVLPRPVCFEKGMNYTVR; residues 641-660), has been shown to have heparin-binding and cell adhesion-promoting activities for diverse cell types (Charonis et al., J. Cell. Biol., 107: 1253-1260, 1988). In this study, the metastatic murine fibrosarcoma cell line, UV-2237-MM, adhered and spread on surfaces coated with laminin and peptide F-9 in a concentration- and time-dependent fashion. Cells migrated toward laminin in Boyden microchemotaxis chambers but not toward peptide F-9. However, exogenous soluble peptide F-9 inhibited both the adhesion and migration of cells toward laminin. Polyclonal antibodies raised against peptide F-9 were capable of inhibiting laminin-mediated cell adhesion and migration. Peptide F-9 is located 265 residues from CDPGYIGSR, another sequence on the B1 chain of laminin which has been reported by others to promote cell adhesion (Graft et al., Cell, 48: 989-996, 1987). In contrast to peptide F-9, various control peptides including CDPGYIGSR did not promote the adhesion, spreading, or migration of the UV-2237-MM fibrosarcoma cells. In addition, neither exogenous peptide CDPGYIGSR nor antibodies raised against peptide CDPGYIGSR were capable of inhibiting laminin-mediated cell adhesion or migration. These results indicate that peptide F-9, but not peptide CDPGYIGSR, represents a major fibrosarcoma cell adhesion-promoting domain on intact laminin. A series of overlapping peptides were synthesized which contained various portions of the parent peptide F-9. The use of these peptides in cell adhesion assays demonstrated that the sequence RYVVLPR from the amino terminus of peptide F-9 was essential for cell adhesion-promoting activity.


The ischemic penumbra: operationally defined by diffusion and perfusion MRI.
Identifying tissue at risk for infarction is important in deciding which patients would benefit most from potentially harmful therapies and provides a way to evaluate newer therapies with regard to the amount of ischemic tissue salvaged. To operationally define and characterize cerebral tissue at risk for stroke progression. We retrospectively selected 25 patients with an acute onset of a hemispheric stroke from our database who had undergone a combination of two diffusion-weighted MRI studies and a perfusion-weighted MRI study. We applied a logistic regression model using maps of the relative mean transit time and relative cerebral blood flow (rCBF) as well as three different maps of the relative cerebral blood volume (rCBV) to predict an operationally defined penumbra (region of mismatch between the diffusion lesion on day 1 and its extension 24 to 72 hours later). Maps of the rCBF and initial rCBV were significant predictors for identifying penumbral tissue. Our operationally defined penumbral region was characterized by a reduction in the initial rCBV (47% of contralateral control region [CCR]), an increase (163% of CCR) in the total rCBV, and a reduction (37% of CCR) in the rCBF, whereas the operationally defined ischemic core showed a more severe reduction in the rCBF (12% of CCR) and in the initial rCBV (19% of CCR). These MR indexes may allow the identification and quantification of viable but ischemically threatened cerebral tissue amenable to therapeutic interventions in the hyperacute care of stroke patients.


Hemodynamic consequences of femoral arteriovenous bovine shunts.
Seventeen patients with femoral arteriovenous bovine shunts (FAVBS) were evaluated to delineate the cardiovascular consequences of the procedure. The resting cardiac index (CI), as estimated by echocardiography, was increased in 8 patients (47%). Twelve of the 17 patients (71%) had more than a 20% reduction in CI after 5 minutes of shunt occlusion. In 6 of these, the CI returned to normal from an abnormally high value. As a group, the decrease in CI was significant (P = 0.001). This was accomplished mainly by a significant decrease in stroke volume (P less than or equal to 0.004). Signs and symptoms of congestive heart failure developed in 10 of the 17 patients during the year following FAVBS. Because of the marginal cardiac reverse in patients with renal failure and the significant increase in cardiac index resulting from FAVBS, alternative forms of vascular access should be used whenever possible.


EGCG down-regulates MuRF1 expression through 67-kDa laminin receptor and the receptor signaling is amplified by eriodictyol.
(-)-epigallocatechin-3-O-gallate (EGCG) is a bioactive polyphenol in green tea. Previous studies have demonstrated the beneficial effects of EGCG on muscle mass and muscle atrophy. In the current study, we investigated the mechanisms underlying effect of EGCG on muscle atrophy. It was demonstrated that EGCG suppressed muscle-specific ubiquitin ligase, muscle RING Finger 1 (MuRF1) expression through 67-kDa laminin receptor (67LR). Previous studies have shown that eriodictyol potentiates the anti-tumor activities of EGCG by amplifying 67LR signaling. Therefore, we investigated the effects of EGCG and eriodictyol on the MuRF1 expression in C2C12 myotubes. The combined treatment of EGCG and eriodictyol significantly suppressed MuRF1 expression in dexamethasone-treated C2C12 myotubes. Tail suspension was maintained for 10 consecutive days using C57BL6/J mice, and during this time EGCG and eriodictyol were orally administered. In the gastrocnemius muscle, the muscle mass loss was inhibited by the combination of EGCG and eriodictyol. Therefore, EGCG may prevent muscle atrophy by inducing 67LR signaling and eriodictyol amplifies this pathway.


Markers of cardiac dysfunction associated with inflammation in a cohort of patients with acute decompensation of cirrhosis.
Inflammation underpinning acute decompensation (AD) of liver disease is an important driver for the development of acute-on-chronic liver failure or death. We aimed to investigate associations between inflammatory biomarkers and impaired cardiac function in patients admitted for AD of cirrhosis. This is a retrospective analysis of a well-characterized prospective cohort of patients with AD of liver disease admitted to a tertiary referral center. All patients had echocardiographic assessment of cardiac function and serum samples at admission. We reclassified patients according to the CLIF-C AD score, measured inflammatory (IL-6, IL-8, TNF-ɑ, CD206) and cardiac-specific (NT-proBNP, troponin T) biomarkers and tested for associations with echocardiographic parameters of cardiac function. We explored the impact on outcome of these factors in multivariate analysis. We included 70 patients (58 ± 10 years, 28 women), with a mean CLIF-C AD score of 47 ± 7. Thirty-nine patients (56%) fulfilled the echocardiographic criteria for cardiac dysfunction. We found associations between parameters of diastolic dysfunction and serum concentrations of IL-6 and CD206. Echocardiographic parameters of cardiac function were not associated with markers of liver dysfunction such as the CLIF-C AD score. In multivariate analysis higher MELD, higher NT-proBNP, and IL-8 concentrations as well as the absence of echocardiographic criteria for cardiac dysfunction significantly associated with death during follow-up. We found evidence in favor of a clinically relevant link between serum biomarkers of inflammation (IL-6, CD206) and echocardiographic signals of cardiac dysfunction in patients with acutely decompensated cirrhosis.


Restoration of p53 functions protects cells from concanavalin A-induced apoptosis.
A great majority of human cancers encounter disruption of the p53 network. Identification and characterization of molecular components important in both p53-dependent and p53-independent apoptosis might be useful in developing novel therapies. Previously, we reported that concanavalin A (Con A) induced p73-dependent apoptosis of cells lacking functional p53. In the present study, we investigated the mechanism and role of p53 in protection from apoptosis induced by Con A. Treatment with Con A resulted in apoptosis of p53-null ovarian cancer, SKOV3, or Li-Fraumeni syndrome, MDAH041 (041), cells. However, their isogenic pairs, SKP53 and TR9-7, expressing wild-type p53 were much less sensitive and were protected by G(1) arrest. Inhibition of p53 function rendered these cells sensitive to Con A. Con A-induced apoptosis was accompanied by upregulation of forkhead box O1a (FOXO1a) and Bcl-2-interacting mediator (Bim), which were strongly inhibited after p53 expression and rescued after p53 ablation. Moreover, ablation of Bim by short hairpin RNA protected cells from apoptosis. Taken together, our study suggests that Con A induces apoptosis of cells lacking p53 by activating FOXO1a-Bim signaling and that expression of p53 protects these cells by inducing G(1) arrest and by downregulating the expression of both FOXO1a and Bim, identifying a novel cross-talk between FOXO1a and p53 transcription factors.