Transplantation of mononuclear cells from human umbilical cord blood promotes functional recovery after traumatic spinal cord injury in Wistar rats.
Cell transplantation is a promising experimental treatment for spinal cord injury. The aim of the present study was to evaluate the efficacy of mononuclear cells from human umbilical cord blood in promoting functional recovery when transplanted after a contusion spinal cord injury. Female Wistar rats (12 weeks old) were submitted to spinal injury with a MASCIS impactor and divided into 4 groups: control, surgical control, spinal cord injury, and one cell-treated lesion group. Mononuclear cells from umbilical cord blood of human male neonates were transplanted in two experiments: a) 1 h after surgery, into the injury site at a concentration of 5 x 10(6) cells diluted in 10 µL 0.9% NaCl (N = 8-10 per group); b) into the cisterna magna, 9 days after lesion at a concentration of 5 x 10(6) cells diluted in 150 µL 0.9% NaCl (N = 12-14 per group). The transplanted animals were immunosuppressed with cyclosporin-A (10 mg/kg per day). The BBB scale was used to evaluate motor behavior and the injury site was analyzed with immunofluorescent markers to label human transplanted cells, oligodendrocytes, neurons, and astrocytes. Spinal cord injury rats had 25% loss of cord tissue and cell treatment did not affect lesion extension. Transplanted cells survived in the injured area for 6 weeks after the procedure and both transplanted groups showed better motor recovery than the untreated ones (P < 0.05). The transplantation of mononuclear cells from human umbilical cord blood promoted functional recovery with no evidence of cell differentiation.


Redox regulation of germline and vulval development in Caenorhabditis elegans.
In vitro studies have indicated that reactive oxygen species (ROS) and the oxidation of signaling molecules are important mediators of signal transduction. We have identified two pathways by which the altered redox chemistry of the clk-1 mutants of Caenorhabditis elegans acts in vivo on germline development. One pathway depends on the oxidation of an analog of vertebrate low density lipoprotein (LDL) and acts on the germline through the Ack-related tyrosine kinase (ARK-1) kinase and inositol trisphosphate (IP3) signaling. The other pathway is the oncogenic ras signaling pathway, whose action on germline as well as vulval development appears to be modulated by cytoplasmic ROS.


Occurrence and implications of voltage reversal in stacked microbial fuel cells.
Voltage reversal in stacked microbial fuel cells (MFCs) is a significant challenge that must be addressed, and the information on its definite cause and occurrence process is still obscure. In this work, we first demonstrated that different anodic reaction rates caused voltage reversal in a stacked MFC. Sluggish reaction rates on the anode in unit 1 of the stacked MFC resulted in a significantly increased anode overpotential of up to 0.132 V, as compared to negligible anode overpotential (0.0247 V) in unit 2. This work clearly verified the process of voltage reversal in the stacked MFC. As the current was gradually increased in the stacked MFC, the voltage in the stacked unit 1 decreased to 0 V prior to that of the stacked unit 2. Then, when the voltage in unit 1 became 0 V, it was converted from a galvanic cell to an electrochemical cell powered by unit 2. We found that the stacked unit 2 provided electrical energy for the stacked unit 1 as a power supply. Finally, the anode potential of the stacked unit 1 significantly increased over cathode potential as current increased further, which caused voltage reversal in unit 1. Voltage reversal occurs in stacked MFCs as a result of non-spontaneous anode overpotential in a unit MFC that has sluggish anode kinetics compared to the other unit MFCs.


High-altitude-related disorders--Part I: Pathophysiology, differential diagnosis, and treatment.
As increasing numbers of people choose to sojourn or retire to the mountains, high-altitude illness is becoming a pathological phenomenon about which healthcare providers should have greater awareness. Hypoxia is the primary cause of high-altitude illness, but other stressors on the sympathetic nervous system, such as cold and exertion, also contribute to disease development and progression. Although variable across persons, symptoms of high-altitude disorders usually occur at altitudes over 7000 feet, and typically in 1 of 3 forms: acute mountain sickness (AMS), high-altitude cerebral edema (HACE), or high-altitude pulmonary edema (HAPE). Major symptoms include nausea, poor sleep, headache, lassitude, cough, dyspnea on exertion and at rest, ataxia, and mental status changes. As a rule, illness occurring at high altitude should be attributed to the altitude until proven otherwise. Treatment is best accomplished by descent and by oxygen or pharmacologic intervention if necessary. Under no circumstances should a person with worsening symptoms of high-altitude illness delay descent. As will be discussed in part II of this article, gradual ascent and subsequent acclimatization to altitude is the most effective prevention, though acetazolamide (Diamox) may be a useful prophylactic measure in some.


Transformational leadership and burnout: The role of thriving and followers' openness to experience.
Grounding our research in conservation of resources theory, we set out to shed light on the relationship between transformational leadership (TFL) and employee burnout. Specifically, we considered both thriving at work, a personal resource, and employees' openness to experience (OTE), a key resource, to uncover whether all employees benefit equally from TFL (a contextual resource). In detail, we argued that the negative effect of TFL on employee burnout is mediated by employee thriving at work, and that employees' OTE constitutes a boundary condition of this process. Our moderated mediation model was tested with 2 waves of data from 148 employees from a midsized German manufacturing company. The results supported our hypotheses and revealed that employees' thriving at work mediated the link between TFL and reduced burnout. As predicted, these relationships were moderated by employees' personality in such a way that TFL affected thriving and hence burnout of employees high on OTE, but not of employees low on OTE. Taken together, our findings suggest that TFL serves as a resource that protects employees from burning out, but also highlights the need to consider employees' personality in perceptions of and reactions to leadership. (PsycINFO Database Record


Children affected by HIV/AIDS: SAFE, a model for promoting their security, health, and development.
A human security framework posits that individuals are the focus of strategies that protect the safety and integrity of people by proactively promoting children's well being, placing particular emphasis on prevention efforts and health promotion. This article applies this framework to a rights-based approach in order to examine the health and human rights of children affected by HIV/AIDS. The SAFE model describes sources of insecurity faced by children across four fundamental dimensions of child well-being and the survival strategies that children and families may employ in response. The SAFE model includes: Safety/protection; Access to health care and basic physiological needs; Family/connection to others; and Education/livelihoods. We argue that it is critical to examine the situation of children through an integrated lens that effectively looks at human security and children's rights through a holistic approach to treatment and care rather than artificially limiting our scope of work to survival-oriented interventions for children affected by HIV/AIDS. Interventions targeted narrowly at children, in isolation of their social and communal environment as outlined in the SAFE model, may in fact undermine protective resources in operation in families and communities and present additional threats to children's basic security. An integrated approach to the basic security and care of children has implications for the prospects of millions of children directly infected or indirectly affected by HIV/AIDS around the world. The survival strategies that young people and their families engage in must be recognized as a roadmap for improving their protection and promoting healthy development. Although applied to children affected by HIV/AIDS in the present analysis, the SAFE model has implications for guiding the care and protection of children and families facing adversity due to an array of circumstances from armed conflict and displacement to situations of extreme poverty.


A series of 112 fully endoscopic resections of vestibular schwannomas.
We report a consecutive series of 112 patients with unilateral vestibular schwannoma (VS) having undergone fully endoscopic resection of their tumors in the period from October, 2001 to January, 2005. Patients' outcomes were evaluated especially with regards to cochlear nerve (hearing) preservation, facial nerve preservation, postoperative complications and completeness of the resection. The patient population consisted of 112 consecutive cases with unilateral, "de novo" VS(s); patients with neurofibromatosis type 2 (NFT2) or with a recurrent tumor were excluded from this study. Tumors ranged in size from 0.6-5.7 cm, most tumors were less than 3 cm in diameter (mean: 2.6 cm). This shift towards smaller and also less symptomatic tumors may be due to an increase in the awareness of patients and earlier detection of their tumors (MRI era). Tumors were removed via 1.5-cm "keyhole" retrosigmoid craniotomies. Utilizing the fully endoscopic technique, 106/112 (95%) tumors were completely removed; subtotal removal was performed in 6/112 (5%) patients in an attempt to preserve their hearing. Anatomic preservation of the facial nerve was achieved in all of the patients and of the cochlear nerve in 83/101 (82%) hearing ears. Functionally, measurable hearing (serviceable/some) was preserved in 59/101 (58%) cases who had either "serviceable" or "some" hearing preoperatively, 2 patients who had "some" hearing preoperatively had an improvement that was more than 30 db in their hearing postoperatively. There were no major neurological complications such as quadriparesis, hemiparesis, bacterial or aseptic meningitis, lower cranial nerve deficits, or deaths. From our experience, we conclude that the endoscope is ideally suited for a minimally invasive approach for the resection of vestibular schwannomas.


Organochlorine pesticide residues in breast milk and maternal psychopathologies and infant growth from suburban area of Ankara, Turkey.
We aimed to determine the levels of organochlorine pesticides (OCPs) in the breast milk; to assess the effect of detectable OCPs on maternal-infant characteristics and; to evaluate the relation between OCPs and the maternal psychopathologies [Brief Symptom Inventory (BSI), Postpartum Bonding Questionnaire (PBQ), Mother-to-Infant Bonding Scale (MIBS) and Edinburgh Postnatal Depression Scale (EPDS)] and infant growth. DDT, beta-hexachlorocyclohexane (HCH), aldrin and heptachlor were detected in 89.3, 70.7, 58.7 and 34.7 % of the samples, respectively. Mothers with low monthly family income had detectable DDTs less frequently. The frequencies of detectable heptachlor epoxide were significantly higher in mothers with gestational nausea. Anaemic mothers had more frequently detectable alpha-HCH. Z scores of head circumference were inversely correlated with beta-HCH and DDT levels. The heptachlor epoxide levels were positively correlated with PBQ, MIBS and indexes of BSI. No relation was detected between EPDS and OCPs. Further studies are needed for changes in maternal psychopathologies.


Optometry and the underprivileged--an investigative report.
In this essay I have taken the topic, "Optometry and the Underprivileged," and approached it as an investigative report. This investigation found me talking with people in all walks of life and visiting many institutions and health care facilities. Some of the people discussed in the report and their conditions represent composites of the real situations I encountered. Their names are fictitious and to the best of my knowledge these people do not exist. The report is intended to be informative, constructively critical, unboring, and positive. If I have accomplished this, then my purpose has been fulfilled.


Influence of indigenous microbiota on activities of alkaline phosphatase, phosphodiesterase I, and thymidine kinase in mouse enterocytes.
An indigenous microflora introduced into the gastrointestinal tracts of animals in a population of germfree mice affected in different ways three enzymes in small bowel enterocytes. Cells were obtained by techniques designed for sequentially removing enterocytes from the tip of the villus to the crypts of Lieberkühn. The specific activity of alkaline phosphatase, a component of the enterocyte microvillous membrane, did not differ in cells isolated from germfree mice and from those associated with a microflora, while that of phosphodiesterase I, also a part of the microvillous membrane, was approximately 1.5-fold greater in the suspensions from all levels of the villi in germfree mice than in those from the associated animals. By contrast, the specific activity of thymidine kinase, a cytosol enzyme, in suspensions in which the cells were isolated from the lower portion of the villi and crypts was about one-half as great in cells from germfree mice as in those from the same regions of animals with a microbiota. These results support the hypothesis that activities of certain enzymes involved in metabolism, uptake, and incorporation by enterocytes of components of dietary nuclei acids are influenced by a microflora.


Chemically synthesized 58-mer LysM domain binds lipochitin oligosaccharide.
Recognition of carbohydrates by proteins is a ubiquitous biochemical process. In legume-rhizobium symbiosis, lipochitin oligosaccharides, also referred to as nodulation (nod) factors, function as primary rhizobial signal molecules to trigger root nodule development. Perception of these signal molecules is receptor mediated, and nod factor receptor 5 (NFR5) from the model legume Lotus japonicus is predicted to contain three LysM domain binding sites. Here we studied the interactions between nod factor and each of the three NFR5 LysM domains, which were chemically synthesized. LysM domain variants (up to 58 amino acids) designed to optimize solubility were chemically assembled by solid-phase peptide synthesis (SPPS) with microwave heating. Their interaction with nod factors and chitin oligosaccharides was studied by isothermal titration calorimetry and circular dichroism (CD) spectroscopy. LysM2 showed a change in folding upon nod factor binding, thus providing direct evidence that the LysM domain of NFR5 recognizes lipochitin oligosaccharides. These results clearly show that the L. japonicus LysM2 domain binds to the nod factor from Mesorhizobium loti, thereby causing a conformational change in the LysM2 domain. The preferential affinity for nod factors over chitin oligosaccharides was demonstrated by a newly developed glycan microarray. Besides the biological implications, our approach shows that carbohydrate binding to a small protein domain can be detected by CD spectroscopy.


Loss of neurons from the intracerebellar nuclei of the ageing mouse.
The intracerebellar nuclei of the ASH/TO mouse brain were examined at 6, 22, 25, 28 and 31 months of age using quantitative histological techniques. Neuron number remained constant between 6 and 22 months of age but there was a statistically significant (P less than 0.01) decrease in neuronal number between 22 and 31 months of age with neuron number declining from 6970 +/- 690 at 22 months to 4140 +/- 246 at 31 months of age. Neuronal nuclear diameter remained constant between 6 and 25 months of age but increased from 10.6 +/- 0.6 microns at 25 months to 12.2 +/- 0.3 microns at 31 months of age. Whether this was due to an actual increase in nuclear diameter or to a proportionately greater loss of small neurons is not known.


Prevention of venous complications from intravenous anesthesia.
Vascular complications following the use of intravenous sedative drugs continue to be a problem in dental anesthesia. Etiological factors associated with pain and thrombophlebitis are reviewed. From reports in the literature and clinical experience, venous complications from intravenous sedation may be reduced by utilizing large veins with the dilution of sedative agents in a fast running intravenous infusion. Intravenous lidocaine may be of use to block reflex venospasm and pain.


[Connections between the submaxillary glands and pancreas].
Studies have been made on the in vitro incorporation of 3H-leucine into insulin-like protein of the submaxillary glands and pancreatic insulin of mice. The effect of glucose on the intensity of incorporation of the labeled leucine into these proteins was also investigated. In was shown that during incubation of the submaxillary glands in the medium containing 3H-leucine, isotope is incorporated into the insulin-like protein, this fact indicating that this protein is synthesized in the glands. The increase in the content of glucose in the medium increases the incorporation of 3H-leucine into pancreatic insulin by 4 times, into insulin-like protein--by 5 times.


Berberine Induces Toxicity in HeLa Cells through Perturbation of Microtubule Polymerization by Binding to Tubulin at a Unique Site.
Berberine has been used traditionally for its diverse pharmacological actions. It exhibits remarkable anticancer activities and is currently under clinical trials. In this study, we report that the anticancer activity of berberine could be partly due to its inhibitory actions on tubulin and microtubule assembly. Berberine inhibited the proliferation of HeLa cells with an IC50 of 18 μM and induced significant depolymerization of interphase and mitotic microtubules. At its IC50, berberine exerted a moderate G2/M arrest and mitotic block as detected by fluorescence-activated cell sorting analysis and fluorescence microscopy, respectively. In a wound closure assay, berberine inhibited the migration of HeLa cells at concentrations lower than its IC50, indicating its excellent potential as an anticancer agent. In vitro studies with tubulin isolated from goat brain indicated that berberine binds to tubulin at a single site with a Kd of 11 μM. Berberine inhibited the assembly of tubulin into microtubules and also disrupted the preformed microtubules polymerized in the presence of glutamate and paclitaxel. Competition experiments indicated that berberine could partially displace colchicine from its binding site. Results from fluorescence resonance energy transfer, computational docking, and molecular dynamics simulations suggest that berberine forms a stable complex with tubulin and binds at a novel site 24 Å from the colchicine site on the β-tubulin. Data obtained from synchronous fluorescence analysis of the tryptophan residues of tubulin and from the Fourier transform infrared spectroscopy studies revealed that binding of berberine alters the conformation of the tubulin heterodimer, which could be the molecular mechanism behind the depolymerizing effects on tubulin assembly.


[ADHD in children and adults].
ADHD, affecting 2-3% of children, is characterised by problems with attention, hyperactivity and impulsivity. Co-morbid psychiatric problems are very frequent. Causal factors are primarily genetics but environmental influences such as smoking during pregnancy or preterm birth are contributing factors. For children and adults psychoeducation is essential, for younger children training of the parents are recommended. The most efficient psychopharmacological treatment is with central stimulants or atomoxetine.


Statistical Shape and Bone Property Models of Clinical Populations as the Foundation for Biomechanical Surgical Planning: Application to Shoulder Arthroplasty.
This work developed, validated, and compared statistical shape, statistical intensity, and statistical shape and intensity models (SSMs, SIMs, SSIMs) of scapulae from a clinical population. SSMs efficiently describe bone shape variation while SIMs describe bone material property variation, and SSIM's combine description of both variables. This work establishes these models' efficacy and whether they can be used in surgical planning. Models were developed using shoulder arthroplasty data of patients with bone erosion, which is challenging to treat and would benefit from improved surgical planning. Models were created using previously validated nonrigid registration and material property assignment processes that were optimized for scapula characteristics. The models were assessed using standard metrics, anatomical measurements, and correlation analyses. The SSM and SIM specificity and generalization error metrics were 3.4 mm and <1 mm and 184 HU and 156 HU, respectively. The SSIM did not achieve the same level of performance as the SSM and SIM in this study (e.g., shape generalization: SSIM-2.2 mm versus SSM-<1 mm). Anatomical correlation analysis showed that the SSM more effectively and efficiently described shape variation compared to the SSIM. The SSM and SIM modes of variation were not strongly correlated (e.g., rmax = 0.56 for modes explaining ≤2.1% of variance). The SSIM is outperformed by the SSM and SIM and the latter two are not strongly correlated; therefore, using the SSM and SIM in conjunction will generate synthetic bone models with realistic characteristics and thus can be used for biomechanical surgical planning applications.


Effect of absorption on the spreading of a laser beam.
The propagation characteristics of the fundamental Gaussian laser beam in absorptive and active media are investigated. There is a general reduction in the spreading of the beam on propagation in both absorptive and active media. In addition, in an active medium there is a shift of the focal plane and a reduction in the waist size of the beam.


Isorhynchophylline Protects PC12 Cells Against Beta-Amyloid-Induced Apoptosis via PI3K/Akt Signaling Pathway.
The neurotoxicity of amyloid- β (A β ) has been implicated as a critical cause of Alzheimer's disease. Isorhynchophylline (IRN), an oxindole alkaloid isolated from Uncaria rhynchophylla, exerts neuroprotective effect against Aβ 25-35-induced neurotoxicity in vitro. However, the exact mechanism for its neuroprotective effect is not well understood. The present study aimed to investigate the molecular mechanisms underlying the protective action of IRN against Aβ 25-35-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. Pretreatment with IRN significantly increased the cell viability, inhibited the release of lactate dehydrogenase and the extent of DNA fragmentation in Aβ 25-35-treated cells. IRN treatment was able to enhance the protein levels of phosphorylated Akt (p-Akt) and glycogen synthase kinase-3 β (p-GSK-3 β ). Lithium chloride blocked Aβ 25-35-induced cellular apoptosis in a similar manner as IRN, suggesting that GSK-3 β inhibition was involved in neuroprotective action of IRN. Pretreatment with LY294002 completely abolished the protective effects of IRN. Furthermore, IRN reversed Aβ 25-35-induced attenuation in the level of phosphorylated cyclic AMP response element binding protein (p-CREB) and the effect of IRN could be blocked by the PI3K inhibitor. These experimental findings unambiguously suggested that the protective effect of IRN against Aβ 25-35-induced apoptosis in PC12 cells was associated with the enhancement of p-CREB expression via PI3K/Akt/GSK-3 β signaling pathway.


Ultralow-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: a randomized controlled trial.
Estrogen therapy is known to prevent osteoporosis, but studies have shown that conventional doses increase adverse events. Whether lower doses, one quarter of standard treatment, prevent bone loss is not known. To examine the effect of 3 years of treatment with 0.25 mg/d of micronized 17beta-estradiol on bone mineral density (BMD) and bone turnover in healthy older postmenopausal women. Randomized, double-blind, placebo-controlled trial conducted from July 24, 1998, through June 14, 2002, at a university general clinical research center in the United States. Healthy, community-dwelling women (N = 167) who were older than 65 years at enrollment. Dosage of 0.25 mg/d of micronized 17beta-estradiol (n = 83) or placebo (n = 84); all women who had not had a hysterectomy received 100 mg/d of oral micronized progesterone for 2-week periods every 6 months. The BMD of the hip, spine, wrist, and total body measured annually for 3 years. Serum and urine biochemical markers of bone resorption and formation and sex hormones were measured at baseline, 3 months, and during years 1 and 3 of treatment. Mean BMD increased at all sites for participants taking low-dose estrogen (17beta-estradiol) compared with placebo (P<.001). Compared with participants receiving placebo, participants taking low-dose estrogen had BMD increases of 2.6% for the femoral neck; 3.6%, total hip; 2.8%, spine; and 1.2%, total body. Markers of bone turnover, N-telopeptides of type 1 collagen, and bone alkaline phosphatase decreased significantly (P<.001) in participants taking low-dose estrogen compared with placebo. Estradiol, estrone, and sex hormone-binding globulin levels increased in the estrogen-treated group compared with placebo. The adverse effect profile was similar; specifically, there were no statistically significant differences in breast tenderness, changes in endometrial thickness or pathological effects, or annual mammographic results between the 2 groups. The number of abnormal mammograms over 3 years was 15 for the low-dose estrogen group and 10 for the placebo group (8 occurred at baseline) (P =.26). There were no reports of breast cancer during the study. In older women, a dosage of 0.25 mg/d of 17beta-estradiol increased bone density of the hip, spine, and total body, and reduced bone turnover, with minimal adverse effects. Future studies evaluating the effect of low-dose estrogen on fractures are indicated.


Evidence for donor strand complementation in the biogenesis of Haemophilus influenzae haemagglutinating pili.
Haemophilus influenzae haemagglutinating pili are surface appendages that promote attachment to host cells and facilitate respiratory tract colonization, an essential step in the pathogenesis of disease. In contrast to other well-characterized forms of pili, H. influenzae haemagglutinating pili are two-stranded helical structures. Nevertheless, haemagglutinating pili are assembled by a pathway that involves a periplasmic chaperone and an outer membrane usher, analogous to the prototype pathway involved in the biogenesis of Escherichia coli P pili. In this study, we performed site-directed mutagenesis of the H. influenzae HifB chaperone and HifA major pilus subunit at positions homologous to sites important for chaperone-subunit interactions and subunit oligomerization in P pili. Mutations at putative subunit binding pocket residues in HifB or at the penultimate tyrosine in HifA abolished formation of HifB-HifA periplasmic complexes, whereas mutations at the -14 glycine in HifA had no effect on HifB-HifA interactions but abrogated HifA oligomerization. To define further the constraints of the interaction between HifA and HifB, we examined the interchangeability of pilus gene cluster components from H. influenzae type b strain Eagan (hifA-hifEEag) and the related H. influenzae biogroup aegyptius strain F3031 (hifA-hifEF3031). Functional pili were assembled both with HifAEag and the strain F3031 gene cluster and with HifAF3031 and the strain Eagan gene cluster, underscoring the flexibility of the H. influenzae chaperone/usher pathway in incorporating HifA subunits with significant sequence diversity. To gain additional insight into the interactive surfaces of HifA and HifB, we aligned HifA sequences from 20 different strains and then modelled the HifA structure based on the recently crystallized PapD-PapK complex. Analysis of the resulting structure revealed high levels of sequence conservation in regions predicted to interact with HifB, and maximal sequence diversity in regions potentially exposed on the surface of assembled pili. These results suggest broad applicability of structure-function relationships identified in studies of P pili, including the concepts of donor strand complementation and donor strand exchange. In addition, they provide insight into the structure of HifA and suggest a basis for antigenic variation in H. influenzae haemagglutinating pili.


Acetyltransferases CBP/p300 Control Transcriptional Switch of β-Catenin and Stat1 Promoting Osteoblast Differentiation.
CREB-binding protein (CBP) (CREBBP) and p300 (EP300) are multifunctional histone acetyltransferases (HATs) with extensive homology. Germline mutations of CBP or p300 cause skeletal abnormalities in humans and mice. However, the precise roles of CBP/p300 in bone homeostasis remain elusive. Here, we report that conditional knockout of CBP or p300 in osteoblasts results in reduced bone mass and strength due to suppressed bone formation. The HAT activity is further confirmed to be responsible for CBP/p300-mediated osteogenesis using A-485, a selective inhibitor of CBP/p300 HAT. Mechanistically, CBP/p300 HAT governs osteogenic gene expression in part through transcriptional activation of β-catenin and inhibition of Stat1. Furthermore, acetylation of histone H3K27 and the transcription factor Foxo1 are demonstrated to be involved in CBP/p300 HAT-regulated β-catenin and Stat1 transcription, respectively. Taken together, these data identify acetyltransferases CBP/p300 as critical regulators that promote osteoblast differentiation and reveal an epigenetic mechanism responsible for maintaining bone homeostasis. © 2023 American Society for Bone and Mineral Research (ASBMR).


Systems offer unique prospects for planning.
Various planning models are available to describe the relative roles of the corporate offices and individual units in a multi-institutional arrangement.


SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML.
Outcomes in acute myeloid leukemia (AML) remain unsatisfactory, and novel treatments are urgently needed. One strategy explores antibodies and their drug conjugates, particularly those targeting CD33. Emerging data with gemtuzumab ozogamicin (GO) demonstrate target validity and activity in some patients with AML, but efficacy is limited by heterogeneous drug conjugation, linker instability, and a high incidence of multidrug resistance. We describe here the development of SGN-CD33A, a humanized anti-CD33 antibody with engineered cysteines conjugated to a highly potent, synthetic DNA cross-linking pyrrolobenzodiazepine dimer via a protease-cleavable linker. The use of engineered cysteine residues at the sites of drug linker attachment results in a drug loading of approximately 2 pyrrolobenzodiazepine dimers per antibody. In preclinical testing, SGN-CD33A is more potent than GO against a panel of AML cell lines and primary AML cells in vitro and in xenotransplantation studies in mice. Unlike GO, antileukemic activity is observed with SGN-CD33A in AML models with the multidrug-resistant phenotype. Mechanistic studies indicate that the cytotoxic effects of SGN-CD33A involve DNA damage with ensuing cell cycle arrest and apoptotic cell death. Together, these data suggest that SGN-CD33A has CD33-directed antitumor activity and support clinical testing of this novel therapeutic in patients with AML.


Innovative intraoral cooling device better tolerated and equally effective as ice cooling.
Most of the patients who receive myeloablative therapy prior to stem cell transplantation develop oral mucositis (OM). This adverse reaction manifests as oral mucosal erythema and ulcerations and may require high doses of morphine for pain alleviation. OM may also interfere with food intake and result in weight loss, a need for parenteral nutrition, and impaired quality of life. To date, there have been very few studies of evidence-based interventions for the prevention of OM. Cryotherapy, using ice chips, has been shown to reduce in an efficient manner the severity and extent of OM, although clinical applications are still limited due to several shortcomings, such as adverse tooth sensations, problems with infectious organisms in the water, nausea, and uneven cooling of the oral mucosa. The present proof-of-concept study was conducted to compare the tolerability, temperature reduction, and cooling distribution profiles of an intra-oral cooling device and ice chips in healthy volunteers who did not receive myeloablative treatment, and therefore, did not experience the symptoms of OM. Twenty healthy volunteers used the cooling device and ice chips for a maximum of 60 min each, using a cross-over design. The baseline and final temperatures were measured at eight intra-oral locations using an infra-red thermographic camera. The thermographic images were analysed using two digital software packages. A questionnaire was used to assess the tolerability levels of the two interventions. The intra-oral cooling device was significantly better tolerated than the ice-chips (p = 0.0118). The two interventions were equally effective regarding temperature reduction and cooling distribution. The intra-oral cooling device shows superior tolerability in healthy volunteers. Furthermore, this study shows that temperature reduction and cooling distribution are achieved equally well using either method.


Nanoplasmon-enhanced drop-screen for high throughput single-cell nucleocytoplasmic miRNA profiling.
Cell nucleocytoplasmic profiles of microRNAs (miRNAs) are critical to determining a single cell's essential functionalities, such as cellular transcription, nucleus export and degradation, which gives a comprehensive view of cellular processes. Despite the importance of addressing nucleocytoplasmic heterogeneity, the challenge of high-throughput screening remains. Although a droplet-based approach was developed for single-cell miRNA assays, the challenge of quantifying miRNA with high sensitivity to indicate nucleocytoplasmic heterogeneity remains. In this study, a nanoplasmon-enhanced droplet screening platform was developed to quantify single-cell nucleocytoplasmic heterogeneity with the high sensitivity of 0.1 nM. Droplet screening and multiplexed plasmonic assays are synergistic: droplet screening is used to isolate single cells for high-throughput screening, while enhanced nanoplasmonic assays are conducted to precisely determine different types of miRNAs, addressing the cell nucleocytoplasmic profile. Here, two nucleic acid-functionalized plasmonic nanosensors, silver nanoparticles functionalized with designed sequences to target miRNAs, are synthesized. After the targets are bound, competitive formation of sensor-target hybrids interferes with plasmonic coupling between the nanoparticles, decreasing a fluorescence signal and thus enabling high-sensitivity single-cell miRNA quantification. Using the fluorescence signal change as a readout allows continuous-flow measurement to provide a single-cell nucleocytoplasmic profile in a high-throughput manner (∼100 cells per minute) for effective quantitative cell biology.


The villain team-up or how Trichomonas vaginalis and bacterial vaginosis alter innate immunity in concert.
Complex interactions of vaginal microorganisms with the genital tract epithelium shape mucosal innate immunity, which holds the key to sexual and reproductive health. Bacterial vaginosis (BV), a microbiome-disturbance syndrome prevalent in reproductive-age women, occurs commonly in concert with trichomoniasis, and both are associated with increased risk of adverse reproductive outcomes and viral infections, largely attributable to inflammation. To investigate the causative relationships among inflammation, BV and trichomoniasis, we established a model of human cervicovaginal epithelial cells colonised by vaginal Lactobacillus isolates, dominant in healthy women, and common BV species (Atopobium vaginae, Gardnerella vaginalis and Prevotella bivia). Colonised epithelia were infected with Trichomonas vaginalis (TV) or exposed to purified TV virulence factors (membrane lipophosphoglycan (LPG), its ceramide-phosphoinositol-glycan core (CPI-GC) or the endosymbiont Trichomonas vaginalis virus (TVV)), followed by assessment of bacterial colony-forming units, the mucosal anti-inflammatory microbicide secretory leucocyte protease inhibitor (SLPI), and chemokines that drive pro-inflammatory, antigen-presenting and T cells. TV reduced colonisation by Lactobacillus but not by BV species, which were found inside epithelial cells. TV increased interleukin (IL)-8 and suppressed SLPI, likely via LPG/CPI-GC, and upregulated IL-8 and RANTES, likely via TVV as suggested by use of purified pathogenic determinants. BV species A vaginae and G vaginalis induced IL-8 and RANTES, and also amplified the pro-inflammatory responses to both LPG/CPI-GC and TVV, whereas P bivia suppressed the TV/TVV-induced chemokines. These molecular host-parasite-endosymbiont-bacteria interactions explain epidemiological associations and suggest a revised paradigm for restoring vaginal immunity and preventing BV/TV-attributable inflammatory sequelae in women.


[Action of thyroxine on the cytochrome content in the brain and liver mitochondria during the postnatal development of rats].
The content of cytochromes c + c1, b and a in brain and liver mitochondria in 7-day-old rats reaches the level seen in adult animals. Administration of L-T4 in a dose of 0.7 micrograms/g rat bw for 4 days before sacrifice results in activation of cytochrome synthesis in both test organs within the first week of the suckling rats' life. On the 20th day of the postnatal period the effect of T4 is seen only in the liver while the brain tissue turns out indifferent to the thyroid hormone. Thus, T4 activates cytochrome biosynthesis in brain mitochondria during the first week of the rats' life, that leads to the acceleration of the functional activity and higher differentiation of the developing brain mitochondria.


Children's ability to answer different types of questions.
Young children answer many questions every day. The extent to which they do this in an adult-like way - following Grice's Maxim of Quantity by providing the requested information, no more no less - has been studied very little. In an experiment, we found that two-, three- and four-year-old children are quite skilled at answering argument-focus questions and predicate-focus questions with intransitives in which their response requires only a single element. But predicate-focus questions for transitives - requiring both the predicate and the direct object - are difficult for children below four years of age. Even more difficult for children this young are sentence-focus questions such as "What's happening?", which give the child no anchor in given information around which to structure their answer. In addition, in a corpus study, we found that parents ask their children predicate-focus and sentence-focus questions very infrequently, thus giving children little experience with them.


Genome based analysis of type-I polyketide synthase and nonribosomal peptide synthetase gene clusters in seven strains of five representative Nocardia species.
Actinobacteria of the genus Nocardia usually live in soil or water and play saprophytic roles, but they also opportunistically infect the respiratory system, skin, and other organs of humans and animals. Primarily because of the clinical importance of the strains, some Nocardia genomes have been sequenced, and genome sequences have accumulated. Genome sizes of Nocardia strains are similar to those of Streptomyces strains, the producers of most antibiotics. In the present work, we compared secondary metabolite biosynthesis gene clusters of type-I polyketide synthase (PKS-I) and nonribosomal peptide synthetase (NRPS) among genomes of representative Nocardia species/strains based on domain organization and amino acid sequence homology. Draft genome sequences of Nocardia asteroides NBRC 15531(T), Nocardia otitidiscaviarum IFM 11049, Nocardia brasiliensis NBRC 14402(T), and N. brasiliensis IFM 10847 were read and compared with published complete genome sequences of Nocardia farcinica IFM 10152, Nocardia cyriacigeorgica GUH-2, and N. brasiliensis HUJEG-1. Genome sizes are as follows: N. farcinica, 6.0 Mb; N. cyriacigeorgica, 6.2 Mb; N. asteroides, 7.0 Mb; N. otitidiscaviarum, 7.8 Mb; and N. brasiliensis, 8.9 - 9.4 Mb. Predicted numbers of PKS-I, NRPS, and PKS-I/NRPS hybrid clusters ranged between 4-11, 7-13, and 1-6, respectively, depending on strains, and tended to increase with increasing genome size. Domain and module structures of representative or unique clusters are discussed in the text. We conclude the following: 1) genomes of Nocardia strains carry as many PKS-I and NRPS gene clusters as those of Streptomyces strains, 2) the number of PKS-I and NRPS gene clusters in Nocardia strains varies substantially depending on species, and N. brasiliensis strains carry the largest numbers of clusters among the species studied, 3) the seven Nocardia strains studied in the present work have seven common PKS-I and/or NRPS clusters, some of whose products are yet to be studied, and 4) different N. brasiliensis strains have some different gene clusters of PKS-I/NRPS, although the rest of the clusters are common within the N. brasiliensis strains. Genome sequencing suggested that Nocardia strains are highly promising resources in the search of novel secondary metabolites.


Extracellular Matrix-Based Approaches in Cardiac Regeneration: Challenges and Opportunities.
Cardiac development is characterized by the active proliferation of different cardiac cell types, in particular cardiomyocytes and endothelial cells, that eventually build the beating heart. In mammals, these cells lose their regenerative potential early after birth, representing a major obstacle to our current capacity to restore the myocardial structure and function after an injury. Increasing evidence indicates that the cardiac extracellular matrix (ECM) actively regulates and orchestrates the proliferation, differentiation, and migration of cardiac cells within the heart, and that any change in either the composition of the ECM or its mechanical properties ultimately affect the behavior of these cells throughout one's life. Thus, understanding the role of ECMs' proteins and related signaling pathways on cardiac cell proliferation is essential to develop effective strategies fostering the regeneration of a damaged heart. This review provides an overview of the components of the ECM and its mechanical properties, whose function in cardiac regeneration has been elucidated, with a major focus on the strengths and weaknesses of the experimental models so far exploited to demonstrate the actual pro-regenerative capacity of the components of the ECM and to translate this knowledge into new therapies.


Peripheral blood mononuclear cell traffic plays a crucial role in mother-to-infant transmission of hepatitis B virus.
The role of peripheral blood mononuclear cells (PBMCs) in HBV intrauterine infection is not fully defined. Particularly the origin of PBMCs in HBV-infected neonates remains to be addressed. We carried out a population-based nested case-control study by enrolling 312 HBsAg-positive mothers and their babies. PBMC HBV DNA as well as serum HBsAg and HBV DNA was tested in cohort entry samples. Totally, 45.5% (142/312) of the newborns were found to be infected with HBV in perinatal transmission. 119 mother-infant pairs were identified to be different in the genetic profile of maternal and fetal PBMCs by AS-PCR and hemi-nested PCR. Among them, 57.1% (68/119) of the maternal PBMCs in index cases were positive for HBV DNA while 83.8% (57/68) of the HBV DNA positive maternal PBMCs passed the placental barrier and entered the fetus. Furthermore, maternal PBMC HBV infection was significantly associated with newborn infants HBV infection. PBMC traffic from mother to fetus resulted in a 9.5-fold increased risk of HBV infection in PBMC HBV DNA positive newborn infants. These data indicate that maternal PBMCs infected with HBV contribute to HBV intrauterine infection of newborn infants via PBMC traffic from mother to fetus.


Health and wellbeing of people with intellectual disability in New South Wales, Australia: a data linkage cohort.
People with intellectual disability (ID) experience high rates of physical and mental health problems, while access to appropriate healthcare is often poor. This cohort was established to develop an epidemiological profile related to the health, health service use, disability services, mortality and corrective services records of people with ID. The cohort contains 92 542 people with ID (40% females) with a median age of 23 years (IQR: 12-43 years) and 2 004 475 people with a neuropsychiatric or developmental disorder diagnosis (50% females) with a median age of 51 years (IQR: 29-73 years) from New South Wales, Australia. The whole sample contains records for 2 097 017 individuals with most data sets spanning financial years 1 July 2001 to 30 June 2016. A wide range of data from linked population data sets are included in the areas of disability, health, corrective services and targeted specialist support services in public schools, Public Guardian and Ombudsman services. This study includes one of the largest cohorts of people with ID internationally. Our data have shown that the presence of ID is significantly associated with emergency department presentations and psychiatric readmissions after the first psychiatric admission based on a subcohort of people with a psychiatric admission. Adults with ID experience premature mortality and over-representation of potentially avoidable deaths compared with the general population. Within the health service system, we will examine different components, that is, inpatient, emergency adult services, children and younger people services and costs associated with healthcare as well as mortality, cause and predictors of death. The neuropsychiatric and developmental disorders comparison cohort allows comparisons of the physical health, mental health and service use profiles of people with ID and those with other neuropsychiatric disorders.


The activation of neuronal NO synthase is mediated by G-protein betagamma subunit and the tyrosine phosphatase SHP-2.
In CHO cells we had found that CCK positively regulated cell proliferation via the activation of a soluble guanylate cyclase. Here we demonstrate that CCK stimulated a nitric oxide synthase (NOS) activity. The production of NO was involved in the proliferative response elicited by CCK regarding the inhibitory effect of NOS inhibitors L-NAME and alpha-guanidinoglutaric acid. We identified the NOS activated by the peptide as the neuronal isoform: the expression of the C415A neuronal NOS mutant inhibited both CCK-induced stimulation of NOS activity and cell proliferation. These two effects were also inhibited after expression of the C459S tyrosine phosphatase SHP-2 mutant and the betaARK1 (495-689) sequestrant peptide, indicating the requirement of activated SHP-2 and G-betagamma subunit. Kinetic analysis (Western blot after coimmunoprecipitation and specific SHP-2 activity) revealed that in response to CCK-treatment, SHP-2 associated to G-beta1 subunit, became activated, and then dephosphorylated the neuronal NOS through a direct association. These data demonstrate that the neuronal NOS is implicated in proliferative effect evoked by CCK. A novel growth signaling pathway is described, involving the activation of neuronal NOS by dephosphorylation of tyrosyl residues.


First-order nonconservative motion of optically trapped nonspherical particles.
It is well known that optical force fields are not conservative. This has important consequences for the thermal motion of optically trapped dielectric spheres. In particular, the spheres do not reach thermodynamic equilibrium. Instead, a steady state is achieved in which the stochastic trajectory contains an underlying deterministic bias toward cyclic motion, and the energy of the sphere deviates from that implied by the equipartition theorem. Such effects are second order and only observed at low trap powers when the sphere is able to explore regions of the trap beyond the linear regime. Analogous effects may be expected for particles of less than spherical symmetry. However, in this case the effects are first order and depend on the linear term in the optical force field. As such they are not suppressed by increases in beam power, although the frequency and amplitude of the cyclic motion will be affected by it. In this paper, we present an analysis of the first-order nonconservative behavior of nonspherical particles in optical traps. The analysis is supported by optical force calculations and brownian dynamics simulations of dielectric microrods held vertically in gaussian optical traps.


The role of economic evaluation in the decision-making process of family physicians: design and methods of a qualitative embedded multiple-case study.
A considerable amount of resource allocation decisions take place daily at the point of the clinical encounter; especially in primary care, where 80 percent of health problems are managed. Ignoring economic evaluation evidence in individual clinical decision-making may have a broad impact on the efficiency of health services. To date, almost all studies on the use of economic evaluation in decision-making used a quantitative approach, and few investigated decision-making at the clinical level. An important question is whether economic evaluations affect clinical practice. The project is an intervention research study designed to understand the role of economic evaluation in the decision-making process of family physicians (FPs). The contributions of the project will be from the perspective of Pierre Bourdieu's sociological theory. A qualitative research strategy is proposed. We will conduct an embedded multiple-case study design. Ten case studies will be performed. The FPs will be the unit of analysis. The sampling strategies will be directed towards theoretical generalization. The 10 selected cases will be intended to reflect a diversity of FPs. There will be two embedded units of analysis: FPs (micro-level of analysis) and field of family medicine (macro-level of analysis). The division of the determinants of practice/behaviour into two groups, corresponding to the macro-structural level and the micro-individual level, is the basis for Bourdieu's mode of analysis. The sources of data collection for the micro-level analysis will be 10 life history interviews with FPs, documents and observational evidence. The sources of data collection for the macro-level analysis will be documents and 9 open-ended, focused interviews with key informants from medical associations and academic institutions. The analytic induction approach to data analysis will be used. A list of codes will be generated based on both the original framework and new themes introduced by the participants. We will conduct within-case and cross-case analyses of the data. The question of the role of economic evaluation in FPs' decision-making is of great interest to scientists, health care practitioners, managers and policy-makers, as well as to consultants, industry, and society. It is believed that the proposed research approach will make an original contribution to the development of knowledge, both empirical and theoretical.


Assessment of sustainable drainage strategies in urban water systems using urban water metabolism and multi-criteria decision analyses.
The simulation of urban water metabolism (UWM) allows for the tracking of all water, energy, and material flows within urban water systems (UWSs) and the quantification of their performance, including emissions into the air, water, and soil. This study evaluates seven drainage strategies (DSs) within conventional and sustainable urban drainage systems (SUDSs) using UWM and multicriteria decision analysis (MCDA). The DSs were designed to assess their corresponding UWM performances, employing key performance indicators (KPIs) related to sewer system balance, energy consumption, greenhouse gas (GHG) emissions, acidification, eutrophication, contamination, and sludge production. The outcomes were ranked using the compromise programming MCDA model. The top three strategies were permeable pavements, green spaces, and infiltration trenches and sand filters. The approach used for the evaluation of DS can provide valuable insights for decision-makers, support the promotion of sustainable integrated UWS management and adaptation, and accommodate design variations in urban drainage. Sensitivity analysis on uncertain parameters and KPI selection also contributed to robust and sustainable urban drainage solutions.


[Ultrasound controlled kidney cyst puncture: significance for diagnosis and therapy].
Renal cyst puncture under ultrasonic guidance has proved an excellent and safe method in the differential diagnosis of cystic renal masses. The use of ultrasound in the follow-up of patients with renal cyst puncture is mandatory for evaluation of complications and results. The therapeutic success of renal cyst puncture is poor and estimated at about 25%. New percutaneous techniques with resection of the cystic wall lead us to expect much better results than with open surgical management.


Tumor Size Reduction and Serum Carbohydrate Antigen 19-9 Kinetics After Neoadjuvant FOLFIRINOX in Patients With Pancreatic Ductal Adenocarcinoma.
Changes in tumor size and serum carbohydrate antigen 19-9 are commonly reported markers used to assess response to neoadjuvant therapy in pancreatic ductal adenocarcinoma. We evaluated the impact of the percentual tumor size reduction and carbohydrate antigen 19-9 kinetics on resectability and response to neoadjuvant FOLFIRINOX. This was an institutional analysis of patients with non-metastatic (upfront resectable, borderline resectable, and locally advanced) pancreatic ductal adenocarcinoma who underwent neoadjuvant FOLFIRINOX. Resectability, pathologic response, disease recurrence, and overall survival were evaluated. Among 193 patients who completed FOLFIRINOX, 60% underwent resection, and 91% were R0. Pathologically, complete, and near-complete responses were achieved in 4% and 40% of patients, respectively. Tumor size reduction (odds ratio 1.02 per 1%, P = .024) and normalization of carbohydrate antigen 19-9 (odds ratio 2.61, P = .035) were associated with increased odds of resectability. Concerning pathologic response, tumor size reduction (odds ratio 1.03 per 1%, P = .018) was associated with increased odds of a complete and near-complete response. Lastly, in resected patients, a postoperative increase in carbohydrate antigen 19-9 after prior normalization after neoadjuvant therapy were at an increased risk of recurrence (hazard ratio 9.58, P < .001) and worse survival (hazard ratio 10.4, P < .001) compared to patients who maintained normalization. In patients with non-metastatic pancreatic ductal adenocarcinoma who underwent neoadjuvant therapy, tumor size reduction was a significant predictor of resectability and pathologic response, including complete and near complete responses, whereas serum carbohydrate antigen 19-9 normalization predicted resectability, disease recurrence, and survival. Patients with a postoperative carbohydrate antigen 19-9 rise after prior normalization after administration of neoadjuvant therapy were at an increased risk of recurrence and worse overall survival.


FtsH proteases confer protection against salt and oxidative stress in Medicago sativa L.
Plant filamentation temperature-sensitive H (FtsH) proteins are ATP-dependent zinc proteases that play an important role in regulating abiotic stress adaptions. Here we explore their potential role in abiotic stress tolerance in alfalfa, an important legume crop. Genomic analysis revealed seventeen MsFtsH genes in five clusters, which generally featured conserved domains and gene structures. Furthermore, the expression of MsFtsHs was found to be tightly associated with abiotic stresses, including osmotic, salt and oxidative stress. In addition, numerous stress responsive cis-elements, including those related to ABA, auxin, and salicylic acid, were identified in their promoter regions. Moreover, MsFtsH8 overexpression was shown to confer tolerance to salt and oxidative stress which was associated with reduced levels of reactive oxygen species, and enhanced expression and activity of antioxidant enzymes. Our results highlight MsFtsHs as key factors in abiotic stress tolerance, and show their potential usefulness for breeding alfalfa and other crops with improved yield and stress tolerance.


Sarcopenia and its relationship with bone mineral density in middle-aged and elderly European men.
The aim of this study was to determine the relationship between reduced muscle mass (sarcopenia) and areal bone mineral density (BMD(a)) in middle-aged and elderly community-dwelling European men. Men with sarcopenia had significantly lower BMD(a) and were more likely to have osteoporosis compared with men without sarcopenia. In men, the relationship between reduced muscle mass (sarcopenia) and BMD(a) is unclear. This study aimed to determine this relationship in middle-aged and elderly community-dwelling men. Men aged 40-79 years from the Manchester (UK) and Leuven (Belgium) cohorts of the European Male Ageing Study were invited to attend for assessment including dual-energy X-ray absorptiometry, from which appendicular lean mass (aLM), fat mass (FM) and whole-body, spine and hip BMD(a) were determined. Relative appendicular skeletal muscle mass (RASM) was calculated as aLM/height². Muscle strength was assessed in subjects from Leuven. Sarcopenia was defined by RASM at <7.26 kg/m² and by the recent definition of the European Working Group on Sarcopenia in Older People (RASM at <7.26 kg/m(2) plus low muscle function). Linear regression was used to determine the associations between aLM, FM, muscle strength and BMD(a) and logistic regression to determine the association between sarcopenia and osteoporosis. Six hundred seventy-nine men with a mean age of 59.6 (SD = 10.7), contributed data to the analysis; 11.9 % were sarcopenic by the conventional definition. After adjustment for age and centre, aLM, RASM and FM were positively associated with BMD(a). Men with RASM at <7.26 kg/m² had significantly lower BMD(a) compared with those with RASM at ≥7.26 kg/m(2). In a multivariable model, aLM was most consistently associated with BMD(a). Men with sarcopenia were more likely to have osteoporosis compared with those with normal RASM (odds ratio = 3.0; 95 % CI = 1.6-5.8). Sarcopenia is associated with low BMD(a) and osteoporosis in middle-aged and elderly men. Further studies are necessary to assess whether maintaining muscle mass contributes to prevent osteoporosis.


Selenoprotein H is a nucleolar thioredoxin-like protein with a unique expression pattern.
The human selenoproteome consists of 25 known selenoproteins, but functions of many of these proteins are not known. Selenoprotein H (SelH) is a recently discovered 14-kDa mammalian protein with no sequence homology to functionally characterized proteins. By sensitive sequence and structure analyses, we identified SelH as a thioredoxin fold-like protein in which a conserved CXXU motif (cysteine separated by two other residues from selenocysteine) corresponds to the CXXC motif in thioredoxins. These data suggest a redox function of SelH. Indeed, a recombinant SelH shows significant glutathione peroxidase activity. In addition, SelH has a conserved RKRK motif in the N-terminal sequence. We cloned wild-type and cysteine mutant forms of SelH either upstream or downstream of green fluorescent protein (GFP) and localized this fusion protein to the nucleus in transfected mammalian cells, whereas mutations in the RKRK motif resulted in the cytosolic protein. Interestingly, the full-length SelH-GFP fusion protein localized specifically to nucleoli, whereas the N-terminal sequence of SelH fused to GFP had a diffuse nucleoplasm location. Northern blot analyses revealed low expression levels of SelH mRNA in various mouse tissues, but it was elevated in the early stages of embryonic development. In addition, SelH mRNA was overexpressed in human prostate cancer LNCaP and mouse lung cancer LCC1 cells. Down-regulation of SelH by RNA interference made LCC1 cells more sensitive to hydrogen peroxide but not to other peroxides tested. Overall, these data establish SelH as a novel nucleolar oxidoreductase and suggest that some functions in this compartment are regulated by redox and dependent on the trace element selenium.


Systematic review and modelling of the cost-effectiveness of cardiac magnetic resonance imaging compared with current existing testing pathways in ischaemic cardiomyopathy.
Cardiac magnetic resonance imaging (CMR) is increasingly used to assess patients for myocardial viability prior to revascularisation. This is important to ensure that only those likely to benefit are subjected to the risk of revascularisation. To assess current evidence on the accuracy and cost-effectiveness of CMR to test patients prior to revascularisation in ischaemic cardiomyopathy; to develop an economic model to assess cost-effectiveness for different imaging strategies; and to identify areas for further primary research. Databases searched were: MEDLINE including MEDLINE In-Process & Other Non-Indexed Citations Initial searches were conducted in March 2011 in the following databases with dates: MEDLINE including MEDLINE In-Process & Other Non-Indexed Citations via Ovid (1946 to March 2011); Bioscience Information Service (BIOSIS) Previews via Web of Science (1969 to March 2011); EMBASE via Ovid (1974 to March 2011); Cochrane Database of Systematic Reviews via The Cochrane Library (1996 to March 2011); Cochrane Central Register of Controlled Trials via The Cochrane Library 1998 to March 2011; Database of Abstracts of Reviews of Effects via The Cochrane Library (1994 to March 2011); NHS Economic Evaluation Database via The Cochrane Library (1968 to March 2011); Health Technology Assessment Database via The Cochrane Library (1989 to March 2011); and the Science Citation Index via Web of Science (1900 to March 2011). Additional searches were conducted from October to November 2011 in the following databases with dates: MEDLINE including MEDLINE In-Process & Other Non-Indexed Citations via Ovid (1946 to November 2011); BIOSIS Previews via Web of Science (1969 to October 2011); EMBASE via Ovid (1974 to November 2011); Cochrane Database of Systematic Reviews via The Cochrane Library (1996 to November 2011); Cochrane Central Register of Controlled Trials via The Cochrane Library (1998 to November 2011); Database of Abstracts of Reviews of Effects via The Cochrane Library (1994 to November 2011); NHS Economic Evaluation Database via The Cochrane Library (1968 to November 2011); Health Technology Assessment Database via The Cochrane Library (1989 to November 2011); and the Science Citation Index via Web of Science (1900 to October 2011). Electronic databases were searched March-November 2011. The systematic review selected studies that assessed the clinical effectiveness and cost-effectiveness of CMR to establish the role of CMR in viability assessment compared with other imaging techniques: stress echocardiography, single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Studies had to have an appropriate reference standard and contain accuracy data or sufficient details so that accuracy data could be calculated. Data were extracted by two reviewers and discrepancies resolved by discussion. Quality of studies was assessed using the QUADAS II tool (University of Bristol, Bristol, UK). A rigorous diagnostic accuracy systematic review assessed clinical and cost-effectiveness of CMR in viability assessment. A health economic model estimated costs and quality-adjusted life-years (QALYs) accrued by diagnostic pathways for identifying patients with viable myocardium in ischaemic cardiomyopathy with a view to revascularisation. The pathways involved CMR, stress echocardiography, SPECT, PET alone or in combination. Strategies of no testing and revascularisation were included to determine the most cost-effective strategy. Twenty-four studies met the inclusion criteria. All were prospective. Participant numbers ranged from 8 to 52. The mean left ventricular ejection fraction in studies reporting this outcome was 24-62%. CMR approaches included stress CMR and late gadolinium-enhanced cardiovascular magnetic resonance imaging (CE CMR). Recovery following revascularisation was the reference standard. Twelve studies assessed diagnostic accuracy of stress CMR and 14 studies assessed CE CMR. A bivariate regression model was used to calculate the sensitivity and specificity of CMR. Summary sensitivity and specificity for stress CMR was 82.2% [95% confidence interval (CI) 73.2% to 88.7%] and 87.1% (95% CI 80.4% to 91.7%) and for CE CMR was 95.5% (95% CI 94.1% to 96.7%) and 53% (95% CI 40.4% to 65.2%) respectively. The sensitivity and specificity of PET, SPECT and stress echocardiography were calculated using data from 10 studies and systematic reviews. The sensitivity of PET was 94.7% (95% CI 90.3% to 97.2%), of SPECT was 85.1% (95% CI 78.1% to 90.2%) and of stress echocardiography was 77.6% (95% CI 70.7% to 83.3%). The specificity of PET was 68.8% (95% CI 50% to 82.9%), of SPECT was 62.1% (95% CI 52.7% to 70.7%) and of stress echocardiography was 69.6% (95% CI 62.4% to 75.9%). All currently used diagnostic strategies were cost-effective compared with no testing at current National Institute for Health and Care Excellence thresholds. If the annual mortality rates for non-viable patients were assumed to be higher for revascularised patients, then testing with CE CMR was most cost-effective at a threshold of £20,000/QALY. The proportion of model runs in which each strategy was most cost-effective, at a threshold of £20,000/QALY, was 40% for CE CMR, 42% for PET and 16.5% for revascularising everyone. The expected value of perfect information at £20,000/QALY was £620 per patient. If all patients (viable or not) gained benefit from revascularisation, then it was most cost-effective to revascularise all patients. Definitions and techniques assessing viability were highly variable, making data extraction and comparisons difficult. Lack of evidence meant assumptions were made in the model leading to uncertainty; differing scenarios were generated around key assumptions. All the diagnostic pathways are a cost-effective use of NHS resources. Given the uncertainty in the mortality rates, the cost-effectiveness analysis was performed using a set of scenarios. The cost-effectiveness analyses suggest that CE CMR and revascularising everyone were the optimal strategies. Future research should look at implementation costs for this type of imaging service, provide guidance on consistent reporting of diagnostic testing data for viability assessment, and focus on the impact of revascularisation or best medical therapy in this group of high-risk patients. The National Institute of Health Technology Assessment programme.


Complicated Neuraxial Anesthesia in a Patient With Tethered Spinal Cord.
Spinal anesthesia is a common anesthetic used in many surgical procedures. Anatomical variations and diseases make this procedure require extra considerations. Extra care should be taken into consideration in the pre-anesthesia evaluation when neuraxial anesthesia is planned. We present the case of a patient undergoing cesarean section for the arrest of labor, who had a complicated labor course due to unrecognized history of a tethered spinal cord leading to inadequate analgesia, requiring replacement of epidural analgesia and spinal anesthesia. Ultimately, the decision was made to proceed with general anesthesia due to the patient's discomfort. Exhaustive chart review after surgery showed a past MRI with evidence of a tethered spinal cord.


Suppression of Bedbug's Reproduction by RNA Interference of Vitellogenin.
Recent resurgence of the bedbug Cimex lectularius is a global problem on the public health. On account of the worldwide rise of insecticide-resistant bedbug populations, exploration of new approaches to the bedbug control and management is anticipated. In this context, gene silencing by RNA interference (RNAi) has been considered for its potential application to pest control and management, because RNAi enables specific suppression of target genes and thus flexible selection of target traits to be disrupted. In this study, in an attempt to develop a control strategy targeting reproduction of the bedbug, we investigated RNAi-mediated gene silencing of vitellogenin (Vg), a major yolk protein precursor essential for oogenesis. From the bedbug transcriptomes, we identified a typical Vg gene and a truncated Vg gene, which were designated as ClVg and ClVg-like, respectively. ClVg gene was highly expressed mainly in the fat body of adult females, which was more than 100 times higher than the expression level of ClVg-like gene, indicating that ClVg gene is the primary functional Vg gene in the bedbug. RNAi-mediated suppression of ClVg gene expression in adult females resulted in drastically reduced egg production, atrophied ovaries, and inflated abdomen due to hypertrophied fat bodies. These phenotypic consequences are expected not only to suppress the bedbug reproduction directly but also to deteriorate its feeding and survival indirectly via behavioral modifications. These results suggest the potential of ClVg gene as a promising target for RNAi-based population management of the bedbug.


Immune Response After Cochlear Implantation.
A cochlear implant (CI) is an electronic device that enables hearing recovery in patients with severe to profound hearing loss. Although CIs are a successful treatment for profound hearing impairment, their effectivity may be improved by reducing damages associated with insertion of electrodes in the cochlea, thus preserving residual hearing ability. Inner ear trauma leads to inflammatory reactions altering cochlear homeostasis and reducing post-operative audiological performances and electroacoustic stimulation. Strategies to preserve residual hearing ability led to the development of medicated devices to minimize CI-induced cochlear injury. Dexamethasone-eluting electrodes recently showed positive outcomes. In previous studies by our research group, intratympanic release of dexamethasone for 14 days was able to preserve residual hearing from CI insertion trauma in a Guinea pig model. Long-term effects of dexamethasone-eluting electrodes were therefore evaluated in the same animal model. Seven Guinea pigs were bilaterally implanted with medicated rods and four were implanted with non-eluting ones. Hearing threshold audiograms were acquired prior to implantation and up to 60 days by recording compound action potentials. For each sample, we examined the amount of bone and fibrous connective tissue grown within the scala tympani in the basal turn of the cochlea, the cochleostomy healing, the neuronal density, and the correlation between electrophysiological parameters and histological results. Detection of tumor necrosis factor alpha, interleukin-6, and foreign body giant cells showed that long-term electrode implantation was not associated with an ongoing inflammation. Growth of bone and fibrous connective tissue around rods induced by CI was reduced in the scala tympani by dexamethasone release. For cochleostomy sealing, dexamethasone-treated animals showed less bone tissue growth than negative. Dexamethasone did not affect cell density in the spiral ganglion. Overall, these results support the use of dexamethasone as anti-inflammatory additive for eluting electrodes able to protect the cochlea from CI insertion trauma.


[OCT-morphometric and angiographic parallels between different variants of central serous chorioretinopathy].
Central serous chorioretinopathy (CSCR) is a frequent cause of vision deterioration. Often it is associated with type 1 neovascularization under the pigment retinal epithelium (RPE). Optical coherence tomography angiography (OCT-angiography) enables non-invasive and contrast-free detection of neovessels in any retinal layer, which makes the method appropriate for diagnostics in CSCR. to investigate OCT-morphometric and angiographic parallels between different CSCR courses. The study included 37 patients with CSCR. All the patients underwent standard ophthalmic examination, measurement of the axial eye length (AL) (Lenstar 900, 'Haag-Streit', Switzerland), spectral OCT and OCT-angiography with SSADA algorithm (RTVue xR Avanti, 'Optovue', USA) as well as fundus imaging and fluorescein angiography (FA) (VISUCAM 500, 'Zeiss', Germany). Judging from the results of spectral OCT and intravenous FA, the patients were divided into 2 groups: group 1 - 20 patients with pigment epithelium detachment (PED) and group 2 - 17 patients without PED. AL averaged 23.75±0.27 mm in group 1 and 23.55±0.40 mm in group 2. Comparative analysis of morphometric parameters in the two groups showed that those patients, whose CSCR manifested with only neurosensory retinal detachment (group 2), demonstrated greater choroidal thickness in the projection of the fovea, central retinal thickness as well as the height and extent of neurosensory retinal detachment. Neovasculature was identified in 11 eyes from group 1 (with PED). Structurally, the neovascular network was either loop-like (7 eyes), or tree-like (4 eyes). In loop-like networks, the maximum neovessel diameter averaged 35.474±4.967 µm and the total area of the neovascular complex was 0.581±0.380 µm2. Tree-like complexes were notable for the generally greater maximum neovessel diameter (65.626±17.316 µm) and area (0.225±0.133 µm2). Non-PED patients show pronounced transudative symptoms and significantly greater subfoveal retinal thicknesses. According to OCT-angiography findings, half of those CSCR patients, with PED, present neovascular networks of either loop-like, or tree-like structure.


Renal cell carcinoma co-existent with other renal disease: clinico-pathological features in pre-dialysis patients and those receiving dialysis or renal transplantation.
Patients on chronic dialysis are prone to developing acquired cystic kidney disease (ACKD), which may lead to the development of renal cell carcinoma (RCC). The risk factors for the development of RCC so far have not been determined in pre-dialysis patients with co-existent renal disease. The aim of this study was to evaluate the clinico-pathological features of RCC in pre-dialysis patients with associated renal diseases or in those undergoing chronic dialysis and renal transplantation. We studied 32 kidneys from 31 patients with RCC and associated renal diseases. Of those, 18 kidneys were from 17 patients not on renal replacement therapy (RRT) when diagnosed with RCC; 14 patients received dialysis or dialysis followed by renal transplantation. Several clinico-pathological features were analysed and compared between the two groups. Overall, there was a preponderance of males (75%); nephrosclerosis was the predominant co-existent disease (31%). The median intervals from renal disease to RCC in the dialysis and transplanted groups were significantly longer than in the pre-dialysis group (15.8+/-1.1 vs 2.4+/-0.7 years, P<0.0001). In contrast to pre-dialysis RCC, the dialysis and transplant RCC groups had greater frequency of ACKD (100 vs 28%, P<0.0001), papillary type RCC (43 vs 11%, P<0.05) and multifocal tumours (43 vs 5%, P<0.05). At the end of the study, 71% of dialysis and transplanted patients and 72% of pre-dialysis patients were alive. ACKD develops in dialysis patients, as it does in those with renal disease prior to RRT. The duration of renal disease, rather than the dialysis procedure itself, appears to be the main determinant of ACKD and RCC. The RCC occurring in patients with ACKD and prolonged RRT is more frequently of the papillary type and multifocal than the RCC occurring in patients with no or few acquired cysts and a short history of renal disease. Long-term outcomes did not differ between the two groups.


Twelve years' experience with posterior cruciate-retaining total knee arthroplasty.
The posterior cruciate ligament can be retained with advantage during routine total knee arthroplasty. This ligament is virtually always intact and functioning, even in rheumatoid patients. It is an important biologic stabilizer of the knee, capable of absorbing anterior-posterior shearing forces that otherwise must be borne by a constrained prosthesis and hence by the bone-cement interface. Its presence allows maintenance of the normal kinematics of the knee. Roll-back of the femur on the tibia can occur, enhancing flexion and improving the quadriceps moment. Substitution of the posterior cruciate ligament with the addition of prosthetic constraint will increase bone-cement reaction forces. These prostheses also require significant intercondylar femoral bone stock resection. The average range of motion of the early cruciate sacrificing design used in Insall's series was 94 degrees, 10 degrees or more less than now routinely seen with cruciate preservation. The bone-cement interface of the early total condylar knee with limited range of motion absorbed less force than it potentially might encounter with greater range of motion and increased function. Predictably, at long-term follow-up examination the newer cruciate-substituting prostheses that allow more physiologic range of motion might show higher radiolucent line rates and higher loosening rates than their cruciate-preserving counterparts. Only this information can settle the argument over whether the posterior cruciate ligament should be preserved, and if the objective is a knee with maximum flexion and maximum functional capability.


Risk of adverse fetal outcomes following administration of a pandemic influenza A(H1N1) vaccine during pregnancy.
Assessment of the fetal safety of vaccination against influenza A(H1N1)pdm09 in pregnancy has been limited. To investigate whether exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was associated with increased risk of adverse fetal outcomes. Registry-based cohort study based on all liveborn singleton infants in Denmark, delivered between November 2, 2009, and September 30, 2010. In propensity score-matched analyses, we estimated prevalence odds ratios (PORs) of adverse fetal outcomes, comparing infants exposed and unexposed to an AS03-adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy. Major birth defects, preterm birth, and small size for gestational age. From a cohort of 53,432 infants (6989 [13.1%] exposed to the influenza A[H1N1]pdm09 vaccine during pregnancy [345 in the first trimester and 6644 in the second or third trimester]), 660 (330 exposed) were included in propensity score-matched analyses of adverse fetal outcomes associated with first-trimester exposure. For analysis of small size for gestational age after second- or third-trimester exposure, 13,284 (6642 exposed) were included; for analyses of preterm birth, 12,909 (6543 exposed) were included. A major birth defect was diagnosed in 18 of 330 infants (5.5%) exposed to the vaccine in the first trimester, compared with 15 of 330 unexposed infants (4.5%) (POR, 1.21; 95% CI, 0.60-2.45). Preterm birth occurred in 31 of 330 infants (9.4%) exposed in the first trimester, compared with 24 of 330 unexposed infants (7.3%) (POR, 1.32; 95% CI, 0.76-2.31), and in 302 of 6543 infants (4.6%) with second- or third-trimester exposure, compared with 295 of 6366 unexposed infants (4.6%) (POR, 1.00; 95% CI, 0.84-1.17). Small size for gestational age was observed in 25 of 330 infants (7.6%) with first-trimester exposure compared with 31 of 330 unexposed infants (9.4%) (POR, 0.79; 95% CI, 0.46-1.37), and in 641 of 6642 infants (9.7%) with second- or third-trimester exposure, compared with 657 of 6642 unexposed infants (9.9%) (POR, 0.97; 95% CI, 0.87-1.09). In this Danish cohort, exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was not associated with a significantly increased risk of major birth defects, preterm birth, or fetal growth restriction.


Combining oncolytic HSV-1 with immunogenic cell death-inducing drug mitoxantrone breaks cancer immune tolerance and improves therapeutic efficacy.
Although antitumor activity of herpes simplex virus 1 (HSV-1) ICP0 null oncolytic vectors has been validated in murine breast cancer models, oncolytic virus treatment alone is insufficient to break immune tolerance. Thus, we investigated enhancing efficacy through combination therapy with the immunogenic cell death-inducing chemotherapeutic drug, mitoxantrone. Despite a lack of enhanced cytotoxicity in vitro, HSV-1 ICP0 null oncolytic virus KM100 with 5 μmol/L mitoxantrone provided significant survival benefit to BALB/c mice bearing Her2/neu TUBO-derived tumors. This protection was mediated by increased intratumoral infiltration of neutrophils and tumor antigen-specific CD8(+) T cells. Depletion studies verified that CD8-, CD4-, and Ly6G-expressing cells are essential for enhanced efficacy of the combination therapy. Moreover, the addition of mitoxantrone to KM100 oncolytic virus treatment broke immune tolerance in BALB-neuT mice bearing TUBO-derived tumors. This study suggests that oncolytic viruses in combination with immunogenic cell death-inducing chemotherapeutics enhance the immunogenicity of the tumor-associated antigens, breaking immunologic tolerance established toward these antigens.


Lipid peroxidation and tissue damage.
In recent years it has become apparent that the oxidation of lipids, or lipid peroxidation, is a crucial step in the pathogenesis of several disease states in adult and infant patients. Lipid peroxidation is a process generated naturally in small amounts in the body, mainly by the effect of several reactive oxygen species (hydroxyl radical, hydrogen peroxide etc.). It can also be generated by the action of several phagocytes. These reactive oxygen species readily attack the polyunsaturated fatty acids of the fatty acid membrane, initiating a self-propagating chain reaction. The destruction of membrane lipids and the end-products of such lipid peroxidation reactions are especially dangerous for the viability of cells, even tissues. Enzymatic (catalase, superoxide dismutasse) and nonenzymatic (vitamins A and E) natural antioxidant defence mechanisms exist; however, these mechanisms may be overcome, causing lipid peroxidation to take place. Since lipid peroxidation is a self-propagating chain-reaction, the initial oxidation of only a few lipid molecules can result in significant tissue damage. Despite extensive research in the field of lipid peroxidation it has not yet been precisely determined if it is the cause or an effect of several pathological conditions. Lipid peroxidation has been implicated in disease states such as atherosclerosis, IBD, ROP, BPD, asthma, Parkinson's disease, kidney damage, preeclampsia and others.


Direct comparison of Neuroform and Enterprise stents in the treatment of wide-necked intracranial aneurysms.
To compare the complications and outcomes of Neuroform and Enterprise stents in the treatment of unruptured wide-necked aneurysms. Under the auspices of the institutional review board, a review of a prospectively collected patient log identified 130 patients who underwent elective stent-assisted coil embolization of a wide-necked aneurysm, including 53 patients treated with an Enterprise stent and 77 patients treated with a Neuroform stent. Immediate and long-term clinical and radiographic outcomes were recorded for all patients. All patient data were handled in accordance with Health Insurance Portability and Accountability Act of 1996 (HIPAA) regulations. The technical success rate was 94%. Overall morbidity was 15% with Enterprise stents and 3% with Neuroform stents (p = 0.020). However, the type of stent used was not predictive of clinical outcomes as measured by the modified Rankin scale. In a multivariate analysis, the use of a Neuroform stent was one of the predictors of retreatment (p = 0.034). Multivariate analyses identified the use of Neuroform stents as an independent predictor of the need for retreatment and the use of Enterprise stents as an independent predictor of morbidity. However, the type of stent was not predictive of clinical outcome as measured by the modified Rankin scale.


A new niche for Vibrio logei, the predominant light organ symbiont of squids in the genus Sepiola.
Two genera of sepiolid squids--Euprymna, found primarily in shallow, coastal waters of Hawaii and the Western Pacific, and Sepiola, the deeper-, colder-water-dwelling Mediterranean and Atlantic squids--are known to recruit luminous bacteria into light organ symbioses. The light organ symbiont of Euprymna spp. is Vibrio fischeri, but until now, the light organ symbionts of Sepiola spp. have remained inadequately identified. We used a combination of molecular and physiological characteristics to reveal that the light organs of Sepiola affinis and Sepiola robusta contain a mixed population of Vibrio logei and V. fischeri, with V. logei comprising between 63 and 100% of the bacteria in the light organs that we analyzed. V. logei had not previously been known to exist in such symbioses. In addition, this is the first report of two different species of luminous bacteria co-occurring within a single light organ. The luminescence of these symbiotic V. logei strains, as well as that of other isolates of V. logei tested, is reduced when they are grown at temperatures above 20 degrees C, partly due to a limitation in the synthesis of aliphatic aldehyde, a substrate of the luminescence reaction. In contrast, the luminescence of the V. fischeri symbionts is optimal above 24 degrees C and is not enhanced by aldehyde addition. Also, V. fischeri strains were markedly more successful than V. logei at colonizing the light organs of juvenile Euprymna scolopes, especially at 26 degrees C. These findings have important implications for our understanding of the ecological dynamics and evolution of cooperative, and perhaps pathogenic, associations of Vibrio spp. with their animal hosts.


Hepatoprotective and antioxidant effects of licorice extract against CCl₄-induced oxidative damage in rats.
Licorice has been used in Chinese folk medicine for the treatment of various disorders. Licorice has the biological capabilities of detoxication, antioxidation, and antiinfection. In this study, we evaluated the antihepatotoxic effect of licorice aqueous extract (LE) on the carbon tetrachloride (CCl(4))-induced liver injury in a rat model. Hepatic damage, as reveled by histology and the increased activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) activities, and decreased levels of serum total protein (TP), albumin (Alb) and globulin (G) were induced in rats by an administration of CCl(4) at 3 mL/kg b.w. (1:1 in groundnut oil). Licorice extract significantly inhibited the elevated AST, ALP and ALT activities and the decreased TP, Alb and G levels caused by CCl(4) intoxication. It also enhanced liver super oxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR), Glutathione S-transferase (GST) activities and glutathione (GSH) level, reduced malondialdehyde (MDA) level. Licorice extract still markedly reverses the increased liver hydroxyproline and serum TNF-α levels induced by CCl(4) intoxication. The data of this study support a chemopreventive potential of licorice extract against liver oxidative injury.


Why results of clinical trials and observational studies of antitumour necrosis factor (anti-TNF) therapy differ: methodological and interpretive issues.
Results of randomised clinical trials (RCTs) appear to differ from results of observational studies. This paper explores differences in methodology, interpretation and presentation of results that elucidate these differences. We identified patients who completed a survey questionnaire during the period January 1998 through December 1998 and also completed one between July 2003 and June 2004, an average span of 4.7 years. The mean time from study initiation to anti-TNF administration was 2.1 years, and the mean treatment time was 2.1 (SD 1.3) years at study closure. During this period 38.3% of patients received anti-TNF therapy. We compared the results of patients in this group with results from RCTs. RCTs utilise flare design, patient selection, control groups and regression to the mean. Observational studies, on the other hand, confound additional prior therapy and anti-TNF effect, do not employ control groups, and may have less regression to the mean. RCTs and observational studies assess and report efficacy and effectiveness in ways that are so different that they are often incommensurable. A key difference is whether results should represent changes from flare states or should, instead, consider chronic status prior to initiation of therapy. There is little evidence that the clinical state at the start of most anti-TNF RCTs represents a chronic state. Economic analyses that utilise the RCT starting point overestimate the cost effectiveness of anti-TNF therapy. The solution for these problems and a guide to understanding the real results of anti-TNF therapy lies in collecting preclinical trial data in all patients who will enter clinical trials. In addition, RCT results would more approximate those of observational studies if all reporting was done after subtracting the effect of the comparator group.


Diminished Immune Surveillance during Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception.
Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses. Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology-related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set. Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression. Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches.


Inhibitors of diacylglycerol lipase and diacylglycerol kinase inhibit carbamylcholine-stimulated responses in guinea pig pancreatic minilobules.
We earlier showed that the diacylglycerol (DG) lipase inhibitor, RHC 80267, increased the steady-state level of DG and inhibited the release of arachidonic acid (AA) in carbamylcholine (CCh)-stimulated pancreatic minilobules (J. F. Dixon and L. E. Hokin, (1984) J. Biol. Chem. 259, 14418-14425). There was no effect on phospholipid metabolism. We have now investigated the effect of RHC 80267 on CCh-stimulated formation of inositol monophosphate formation, cGMP formation, and amylase release. CCh (10 microM) increased cGMP formation by approximately 20-fold, and this response was inhibited 55-75% by RHC 80267 (75-100 microM). RHC 80267 had no effect on either nitroprusside- or calcium ionophore-stimulated cGMP formation, arguing against a direct inhibition of guanylate cyclase by RHC 80267. Arachidonic acid, the release of which is inhibited by RHC 80267, neither stimulated cGMP formation nor reversed the effect of RHC 80267 on CCh-stimulated cGMP formation. This suggests, but does not prove, that the rise in cGMP in response to CCh is not due to an increase in AA as has been suggested. Both phorbol myristate acetate (25 nM) and the DG kinase inhibitor R 59022 (10 microM) inhibited CCh-stimulated cGMP formation by 40%. RHC 80267 also inhibited CCh-stimulated inositol phosphate accumulation and amylase release by 60 and 40%, respectively. The data suggest that the inhibition of CCh-stimulated cGMP formation and other muscarinic responses by RHC 80267 is probably the result of feedback inhibition of the cholinergic receptor via activation of protein kinase C by the elevated DG.


C1 inhibitor, C3 activator, IgG, IgA, and IgM titers in Nigerian sickle cell disease patients with plasmodium falciparum.
Sickle cell disease (HbSS) is a major health problem in Nigeria and malaria has been implicated as a leading cause of morbidity/mortality in sickle cell disease patients. Few reasons were put forward to explain the observed morbidity/mortality of HbSS subjects due to Plasmodium falciparum (P. falciparum) malaria. To determine the level of immunoglobulin classes (IgM, IgA, and IgG) and regulators of complement system (C1 inhibitor and C3 activator) in Nigerian HbSS patients with and without P. falciparum parasitemia. A total of 64 subjects were considered, including 10 HbSS genotypic subjects with P. falciparum parasitemia (HbSS+PfM), 18 HbAA genotypic subjects with P. falciparum parasitemia (HbAA+PfM), 20 HbSS without P. falciparum parasitemia (HbSS-PfM), and 16 HbAA genotypic subjects without P. falciparum parasitemia (HbAA-PfM). IgM, IgA, IgG, C1 inhibitor, and C3 activator titers were quantified by single radial immunodiffusion method. The mean levels of IgG in HbSS+PfM (2373.90+/-1772.81mg/dl) and HbAA+PfM (1868.80+/-0.00mg/dl) were significantly higher compared with HbSS-PfM (644.55+/-171.15mg/dl) or HbAA-PfM (659.75+/-158.01mg/dl) patients. HbAA-PfM subjects had the lowest level of IgM (67.27+/-63.7mg/dl), though no significant difference was observed comparing mean levels of IgM between the four groups. IgA titer was significantly higher in HbSS-PfM patients (249.00+/-94.8mg/dl) compared with HbAA-PfM (p<0.05), HbAA+PfM (p<0.05), or HbSS+PfM (p<0.05). The mean values of C1 inhibitor were lower in HbSS+PfM and HbAA+PfM compared with HbSS-PfM or HbAA-PfM. However, HbAA+PfM had a significantly lower value of C1 inhibitor compared with HbAA-PfM (p<0.01). C3 activator was highest in HbSS-PfM (17.10+/-7.35mg/dl) and was significantly higher compared with HbSS+PfM (p<0.05). Increased C1 inhibitor and decreased C3 activator in HbSS+PfM compared with HbAA+PfM shows that deranged regulation of complement factors may be responsible for increased susceptibility of HbSS to P. falciparum malaria.


Development and evaluation of microwave-assisted and ultrasound-assisted methods based on a quick, easy, cheap, effective, rugged, and safe sample preparation approach for the determination of bisphenol analogues in serum and sediments.
Microwave- and ultrasound-assisted methods based on a quick, easy, cheap, effective, rugged, and safe sample preparation approach followed by high-performance liquid chromatography with tandem mass spectrometry were developed for the simultaneous determination of eight bisphenol analogues in serum and sediment. The developed methods provided satisfactory extraction efficiency for the energy provided by microwaves and ultrasound. Compositions of commercial sorbents (primary secondary amine, MgSO4 , octadecyl-modified silica, and graphitized carbon black) were evaluated. The ultrasound-assisted method was suited for serum using primary secondary amine, MgSO4 , and octadecyl-modified silica as sorbents and a mixture of hexane and ethyl acetate as extraction solvent. The microwave-assisted method worked better for sediment with tetrahydrofuran and methanol as solvents and primary secondary amine, MgSO4 , octadecyl-modified silica, and graphitized carbon black as sorbents. Other experimental parameters, such as extraction temperature and time, were also optimized. The inter- and intraday relative standard deviations ranged from 2.7 to 5.5%. The limits of detection were between 0.1 and 1.0 ng/mL for serum and between 0.1 and 0.5 ng/g dry weight for sediment. The proposed methods were successfully applied to seven sediment and 20 human serum samples. The results showed that the developed methods were practical for the analysis and biomonitoring of bisphenols in sera and sediment.


Epidermoid tumor of the cerebellopontine angle: signal loss in the contralateral cistern.
We report a case of an epidermoid tumor of the right cerebellopontine angle (CPA) in which the contralateral CPA cistern showed abnormal, low signal intensity on T2-weighted fast spin-echo MR images. Diffusion-weighted images showed the epidermoid tumor of the right CPA extending to the prepontine cistern. The cause of the abnormal signal intensity was proved to be an artifactual signal loss due to cerebrospinal fluid flow by phase-contrast MR imaging.