Emerging role of cephalosporins in bacterial meningitis.
Since 1974, ampicillin and chloramphenicol have been standard therapeutic agents for initial treatment of bacterial meningitis occurring after the newborn period. Emerging problems necessitate a reappraisal and a search for alternatives to those drugs. The problems include the following: (1) Some strains of pneumococci (between 3 and 16 percent) are relatively resistant, with minimal inhibitory concentrations between 0.1 and 1.0 microgram/ml) to penicillin G and ampicillin. Such strains are not eradicated from the cerebrospinal fluid by the usual dosages of penicillin G or ampicillin. (2) Some strains of Hemophilus influenzae type B are resistant to ampicillin and chloramphenicol by virtue of beta-lactamase and acetyltransferase production. Such strains are currently rare in the United States, but it has been predicted that they might account for as many as one quarter of the isolates within a few years. (In Barcelona, Spain, their prevalence is 18 percent.) (3) Patients with meningitis often receive phenobarbital or phenytoin. Those drugs, and others metabolized by the liver, can significantly affect the pharmacology of chloramphenicol and result in either subtherapeutic or toxic concentrations of chloramphenicol in some patients. (4) For a variety of reasons, neither ampicillin plus gentamicin nor ampicillin plus chloramphenicol is an ideal combination for infants between one and four months of age when etiologic agents include coliform bacilli and group B streptococci, as well as Hemophilus, pneumococci, and meningococci. First-generation cephalosporins were unsuitable for the treatment of meningitis because of their low concentrations in the cerebrospinal fluid in relation to the bactericidal concentrations required for the common pathogens. Several of the newer cephalosporins achieve therapeutic concentrations in the cerebrospinal fluid and, in the case of three cephalosporin derivatives (cefuroxime, cefotaxime, and moxalactam), large, controlled clinical trials have demonstrated activity comparable to that of standard therapy. Limited experience suggests that several other cephalosporins (e.g., ceftizoxime, ceftazidime) will be shown to be effective when more experience is gained. Furthermore, the use of these drugs, with the exception of moxalactam, which has insufficient activity against gram-positive cocci, obviates the four problems just cited.


Mammary cancer and social interactions: identifying multiple environments that regulate gene expression throughout the life span.
Now that the human genome has been sequenced, along with those of major animal models, there is an urgent need to define those environments that interact with genes. The traditional view focuses on ways that gene products interact with the nuclear environment to regulate cell function, causing the physiologic changes, behaviors, and diseases manifest throughout development and aging. Although this view is essential, it is equally essential to understand the converse relationship, namely, to identify those environments at higher levels of organization that regulate the expression of specific genes. Given the vastness of this problem, one effective strategy is to start with a trait for which some of the genes have already been identified, such as malignant disease. In rats, social isolation and hypervigilance increase the incidence of mammary tumors, accelerate aging, and shorten the life span. We propose that similar environmental regulation of gene expression may underlie the disproportionately high mortality from premenopausal breast cancer of Blacks, a minority group that can experience high levels of loneliness and hypervigilance. Our goal is to identify which environments-social, psychological, hormonal, and cellular-regulate genetic mechanisms of mammary cancer risk as well as the specific times in the life span when they do so.


Bacteremia caused by Enterobacter: 15 years of experience in a cancer hospital.
A total of 296 episodes of bacteremia due to Enterobacter occurred in 281 patients with cancer between 1972 and 1986. The majority of these episodes were caused by Enterobacter cloacae. Seventy-four percent of the patients developed their infection while in the hospital and 55% had received therapeutic antibiotics during the 10 days preceding the onset of the infection. Enterobacter bacteremia was associated with shock in 24% of the patients and with disseminated intravascular coagulation in only 3%. The overall rate of response to therapy was 79% and increased to 85% during the last 5-year period. Only five patients remained afebrile during their infection, but four of these five died. Only 37% of the patients with shock responded to therapy compared with 93% of the patients without shock. The rate of response to therapy was 86% among patients without pulmonary infection compared with only 53% among those with pulmonary infection. The response rate to therapy with a single antibiotic was 73% and that to therapy with two antibiotics was 85%. As single therapeutic agents aminoglycosides were less effective than beta-lactam agents.


Structural basis of glyphosate resistance resulting from the double mutation Thr97 -> Ile and Pro101 -> Ser in 5-enolpyruvylshikimate-3-phosphate synthase from Escherichia coli.
The shikimate pathway enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) is the target of the broad spectrum herbicide glyphosate. The genetic engineering of EPSPS led to the introduction of glyphosate-resistant crops worldwide. The genetically engineered corn lines NK603 and GA21 carry distinct EPSPS enzymes. CP4 EPSPS, expressed in NK603 corn and transgenic soybean, cotton, and canola, belongs to class II EPSPS, glyphosate-insensitive variants of this enzyme isolated from certain Gram-positive bacteria. GA21 corn, on the other hand, was created by point mutations of class I EPSPS, such as the enzymes from Zea mays or Escherichia coli, which are sensitive to low glyphosate concentrations. The structural basis of the glyphosate resistance resulting from these point mutations has remained obscure. We studied the kinetic and structural effects of the T97I/P101S double mutation, the molecular basis for GA21 corn, using EPSPS from E. coli. The T97I/P101S enzyme is essentially insensitive to glyphosate (K(i) = 2.4 mm) but maintains high affinity for the substrate phosphoenolpyruvate (PEP) (K(m) = 0.1 mm). The crystal structure at 1.7-A resolution revealed that the dual mutation causes a shift of residue Gly(96) toward the glyphosate binding site, impairing efficient binding of glyphosate, while the side chain of Ile(97) points away from the substrate binding site, facilitating PEP utilization. The single site T97I mutation renders the enzyme sensitive to glyphosate and causes a substantial decrease in the affinity for PEP. Thus, only the concomitant mutations of Thr(97) and Pro(101) induce the conformational changes necessary to produce catalytically efficient, glyphosate-resistant class I EPSPS.


Effect of noncompetitive proteasome inhibition on bortezomib resistance.
Bortezomib and the other proteasome inhibitors that are currently under clinical investigation bind to the catalytic sites of proteasomes and are competitive inhibitors. We hypothesized that proteasome inhibitors that act through a noncompetitive mechanism might overcome some forms of bortezomib resistance. 5-amino-8-hydroxyquinoline (5AHQ) was identified through a screen of a 27-compound chemical library based on the quinoline pharmacophore to identify proteasome inhibitors. Inhibition of proteasome activity by 5AHQ was tested by measuring 7-amino-4-methylcoumarin (AMC) release from the proteasome substrate Suc-LLVY-AMC in intact human and mouse leukemia and myeloma cells and in tumor cell protein extracts. Cytotoxicity was assessed in 5AHQ-treated cell lines and primary cells from myeloma and leukemia patients using AlamarBlue fluorescence and MTS assays, trypan blue staining, and annexin V staining. 5AHQ-proteasome interaction was assessed by nuclear magnetic resonance. 5AHQ efficacy was evaluated in three leukemia xenograft mouse models (9-10 mice per group per model). All statistical tests were two-sided. 5AHQ inhibited the proteasome when added to cell extracts and intact cells (the mean concentration inhibiting 50% [IC(50)] of AMC release in intact cells ranged from 0.57 to 5.03 microM), induced cell death in intact cells from leukemia and myeloma cell lines (mean IC(50) values for cell growth ranged from 0.94 to 3.85 microM), and preferentially induced cell death in primary myeloma and leukemia cells compared with normal hematopoietic cells. 5AHQ was equally cytotoxic to human myelomonocytic THP1 cells and to THP1/BTZ500 cells, which are 237-fold more resistant to bortezomib than wild-type THP1 cells because of their overexpression and mutation of the bortezomib-binding beta5 proteasome subunit (mean IC(50) for cell death in the absence of bortezomib, wild-type THP1: 3.7 microM, 95% confidence interval = 3.4 to 4.0 microM; THP1/BTZ500: 6.6 microM, 95% confidence interval = 5.9 to 7.5 microM). 5AHQ interacted with the alpha subunits of the 20S proteasome at noncatalytic sites. Orally administered 5AHQ inhibited tumor growth in all three mouse models of leukemia without overt toxicity (eg, OCI-AML2 model, median tumor weight [interquartile range], 5AHQ vs control: 95.7 mg [61.4-163.5 mg] vs 247.2 mg [189.4-296.2 mg], P = .002). 5AHQ is a noncompetitive proteasome inhibitor that is cytotoxic to myeloma and leukemia cells in vitro and inhibits xenograft tumor growth in vivo. 5AHQ can overcome some forms of bortezomib resistance in vitro.


Sequence and expression of the dCMP deaminase gene (DCD1) of Saccharomyces cerevisiae.
The dCMP deaminase gene (DCD1) of Saccharomyces cerevisiae has been isolated by screening a Sau3A clone bank for complementation of the dUMP auxotrophy exhibited by dcd1 dmp1 haploids. Plasmid pDC3, containing a 7-kilobase (kb) Sau3A insert, restores dCMP deaminase activity to dcd1 mutants and leads to an average 17.5-fold overproduction of the enzyme in wild-type cells. The complementing activity of the plasmid was localized to a 4.2-kb PvuII restriction fragment within the Sau3A insert. Subcloning experiments demonstrated that a single HindIII restriction site within this fragment lies within the DCD1 gene. Subsequent DNA sequence analysis revealed a 936-nucleotide open reading frame encompassing this HindIII site. Disruption of the open reading frame by integrative transformation led to a loss of enzyme activity and confirmed that this region constitutes the dCMP deaminase gene. Northern analysis indicated that the DCD1 mRNA is a 1.15-kb poly(A)+ transcript. The 5' end of the transcript was mapped by primer extension and appears to exhibit heterogeneous termini. Comparison of the amino acid sequence of the T2 bacteriophage dCMP deaminase with that deduced for the yeast enzyme revealed a limited degree of homology which extends over the entire length of the phage polypeptide (188 amino acids) but is confined to the carboxy-terminal half of the yeast protein (312 amino acids). A potential dTTP-binding site in the yeast and phage enzymes was identified by comparison of homologous regions with the amino acid sequences of a variety of other dTTP-binding enzymes. Despite the role of dCMP deaminase in dTTP biosynthesis, Northern analysis revealed that the DCD1 gene is not subject to the same cell cycle-dependent pattern of transcription recently found for the yeast thymidylate synthetase gene (TMP1).


Dynamical ensemble of the active state and transition state mimic for the RNA-cleaving 8-17 DNAzyme in solution.
We perform molecular dynamics simulations, based on recent crystallographic data, on the 8-17 DNAzyme at four states along the reaction pathway to determine the dynamical ensemble for the active state and transition state mimic in solution. A striking finding is the diverse roles played by Na+ and Pb2+ ions in the electrostatically strained active site that impact all four fundamental catalytic strategies, and share commonality with some features recently inferred for naturally occurring hammerhead and pistol ribozymes. The active site Pb2+ ion helps to stabilize in-line nucleophilic attack, provides direct electrostatic transition state stabilization, and facilitates leaving group departure. A conserved guanine residue is positioned to act as the general base, and is assisted by a bridging Na+ ion that tunes the pKa and facilitates in-line fitness. The present work provides insight into how DNA molecules are able to solve the RNA-cleavage problem, and establishes functional relationships between the mechanism of these engineered DNA enzymes with their naturally evolved RNA counterparts. This adds valuable information to our growing body of knowledge on general mechanisms of phosphoryl transfer reactions catalyzed by RNA, proteins and DNA.


Assembly of the rotor component of yeast mitochondrial ATP synthase is enhanced when Atp9p is supplied by Atp9p-Cox6p complexes.
The Atp9p ring is one of several assembly modules of yeast mitochondrial ATP synthase. The ring, composed of 10 copies of Atp9p, is part of the rotor that couples proton translocation to synthesis or hydrolysis of ATP. We present evidence that before its assembly with other ATP synthase modules, most of Atp9p is present in at least three complexes with masses of 200-400 kDa that co-immunopurify with Cox6p. Pulse-labeling analysis disclosed a time-dependent reduction of radiolabeled Atp9p in the complexes and an increase of Atp9p in the ring form of wild type yeast and of mss51, pet111, and pet494 mutants lacking Cox1p, Cox2p, and Cox3p, respectively. Ring formation was not significantly different from wild type in an mss51 or atp10 mutant. The atp10 mutation blocks the interaction of the Atp9p ring with other modules of the ATP synthase. In contrast, ring formation was reduced in a cox6 mutant, consistent with a role of Cox6p in oligomerization of Atp9p. Cox6p involvement in ATP synthase assembly is also supported by studies showing that ring formation in cells adapting from fermentative to aerobic growth was less efficient in mitochondria of the cox6 mutant than the parental respiratory-competent strain or a cox4 mutant. We speculate that the constitutive and Cox6p-independent rate of Atp9p oligomerization may be sufficient to produce the level of ATP synthase needed for maintaining a membrane potential but limiting for optimal oxidative phosphorylation.


Natural rubber latex hypersensitivity with skin prick test in operating room personnel.
Hypersensitivity reactions to natural rubber latex have increased recently, especially among people with high exposure to latex allergens. Hypersensitivity reactions to latex are related to many conditions like occupational asthma. Our study was performed to determine the prevalence of hypersensitivity to natural rubber latex and potential food cross reactions in operation room personnel in Shiraz hospitals. In this cross-sectional, descriptive study, 580 operation room personnel filled out our questionnaire which included data about their personal history, symptoms of latex hypersensitivity, and other related allergies such as food hypersensitivity. An informed consent was obtained and skin prick tests were performed for natural rubber latex and potential food cross reactions (kiwi, banana, and potato). The obtained data were analyzed by SPSS and Chi-square test. 104 (17.9%) of the operating room personnel showed positive latex skin tests. We revealed a significant correlation between those with positive skin tests to latex with atopia, urthicaria, and food hypersensitivity. The prevalence did not vary by sex, age, education, surgical and non-surgical gloves users, or history of contact dermatitis. Latex hypersensitivity is common among operation room personnel. Evaluation of symptoms and prediction of future diseases necessitate screening tests in individuals at risk.


Programmable light-controlled shape changes in layered polymer nanocomposites.
We present soft, layered nanocomposites that exhibit controlled swelling anisotropy and spatially specific shape reconfigurations in response to light irradiation. The use of gold nanoparticles grafted with a temperature-responsive polymer (poly(N-isopropylacrylamide), PNIPAM) with layer-by-layer (LbL) assembly allowed placement of plasmonic structures within specific regions in the film, while exposure to light caused localized material deswelling by a photothermal mechanism. By layering PNIPAM-grafted gold nanoparticles in between nonresponsive polymer stacks, we have achieved zero Poisson's ratio materials that exhibit reversible, light-induced unidirectional shape changes. In addition, we report rheological properties of these LbL assemblies in their equilibrium swollen states. Moreover, incorporation of dissimilar plasmonic nanostructures (solid gold nanoparticles and nanoshells) within different material strata enabled controlled shrinkage of specific regions of hydrogels at specific excitation wavelengths. The approach is applicable to a wide range of metal nanoparticles and temperature-responsive polymers and affords many advanced build-in options useful in optically manipulated functional devices, including precise control of plasmonic layer thickness, tunability of shape variations to the excitation wavelength, and programmable spatial control of optical response.


Erg1, erg2 and erg3 K channel subunits are able to form heteromultimers.
Clonal somato-mammotroph GH3/B6 cells and lactotroph MMQ cells express two (ergl, erg2) of the three cloned rat ether-à-go-go-related gene (erg) K channel subunits. To study whether the erg subunits form heteromultimers, dominant-negative mutants of erg and erg2 were constructed by point mutation (erg1G630S, erg2G480S). After co-expression of these mutants with the wild-type erg1, erg2, or erg3 in Chinese hamster ovary (CHO) cells no erg currents could be detected. In contrast, in co-expression experiments with members of the other ether-à-go-go (EAG) subfamilies (eagl, elkl) the mutant erg1G630S had no effect. These results strongly suggest that erg channel subunits are able to form heteromultimers within the erg channel subfamily. Suppression of the endogenous E-4031-sensitive currents in GH3/B6 and MMQ cells by erg1G630S confirms that they are mediated by erg channels despite the differences in gating kinetics in these cells. Reduction of the erg current in GH3/B6 cells by erg2G480S indicates that erg heteromultimers can also be formed in these cells.


CGRP receptor antagonist MK-8825 attenuates cortical spreading depression induced pain behavior.
The present study aimed to investigate the effects of selective calcitonin gene related peptide (CGRP) receptor antagonist (MK-8825) on cortical spreading depression (CSD) induced pain behavior and anxiety in freely-moving rats, and neuronal activation in the correlated anatomical regions. CSD was induced while keeping all meningeal layers and BBB intact and MK-8825 was administered in two different doses. Regional cerebral blood flow (rCBF), arterial pressure and DC shift were recorded. Behavioral studies were conducted in freely-moving rats. Spontaneous behavior, mechanical allodynia, ultrasonic vocalization, and anxiety were evaluated. Immunohistochemistry of c-fos, CGRP, calcitonin receptor like-receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were studied. MK-8825 did not block DC shifts in the cerebral cortex and accompanied hemodynamic response. CSD significantly induced freezing and grooming behavior in freely-moving rats. MK-8825 reversed increased episodes of freezing, grooming, wet dog shake and head shake behavior. MK-8825 increased CSD-induced reductions in von Frey thresholds, but did not change elevated plus maze results. MK-8825 blocked c-fos induction by CSD in the brainstem trigeminal nucleus caudalis (TNC) and reticular nucleus of thalamus (TRN) but not in the amygdala. Immunofluorescence analysis showed no co-localization of CGRP, CLR or RAMP1 with c-fos positive cells. CGRP receptor antagonist MK-8825 dose dependently attenuated CSD-induced trigeminal nerve mediated pain response without altering CSD waves and accompanied rCBF response. While blocking TNC activation, MK-8825 did not exert any effect on amygdala and anxiety behavior. CGRP receptor antagonists may also modulate thalamo-cortical gating.


The seroprevalence of Helicobacter pylori infection in patients with obstructive sleep apnoea: a preliminary study.
We investigated the seroprevalence of Helicobacter pylori in patients with obstructive sleep apnoea. A prospective clinical study consisting of 19 patients, aged 23-72 years with confirmed obstructive sleep apnoea by overnight polysomnography, and 36 control subjects, aged 25-61 years with no history of obstructive sleep apnoea and gastroesophageal reflux complaints, was conducted. Titres of serum H. pylori IgG antibody were assayed by a serum enzyme-linked immunoabsorbant assay. The difference between the study and control groups was analysed by chi-squared test. Seventeen of the 19 patients (89.5%) were found to be H. pylori positive. However, 21 of the 36 control subjects (58.3%) were H. pylori positive. The seropositivity of H. pylori in obstructive sleep apnoea patients was found to be significantly higher than the control group (P = 0.017). The result of our study shows that there is a high association between H. pylori infection and obstructive sleep apnoea. This data may be important for future treatment strategies of the disease.


Current status of phase I clinical trials in Asia: an academic perspectives.
Clinical trials increasingly occured in Asia during the past years as pharmaceutical industries embraced globalization in the clinical research fields. The trend is true with phase III clinical trials but not for early stage/phase I clinical trials in Asian countries is still under-represented. The conduct of phase I clinical trials is considered more sophisticated and difficult than the later stage clinical trials. There are continuing concerns from the pharmaceutical industries about the capacity of Asian countries in conducting this type of clinical trials. We highlighted several problems concerning the ethical and scientific issues, the implementation of ICH-GCP and local regulations, investigators and clinical trial subjects. The purpose of this paper is to give some perspectives addressing the problems in conducting phase I clinical trials. Improving collaboration and capacity building among the Asian countries is a solution that we proposed in order to increase the quality and quantity of phase I clinical trials in Asian countries.


The construct of resilience: implications for interventions and social policies.
The focus of this article is on the interface between research on resilience-a construct representing positive adaptation despite adversity--and the applications of this work to the development of interventions and social policies. Salient defining features of research on resilience are delineated, as are various advantages, limitations, and precautions linked with the application of the resilience framework to developing interventions. For future applied efforts within this tradition, a series of guiding principles are presented along with exemplars of existing programs based on the resilience paradigm. The article concludes with discussions of directions for future work in this area, with emphases on an enhanced interface between science and practice, and a broadened scope of resilience-based interventions in terms of the types of populations, and the types of adjustment domains, that are encompassed.


Combined usage of intercostal nerve block and tumescent anaesthesia: an effective anaesthesia technique for breast augmentation.
Patients are occasionally unhappy with the size, shape, and positioning of breast implants. An option to improve their satisfaction with breast augmentation includes directly involving them in the process with awake surgery done under nerve block and tumescence. This study describes the resultsof using such an awake anaesthesia technique in 35 patients. After the intercostal nerves dominating the Th3 to Th6 regions were anaesthetized using 0.5% bupivacaine, a tumescent solution consisting of lidocaine, epinephrine, and saline was injected around the mammary gland, and breast augmentation was conducted using silicon implants. The majority of patients (31/35) reported no pain during the procedure and all patients were able to choose and confirm their final implant size and positioning. In all cases, blood loss was less than 10 ml. No patient experienced pneumothorax or toxicity of local anaesthetics. Combined usage of the intercostal nerve block and tumescent anaesthesia effectively reduces pain during breast augmentation. Keeping patient conscious enables meeting their requests during operation, contributing to increased satisfaction. For these advantages, combined usage of the intercostal nerve block and tumescent anaesthesia is recommended as a useful anaesthetic technique for breast augmentation.


Immunogenicity and efficacy of replication-competent recombinant influenza virus carrying multimeric M2 extracellular domains in a chimeric hemagglutinin conjugate.
Current influenza vaccines provide hemagglutinin (HA) strain-specific protection. To improve cross protection, we engineered replication-competent influenza A virus to express tandem repeats of heterologous M2 extracellular (M2e) domains in a chimeric HA. M2e epitopes conjugated to HA glycoproteins (M2e4x-HA) were found to be expressed on the surfaces of a replicable influenza virus as examined by electron microscopy. The recombinant influenza virus containing M2e4x-HA was moderately attenuated but superior to the parental virus in inducing M2e specific antibodies without compromising HA immunogenicity. Recombinant influenza virus immune mice showed better cross protection than parental virus immune mice. Immune sera from the mice with inoculation of live recombinant influenza virus expressing M2e4x-HA were effective in conferring protection against H1, H3, and H5 subtype influenza viruses. This study indicates that recombinant influenza virus expressing conserved protective epitopes in an HA chimeric form can provide a new approach for improving the efficacy of influenza vaccines.


Thyroid hormone and dexamethasone increase the levels of a messenger ribonucleic acid for a mitochondrially encoded subunit but not for a nuclear-encoded subunit of cytochrome c oxidase.
The nuclear genome is the primary locus of activity for thyroid hormone and dexamethasone; however, one well described secondary effect of treatment with these hormones is increased mitochondrial respiratory activity. To examine the mechanism of the increase in respiration, we have treated a rat hepatoma cell line, HTC cells, with thyroid hormone and dexamethasone and measured their effects on the activity of a respiratory chain enzyme and on mitochondrial (mt) RNA and mtDNA levels. Thyroid hormone, but not dexamethasone, increased cytochrome c oxidase activity in HTC cells; the increase in activity was nearly 2-fold over control values. To determine whether this increased activity was the result of coordinate increases in expression of nuclear and cytoplasmic genes for this enzyme, we measured changes in the levels of messenger RNAs for both nuclear and mitochondrially encoded cytochrome oxidase subunits. Treatment of HTC cells with thyroid hormone and/or dexamethasone resulted in 3- to 4-fold increases in the levels of several RNAs encoded in the mt genome, including subunit II of cytochrome c oxidase. In contrast, this treatment had no effect on the messenger RNA encoding a nuclear subunit of this same enzyme. Neither of these hormones had any effect on cell number or on the level of mtDNA. Dose response and time course of thyroid hormone and dexamethasone administration on mtRNA levels were consistent with these hormones acting through their nuclear hormone receptors. Increased expression of the mt genome by alteration of transcription or RNA stability is a likely candidate for a mechanism by which these hormones can regulate mitochondrial activity.


[Listeriosis: an infrequent infection in patients with HIV].
Although resistance to Listeria monocytogenes infection requires intact T-cell mediated immunity, listeriosis is an infrequent problem in patients with HIV infection and only about 50 patients have been reported to date. Only two patients with HIV and L. monocytogenes have been attended in our hospital since the beginning of aids epidemic in 1981. Case 1: a man with HIV and 364 CD4+ cells/mm3 presented fever and occipital headache. The cerebral scan was normal and L. monocytogenes grew in licuor culture. He was outcome after treatment with ampicillin and tobramycin. Case 2: a 47 years old man with HIV, 44 CD4+ cells/mm3 and hepatic virus C cirrhosis was admitted to the hospital because fever and abdominal distension. He was on menstrual pentamidine prophylaxis for Pneumocystis carinii pneumonia (PCP). Bacterial peritonitis was diagnosed and the patient begun treatment with ceftriaxone. The patient dead 72 hours later with hepatic encepholopathy. Postmortem L. monocytogenes grew. Listeriosis is an infrequent disease in patients with HIV that causes difficult diagnostic problems, principally in patients without prophylaxis with cotrimoxazole for PCP.


Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease.
Patients with lung disease caused by Mycobacterium abscessus subsp. abscessus (here M. abscessus) typically have poor treatment outcomes. Although clofazimine (CFZ) has been increasingly used in the treatment of M. abscessus lung disease in clinical practice, there are no reported data on its effectiveness for this disease. This study sought to evaluate the clinical efficacy of a CFZ-containing regimen for the treatment of M. abscessus lung disease. We performed a retrospective review of the medical records of 42 patients with M. abscessus lung disease who were treated with CFZ-containing regimens between November 2013 and January 2015. CFZ was administered in combination with other antibiotics as an initial antibiotic regimen in 15 (36%) patients (initial treatment group), and it was added to an existing antibiotic regimen for refractory M. abscessus lung disease in 27 (64%) patients (salvage treatment group). Overall, there was an 81% treatment response rate based on symptoms and a 31% response rate based on radiographic findings. Conversion to culture-negative sputum samples was achieved in 10 (24%) patients after CFZ-containing antibiotic treatment, and during treatment, there were significant decreases in the positivity of semiquantitative sputum cultures for acid-fast bacilli in both the initial (P = 0.018) and salvage (P = 0.001) treatment groups. Our study suggests that CFZ-containing regimens may improve treatment outcomes in patients with M. abscessus lung disease and that a prospective evaluation of CFZ in M. abscessus lung disease is warranted.


Dynamic DTI (dDTI) shows differing temporal activation patterns in post-exercise skeletal muscles.
To assess post-exercise recovery of human calf muscles using dynamic diffusion tensor imaging (dDTI). DTI data (6 directions, b = 0 and 400 s/mm2) were acquired every 35 s from seven healthy men using a 3T MRI, prior to (4 volumes) and immediately following exercise (13 volumes, ~7.5 min). Exercise consisted of 5-min in-bore repetitive dorsiflexion-eversion foot motion with 0.78 kg resistance. Diffusion tensors calculated at each time point produced maps of mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), and signal at b = 0 s/mm2 (S0). Region-of-interest (ROI) analysis was performed on five calf muscles: tibialis anterior (ATIB), extensor digitorum longus (EDL) peroneus longus (PER), soleus (SOL), and lateral gastrocnemius (LG). Active muscles (ATIB, EDL, PER) showed significantly elevated initial MD post-exercise, while predicted inactive muscles (SOL, LG) did not (p < 0.0001). The EDL showed a greater initial increase in MD (1.90 × 10-4mm2/s) than ATIB (1.03 × 10-4mm2/s) or PER (8.79 × 10-5 mm2/s) (p = 7.40 × 10-4), and remained significantly elevated across more time points than ATIB or PER. Significant increases were observed in post-exercise EDL S0 relative to other muscles across the majority of time points (p < 0.01 to p < 0.001). dDTI can be used to differentiate exercise-induced changes between muscles. These differences are suggested to be related to differences in fiber composition.


Effectiveness of cognitive therapy for depression in a community mental health center: a benchmarking study.
The current study examined the feasibility and effectiveness of transporting an empirically supported treatment for depression, cognitive therapy (CT), to a community mental health center setting. CT was delivered to 192 adult outpatients with major depression, and a benchmarking strategy compared results with those of 2 randomized controlled trials (RCTs). The 3 samples were largely similar in terms of initial severity of depression, and CT was as effective in reducing depressive symptoms in the current sample as in the RCTs. More favorable outcome was associated with less severe initial depression, more therapy sessions, more years of education, and absence of a comorbid personality disorder. This study demonstrates that an empirically supported treatment can be transported effectively to a clinical setting.


Alvarado scores and pain onset in relation to multislice CT findings in acute appendicitis.
To determine the correlation between clinical and multislice computed tomography (MSCT) findings of early- and late-stage acute appendicitis. The study was conducted between June 2003 and February 2006 with 143 patients. Patients were divided into 3 groups according to Alvarado scores: group 1 (n = 18; 13%; score: 1-4), group 2 (n = 70; 49%; score: 5-7), and group 3 (n = 55; 38%; score: 8-10). Abdominal MSCT results were compared to histopathological diagnoses. Patients were then divided into 2 other groups according to pain onset (MSCT performed within the first 12 h of pain onset and MSCT performed thereafter). Histopathological findings were normal in 13 of the 143 patients (9%). The positive predictive value of MSCT did not significantly differ between the 3 Alvarado groups (92.8% in group 1, 95.1% in group 2, and 98.0% in group 3). Additionally, the positive predictive value of MSCT did not differ whether the scans were performed within the first 12 h of pain onset or thereafter (88% and 89%, respectively; P = 0.89). MSCT should be performed even in patients in whom the clinical suspicion of appendicitis is low. MSCT is effective in patients with early-stage appendicitis.


Effect of brachytherapy on NF-κB and VEGF in gastric carcinoma xenografts.
Iodine-125 (125I) seed irradiation can be used as an important supplementary treatment for unresectable advanced gastric cancer. However, the radiobiological mechanism underlying brachytherapy remains unclear. Therefore, we investigated the influence of continuous and low-energy 125I irradiation on the cell cycle distribution, apoptosis, expression of NF-κB and VEGF and tumor growth in a human gastric cancer xenograft model. To create an animal model of gastric cancer, SGC-7901 cells were surgically implanted into mice. The 60 mice bearing SGC-7901 gastric cancer xenografts were randomly separated into 2 groups. Sham seeds (0 mCi) were implanted into the control group (n=30); 125I seeds (0.6 mCi) were implanted into the treatment group (n=30). At 28 days after irradiation, apoptosis was detected by flow cytometry. fluorescence micrograph detected intense VEGF and NF-κB immunofluorescence in the tumor samples, and changes in NF-κB and VEGF mRNA and protein expression were assessed by real-time PCR and western blot analysis, respectively. The tumor volume and weight were measured 0-28 days after 125I seed implantation. 125I seed irradiation induced significant apoptosis and G2/M phase arrest. Reduction in the intensities of VEGF and NF-κB immunofluorescence in tumor vessels was observed after treatment. NF-κB and VEGF mRNA and protein expression levels were substantially lower in the implantation treatment group than in the control group. Consequently, 125I seed implantation inhibited cancer growth and reduced cancer volume. The present study revealed that 125I seed irradiation significantly induced apoptosis and cell cycle arrest in the human gastric cancer xenografts. 125I-induced changes in NF-κB and VEGF expression are suggested as potential mechanisms underlying effective brachytherapy.


Endometriosis and Fertility Preservation.
Endometriosis is common, affecting 5% to 10% of reproductive age women. Nearly half of women with surgical evidence of endometriosis fail to achieve spontaneous pregnancy. Surgical treatment of endometriosis can be detrimental to ovarian reserve. In the absence of surgical intervention, ovarian reserve may still be negatively impacted over time. Fertility preservation was developed for women requiring gonadotoxic treatments. Improved methods have led to greater consideration of offering these services to women with other disease processes that threaten ovarian reserve. This chapter will present the debate regarding use of fertility preservation in management of endometriosis, and outline the need for further studies.


Direct molecular mass determination of trehalose monomycolate from 11 species of mycobacteria by MALDI-TOF mass spectrometry.
Direct estimation of the molecular mass of single molecular species of trehalose 6-monomycolate (TMM), a ubiquitous cell-wall component of mycobacteria, was performed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. When less than 1 microg TMM was analysed by MALDI-TOF mass spectrometry, quasimolecular ions [M+Na]+ of each molecular species were demonstrated and the numbers of carbons and double bonds (or cyclopropane rings) were determined. Since the introduction of oxygen atoms such as carbonyl, methoxy and ester groups yielded the appropriate shift of mass ions, the major subclasses of mycolic acid (alpha, methoxy, keto and wax ester) were identified without resorting to hydrolytic procedures. The results showed a marked difference in the molecular species composition of TMM among mycobacterial species. Unexpectedly, differing from other mycoloyl glycolipids, TMM from Mycobacterium tuberculosis showed a distinctive mass pattern, with abundant odd-carbon-numbered monocyclopropanoic (or monoenoic) alpha-mycolates besides dicyclopropanoic mycolate, ranging from C75 to C85, odd- and even-carbon-numbered methoxymycolates ranging from C83 to C94 and even- and odd-carbon-numbered ketomycolates ranging from C83 to C90. In contrast, TMM from Mycobacterium bovis (wild strain and BCG substrains) possessed even-carbon-numbered dicyclopropanoic alpha-mycolates. BCG Connaught strain lacked methoxymycolates almost completely. These results were confirmed by MALDI-TOF mass analysis of mycolic acid methyl esters liberated by alkaline hydrolysis and methylation of the original TMM. Wax ester-mycoloyl TMM molecular species were demonstrated for the first time as an intact form in the Mycobacterium avium-intracellulare group, M. phlei and M. flavescens. The M. avium-intracellulare group possessed predominantly C85 and C87 wax ester-mycoloyl TMM, while M. phlei and the rapid growers tested contained C80, C81, C82 and C83 wax ester-mycoloyl TMM. This technique has marked advantages in the rapid analysis of not only intact glycolipid TMM, but also the mycolic acid composition of each mycobacterial species, since it does not require any degradation process.


Comparing patterning and biconditional discriminations in humans.
In two experiments, human participants performed a causal judgment task that simultaneously comprised two reciprocal patterning discriminations and a biconditional discrimination. They learned both patterning discriminations more quickly than the biconditional discrimination. Postdiscrimination tests were used to identify participants who had, or had not, learned to apply the patterning rules, as well as participants who continued to expect summation when presented with two cues that predicted the same outcome. All groups were faster to learn the patterning than the biconditional discriminations. These results are inconsistent with models of stimulus representation that invoke configural representations (e.g., Pearce, 1987, 1994; Rescorla & Wagner, 1972) because these models solve biconditional discriminations more readily than patterning discriminations.


The WNT/β-catenin pathway is involved in the anti-adipogenic activity of cerebrosides from the sea cucumber Cucumaria frondosa.
Both adipocyte hypertrophy and hyperplasia lead to obesity. Here, we isolated cerebrosides from the sea cucumber Cucumaria frondosa (CFC) and examined its anti-adipogenic activity in vitro. CFC inhibited the lipid accumulation of 3T3-L1 cells and suppressed PPARγ and C/EBPα expressions, proving its anti-adipogenic activity. Furthermore, CFC suppressed lipogenesis in mature adipocytes. The WNT/β-catenin pathway acts as an anti-adipogenic factor. CFC enhanced β-catenin expression, promoted its nuclear translocation and up-regulated the expression of CCND1 and c-myc, two target genes of β-catenin. Moreover, after cells were treated with the β-catenin inhibitor 21H7, β-catenin nuclear translocation and transcription activity can be recovered by CFC. These findings suggested that CFC promoted the activation of the WNT/β-catenin pathway. Besides, CFC enhanced the expressions of Fz1, LRP5 and LRP6, while it had no effect on the expressions of Wnt10b and GSK3β. These findings indicated that CFC exhibits anti-adipogenic activity through enhancing the activation of the WNT/β-catenin pathway, which was mediated by FZ and LRPs.


Spatial Scene Memories Are Biased Towards a Fixed Amount of Semantic Information.
Scene memory has known spatial biases. Boundary extension is a well-known bias whereby observers remember visual information beyond an image's boundaries. While recent studies demonstrate that boundary contraction also reliably occurs based on intrinsic image properties, the specific properties that drive the effect are unknown. This study assesses the extent to which scene memory might have a fixed capacity for information. We assessed both visual and semantic information in a scene database using techniques from image processing and natural language processing, respectively. We then assessed how both types of information predicted memory errors for scene boundaries using a standard rapid serial visual presentation (RSVP) forced error paradigm. A linear regression model indicated that memories for scene boundaries were significantly predicted by semantic, but not visual, information and that this effect persisted when scene depth was considered. Boundary extension was observed for images with low semantic information, and contraction was observed for images with high semantic information. This suggests a cognitive process that normalizes the amount of semantic information held in memory.


The long-term outcome of renal transplantation of IgA nephropathy and the impact of recurrence on graft survival.
Few data are available on allograft survival at 15 years, the impact and the predictors of recurrence of the original disease in renal transplanted patients with IgA nephropathy (IgAN). In this retrospective study, we compared the long-term outcome of renal transplant in 190 patients with IgAN with that of 380 non-diabetic controls and evaluated the impact of recurrence of IgAN on the graft outcome. At 15 years, the patient survival was 88.3% in IgAN patients and 82.6% in controls (P = 0.12), while the death-censored graft survival was 62.6 and 72.4%, respectively (P = 0.038). IgAN had a higher cumulative incidence of graft failures in comparison with controls even considering death as a competing risk (P = 0.025). At multivariate analysis, IgAN [relative risk (RR) = 1.468, P = 0.026], delayed graft function recovery (RR = 2.394, P = 0.000) and acute rejection (RR = 2.51, P = 0.000) were predictive of graft loss. IgAN recurred in 42 grafts (22.1%), of them, 12 were lost for recurrence and in another 6 recurrence was considered a concomitant cause of graft loss. The 15-year death censored graft survival was 68.3% in non-recurrent and 51.2% in recurrent patients (P = 0.069). Pure graft survival of non-recurrent IgAN patients was similar to that of controls (P = 0.406). At Cox analysis, the recurrence of IgAN significantly reduced from 1981 to 2010 (P = 0.0065, RR = 0.936). IgAN emerged as an independent predictor of worse graft outcome in the long-term. Recurrence of IgAN seems to progressively reduce in transplants performed from 1981 to 2010.


Comparative in vivo and in vitro investigation of interfacial bond variability.
This comparative in vivo/in vitro study investigated the interfacial adaptation between dentin and composite resins in totally bonded adhesive restorations placed under clinical and laboratory conditions in the same tooth. Cavities were prepared in buccal or lingual surfaces of 47 third-molar teeth scheduled for extraction and randomly assigned for treatment with the following bonding systems/restorative materials: Clearfil Liner Bond 2/Clearfil AP-X (Group I, n = 10), Resulcin AquaPrime + Monobond/MFR Merz (Group II, n = 9), Prime&Bond 2.1/Dyract AP (Group III, n = 9), Scotchbond Multi-Purpose/Z-100 (Group IV, n = 10), and Ecusit Primer AB-Mono/Ecusit (Group V, n = 9). In Group V, a thin layer of a low-viscous compomer (Primaflow) was interposed between the dentin and the composite resin during restoration placement (according to the manufacturer's directions). After extraction a second filling was placed in each tooth with identical materials in the same manner as in vivo. The restoration-dentin interface was evaluated in longitudinally cut sections of the specimens by SEM-analysis, and the frequency of gap formation between restoration and dentin was calculated. Median percentages for the in vivo/in vitro frequency of interfacial gap formation were 29.2%/13.9% in Group I, 33.3%/20.0% in Group II, 40%/5.3% in Group III, 53.9%/30.4% in Group IV and 13.8%/0% in Group V. Comparison of gap formation frequency between fillings placed in vivo and in vitro revealed significant differences (p < 0.05) in Groups II, III and IV. However, in Groups I and V the internal adaptation was not significantly different between in vivo and in vitro applied restorations. A significant (p < 0.01) correlation (Spearman-Rho rank correlation coefficient) was found for the corresponding in vivo and in vitro fillings placed in the individual teeth with regard to interfacial gap formation. It was concluded that achievement of a completely gap-free internal adaptation between restorative material and dentin in totally bonded composite resin restorations is difficult to predict under in vivo as well as in vitro conditions.


[Studies on nutritional effects of traditional Chinese tonics with strengthened nutrients on pregnant women and rats].
Clinical and Experimental studies on a mixture made of traditional Chinese tonics (such as Fructus Lycii, Rhizoma Dioscoreae and Arillus Longannae, etc.) and strengthened nutrients (such as iron, zinc and Calcium, etc.) were conducted in order to explore its nutritional and health promoting effects. (1) One hundred and three primiparous women were divided randomly into observed group and control group, results showed that the serum levels of iron, zinc, hemoglobin of observed group were all raised after treatment, these parameters and the concentration of iron in umbilical cord blood as well as body weight of new-born baby of the observed group were higher than that of control group (P < 0.05 or P < 0.01). (2) Results of experimental rats showed that the utilization rate, hemoglobin level, fetal growth and developing parameters of test group were all higher than that of control group significantly (P < 0.05 or P < 0.01). These results suggested that the nutrient mixture has a good nutritional and health promoting effect on pregnancy.


Phenotypic Analysis and Molecular Characterization of Enlarged Cell Size Mutant in Nannochloropsis oceanica.
The cell cycle is the fundamental cellular process of eukaryotes. Although cell-cycle-related genes have been identified in microalgae, their cell cycle progression differs from species to species. Cell enlargement in microalgae is an essential biological trait. At the same time, there are various causes of cell enlargement, such as environmental factors, especially gene mutations. In this study, we first determined the phenotypic and biochemical characteristics of a previously obtained enlarged-cell-size mutant of Nannochloropsis oceanica, which was designated ECS. Whole-genome sequencing analysis of the insertion sites of ECS indicated that the insertion fragment is integrated inside the 5'-UTR of U/P-type cyclin CYCU;1 and significantly decreases the gene expression of this cyclin. In addition, the transcriptome showed that CYCU;1 is a highly expressed cyclin. Furthermore, cell cycle analysis and RT-qPCR of cell-cycle-related genes showed that ECS maintains a high proportion of 4C cells and a low proportion of 1C cells, and the expression level of CYCU;1 in wild-type (WT) cells is significantly increased at the end of the light phase and the beginning of the dark phase. This means that CYCU;1 is involved in cell division in the dark phase. Our results explain the reason for the larger ECS size. Mutation of CYCU;1 leads to the failure of ECS to fully complete cell division in the dark phase, resulting in an enlargement of the cell size and a decrease in cell density, which is helpful to understand the function of CYCU;1 in the Nannochloropsis cell cycle.


Parallel lines: nothing has changed?
The exponential increase in mortality rate with age is a universal feature of aging and is described mathematically by the Gompertz equation. When this equation is transformed semilogarithmically, it conforms to a straight line, the slope of which is generally used to reflect the rate of senescence. Historical and contemporary data of human and nonhuman populations show that adverse environmental conditions do not always change the slope of the log mortality rate over age. From these latter observations it is sometimes mistakenly inferred that the rate of senescence is unaffected by environmental conditions. Current biological inference emphasizes that gene action is dependent on the environment in which it is expressed. Here, we propose using the tangent line of the Gompertz equation to assess whether the rate of senescence has altered. Such an approach unmasks different rates of senescence when parameter G has remained constant, an observation that is in line with the notion that a plastic life history trait such as the rate of senescence results from the interplay of both genes and environment.


Assessment of burn injury in the accident and emergency department: a review of 100 referrals to a regional burns unit.
Accurate assessment of the extent of thermal injury in the accident and emergency (A&E) department is essential if appropriate resuscitation and referral to a specialist unit is to occur. However, review of 100 referrals to a regional burns unit confirms that assessment is often inaccurate, and usually undertaken by no one more senior than a casualty officer, leading to suboptimal treatment and referral. Severe thermal injury should be assessed by a team of senior doctors, according to the major trauma protocol, and casualty officers should receive better training in the assessment of less extensive burns.


Intractable Biliary Candidiasis in Patients with Obstructive Jaundice and Regional Malignancy: A Retrospective Case Series.
Candida species are infrequently grown in bile cultures. An association between biliary candidiasis and regional malignancy may exist. The role of fungus membranes in frequent biliary stent occlusion is also presented in this case series. We retrospectively identified patients who underwent percutaneous trans-hepatic cholangiogram (PTC) for obstructive jaundice between January 2014 and January 2019. The results of bile cultures - obtained by PTC - for all patients were analyzed, and patients with fungus growth were determined; their medical records were reviewed. A total of 71 patients with obstructive jaundice underwent PTC between January 2015 and January 2019. Five patients (all male; mean age 55.8 years) had candida species growth in bile cultures. Two patients were diagnosed with cholangiocarcinoma, one with adenocarcinoma of the head of the pancreas, one with gallbladder cancer, and one with locally advanced gastric adenocarcinoma. Formation of fungal balls predisposed to frequent PTC drain clogging. Eradication of Candida was achieved in 4 patients after 10 days to 3 weeks of antifungal therapy. We present a case series of biliary candidiasis in patients with obstructive jaundice and regional malignancy. We suggest that patients with obstructive jaundice and regional malignancy should be screened for biliary candidiasis. Persistent cholestasis may be caused by the recurrent formation of fungal membranes (balls).


Arfophilins are dual Arf/Rab 11 binding proteins that regulate recycling endosome distribution and are related to Drosophila nuclear fallout.
Arfophilin is an ADP ribosylation factor (Arf) binding protein of unknown function. It is identical to the Rab11 binding protein eferin/Rab11-FIP3, and we show it binds both Arf5 and Rab11. We describe a related protein, arfophilin-2, that interacts with Arf5 in a nucleotide-dependent manner, but not Arf1, 4, or 6 and also binds Rab11. Arfophilin-2 localized to a perinuclear compartment, the centrosomal area, and focal adhesions. The localization of arfophilin-2 to the perinuclear compartment was selectively blocked by overexpression of Arf5-T31N. In contrast, a green fluorescent protein-arfophilin-2 chimera or arfophilin-2 deletions were localized around the centrosome in a region that was also enriched for transferrin receptors and Rab11 but not early endosome markers, suggesting that the distribution of the endosomal recycling compartment was altered. The arfophilins belong to a conserved family that includes Drosophila melanogaster nuclear fallout, a centrosomal protein required for cellularization. Expression of green fluorescent protein-nuclear fallout in HeLa cells resulted in a similar phenotype, indicative of functional homology and thus implicating the arfophilins in mitosis/cytokinesis. We suggest that the novel dual GTPase-binding capacity of the arfophilins could serve as an interface of signals from Rab and Arf GTPases to regulate membrane traffic and integrate distinct signals in the late endosomal recycling compartment.


Predicting outcome after traumatic brain injury.
Developing insight into which factors determine prognosis after traumatic brain injury (TBI) is useful for clinical practice, research, and policy making. Several steps can be identified in prediction research: univariate analysis, multivariable analysis, and the development of prediction models. For each step, several methodological issues should be considered, such as selection/coding of predictors and dealing with missing data. "Traditional" predictors include demographic factors (age), type of injury, clinical severity, second insults, and the presence of structural abnormalities on neuroimaging. In combination, these predictors can explain approximately 35% of the variance in outcome in populations with severe and moderate TBI. Novel and emerging predictors include genetic constitution, biomarkers, and advanced magnetic resonance (MR) imaging. To estimate prognosis for individual patients reliably, multiple predictors need to be considered jointly in prognostic models. Two prognostic models for use in TBI, developed upon large patient numbers, have been extensively validated externally: the IMPACT and CRASH prediction models. Both models showed good performance in validations across a wide range of settings. Importantly, these models were developed not only for mortality but also for functional outcome. Prognostic models can be used for providing information to relatives of individual patients, for resource allocation, and to support decisions on treatment. At the group level, prognostic models aid in the characterization of patient populations, are important to clinical trial design and analysis, and importantly, can serve as benchmarks for assessing quality of care. Continued development, refinement, and validation of prognostic models for TBI is required and this should become an ongoing process.


WITHDRAWN: Physical medicine modalities for mechanical neck disorders.
Twenty-six to 71 percent of the adult population can recall experiencing an episode of neck pain or stiffness in their lifetime. The treatments that patients receive for neck pain are varied, as are the perceptions of the benefits of these treatments. In this age of increasing accountability, governmental agencies, third party payers and patients are demanding evidence-based practice performance. To track down the best estimate of efficacy of the various conservative management strategies for mechanical neck disorders, a four-part systematic review was prepared. Part two investigates and reports on the efficacy of physical medicine modalities. Multiple physical medicine modalities are commonly included as part of therapeutic interventions for mechanical neck disorders (neck pain). The objective of this review was to assess the effects of physical medicine modalities for pain in adults with mechanical neck disorders. We searched Medline, Embase, Chirolars, Index to Chiropractic Literature, Cinahl, Science Citation Index, Conference Proceedings Index, National Technical Information Services and reference lists of the retrieved articles from 1985 to December 1993 and we contacted content experts. Randomised trials and controlled trials of physical medicine modalities in adults with mechanical neck disorder. Three reviewers independently assessed trial quality and two reviewers independently extracted data. Investigators were contacted to obtain information or data that could not be found in the published reports. Thirteen trials were included. The overall quality of the included trials was generally good. Two trials using electromagnetic therapy produced a significant reduction in pain (p <0.01) with three to four weeks of daily (eight hours per day) therapy sessions; and three using laser therapy did not differ significantly from a placebo (p=0.20) for six to 10 sessions of treatment. Not enough scientific testing exists to clearly determine the effectiveness of other therapies. This includes treatments such as exercise, traction, acupuncture, heat / cold applications, electrotherapies, cervical orthoses and chronic pain / cognitive behavioural rehabilitation strategies. There is little information available from trials to support the use of physical medicine modalities for mechanical neck pain. There is some support for the use of electromagnetic therapy and against the use of laser therapy with respect to pain reduction.


Challenges to academic family medicine in the current health care environment.
Changes in health care delivery and funding have placed strains on academic medical centers' ability to meet their multiple missions. To gain insight into how this new academic landscape is affecting academic primary care, this study examined the current status and perceived challenges at nine departments of family medicine at allopathic and osteopathic medical schools. Site visits were made to nine academic departments of family medicine where key informant interviews were conducted with several individuals in key leadership positions. Sites were chosen to maximize diversity among departments along a variety of factors, such as location, size, mission, and type of school (private versus public). Interviews were transcribed and analyzed by a three-person multidisciplinary team for key themes. Analysis of interviews revealed five major challenges for academic departments of family medicine: 1) adjusting to new clinical demands in the academic health center, 2) organizing and administering new initiatives in community-based education, 3) recruiting and retaining faculty, 4) developing and maintaining research capacity, and 5) serving multiple missions (education, clinical care, and academic pursuits) in times of financial restraint. Significant challenges face academic departments of family medicine. The success or failure of departments of family medicine to meet these challenges could serve as a bellwether for how primary care fits into the future overall scheme of academic health centers.


An unsaturated metal site-promoted approach to construct strongly coupled noble metal/HNb3O8 nanosheets for efficient thermo/photo-catalytic reduction.
Creating two-dimensional (2D) crystal-metal heterostructures with an ultrathin thickness has spurred increasing research endeavors in catalysis because of its fascinating opportunities in tuning the electronic state at the surface and enhancing the chemical reactivity. Here we report a novel and facile Nb4+-assisted strategy for the in situ growth of highly dispersed Pd nanoparticles (NPs) on monolayer HNb3O8 nanosheets (HNb3O8 NS) constituting a 2D Pd/HNb3O8 NS heterostructure composite without using extra reducing agents and stabilizing agents. The Pd NP formation is directed via a redox reaction between an oxidative Pd salt precursor (H2PdCl4) and reductive unsaturated surface metal (Nb4+) sites induced by light irradiation on monolayer HNb3O8 NS. The periodic arrangement of metal Nb nodes on HNb3O8 NS leads to a homogeneous distribution of Pd NPs. Density functional theory (DFT) calculations reveal that the direct redox reaction between the Nb4+ and Pd2+ ions leads to a strong chemical interaction between the formed Pd metal NPs and the monolayer HNb3O8 support. Consequently, the as-obtained Pd/HNb3O8 composite serves as a highly efficient bifunctional catalyst in both heterogeneous thermocatalytic and photocatalytic selective reduction of aromatic nitro compounds in water under ambient conditions. The achieved high activity originates from the unique 2D nanosheet configuration and in situ Pd incorporation, which leads to a large active surface area, strong metal-support interaction and enhanced charge transport capability. Moreover, this facile Nb4+-assisted synthetic route has demonstrated to be general, which can be applied to load other metals such as Au and Pt on monolayer HNb3O8 NS. It is anticipated that this work can extend the facile preparation of noble metal/nanosheet 2D heterostructures, as well as promote the simultaneous capture of duple renewable thermal and photon energy sources to drive an energy efficient catalytic process.


Purification and identification of rat hepatic cytosolic enzymes responsible for defluorination of methoxyflurane and fluoroacetate.
Enzymes responsible for the defluorination of methoxyflurane (MOF) and fluoroacetate (FAc) were separated and purified from rat liver cytosol. Both hepatic cytosolic enzymes with defluorination activity were labile and addition of 2-mercaptoethanol had little effect on the stability of these enzymes. Glutathione S-transferase (GT) activity of the same cytosolic fractions was stable for at least 11 days. Separation of defluorination and GT enzymatic activities on DEAE-Sephadex A-50 and reduced glutathione-affinity columns revealed that the defluorinations of MOF and FAc were primarily catalyzed by anionic proteins which also exhibited GT activity. Further identification by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed protein bands with pl values of approximately 6.5 and 6.9 and molecular weights of approximately 20,000. However, other proteins that exhibited no GT activity also defluorinated MOF and FAc, but accounted for only 10% of the total defluorination activity present in anionic proteins. Results from a separate purification experiment using a CM-cellulose column also indicated that the enzymes responsible for defluorination coeluted with cationic GTs. Collectively, these cationic enzymes were responsible for about 20% of the recovered cytosolic defluorination activities. The results suggest that the cytosolic defluorinations of both MOF and FAc are primarily the result of a dehalogenation reaction catalyzed by one or more species of rat liver cytosolic GTs.


Characterization of genotype-specific carboxyl-terminal cleavage sites of hepatitis B virus e antigen precursor and identification of furin as the candidate enzyme.
Hepatitis B e antigen (HBeAg) is a secreted version of hepatitis B virus (HBV) core protein that promotes immune tolerance and persistent infection. It is derived from a translation product of the precore/core gene by two proteolytic cleavage events: removal of the amino-terminal signal peptide and removal of the carboxyl-terminal arginine-rich sequence. Four RXXR motifs are present at the carboxyl terminus of the HBeAg precursor, with the first two fused as (151)RRGRSPR(157). Genotype A possesses two extra amino acids at the first motif ((151)RRDRGRSPR(159)), which weakens the first motif and separates it from the second one. Western blot analysis of patient sera revealed a single HBeAg form for genotypes B to D but two additional forms of larger sizes for genotype A. Site-directed mutagenesis and transfection experiments with human hepatoma cell lines indicated that HBeAg of genotype B is derived from cleavage at the first ((151)RRGR(154)) motif. The major HBeAg form of genotype A corresponds to cleavage at the second ((156)RSPR(159)) motif, and the other two forms are cleavage products of the first ((151)RRDR(154)) and third ((166)RRRR(169)) motifs, respectively. Only the cleavage product of the third motif of genotype A was observed in furin-deficient LoVo cells, and an inhibitor of furin-like proprotein convertases blocked cleavage of the first and second motifs in human hepatoma cells. In conclusion, our study reveals genotypic differences in HBeAg processing and implicates furin as the major enzyme involved in the cleavage of the first and second RXXR motifs.


Influence of kaempferol, a flavonoid compound, on membrane-bound ATPases in streptozotocin-induced diabetic rats.
Kaempferol is a flavonoid found in many edible plants (e.g. tea, cabbage, beans, tomato, strawberries, and grapes) and in plants or botanical products commonly used in traditional medicine. Numerous preclinical studies have shown that kaempferol have a wide range of pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, neuroprotective, and antidiabetic activities. The present study investigates the effect of kaempferol on membrane-bound ATPases in erythrocytes and in liver, kidney, and heart of streptozotocin (STZ)-induced diabetic rats. Diabetes was induced into adult male albino rats of the Wistar strain, by intraperitoneal administration of STZ (40 mg/kg body weight (BW)). Kaempferol (100 mg/kg BW) or glibenclamide (600 µg/kg BW) was administered orally once daily for 45 d to normal and STZ-induced diabetic rats. The effects of kaempferol on membrane-bound ATPases (total ATPase, Na(+)/K(+)-ATPase, Ca(2+)-ATPase, and Mg(2+)-ATPase) activity in erythrocytes and in liver, kidney, and heart were determined. In our study, diabetic rats had significantly (p < 0.05) decreased activities of total ATPases, Na(+)/K(+)-ATPase, Ca(2+)-ATPase, and Mg(2+)-ATPase in erythrocytes and tissues. Oral administration of kaempferol (100 mg/kg BW) or glibenclamide (600 µg/kg BW) for a period of 45 d resulted in significant (p < 0.05) reversal of these enzymes' activities to near normal in erythrocytes and tissues when compared with diabetic control rats. Thus, obtained results indicate that administration of kaempferol has the potential to restore deranged activity of membrane-bound ATPases in STZ-induced diabetic rats. Further detailed investigation is necessary to discover kaempferol's action mechanism.


Molecular studies in 20 submicroscopic neurofibromatosis type 1 gene deletions.
Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder characterized by a marked variability in expression. A more severe phenotype is frequently observed in the group of patients carrying a large NF1 deletion. To study the extent of the microdeletion in these NF1 patients, we generated a partial physical map of the NF1 flanking region. We describe seven PACs and three new polymorphic dinucleotide repeats located outside the NF1 gene and analyzed 20 unrelated individuals with an NF1 microdeletion in a collaborative study. We detected one individual with a substantially smaller deletion including only the NF1 gene and its three embedded genes. In the other 19 patients, the deletion extended at least 1 Mb. The parental origin of the deletion was determined in 15 individuals and was maternal in 13 and paternal in two cases. The new molecular tools described here can be used to unequivocally diagnose a possible extragenic extension of an NF1 deletion.


A Potential Role of NFIL3 in Atherosclerosis.
Nuclear factor interleukin-3 (NFIL3), a proline- and acidic-residue-rich (PAR) bZIP transcription factor, is called the E4 binding protein 4 (E4BP4) as well, which is relevant to regulate the circadian rhythms and the viability of cells. More and more evidence has shown that NFIL3 is associated with different cardiovascular diseases. In recent years, it has been found that NFIL3 has significant functions in the progression of atherosclerosis (AS) via the regulation of inflammatory response, macrophage polarization, some immune cells and lipid metabolism. In this overview, we sum up the function of NFIL3 during the development of AS and offer meaningful views how to treat cardiovascular disease related to AS.


A Step towards Personalised Cancer Treatment in Lower Middle-income Countries (LMICS): Molecular Tumour Boards.
Tumour boards are meetings where physicians from various disciplines treating cancer patients meet to recommend evidence-based or the best possible treatment plan. These meetings have evolved with time and now, in every part of the world; site-specific multi-disciplinary tumour boards are established. These meetings are considered pivotal for improving patient outcomes. The advances in molecular and genetic knowledge and technique and their integration in treatment options have paved the way for multiple therapeutic options. However, the adoption of personalised treatment choices is associated with a huge financial burden, especially in low and middle-income countries (LMICs). A molecular tumour board can help to identify and suggest the most appropriate plan of management. Key Words: Molecular, Genetics, Personalised, Challenges.


Intermediate filament expression in human fetal olfactory epithelium.
Antibodies to intermediate filaments and to desmoplakin were used to investigate the histogenetic origin of the olfactory neuroepithelium. Intermediate-filaments are tissue-specific molecular cytoskeletal markers; desmoplakin is the major desmosomal protein. The olfactory epithelia of eight human fetuses, aged 7 to 10 weeks (fertilization age) were immunofluorescently labeled with antibodies to the five classes of intermediate-filament proteins and to desmoplakin. Positive immunoreactivity to keratin and to desmoplakin was observed; both results indicate the epithelial nature of this tissue. The absence of neurofilaments and glial-fibrillary acidic protein in the tissue containing sensory neurons and gliallike supporting cells is a unique feature, and may be related to the fact that olfactory neuroepithelium, like other epithelia, undergoes continuous turnover.


Heavy episodic drinking on college campuses: does changing the legal drinking age make a difference?
This article extends the compartmental model previously developed by Scribner et al. in the context of college drinking to a mathematical model of the consequences of lowering the legal drinking age. Using data available from 32 U.S. campuses, the analyses separate underage and legal age drinking groups into an eight-compartment model with different alcohol availability (wetness) for the underage and legal age groups. The model evaluates the likelihood that underage students will incorrectly perceive normative drinking levels to be higher than they actually are (i.e., misperception) and adjust their drinking accordingly by varying the interaction between underage students in social and heavy episodic drinking compartments. The results evaluate the total heavy episodic drinker population and its dependence on the difference in misperception, as well as its dependence on underage wetness, legal age wetness, and drinking age. Results suggest that an unrealistically extreme combination of high wetness and low enforcement would be needed for the policies related to lowering the drinking age to be effective.


[Observation of visual quality after implantation of a rotational asymmetric refractive intraocular lens with a low addition region using the micromonovision design].
Objective: To investigate the effects of the application of a low addition refractive multifocal intraocular lens (IOL) using the micromonovision design in the non-dominant eye with different degrees of preset myopia on the visual acuity, visual function and visual quality after bilateral cataract surgery. Methods: In this randomized controlled trial, patients who were proposed to undergo bilateral phacoemulsification combined with rotational asymmetric refractive IOL (MF15 IOL) implantation at the First Affiliated Hospital of Zhengzhou University between September 2020 and August 2022 were included. All patients were divided into three groups using the random number method. The target refraction of the IOL in the dominant eye was 0.00 D. Non-dominant eyes were given different preoperative IOL reserve refractions, with the reserved near additional degree>0.20 D and≤0.40 D as the low addition,>0.40 D and≤0.60 D as the medium addition, and>0.60 D and≤0.80 D as the high addition. We compared uncorrected distance visual acuity (UDVA), uncorrected intermediate visual acuity (UIVA) and uncorrected near visual acuity (UNVA) of monocular and binocular eyes at 1 day, 1 month and 3 months postoperatively in the 3 groups of patients. Furthermore, the contrast sensitivity, stereopsis, defocus curves and visual quality questionnaire results of binocular eyes were compared at 3 months postoperatively. The statistical methods mainly used were chi-square test, two-factor repeated measures ANOVA, one-way ANOVA, LSD test, Kruskal-Wallis test, and paired t-test. Results: A total of 110 patients (220 eyes) were enrolled in the study, including 48 males and 62 females, with an average age of (59.74±9.38) years. There were 40 patients (80 eyes) in the low additional degree group, 37 patients (74 eyes) in the medium additional degree group, and 33 patients (66 eyes) in the high additional degree group. The differences in distance, intermediate and near visual acuity of the dominant eyes among the three groups were not statistically significant at different measurement timepoints postoperatively (P>0.05). The differences in intermediate and near visual acuity of the non-dominant eyes were also not statistically significant (P>0.05) among the three groups. In contrast, at 3 months, the UDVA of the non-dominant eyes in the low additional degree group (0.04±0.06) and medium additional degree group (0.04±0.07) was significantly higher than that in the high additional degree group (0.08±0.09) (F=4.776, P=0.011, bias η2=0.086). There was no statistically significant difference in binocular uncorrected distance, intermediate and near visual acuity among the three groups at different postoperative timepoints (P>0.05). The binocular UDVA, UIVA and UNVA (logMAR visual acuity) at 3 months postoperatively were -0.04±0.04, 0.03±0.08, 0.10±0.13 in the low addition group, -0.01±0.05, -0.02±0.06, 0.09±0.10 in the medium addition group, and 0.02±0.07, 0.01±0.09, 0.16±0.11 in the high addition group. At 3 months postoperatively, the binocular contrast sensitivity of the low additional degree group was significantly higher than that of the high additional degree group (P<0.05), except that there was no significant difference at the spatial frequency of 6 cycles per degree in the absence of glare (P>0.05). The binocular contrast sensitivity of the medium additional degree group was significantly higher than that of the high additional degree group at the spatial frequencies of 6 and 18 cycles per degree in the glare condition (P<0.05). The difference in the binocular contrast sensitivity between the low and medium additional degree groups did not reach statistical significance (P>0.05). The peak of the binocular defocus curve in the three groups was significantly wider than that in the monocular eyes, and the decline trend was more gentle, with no trough in the middle, and the visual acuity could be maintained above 0.2 (logMAR visual acuity) in the 0.00 D to -3.00 D defocus range. There was no significant difference in the postoperative near stereopsis results among the three groups (P>0.05), with the percentage of near stereopsis sharpness≤60″ reaching 90.00% (36/40), 89.19% (33/37) and 78.79% (26/33), respectively. The proportions of VF-14 scores≥90 in the postoperative questionnaire were 90% (36/40), 91.89% (34/37) and 81.82% (27/33) for the low, medium and high additional degree groups, respectively. The differences in the probability of photic phenomena and spectacles-independent rate were not statistically significant (P>0.05). Conclusion: The use of micromonovision design for bilateral implantation of a rotational asymmetric refractive MF15 IOL, with the non-dominant eye reserved for different near additional degrees, can enable cataract patients to have significantly improved binocular full-range vision, visual function and visual quality. When the degree of reserved near additions in the non-dominant eye preoperatively is>0.20 D and≤0.60 D, it can ensure sufficient binocular UDVA, UIVA and UNVA after surgery, and meanwhile help to obtain superior contrast sensitivity and stereopsis, as well as a satisfactory spectacles-independent rate and low incidence of photic phenomena.


Metagenomic Discovery of 83 New Human Papillomavirus Types in Patients with Immunodeficiency.
Several immunodeficiencies are associated with high susceptibility to persistent and progressive human papillomavirus (HPV) infection leading to a wide range of cutaneous and mucosal lesions. However, the HPV types most commonly associated with such clinical manifestations in these patients have not been systematically defined. Here, we used virion enrichment, rolling circle amplification, and deep sequencing to identify circular DNA viruses present in skin swabs and/or wart biopsy samples from 48 patients with rare genetic immunodeficiencies, including patients with warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, or epidermodysplasia verruciformis (EV). Their profiles were compared with the profiles of swabs from 14 healthy adults and warts from 6 immunologically normal children. Individual patients were typically infected with multiple HPV types; up to 26 different types were isolated from a single patient (multiple anatomical sites, one time point). Among these, we identified the complete genomes of 83 previously unknown HPV types and 35 incomplete genomes representing possible additional new types. HPV types in the genus Gammapapillomavirus were common in WHIM patients, whereas EV patients mainly shed HPVs from the genus Betapapillomavirus. Preliminary evidence based on three WHIM patients treated with plerixafor, a leukocyte mobilizing agent, suggest that longer-term therapy may correlate with decreased HPV diversity and increased predominance of HPV types associated with childhood skin warts.IMPORTANCE Although some members of the viral family Papillomaviridae cause benign skin warts (papillomas), many human papillomavirus (HPV) infections are not associated with visible symptoms. For example, most healthy adults chronically shed Gammapapillomavirus (Gamma) virions from apparently healthy skin surfaces. To further explore the diversity of papillomaviruses, we performed viromic surveys on immunodeficient individuals suffering from florid skin warts. Our results nearly double the number of known Gamma HPV types and suggest that WHIM syndrome patients are uniquely susceptible to Gamma HPV-associated skin warts. Preliminary results suggest that treatment with the drug plerixafor may promote resolution of the unusual Gamma HPV skin warts observed in WHIM patients.


The description of chemotherapy delivery: options and pitfalls.
Delivered and planned drug doses in chemotherapy trials are analyzed in relation to dose size, dose rate, and total drug delivery. Time-dose factors are presented in different ways, further exploring what may be misleading when comparing one treatment program with another. The time frame over which treatment intensity is to be calculated is recognized as arbitrary and not necessarily from start to end of treatment. Considerations for doses missed are presented. The cumulative-dose plot represents a new method of data presentation. This method graphically captures both intensity and total drug delivery per patient, and is helpful when analyzing trials designed to isolate treatment variables and improve the therapeutic index of available drugs.


On the absorption of bacterial endotoxin from the gastro-intestinal tract of the normal and shocked animal.
Coliform-free rabbits fed P(32) labeled E. coli 0111B(4) prior to the induction of experimental hemorrhagic shock were shown to have a substantial amount of the type-specific 0111B(4) antigen in the circulating blood, liver, and spleen, whereas normal rabbits fed the same amount of these bacteria and held under identical conditions, but not exposed to shock, have the antigen within the liver, and occasionally in the kidney, but not in the blood. That the antigen recovered from the blood and tissues was derived from this specific strain of bacteria was demonstrated by the use of the hemagglutination inhibition reaction, by the absence of cross-reacting antigens in appropriate control animals, and by agreement in the amount of antigen as estimated by two different technics. Transport of bacterial endotoxin across the intestinal membrane appears to be achieved primarily by passive diffusion. The accumulation of biologically active endotoxin in the blood and tissues of the shocked animal appears to be due to a reduction in the detoxifying potential of the reticulo-endothelial system, and not to a greater than normal absorption of endotoxin from the intestine. The absence of toxicity in the specific antigen extracted from normal liver demonstrates that the degradation of endotoxic potency can be achieved without altering the chemical integrity of the polysaccharide moiety of the molecule. The implications of the hypothesis that there is a continuous but fluctuating absorption of bacterial endotoxin from the intestine are briefly discussed, and the contribution of free circulating bacterial endotoxin of intestinal origin to the fate of the shocked animal is noted.


Gaze properties of women judging the attractiveness of masculine and feminine male faces.
Most studies of female facial masculinity preference have relied upon self-reported preference, with participants selecting or rating the attractiveness of faces that differ in masculinity. However, researchers have not established a consensus as to whether women's general preference is for male faces that are masculine or feminine, and several studies have indicated that women prefer neither. We investigated women's preferences for male facial masculinity using standard two-alternative forced choice (2AFC) preference trials, paired with eye tracking measures, to determine whether conscious and non-conscious measures of preference yield similar results. We found that women expressed a preference for, gazed longer at, and fixated more frequently on feminized male faces. We also found effects of relationship status, relationship context (whether faced are judged for attractiveness as a long- or short-term partner), and hormonal contraceptive use. These results support previous findings that women express a preference for feminized over masculinized male faces, demonstrate that non-conscious measures of preference for this trait echo consciously expressed preferences, and suggest that certain aspects of the preference decision-making process may be better captured by eye tracking than by 2AFC preference trials.


Communication between residents and attending doctors on call after hours.
Off-hours medical care in hospitals is provided by residents, while attendings on call are available for assistance. This study evaluated the gap between residents' expectations and professional guidelines' requirements of attendings on call and what actually occurs during night shifts, while comparing surgical and medical specialties. Two questionnaires based on professional guidelines were filled by residents. The first queried about residents' expectations of attendings on call, and the second asked about communication with the attendings during actual night shifts. While 91 (100%) of residents expected the attending on call to be available by phone during the shift, only 44 (48%) expected the attending to initiate contact, and only 17 (19%) expected the attending to visit the ward or emergency department (ED) without being requested to do so. In 127 shifts (84%), some form of communication occurred. Residents called their attendings during 105 shifts (70%). However, attendings initiated contact with residents at the beginning or during the shift in only 67 (44%) and 62 (41%) shifts, respectively, and initiated a visit to the ward/ED during the shift in only 41 cases (27%). Surgical attendings initiated contact in these three ways significantly more frequently than medical attendings [21 (28%) versus 46 (61%), 20 (26%) versus 42 (56%) and 4 (5%) versus 37 (50%), respectively; P < 0.001]. While communication during night shifts between residents and attendings occurs in most shifts, attendings initiate far less contact with residents than is required by the guidelines.


Incidence of type 2 diabetes using proposed HbA1c diagnostic criteria in the european prospective investigation of cancer-norfolk cohort: implications for preventive strategies.
To evaluate the incidence and relative risk of type 2 diabetes defined by the newly proposed HbA(1c) diagnostic criteria in groups categorized by different baseline HbA(1c) levels. Using data from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort with repeat HbA(1c) measurements, we estimated the prevalence of known and previously undiagnosed diabetes at baseline (baseline HbA(1c) ≥6.5%) and the incidence of diabetes over 3 years. We also examined the incidence and corresponding odds ratios (ORs) by different levels of baseline HbA(1c). Incident diabetes was defined clinically (self-report at follow-up, prescribed diabetes medication, or inclusion on a diabetes register) or biochemically (HbA(1c) ≥6.5% at the second health assessment), or both. The overall prevalence of diabetes was 4.7%; 41% of prevalent cases were previously undiagnosed. Among 5,735 participants without diabetes at baseline (identified clinically or using HbA(1c) criteria, or both), 72 developed diabetes over 3 years (1.3% [95% CI 1.0-1.5]), of which 49% were identified using the HbA(1c) criteria. In 6% of the total population, the baseline HbA(1c) was 6.0-6.4%; 36% of incident cases arose in this group. The incidence of diabetes in this group was 15 times higher than in those with a baseline HbA(1c) of <5.0% (OR 15.5 [95% CI 7.2-33.3]). The cumulative incidence of diabetes defined using a newly proposed HbA(1c) threshold in this middle-aged British cohort was 1.3% over 3 years. Targeting interventions to individuals with an HbA(1c) of 6.0-6.4% might represent a feasible preventive strategy, although complementary population-based preventive strategies are also needed to reduce the growing burden of diabetes.


Determination of organic acids in seven wheat varieties by capillary gas chromatography.
Fresh wheat tops were extracted with acidic 90% ethanol, and the ethanol was evaporated and a portion of the aqueous residue loaded onto DEAE-Sephadex. Organic acids were eluted with pyridinium formate and then lyophilized and the dried residue was derivatized with 1% trimethylchlorosilane in bis(trimethylsilyl)trifluoroacetamide. The acids were then quantitatively determined using capillary gas chromatography and identified using capillary gas chromatography-mass spectrometry. The acidic ethanol extraction of fresh plant tissue was quantitative for all acids except citric while losses in the remaining procedures were controlled by using an internal standard. The ion exchange chromatography made the greatest contribution to experimental error, imposing a minimum loading requirement of 0.1 mumol of each acid for adequate precision. Organic acid profiles were determined for seven wheat cultivars (Triticum aestivum cv Carazinho, Teal, Lance, Warigal, Isis, Maringa, and BH1146) grown on gravel in solution culture for 30 days. Profiles were simple, consisting of only malic, aconitic, and citric acids, with levels of each acid for all varieties falling within the range 2-5 mumol/g fresh tissue. Storage of samples led to a large increase in sampling error and increased the amount of extractable citric acid.


Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.
Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival. Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups. The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.).


Anti-prolactin (PRL) autoantibodies cause asymptomatic hyperprolactinemia: bioassay and clearance studies of PRL-immunoglobulin G complex.
The causes of hyperprolactinemia are varied, but some cases are classified as "idiopathic" because of unknown causes. We examined whether anti-prolactin (PRL) autoantibodies can cause hyperprolactinemia, especially the asymptomatic type. Serum PRL in four women with anti-PRL autoantibodies and five control patients with prolactinoma was characterized by a sensitive enzyme immunoassay, Nb2-bioassay, gel chromatography, affinity chromatography for immunoglobulin G (IgG), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under nonreducing conditions, and clearance studies using anesthetized rats. In four women with anti-PRL autoantibodies, serum immunoreactive PRL concentrations were elevated (326 +/- 216 micrograms/L, normal < 30 micrograms/L), and PRL (84 +/- 5.5%) mostly consisted of the large molecular form in which a significant amount of 23 kDa PRL (60.6 +/- 14.7%) was noncovalently bound to IgG. Although three of the four women lacked clinical symptoms of hyperprolactinemia such as amenorrhea and galactorrhea, the IgG-bound PRL was fully bioactive in vitro. It was cleared more slowly from circulation than free PRL. The data suggest that PRL forms a complex with IgG, and this probably results in delayed clearance of PRL and leads to hyperprolactinemia in women with anti-PRL autoantibodies.


KV11.1 Potassium Channel and the Na+/H+ Antiporter NHE1 Modulate Adhesion-Dependent Intracellular pH in Colorectal Cancer Cells.
Increasing evidence indicates that ion channels and transporters cooperate in regulating different aspects of tumor pathophysiology. In cancer cells, H+/HCO3 - transporters usually invert the transmembrane pH gradient typically observed in non-neoplastic cells, which is thought to contribute to cancer malignancy. To what extent the pH-regulating transporters are functionally linked to K+ channels, which are central regulators of cell membrane potential (Vm), is unclear. We thus investigated in colorectal cancer cells the implication of the pH-regulating transporters and KV11.1 (also known as hERG1) in the pH modifications stimulated by integrin-dependent cell adhesion. Colorectal cancer cell lines (HCT 116 and HT 29) were seeded onto β1 integrin-dependent substrates, collagen I and fibronectin. This led to a transient cytoplasmic alkalinization, which peaked at 90 min of incubation, lasted approximately 180 min, and was inhibited by antibodies blocking the β1 integrin. The effect was sensitive to amiloride (10 µM) and cariporide (5 µM), suggesting that it was mainly caused by the activity of the Na+/H+ antiporter NHE1. Blocking KV11.1 with E4031 shows that channel activity contributed to modulate the β1 integrin-dependent pHi increase. Interestingly, both NHE1 and KV11.1 modulated the colorectal cancer cell motility triggered by β1 integrin-dependent adhesion. Finally, the β1 integrin subunit, KV11.1 and NHE1 co-immunoprecipitated in colorectal cancer cells seeded onto Collagen I, suggesting the formation of a macromolecular complex following integrin-mediated adhesion. We conclude that the interaction between KV11.1, NHE1, and β1 integrin contributes to regulate colorectal cancer intracellular pH in relation to the tumor microenvironment, suggesting novel pharmacological targets to counteract pro-invasive and, hence, pro-metastatic behavior in colorectal cancer.


Frequency of supernumerary teeth in Mexican population.
Supernumerary teeth (ST) are a not uncommon developmental anomaly which appears in 0.3 to 3.8 percent of the population. We studied the corresponding radiographs from 2241 patients, both sexes who seeked dental attention at the Outpatient Clinic of the División de Estudios de Posgrado e Investigación, Facultad de Odontología, UNAM in Mexico City. Of them, we found 72 patients (3.2%) with 102 ST. Of the 72 patients, 39 were males (54.2%) and 33 females (45.8%). Mesiodens was the most common ST (48.6%), followed by supernumerary premolars (26.4%), supernumerary laterals (11.1%) and fourth molars (9.7%). This series includes cases with one, two and three ST and one case comprising 10 ST. Our results suggest that frequency of ST in the population studied differs in some aspects with previously reported series and that frequency of ST shows different rates depending the population studied. As our results demonstrate, it is encouraged the need to have panoramic radiographs of all patients attended in dental offices, clinics and schools of Dentistry in order to detect and diagnose undiscovered pathologies.


Versatile Nature of Oxygen Vacancies in Bismuth Vanadate Bulk and (001) Surface.
Bismuth vanadate (BiVO4) has emerged as one of the most promising photoanode materials for solar fuel production. Oxygen vacancies play a pivotal role in the photoelectrochemical efficiency, yet their electronic nature and contribution to n-type conductivity are still under debate. Using first-principles calculations, we show that oxygen vacancies in BiVO4 have two distinguishable geometric configurations characterized by either undercoordinated, reduced VIVO3 and BiIIO7 subunits or a VIV-O-VIV/V bridge (split vacancy), quenching the oxygen vacancy site. While both configurations have similar energies in the bulk, the (001) subsurface acts like an energetic sink that stabilizes the split oxygen vacancy by ∼1 eV. The barrierless creation of a bridging V2O7 unit allows for partial electron delocalization throughout the near-surface region, consistent with recent experimental observations indicating that BiVO4(001) is an electron-rich surface.