Role of the tumor suppressor IQGAP2 in metabolic homeostasis: Possible link between diabetes and cancer.
Deficiency of IQGAP2, a scaffolding protein expressed primarily in liver leads to rearrangements of hepatic protein compartmentalization and altered regulation of enzyme functions predisposing development of hepatocellular carcinoma and diabetes. Employing a systems approach with proteomics, metabolomics and fluxes characterizations, we examined the effects of IQGAP2 deficient proteomic changes on cellular metabolism and the overall metabolic phenotype. Iqgap2-/- mice demonstrated metabolic inflexibility, fasting hyperglycemia and obesity. Such phenotypic characteristics were associated with aberrant hepatic regulations of glycolysis/gluconeogenesis, glycogenolysis, lipid homeostasis and futile cycling corroborated with corresponding proteomic changes in cytosolic and mitochondrial compartments. IQGAP2 deficiency also led to truncated TCA-cycle, increased anaplerosis, increased supply of acetyl-CoA for de novo lipogenesis, and increased mitochondrial methyl-donor metabolism necessary for nucleotides synthesis. Our results suggest that changes in metabolic networks in IQGAP2 deficiency create a hepatic environment of a 'pre-diabetic' phenotype and a predisposition to non-alcoholic fatty liver disease (NAFLD) which has been linked to the development of hepatocellular carcinoma.


Role of aqueous extract of Cynodon dactylon in prevention of carbofuran- induced oxidative stress and acetylcholinesterase inhibition in rat brain.
The present study was designed to investigate the ameliorating effect of aqueous extract of C. dactylon on carbofuran induced oxidative stress (OS) and alterations in the activity of acetylcholinesterase (AChE) in the brain of rats. Vitamin C was used as a positive control. Wistar rats were administered with single sub-acute oral dose (1.6 mgkg-1 b.wt.) of carbofuran for 24 h. The OS parameters such as lipid peroxidation (LPO) and the activities of antioxidant enzymes including super oxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST), and that of AChE were studied in brain. Carbofuran treatment significantly increased the activities of SOD and CAT by 75 and 60%, respectively. It also induced the level of LPO by 113%. In contrast, the activities of GST and AChE were recorded to be diminished by 25 and 33%, respectively. Pretreatment of the rats with aqueous extract of C. dactylon (oral; 500mgkg-1) restored SOD activity completely but CAT activity only partially (7%). Carbofuran induced LPO was moderated by 95% in the brain of C. dactylon treated rats. The observed changes in OS parameters in C. dactylon treated group were comparable to that observed in vitamin C (200 mg-kg-1 b. wt.) treated group. Surprisingly, C. dactylon treatment significantly recovered the activity of AChE to a similar level as observed in the brain of control group. In contrast vitamin C treatment did not cause significant change in the activity of AChE in carbofuran treated group. There were no noticeable changes in the aforementioned study parameters in the brain of rats receiving C. dactylon and vitamin C, only. The results suggest that the study is extremely important in the context of development of new anticholinestesterase and antioxidant antidotes against carbofuran from C. dactylon.


Social cognition and social problem solving skills training to improve job functioning and tenure in veterans with psychotic disorders.
Veterans with psychotic disorders often experience employment difficulties. Job tenure is highly variable with shorter tenure frequently tied to interpersonal difficulties in the workplace. The present study sought to address this problem by examining the efficacy of social cognition skills training (SCST) and social problem solving skills training (SPSST) interventions, implemented sequentially, and added to usual VA employment services (augmented vocational rehabilitation [VR]). Participants were 91 Veterans with schizophrenia and other psychotic disorders who were recently enrolled in one of three types of VA employment services (incentive therapy, transitional work, supported employment), and randomized 1:1 to augmented VR versus control VR. Training for the augmented VR group included 12 weeks of SCST plus 6 weeks of work-related SPSST; training for the control VR group included a control intervention (symptom management training) matched in instructional format and length of training to the SCST and SPSST interventions. All participants received baseline and posttraining measures of social cognition. For those who got jobs, the primary work outcome measures were social skills work behavior and job tenure. Results showed a significant group x time interaction favoring the augmented VR group on measures of social cognition and social skills work behavior, but there were no significant differences in job tenure. The findings for workplace social skills support a promising new direction for enhancing work outcomes in this population; the null effect on job tenure may have been due to high job retention rates across the three types of employment service programs. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


The Spread of Spectrin in Ataxia and Neurodegenerative Disease.
Experimental and hereditary defects in the ubiquitous scaffolding proteins of the spectrin gene family cause an array of neuropathologies. Most recognized are ataxias caused by missense, deletions, or truncations in the SPTBN2 gene that encodes beta III spectrin. Such mutations disrupt the organization of post-synaptic receptors, their active transport through the secretory pathway, and the organization and dynamics of the actin-based neuronal skeleton. Similar mutations in SPTAN1 that encodes alpha II spectrin cause severe and usually lethal neurodevelopmental defects including one form of early infantile epileptic encephalopathy type 5 (West syndrome). Defects in these and other spectrins are implicated in degenerative and psychiatric conditions. In recent published work, we describe in mice a novel variant of alpha II spectrin that results in a progressive ataxia with widespread neurodegenerative change. The action of this variant is distinct, in that rather than disrupting a constitutive ligand-binding function of spectrin, the mutation alters its response to calcium and calmodulin-regulated signaling pathways including its response to calpain activation. As such, it represents a novel spectrinopathy that targets a key regulatory pathway where calcium and tyrosine kinase signals converge. Here we briefly discuss the various roles of spectrin in neuronal processes and calcium activated regulatory inputs that control its participation in neuronal growth, organization, and remodeling. We hypothesize that damage to the neuronal spectrin scaffold may be a common final pathway in many neurodegenerative disorders. Targeting the pathways that regulate spectrin function may thus offer novel avenues for therapeutic intervention.


Virulence factors and genotypes of Staphylococcus aureus from infection and carriage in Gabon.
Staphylococcus aureus isolates from developed countries have been extensively analyzed with respect to their virulence patterns and clonal relatedness but there is only sparse information on the molecular diversity of S. aureus isolates from Africa. In particular, little is known about S. aureus isolates from asymptomatic carriers compared with isolates causing infections. From 2008 to 2010, we prospectively collected S. aureus isolates from asymptomatic carriers and infections in Lambaréné, Gabon, Central Africa. For these isolates, we determined major virulence factors, and performed multilocus sequence typing (MLST) and spa typing. Among 163 S. aureus isolates from asymptomatic carriers, we found the MLST clonal complexes (CCs) 5, 6, 7, 8, 9, 15, 25, 30, 45, 88, 101, 121 and 152; 3.7% were methicillin-resistant (MRSA). The clinical isolates were associated with CCs 5, 8, 9, 15, 88, 121 and 152; 11% were MRSA. Sequence types 1 and 88 were significantly associated with infection and sequence type 508 was associated with carriage. Remarkably, there was a high prevalence of Panton-Valentine leukocidin (PVL) -encoding genes both in disease-related isolates (57.4%) and in carrier isolates (40.5%). We found differences in the clonal structure and virulence pattern of Gabonese S. aureus isolates from asymptomatic carriers and infections. Of note, S. aureus isolates from Gabon show a very high prevalence of PVL-encoding genes, which exceeds the rates observed for developed countries.


Replacement of the anterior cruciate ligament with a bone-ligament-bone anterior cruciate ligament allograft in dogs.
Acute replacement of the canine anterior cruciate ligament (ACL) with a frozen, bone-ligament-bone anterior cruciate ligament preparation was studied using biochemical, immunologic, and biomechanical testing methods. Nine dogs were used for the study, six dogs received allografts and three received autografts. No tissue antigen matching was performed. All nine dogs were killed nine months after surgery. Necropsy examination revealed that the ACL was not present in three joints (one autograft, two allografts). The two autograft and four allograft ligaments available for mechanical testing sustained mean maximum loads that were 10% and 14%, respectively, of the mean maximum loads sustained by the contralateral ACL. Autoradiography indicated that cellular activity was more pronounced in the autograft specimens. Hydroxyproline uptake was 200% and 45% of normal in the autograft and allograft ligaments, respectively. Both autograft and allograft specimens were producing Type I collagen at the time of killing. Antidonor dog leukocyte antigen (DLA) antibody was detected in the synovial fluid taken at the time of killing from six of six dogs that received allografts and in zero of three dogs that received autografts.


Safety and efficacy of a feed additive consisting of a dried extract from the roots of Panax ginseng C.A. Meyer (P. ginseng dry extract) for use in cats and dogs (C.I.A.M.).
Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of a dried extract prepared from the roots of Panax ginseng C.A. Meyer (P. ginseng dry extract) when used as a sensory additive in feed for cats and dogs. P. ginseng dry extract is specified to contain at least 27-30% total ginsenosides (as ginsenosides RG1). Since uncertainty remains concerning the nature of up to 73% of the extract, the FEEDAP Panel was unable to conclude on the safety of the additive at the proposed use levels of up to 20 mg/kg complete feed for cats and dogs. In the absence of data, no conclusions can be drawn on the safety for the user. Since ginseng and its extracts are recognised to flavour food and their function in feed would be essentially the same as that in food, no further demonstration of efficacy is considered necessary.


Rice GROWTH-REGULATING FACTOR7 Modulates Plant Architecture through Regulating GA and Indole-3-Acetic Acid Metabolism.
Plant-specific GROWTH-REGULATING FACTORs (GRFs) participate in central developmental processes, including leaf and root development; inflorescence, flower, and seed formation; senescence; and tolerance to stresses. In rice (Oryza sativa), there are 12 GRFs, but the role of the miR396-OsGRF7 regulatory module remains unknown. Here, we report that OsGRF7 shapes plant architecture via the regulation of auxin and GA metabolism in rice. OsGRF7 is mainly expressed in lamina joints, nodes, internodes, axillary buds, and young inflorescences. Overexpression of OsGRF7 causes a semidwarf and compact plant architecture with an increased culm wall thickness and narrowed leaf angles mediated by shortened cell length, altered cell arrangement, and increased parenchymal cell layers in the culm and adaxial side of the lamina joints. Knockout and knockdown lines of OsGRF7 exhibit contrasting phenotypes with severe degradation of parenchymal cells in the culm and lamina joints at maturity. Further analysis indicated that OsGRF7 binds the ACRGDA motif in the promoters of a cytochrome P450 gene and AUXIN RESPONSE FACTOR12, which are involved in the GA synthesis and auxin signaling pathways, respectively. Correspondingly, OsGRF7 alters the contents of endogenous GAs and auxins and sensitivity to exogenous phytohormones. These findings establish OsGRF7 as a crucial component in the OsmiR396-OsGRF-plant hormone regulatory network that controls rice plant architecture.


Fluoride and aluminum release from restorative materials using ion chromatography.
The aim of this study was to determine the amounts of fluoride and aluminum released from different restorative materials stored in artificial saliva and double-distilled water. Cylindrical specimens (10 x 1 mm) were prepared from 4 different restorative materials (Kavitan Plus, Vitremer, Dyract Extra, and Surefil). For each material, 20 specimens were prepared, 10 of which were stored in 5 mL artificial saliva and 10 of which were stored in 5 mL of double-distilled water. Concentrations of fluoride and aluminum in the solutions were measured using ion chromatography. Measurements were taken daily for one week and then weekly for two additional weeks. Data were analyzed using two-way ANOVA and Duncan's multiple range tests (p<0.05). The highest amounts of both fluoride and aluminum were released by the resin-modified glass ionomer cement Vitremer in double-distilled water (p<0.05). All materials released significantly more fluoride in double-distilled water than in artificial saliva (p<0.05). In artificial saliva, none of the materials were observed to release aluminum. It was concluded that storage media and method of analysis should be taken into account when the fluoride and aluminum release from dental materials is assessed.


[Diagnosis and roentgeno-endovascular treatment of patients with renin-dependent arterial hypertension and secondary aldosteronism without damage to the main renal arteries].
Bilateral electrocoagulation of the central veins of the adrenals (ECVA) was performed in 13 patients with stable and malignant arterial hypertension (AH). The renin-dependent character of AH was supported by positive reaction of arterial pressure (AP) to the test dose of captopril (25 mg). The vasorenal origin of the impairment was excluded on the basis of the peripheral captopril test findings, pharmacorenography with captopril. Bilateral ECVA was done during angiography. The manipulation turned out technically successful in 11 left (85%) and 9 right (70%) adrenals. The AP began lowering from the first days of the intervention and got stabilized by day 4 to 5. There was a significant decline of AP within the observation period up to 1 year and a reduction of the elevated aldosterone content and plasma renin activity with the content of ACTH being unchanged. After the manipulation 2 patients could fully discontinue the intake of hypotensive drugs. In 11 patients, the dose of the drugs could be reduced.


Effects of methylene blue in reducing cholestatic oxidative stress and hepatic damage after bile-duct ligation in rats.
The aim of this study was to evaluate the effects of methylene blue against cholestatic oxidative stress and liver damage after ligation of the common bile duct in male Wistar rats. Eight animals were included in each of the following five groups: untreated control, methylene blue control, sham-operated, bile-duct ligation, and bile-duct ligation plus methylene blue. Methylene blue was administered intraperitoneally for 14 days at a daily dose of 2mg/kg per day. All rats were sacrificed 2 weeks following the experimental treatment and the livers of all groups were examined biochemically and histopathologically. The severity of cholestasis and hepatic injury were determined by changes in the plasma, including enzymatic activities: aspartate aminotransferase, alanine aminotransferase, gamma glutamine transferase, and also bilirubin levels. Malondialdehyde, nitric oxide and superoxide dismutase were measured to indicate the oxidative status in the liver tissue. Myeloperoxidase activity and levels of tissue hydroxyproline were determined as measures of neutrophil activation and collagen accumulation, respectively. Liver damage was significantly prevented in the bile-duct ligated rats treated with methylene blue compared with the control bile-duct ligated rats without methylene blue. Treatment with methylene blue markedly reduced activities of serum transaminase, gamma glutamine transferase and bilirubin levels as compared to bile-duct ligated rats without methylene blue. Positive immunolabelling for alpha-smooth muscle actin (alpha-SMA) was increased, especially in vascular smooth muscle cells, fibrotic septa and also around the proliferated bile ducts, after bile-duct ligation. Only weak alpha-SMA immunolabelling was seen in livers of rats treated with methylene blue. These results indicate that methylene blue can attenuate hepatic damage in extrahepatic cholestasis by reducing oxidative stress and inflammatory processes.


Anterior petrosal approach for brainstem cavernoma.
Brainstem cavernomas (BC) comprise about 5-18% of intracranial vascular malformations. The annual hemorrhage rate varies depending on the study design ranging from as low as 0.25% per patient-year in a retrospective study[2] to 1.6-3.1% per patient-year in prospective studies.[45] The annual event rate is significantly higher in deep (brainstem, diencephalon) and infratentorial cavernomas when compared to their counterparts in other locations.[5] The management of BC can be conservative or surgical depending upon the mode of clinical presentation. Surgical excision of a BC is a challenge because of critical anatomy. We present a case of BC, which was totally excised with anterior petrosal approach. Anterior petrosal approach has been used for excision of BC in only 17 cases until now.[6] The use of preoperative diffusion tensor imaging, tractography, intra-operative navigation, and cranial nerve monitoring will help in reducing the morbidity.


[Liver organ systems: valuation by gene expression]
The multitude of vital functions of the liver is largely dependent on the complex interaction of hepatocytes with "littoral-cells" and the liver-specific extracellular matrix. In vitro systems used to study the liver are almost exclusively based on the culture of single cells obtained by enzymatic disruption of the essentiel organ structure. In contrast, the slicing technique enables a standardized organ culture, while retaining the intact organ structure. However, previous experiments using this system have been restricted to short-term pharmacological studies and have used general cellular parameters to assess viability. The lack of liver specific validation has hindered the acceptance and application of this organ culture as an alternative to in vivo experiments. In this work we chose the regulation of liver-specific gene expression as an adequate viability criterion because, in contrast to the commonly used general cell physiology parameters, gene expression includes a cascade of differentially coordinated processes. Using hormonal responsiveness of precision-cut liver slices as a basis for comparison, the new developed interphase system was found to be superior to a perfusion system. With the application of this economical and easy-to-handle interphase system, the control of liver-specific gene expression by dexamethasone, cAMP and endotoxin in long-term cultures was found to be modulated in a manner similar to in vivo conditions.


Satiety from fat? Adverse effects of intestinal infusion of sodium oleate.
To determine whether damage to the intestinal mucosa by oleic acid causes the suppression of food intake observed in response to intraintestinal infusion of the fatty acid, we measured lactate dehydrogenase (LDH) activity, a marker for cell damage, in the intestinal lumen after intestinal infusion of fatty acid under conditions similar to those employed in studies of eating behavior. Infusions of 25 or 51 mM sodium oleate (neutralized oleic acid) markedly and rapidly increased LDH activity, whereas infusions of saline had little or no effect. Infusion of octanoate, which has been reported to be ineffective in reducing eating behavior, did not increase intestinal LDH activity relative to saline infusion. Similarly, infusion of ethyl oleate or free (nonneutralized) oleic acid neither increased luminal LDH activity nor suppressed food intake. Infusion of sodium oleate also produced a strong conditioned aversion to sucrose. The results strongly suggest that the suppression of food intake induced by intraintestinal infusion of sodium oleate is due to the injurious effects of this unphysiological form of the fatty acid.


Deficiency of calpain-6 inhibits primary ciliogenesis.
The primary cilium is a microtubule-based structure projecting from a cell. Although the primary cilium shows no motility, it can recognize environmental stimuli. Thus, ciliary defects cause severe abnormalities called ciliopathies. Ciliogenesis is a very complex process and involves a myriad of components and regulators. In order to excavate the novel positive regulators of ciliogenesis, we performed mRNA microarray using starved NIH/3T3 cells. We selected 62 murine genes with corresponding human orthologs, with significantly upregulated expression at 24 h after serum withdrawal. Finally, calpain-6 was selected as a positive regulator of ciliogenesis. We found that calpain-6 deficiency reduced the percentage of ciliated cells and impaired sonic hedgehog signaling. It has been speculated that this defect might be associated with decreased levels of α-tubulin acetylation at lysine 40. This is the first study to report a novel role of calpain-6 in the formation of primary cilia. [BMB Reports 2019; 52(10): 619-624].


Unconventional Charge Density Wave Order in the Pnictide Superconductor Ba(Ni_{1-x}Co_{x})_{2}As_{2}.
Ba(Ni_{1-x}Co_{x})_{2}As_{2} is a structural homologue of the pnictide high temperature superconductor, Ba(Fe_{1-x}Co_{x})_{2}As_{2}, in which the Fe atoms are replaced by Ni. Superconductivity is highly suppressed in this system, reaching a maximum T_{c}=2.3 K, compared to 24 K in its iron-based cousin, and the origin of this T_{c} suppression is not known. Using x-ray scattering, we show that Ba(Ni_{1-x}Co_{x})_{2}As_{2} exhibits a unidirectional charge density wave (CDW) at its triclinic phase transition. The CDW is incommensurate, exhibits a sizable lattice distortion, and is accompanied by the appearance of α Fermi surface pockets in photoemission [B. Zhou et al., Phys. Rev. B 83, 035110 (2011)PRBMDO1098-012110.1103/PhysRevB.83.035110], suggesting it forms by an unconventional mechanism. Co doping suppresses the CDW, paralleling the behavior of antiferromagnetism in iron-based superconductors. Our study demonstrates that pnictide superconductors can exhibit competing CDW order, which may be the origin of T_{c} suppression in this system.


The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR.
A wide range of xenobiotic compounds are metabolized by cytochrome P450 (CYP) enzymes, and the genes that encode these enzymes are often induced in the presence of such compounds. Here, we show that the nuclear receptor CAR can recognize response elements present in the promoters of xenobiotic-responsive CYP genes, as well as other novel sites. CAR has previously been shown to be an apparently constitutive transactivator, and this constitutive activity is inhibited by androstanes acting as inverse agonists. As expected, the ability of CAR to transactivate the CYP promoter elements is blocked by the inhibitory inverse agonists. However, CAR transactivation is increased in the presence of 1,4-bis[2-(3, 5-dichloropyridyloxy)]benzene (TCPOBOP), the most potent known member of the phenobarbital-like class of CYP-inducing agents. Three independent lines of evidence demonstrate that TCPOBOP is an agonist ligand for CAR. The first is that TCPOBOP acts in a dose-dependent manner as a direct agonist to compete with the inhibitory effect of the inverse agonists. The second is that TCPOBOP acts directly to stimulate coactivator interaction with the CAR ligand binding domain, both in vitro and in vivo. The third is that mutations designed to block ligand binding block not only the inhibitory effect of the androstanes but also the stimulatory effect of TCPOBOP. Importantly, these mutations do not block the apparently constitutive transactivation by CAR, suggesting that this activity is truly ligand independent. Both its ability to target CYP genes and its activation by TCPOBOP demonstrate that CAR is a novel xenobiotic receptor that may contribute to the metabolic response to such compounds.


(BiSe)1.23CrSe2 and (BiSe)1.22(Cr1.2Se2)2: magnetic anisotropy in the first structurally characterized Bi-Se-Cr ternary compounds.
Compounds containing both heavy main group elements and paramagnetic transition metals form a fertile area for the study of magnetic anisotropy. We pursued the synthesis, characterization, and magnetic measurements of Bi-Se-Cr compounds: a ternary system with no structurally characterized materials. Those efforts led to the isolation of two novel misfit layer compounds, namely, (BiSe)1.23CrSe2 (1) and (BiSe)1.22(Cr1.2Se2)2 (2). The crystal structure of 1 consists of alternating BiSe and CrSe2 layers along the c-axis, and 2 is composed of alternating BiSe and (Cr1.2Se2)2 layers along the c-axis. Lattice mismatch occurs in both compounds along the b-axis and leads to positional modulation of the atoms. Field- and temperature-dependent measurements were performed to assess the degree of magnetic anisotropy. Temperature-dependent susceptibility measurements on aligned crystals of 1 display increased bifurcation of zero-field cooled and field cooled data when crystals are oriented with H perpendicular to c than when the crystals are oriented with H parallel to c. Magnetic anisotropy is less pronounced in 2 where both crystallographic orientations exhibit bifurcation at 26 K. The complexity of the magnetic behavior in both compounds likely signifies a competition between CrSe2 intralayer ferromagnetic coupling and interlayer antiferromagnetic coupling. These results highlight the exciting magnetic properties that can arise from the exploration of new ternary phases.


Proximal phalangeal osteotomy with proximal interphalangeal joint arthrodesis for multiplanar deformities of the second toe: historical perspectives and review of a case series.
Combined transverse and sagittal plane deformities of the second toe represent a common painful condition encountered by the foot surgeon. After a period of conservative management, surgical intervention is often required. Historically, a number of surgical options have been described for the treatment of this condition, with the universal acknowledgment that an ideal surgical outcome is difficult to achieve and prone to failure. In this report, a review of previously described surgical techniques is presented, along with a retrospective analysis of 20 second toe surgical reconstructions, in 16 patients, performed between June 2003 and October 2010. Subjective outcomes were assessed by means of a mailed questionnaire, and a subset (15 second toes in 11 patients) returned for follow-up evaluation, including ascertainment of American Orthopaedic Foot & Ankle Society Clinical Rating System for Lesser Metatarsophalangeal-Interphalangeal Joint Surgery scores. Overall, the duration of follow-up was 38.25 ± 25.82 months, and the subset was followed up for 36.07 ± 27.95 months. The preoperative visual analog pain score was 4.9 ± 2.7, whereas the postoperative pain score was 1.6 ± 2.47 (p < .001). The preoperative American Orthopaedic Foot & Ankle Society score was 44.57 ± 17.76, whereas the postoperative score was 91.27 ± 12.27 (p < .001). Based on the results of this investigation, pairing a basilar proximal phalangeal osteotomy with arthrodesis of the proximal interphalangeal joint, for correction of combined transverse and sagittal plane deformities, appears to yield satisfactory long-term results.


Activation of flavonoid biosynthesis by solar radiation in bilberry ( Vaccinium myrtillus L) leaves.
The effect of solar radiation on flavonoid biosynthesis was studied in bilberry ( Vaccinium myrtillus L.) leaves. Expression of flavonoid pathway genes of bilberry was studied in the upper leaves of bilberry, exposed to direct sunlight, in the shaded leaves growing lower in the same plants and in fruits. Bilberry-specific digoxigenin-dUTP-labeled cDNA fragments of five genes from the general phenylpropanoid pathway coding phenylalanine ammonia-lyase and from the flavonoid pathway coding chalcone synthase, flavanone 3-hydroxylase, dihydroflavonol 4-reductase, and anthocyanidin synthase were used as probes in gene expression analysis. Anthocyanins, catechins, proanthocyanidins, flavonols and hydroxycinnamic acids from the leaves and fruits were identified and quantified using high-performance liquid chromatography combined with a diode array detector. An increase in the expression of the studied flavonoid pathway genes was observed in leaves growing under direct sun exposure. Also, the concentrations of anthocyanins, catechins, flavonols and hydroxycinnamic acids were higher in the leaves exposed to direct sunlight. However, the concentration of polymeric procyanidins was lower in sun-exposed leaves, whereas that of prodelphinidins was slightly increased. The results give further support for the protective role of flavonoids and hydroxy cinnamic acids against high solar radiation in plants. Also, the roles of different flavonoid compounds as a defense against stress caused by sun exposure is discussed.


Amyloidosis and female protein in the Syrian hamster. Concurrent regulation by sex hormones.
Previous results have shown that when compared to male Syrian hamsters, female Syrian hamsters have a distinct predisposition to acquire amyloidosis either normally with aging or experimentally with sodium caseinate or diethylstilbestrol (DES) treatments. In the present study, we tested the influence of testosterone on expression of amyloid to determine if this hormone was solely responsible for the sex-limited amyloidosis of the Syrian hamster. Males deprived of testosterone by castration acquired amyloid at an unusually young age, an age of onset similar to that in female hamsters. Also, the amyloidogenic effect of DES in male Syrian hamsters was inhibited by concomitant injections of testosterone, indicating that estrogens induce amyloid in male hamsters by inhibiting testosterone synthesis. When administered to female hamsters, testosterone inhibited expression of amyloid in aging female Syrian hamsters and extended the life span of this gender. Of the two components of amyloid, the major component Amyloid A-derived fibril or the minor constituent, Amyloid P component, only the P component is under sex hormone control in the Syrian hamster; testosterone inhibits the hepatic synthesis of the P component homologue (called female protein), which is normally expressed 100-200-fold greater in female vs. male Syrian hamster. In general, the serum level of female protein under various experimental conditions correlated with the presence of amyloid and indicated that in the Syrian hamster the P component homologue is of primary importance in the deposition of amyloid.


Overrepresentation of glutamate signaling in Alzheimer's disease: network-based pathway enrichment using meta-analysis of genome-wide association studies.
Genome-wide association studies (GWAS) have successfully identified several risk loci for Alzheimer's disease (AD). Nonetheless, these loci do not explain the entire susceptibility of the disease, suggesting that other genetic contributions remain to be identified. Here, we performed a meta-analysis combining data of 4,569 individuals (2,540 cases and 2,029 healthy controls) derived from three publicly available GWAS in AD and replicated a broad genomic region (>248,000 bp) associated with the disease near the APOE/TOMM40 locus in chromosome 19. To detect minor effect size contributions that could help to explain the remaining genetic risk, we conducted network-based pathway analyses either by extracting gene-wise p-values (GW), defined as the single strongest association signal within a gene, or calculated a more stringent gene-based association p-value using the extended Simes (GATES) procedure. Comparison of these strategies revealed that ontological sub-networks (SNs) involved in glutamate signaling were significantly overrepresented in AD (p<2.7×10(-11), p<1.9×10(-11); GW and GATES, respectively). Notably, glutamate signaling SNs were also found to be significantly overrepresented (p<5.1×10(-8)) in the Alzheimer's disease Neuroimaging Initiative (ADNI) study, which was used as a targeted replication sample. Interestingly, components of the glutamate signaling SNs are coordinately expressed in disease-related tissues, which are tightly related to known pathological hallmarks of AD. Our findings suggest that genetic variation within glutamate signaling contributes to the remaining genetic risk of AD and support the notion that functional biological networks should be targeted in future therapies aimed to prevent or treat this devastating neurological disorder.


Novel restriction factor RNA-associated early-stage anti-viral factor (REAF) inhibits human and simian immunodeficiency viruses.
The discovery of novel anti-viral restriction factors illuminates unknown aspects of innate sensing and immunity. We identified RNA-associated Early-stage Anti-viral Factor (REAF) using a whole genome siRNA screen for restriction factors to human immunodeficiency virus (HIV) that act in the early phase of viral replication. We observed more than 50 fold rescue of HIV-1 infection, using a focus forming unit (FFU) assay, following knockdown of REAF by specific siRNA. Quantitative PCR was used to show that REAF knockdown results in an increase of early and late reverse transcripts which impacts the level of integration. REAF thus appears to act at an early stage of the viral life cycle during reverse transcription. Conversely when REAF is over-expressed in target cells less infected cells are detectable and fewer reverse transcripts are produced. Human REAF can also inhibit HIV-2 and simian immunodeficiency virus (SIV) infection. REAF associates with viral nucleic acids and may act to prevent reverse transcription. This report firmly places REAF alongside APOBECs and SAMHD1 as a potent inhibitor of HIV replication acting early in the replication cycle, just after cell entry. We propose that REAF is part of an anti-viral surveillance system destroying incoming retroviruses. This novel mechanism could apply to invasion of cells by any intracellular pathogen.


Early evaluation of coronary microcirculation by echocardiography with contrast medium in patients with acute myocardial infarction treated with primary percutaneous transluminal coronary angioplasty.
In about 30% of patients with ST elevated myocardial infarction (STEMI), in which a TIMI 3 flow is obtained in the infarct related artery (IRA) after primary percutaneous transluminal coronary angioplasty (PTCA), it's not possible to obtain a good perfusion of coronary microcirculation (no reflow). Aim of the study is to estimate the prognostic value of microcirculation study by echocardiography with contrast medium (MCE) within 48 h from procedure and to point out if there're clinical or procedural factors correlated with no reflow. From February 2002 to June 2003 we have analyzed the integrity of microcirculation by MCE in patients with STEMI treated with PTCA. We have included in this study 62 patients with anterior myocardial infarction (MI) (first event), within 12 h from symptoms onset, with great echocardiographic window and TIMI 3 flow in the IRA after PTCA, excluding shock. We have obtained the evaluation of myocardial perfusion by MCE within 48 h from the treatment. We have used Sonovue as contrast medium, infused through peripheral vein. In each patient we have measured: perfusion index (PI) (sum of single segments scores divided by total number of myocardial segments) and regional perfusion index (RPI) (number of normal perfused segments between the diskinetic ones divided by diskinetic segments). RPI varies from 0 to 1: when >0.5 it has been considered index of good perfusion. Ejection fraction (EF) and wall motion score index (WMSI) have been calculated within 48 h and at 6 weeks follow up. ST resolution (STR) has been evaluated at 90 min from procedure and it was considered significant when >70%. Patients have been divided into 2 groups by myocardial perfusion: group R (33 patients with RPI>0.5) and group NR (29 patients with RPI =/<0.5). The 2 groups were similar for age (group R: mean age 61 years old; group NR: mean age 64 years old, P=n.s.), glycoprotein inhibitors use (group R 90%, group NR 97%, P=n.s.), diabetes (group R 12%, group NR 17%, P=n.s.), hypertension (group R 22%, group NR 23%, P=n.s.), incomplete revascularization (group R 12%, group NR 10%, P=n.s.). Group NR has shown a major women percentage (33%) than group R (9%) P=0.026. In group R we have appreciated a trend to a major percentage of TIMI 2-3 flow preprocedure (66% vs 36%, P=n.s.), a shorter ischemic time (209 min vs 258 min, P=n.s.) and a major STR at 90 min (72% vs 53%, P=n.s.), not statistically significant. Echocardiographic analysis and MCE show a better myocardial perfusion in group R (RPI 0.7 vs 0.14 and PI 0.96 vs 0.86, P<0.0001); better left ventricular kinetics at 6 weeks follow up (EF 54.2% vs 50.8%, P=n.s. and WMSI 1.07 vs 1.2, P=0.014) but not in the acute phase (EF 46.8 vs 42.9 and WMSI 1.3 vs 1.34, P=n.s.) 30 days mortality is similar in the 2 groups (both 3%). Myocardial perfusion evaluation correlates with left ventricular contractility measured at 6 weeks from acute MI, but doesn't correlate with contractility in the acute phase or 30 days mortality.


Intact recognition of vocal expressions of fear following bilateral lesions of the human amygdala.
A recent case study found that bilateral damage to the amygdala impairs the normal appraisal of vocal expressions of fear. However, the single source of evidence for this auditory emotion-processing impairment is from a patient with extra-amygdaloid damage that may include the basal ganglia, which have been shown to be important for prosody evaluation. In this study we provide evidence of preserved evaluation of vocal expressions of fear in a female patient (S.P.) with bilateral damage to the amygdala but with intact basal ganglia. This same patient has previously been shown to be impaired in the evaluation of facial expressions, including fear. These results indicate that the analysis of nonverbal signals of fear from different input channels are dissociable, being at least partially dependent on different brain structures. We suggest that the amygdala, in conjunction with the basal ganglia, may support the normal appraisal of auditory signals of danger.


Smac mimetic reverses resistance to TRAIL and chemotherapy in human urothelial cancer cells.
inhibitors of apoptosis proteins (IAPs) have been shown to contribute to resistance of neoplastic cells to chemotherapy and to biologic antineoplastic agents. Consequently, new agents are being developed targeting this family of proteins. In a panel of bladder cancer cell lines, we evaluated a Smac mimetic that antagonizes several IAPs for its suitability for bladder cancer therapy. Experimental design: A panel of seven bladder cancer cell lines were evaluated for sensitivity to the Smac mimetic compound-A alone, TRAIL alone, chemotherapy alone, compound-A plus TRAIL, and compound-A plus chemotherapy by DNA fragmentation analysis. IAP levels and caspase activation were examined by western blotting. Release of caspase-3 from X-linked inhibitor of apoptosis protein (XIAP), the most effective IAP, was assessed by immunoprecipitation and western blotting. Finally, siRNA knockdown of XIAP was correlated with the sensitivity of cells to apoptosis induced by compound-A plus TRAIL by DNA fragmentation and western blotting. single-agent compound-A had little effect, but compound-A augmented TRAIL- and chemotherapy-induced apoptosis. Immunoblotting showed that combination treatment with compound-A and TRAIL resulted in cleavage of procaspase-3 and procaspase-7, activation of which irreversibly commits cells to apoptosis. Immunoprecipitation of XIAP showed displacement of active caspase-3 fragments from XIAP, supporting the proposed mechanism of action. Furthermore, siRNA-mediated silencing of XIAP similarly sensitized these cells to apoptosis. a panel of seven bladder cancer cell lines were evaluated for sensitivity to the Smac mimetic compound-Alone, TRAIL alone, Chemotherapy alone, compound-A plus TRAIL and compound-A plus chemotherapy by DNA fragmentation analysis. IAP levels and caspase activation were examined by western blotting. Release of caspase-3 from X-linked inhibitor of apoptosis protein (XIAP), the most effective IAP, was assessed by immunoprecipitation and western blotting. Finally siRNA knockdown of XIAP was correlated with the sensitivity of cells to apoptosis induced by compound-A plus TRAIL by DNA fragmentation and western blotting. our results suggest that targeting of XIAP with the Smac mimetic compound-A has the potential to augment the effects of a variety of chemotherapeutic and biologic therapies in bladder cancer.


[Vegetative status in pregnant and perimenopausal women with hypertension].
We observed 137 patients, 72 of whom (53%) had hypertension in II trimester of pregnancy, and 65 patients (47%) who had hypertension in perimenopausal period. The comprehensive clinical and instrumental examination was carried out in all patients, including simultaneous 24-hour ambulatory blood pressure (BP) recording (with BP pattern), assessment of vegetative tone using the vegetative index (index Kerdo). Sympathetic/adrenergic activity (SAA) was quantified as β-receptor binding (β-RB). Hypertension in pregnant women is associated with increased activity of the sympathetic-adrenal system, as evidenced by high values of β-ARM, the Kerdo index and the presence of correlation between these parameters. Parasympathicotonia in perimenopausal women prevails.


Fungal endophytes of wild and hybrid Vitis leaves and their potential for vineyard biocontrol.
Plants are colonized by diverse assemblages of fungal endophytes that have potential as biocontrol agents for a variety of crops, including grapevine. Although the diversity of symbionts can be very high in wild plants, the fungal endophytes of wild Vitis plants have not yet been investigated. We surveyed the fungal endophytes of 6 wild populations of Vitis riparia, as well as a cold-tolerant, hybrid grapevine in 5 vineyards (1 certified organic), using 454 pyrosequencing. We detected between 43 and 235 operational taxonomic units per sample, with the highest richness and diversity in the wild, the lowest in conventional vineyards, and intermediate levels in the organic vineyard. Wild plants supported a range of taxa not seen in the conventional vineyards, and vineyards were dominated by relatively few taxa. We also isolated fungi from the wild plants and tested them for their ability to inhibit pathogens of grapevine. Several wild isolates (e.g., Ramularia spp.) were strongly inhibitory to grapevine pathogens. We show that wild Vitis supports a distinct and highly diverse community of fungal endophytes and may represent a rich repository of potential vineyard biocontrol agents.


Mitf dosage as a primary determinant of melanocyte survival after ultraviolet irradiation.
Microphthalmia-associated transcription factor (Mitf) is essential for melanocyte development and function and regulates anti-apoptotic Bcl2 expression. We hypothesized that cellular deficiency of Mitf can influence melanocyte survival in response to ultraviolet (UV) radiation. Primary melanocyte cultures were prepared from neonatal wild-type mice and congenic animals heterozygous for Mitf mutations Mitf (mi-vga9/+) and Mitf(Mi-wh/+) and exposed to UV irradiation. Wild-type melanocytes were more resistant to UV-induced apoptosis than melanocytes partially deficient in Mitf activity, as determined by relative levels of intracellular melanin and relative activation of Mitf target genes Tyr, Tyrp1, Dct, and Cdk2. Comparative experiments with wild-type cells and congenic albino melanocytes demonstrated that these differences are not due to differences in melanin content, implicating Mitf as a primary determinant of UV-dependent melanocyte survival. Mitf activity correlated directly with resistance to UV-induced apoptosis in melanocytes. Mitf was important not only for regulating the expression of anti-apoptotic Bcl-2 following UV irradiation, but also the expression of the pro-apoptotic BH3-only Bad protein and activation of the extrinsic apoptotic pathway. Hence, Mitf is a multifaceted regulator of UV-induced apoptosis in melanocytes.


Does low-field dedicated extremity MRI (E-MRI) reliably detect bone erosions in rheumatoid arthritis? A comparison of two different E-MRI units and conventional radiography with high-resolution CT scanning.
To compare the ability of two different E-MRI units and conventional radiography (CR) to identify bone erosions in rheumatoid arthritis (RA) metacarpophalangeal (MCP) and wrist joints with CT scanning as the standard reference method. 20 patients with RA and 5 controls underwent CR, CT and two E-MRI examinations (Esaote Biomedica Artoscan and MagneVu MV1000) of one hand during a 2-week period. In all modalities, each bone of the wrist and MCP joints was blindly evaluated for erosions. MagneVu images were also assessed for the proportion of each bone being visualised. 550 bones were examined. CT, Artoscan, MagneVu and CR detected 188, 116, 55 and 45 bones with erosions, respectively. The majority were located in the carpal bones. The sensitivity of the Artoscan for detecting erosions was higher than that of the MagneVu and CR (MCP joints: 0.68, 0.54 and 0.57, respectively; wrists: 0.50, 0.23 and 0.29). Corresponding specificities for detecting erosions were 0.94, 0.93 and 0.99, respectively, in the MCP joints and 0.92, 0.98 and 0.98 in the wrist. The MagneVu allowed visualisation of 1.5 cm of the ventral-dorsal diameter of the bone. In the wrist, 31.6% of bones were visualised entirely and 37.9% of bones were 67-99% visualised. In MCP joints, 84.2% of bones were visualised entirely and 15.8% of bones were 67-99% visualised. With CT as the reference method for detecting erosions in RA hands, the Artoscan showed higher sensitivity than the MagneVu and CR. All imaging modalities had high specificities. The better performance of the Artoscan should be considered when selecting an imaging method in RA.


Optimization approach to the suppression of vibration errors in phase-shifting interferometry.
An optimization-based strategy is introduced for suppressing errors due to vibration in phase-shifting-interferometry algorithms. A norm-square integral criterion of the error as a function of vibration frequency is used as the basis of the optimization procedure. Analytical results are obtained for certain classes of problems, and numerical algorithms are used when these are not available. It is also shown that the effect of vibration-induced errors in the computation of a time-averaged phase estimate diminishes as the measurements are averaged. Simulations are used to validate the analysis and demonstrate the overall efficacy of the approach. Generalizations to multiple objective optimization problems are briefly discussed.


Mutational analysis of RsbT, an activator of the Bacillus subtilis stress response transcription factor, sigmaB.
SigmaB, the stress-activated sigma factor of Bacillus subtilis, requires the RsbT protein as an essential positive regulator of its physical stress pathway. Stress triggers RsbT to both inactivate the principal negative regulator of the physical stress pathway (RsbS) by phosphorylation and activate a phosphatase (RsbU) required for sigmaB induction. Neither the regions of RsbT that are involved in responding to stress signaling nor those required for downstream events have been established. We used alanine scanning mutagenesis to examine the contributions of RsbT's charged amino acids to the protein's stability and activities. Eleven of eighteen rsbT mutations blocked sigmaB induction by stress. The carboxy terminus of RsbT proved to be particularly important for accumulation in Bacillus subtilis. Four of the five most carboxy-terminal mutations yielded rsbT alleles whose products were undetectable in B. subtilis extracts. Charged amino acids in the central region of RsbT were less critical, with four of the five substitutions in this region having no measurable effect on RsbT accumulation or activity. Only when the substitutions extended into a region of kinase homology was sigmaB induction affected. Six other RsbT variants, although present at levels adequate for activity, failed to activate sigmaB and displayed significant changes in their ability to interact with RsbT's normal binding partners in a yeast dihybrid assay. These changes either dramatically altered the proteins' tertiary structure without affecting their stability or defined regions of RsbT that are involved in multiple interactions.


Veterans seeking disability benefits for post-traumatic stress disorder: who applies and the self-reported meaning of disability compensation.
Assumptions about the characteristics and motivations of individuals pursuing disability status are well known. However, policy, programming and interventions need to be based on information about the actual sociodemographic characteristics of disabled individuals, as well as their goals in seeking disability status. In this study, we focus on veterans seeking disability compensation for post-traumatic stress disorder (PTSD) from the United States Department of Veterans Affairs. We present information on their life circumstances and their self-reported reasons for valuing the obtainment of veterans' disability status on the basis of PTSD. There was considerable variability in the background of veterans seeking disability status on the basis of PTSD. Of concern, only about half of these individuals were receiving any mental health treatment at the time of application. Most claimants reported seeking disability compensation for symbolic reasons, especially for acknowledgement, validation and relief from self-blame. Reasons having to do with improved finances were less frequently endorsed, although the importance of obtaining improved solvency through disability status decreased as income increased. The sense of investment in obtaining a sense of self-acceptance and acceptance from others through disability status varied by sociodemographic variables. Overall, findings suggest that individuals seeking disability benefits may have unmet mental health care needs, and that policy makers, investigators and providers should consider material benefit as one of many possible reasons for engaging in a disability compensation system.


Leading inhibition to neural oscillation is important for time-domain processing in the auditory midbrain.
A number of central auditory neurons exhibit paradoxical latency shift (PLS), a response characterized by longer response latencies at higher sound levels. PLS neurons are known to play a role in target ranging for echolocating bats that emit frequency-modulated sounds. We recently reported that early inhibition of unit's oscillatory discharges is critical for PLS in the inferior colliculus (IC) of little brown bats. The goal of this study was to determine in echolocating bats and in non-echolocating animals (frogs): 1) the detailed characteristics of PLS and whether PLS was dependent on sound level, frequency, and duration; 2) the time course of inhibition underlying PLS using a paired-pulse paradigm. We found that 22% of IC neurons in bats and 15% in frogs exhibited periodic discharge patterns in response to tone pulses at high sound levels. The firing periodicity was unit specific and independent of sound level and duration. Other IC neurons (28% in bats; 14% in frogs) exhibited PLS. These PLS neurons shared several response characteristics: 1) PLS was largely independent of sound frequency and 2) the magnitude of shift in first-spike latency was either duration dependent or duration tolerant. For PLS neurons, application of bicuculline abolished PLS and unmasked the unit's periodical firing pattern that served as the building block for PLS. In response to paired sound pulses, PLS neurons exhibited delay-dependent response suppression, confirming that high-threshold leading inhibition was responsible for PLS. Results also revealed the timing of excitatory and inhibitory inputs underlying PLS and its role in time-domain processing.


Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance.
Breast cancer has been shown to live in the tumor microenvironment, which consists of not only breast cancer cells themselves but also a significant amount of pathophysiologically altered surrounding stroma and cells. Diverse components of the breast cancer microenvironment, such as suppressive immune cells, re-programmed fibroblast cells, altered extracellular matrix (ECM) and certain soluble factors, synergistically impede an effective anti-tumor response and promote breast cancer progression and metastasis. Among these components, stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways, whereas the ECM features biochemical and biomechanical changes. However, triple-negative breast cancer (TNBC), the most aggressive subtype of this disease that lacks effective therapies available for other subtypes, is considered to feature a unique microenvironment distinct from that of other subtypes, especially compared to Luminal A subtype. Because these changes are now considered to significantly impact breast cancer development and progression, these unique alterations may serve as promising prognostic factors of clinical outcome or potential therapeutic targets for the treatment of TNBC. In this review, we focus on the composition of the TNBC microenvironment, concomitant distinct biological alteration, specific interplay between various cell types and TNBC cells, and the prognostic implications of these findings.


Multivariable Analysis of Patients With Severe Persistent Postprocedural Hypotension After Carotid Artery Stenting.
Purpose: To assess the incidence and predictors of severe, persistent postprocedural hypotension (PPH) after carotid artery stenting (CAS). Materials and Methods: A total of 146 patients (mean age 72.8 years; 104 men) who underwent 160 CAS procedures using a standardized protocol at 3 vascular centers were retrospectively analyzed. The primary endpoint was postprocedural hypotension, defined as a reduction in systolic blood pressure (SBP) >40 mm Hg from baseline or an SBP of <90 mm Hg sustained for >1 hour after CAS. Potential prognostic factors for postprocedural hypotension were identified and subjected to logistic regression analyses; outcomes are presented as the odds ratios (ORs) with 95% confidence intervals (CIs). Results: PPH developed in 36 (24.7%) patients after 37 (23.1%) CAS procedures. These patients had significantly longer intensive care unit and hospital stays than those who did not develop hypotension (p<0.001). PPH was associated with severe lesion calcification (OR 6.28, 95% CI 1.81 to 21.98, p=0.004) and contrast volume (OR 1.02, 95% CI 1.01 to 1.02, p<0.001). A 4-fold increase in the risk of PPH (OR 4.22, 95% CI 1.38 to 13.33, p=0.012) was found between the embolic protection device most associated with PPH (Angioguard) and the device least associated with PPH (Emboshield NAV6). A similar trend was also observed for the Precise vs Xact stents (OR 6, 95% CI 2.08 to 17.6, p=0.001). Bootstrapped multivariable modeling identified the Precise stent and contrast volume as significant predictors of persistent postprocedural hypotension. Further investigation of the contrast volume revealed associations with sex, severe calcification, arch type, previous coronary artery bypass surgery, and primary stenting, suggesting that the contrast volume reflects the complexity of the procedure. Conclusion: The complexity of the procedure and type of stent may play a role in the development of postprocedural hypotension after CAS.


Structure--antimicrobial activity of some natural isocoumarins and their analogues.
Three naturally occurring isocoumarins (paepalantine, paepalantine 9-O-beta-D-glucopyranoside and paepalantine 9-O-beta-D-allopyranosyl(1 --> 6) glucopyranoside) and two semi-synthetic analogues, 9,10-acylated compound and 9-OH-10-methylated compound, structurally similar to paepalantine, were evaluated for antimicrobial activity using a spectrophotometric microdilution technique. The paepalantine was active against S. aureus, S. epidermidis, and E. faecalis while the other four compounds proved ineffective against all microorganisms tested at concentrations of 500 microg/ml. Variations in phenolic substitution at OH-9 and/or OH-10 in the paepalantine molecule resulted in compounds without antimicrobial activity. A combination of structural features, two phenolic groups as cathecolic system, forms an oxygenated system arrangement that may reflect the potentially antimicrobial properties of paepalantine.


Proliferation and differentiation of CD8+ T cells in the absence of IL-2/15 receptor beta-chain expression or STAT5 activation.
Major gains in the efficacy of T cell-based therapies for cancer and infectious diseases could be realized through improved understanding of the signals that control expansion and differentiation of CD8(+) cytolytic T cells. IL-2, IL-15, and the downstream transcription factor STAT5 have all been implicated as important regulators of these processes, yet there are conflicting data regarding their contribution to in vivo T cell responses. We used a murine adoptive T cell transfer model to examine the contribution of IL-2 and IL-15 signaling to the proliferation and differentiation of naive, CD8(+) T cells bearing an OVA-specific TCR transgene (OT-I). OT-I T cells failed to express the high affinity IL-2R (CD25) while proliferating in vivo, irrespective of the mode of Ag delivery. Moreover, OT-I T cells rendered genetically deficient in the shared IL-2/IL-15Rbeta subunit (IL-2Rbeta) demonstrated normal Ag-induced proliferation and cytolytic activity in vivo. Accordingly, activation of STAT5 was not detected in proliferating IL-2Rbeta-deficient OT-I T cells, thus implicating a STAT5-independent cytokine or costimulatory pathway in this process. Even though IL-2 and IL-15 were dispensable for CD8(+) T cell proliferation, systemic infusion of IL-2 nevertheless promoted the expansion of OT-I T cells in vivo. Thus, IL-2 and IL-15 signals are not essential for CD8(+) T cell proliferation or differentiation, but IL-2 can promote supraphysiological expansion when supplied exogenously. These findings challenge current models that place CD8(+) T cell proliferation under the control of STAT5-dependent cytokines and suggest new approaches to the therapeutic manipulation of T cell numbers in vivo.


Prevalence of fracture and fragment embolization of Bard retrievable vena cava filters and clinical implications including cardiac perforation and tamponade.
Vena cava filters represent an alternative treatment option for patients with contraindications to anticoagulation, or they might serve as adjunctive treatment for continued emboli despite anticoagulation. The fracture of a filter strut with subsequent end-organ embolization is a rarely reported but potentially life-threatening occurrence. We sought to determine the prevalence of fracture and embolization of the Bard Recovery (first generation) and the Bard G2 (second generation) vena cava filters. A retrospective, single-center, cross-sectional study was conducted by evaluating all patients who received either a Bard Recovery or Bard G2 filter from April 2004 until January 2009. A total of 189 patients had undergone implantation: 1 pregnant woman and 35 patients who died were excluded from our study. In addition, 10 patients who had the filter removed were also excluded. Ultimately, 80 patients participated in the trial. Subjects underwent fluoroscopy to assess the filter's integrity. Embolized struts were localized by fluoroscopy. Echocardiography and cardiac computed tomography were performed in patients with fragment embolization to the heart. Thirteen of 80 patients had at least 1 strut fracture (16%). At least 1 strut in 7 of the 28 Bard Recovery filters fractured and embolized (25%). In 5 of these 7 cases, patients had at least 1 fragment embolize to the heart (71%). Three patients experienced life-threatening symptoms of ventricular tachycardia and/or tamponade, including 1 patient who experienced sudden death at home. Six of 52 Bard G2 filters fractured (12%). In 2 of these 6 cases, the patients had asymptomatic end-organ fragment embolization. The Bard Recovery and Bard G2 filters had high prevalences of fracture and embolization, with potentially life-threatening sequelae.


The activation of the arginine-citrulline cycle in macrophages from the spontaneously diabetic BB rat.
The activity of the arginine-citrulline cycle was investigated in macrophages from the spontaneous immunologically mediated diabetic BB rat. Peritoneal macrophages were prepared from male diabetes-prone (BBdp), diabetic (BBd) and age-matched non-diabetes-prone (BBn) rats. Cells were incubated at 37 degrees C for 2 h in Krebs-Henseleit bicarbonate buffer containing 0.5 mM L-arginine, 0.1 mM L-[ureido-14C]citrulline and 5 mM D-glucose to measure the activity of the arginine-citrulline cycle. The uptakes of citrulline and arginine by macrophages were measured during a 5 min incubation period with L-[ureido-14C]citrulline and L-[2,3-3H] arginine respectively. The production of NO3- (the major stable oxidation product of NO) increased (P < 0.01) by 112% and 151% in 75-day-old BBdp and 115-day-old BBd macrophages respectively, compared with age-matched BBn cells. The conversion of [14C]citrulline into [14C]arginine increased (P < 0.01) by 704%, 892% and 904% in 50- and 75-day-old BBdp and 115-day-old BBd macrophages respectively, compared with age-matched BBn cells. The enhanced NO synthesis in BBdp and BBd macrophages was associated with a 25-35% increase in the uptake of L-arginine. However, there were no differences in the uptake of citrulline between BBdp or BBd macrophages and age-matched BBn cells. Our results demonstrate for the first time the activation of the arginine-citrulline cycle in macrophages in an autoimmune condition. The inherent increase in the recycling of L-citrulline to L-arginine in BBdp and BBd macrophages may reflect an innate metabolic disorder in these cells. This increased L-arginine synthesis from L-citrulline may play a role in sustaining a sufficient intracellular L-arginine concentration for prolonged generation of NO in BBdp and BBd macrophages. A role for NO in the autoimmune destruction of pancreatic beta-cells in insulin-dependent diabetes mellitus warrants further investigation.


Low-value practices in oncology contributing to financial toxicity.
Financial toxicity of cancer treatment is now a well-recognised problem in cancer medicine leading to patient bankruptcy and even poor survival, including in high-income countries and countries with public health care systems. Many oncologists, despite acknowledging the severity of financial toxicity as a problem, resign the responsibility of reducing the costs of cancer treatment to the government, industry, and oncology societies. However, an oncologist can play an important role in reducing the costs of cancer treatment because all cancer treatment decisions are made between the oncologist and the patient. In this article, I point out a few examples of low value practices from various oncology disciplines that we oncologists can easily replace or abandon in our practice and contribute to lessening the financial toxicities to patients and society. As these examples suggest, reducing cost does not necessarily mean compromising efficacy. We should continuously keep looking for other similar cost-saving strategies in our practice.


Effects of sodium intake and Goldblatt hypertension on renin release in rat kidney slices.
The effects of altering sodium intake and inducing two-kidney, one-clip Goldblatt hypertension in the male Sprague-Dawley rat on renin release (RR) from renal cortical slices were examined. The low sodium diet significantly elevated plasma and kidney renin activity (KRA) and base-line renin release (BRR). KRA and BRR in the unclipped kidney of Goldblatt hypertensive rats were suppressed; KRA and BRR in the contralateral clipped kidney were comparable to values in normotensive animals fed a basal diet. Regression analysis of BRR vs. KRA for all kidneys studied yielded an r value of 0.728 for a linear model (y = a + bx) and 0.831 for a power model (y = axb), indicating that BRR is dependent on renal renin stores over a wide range of KRA, and suggesting that BRR may reach a maximal value. Percent inhibition of RR by angiotensin II (AII) and percent stimulation of RR by isoproterenol were the same in high, low, and basal salt states, while absolute changes in RR and changes in RR expressed as percent of renin stores released per hour were less in the high salt state, suggesting that isoproterenol-induced stimulation and AII-induced inhibition of RR are dependent on renal renin stores.


Cerebral oxygenation is depressed during sleep in healthy term infants when they sleep prone.
Prone sleeping is a major risk factor for the sudden infant death syndrome and is associated with lower blood pressure and impaired arousability from sleep, both of which may be signs of cerebral hypoxia. However, the impact of sleep position on cerebral oxygenation during infancy remains unknown. We assessed the effects of sleeping position, sleep state, and postnatal age on cerebral oxygenation by measuring tissue oxygenation index (TOI) during the first 6 months of infancy. Seventeen healthy term infants (8 girls and 9 boys) were recruited as study participants. Infants were studied at ages 2 to 4 weeks, 2 to 3 months, and 5 to 6 months by use of daytime polysomnography, with additional measurements of blood pressure (Finometer, FMS Finometer Medical Systems, Amsterdam, Netherlands) and tissue oxygenation index (TOI) (NIRO 200 spectrophotometer, Hamamatsu Photonics KK, Tokyo, Japan). In infants who slept in the prone position, TOI was lower in both quiet sleep (QS) and active sleep (AS) at age 2 to 4 weeks and in QS at age 2 to 3 months (P < .05). TOI was lower in AS compared with QS in infants aged 2 to 4 weeks (P < .05). When the infants reached 5 to 6 months of age, TOI was greater in AS (P < .05), as there was a profound decrease in TOI during QS (P < .05) over this period. No relationship was identified between blood pressure and TOI at any age. In healthy infants cerebral oxygenation is reduced during sleep in the prone position. This reduction may underpin the reduced arousability from sleep exhibited by healthy infants who sleep prone, a finding that provides new insight into potential risks of prone sleeping and mechanisms of sudden infant death syndrome.


A mammalian neural tissue opsin (Opsin 5) is a deep brain photoreceptor in birds.
It has been known for many decades that nonmammalian vertebrates detect light by deep brain photoreceptors that lie outside the retina and pineal organ to regulate seasonal cycle of reproduction. However, the identity of these photoreceptors has so far remained unclear. Here we report that Opsin 5 is a deep brain photoreceptive molecule in the quail brain. Expression analysis of members of the opsin superfamily identified as Opsin 5 (OPN5; also known as Gpr136, Neuropsin, PGR12, and TMEM13) mRNA in the paraventricular organ (PVO), an area long believed to be capable of phototransduction. Immunohistochemistry identified Opsin 5 in neurons that contact the cerebrospinal fluid in the PVO, as well as fibers extending to the external zone of the median eminence adjacent to the pars tuberalis of the pituitary gland, which translates photoperiodic information into neuroendocrine responses. Heterologous expression of Opsin 5 in Xenopus oocytes resulted in light-dependent activation of membrane currents, the action spectrum of which showed peak sensitivity (lambda(max)) at approximately 420 nm. We also found that short-wavelength light, i.e., between UV-B and blue light, induced photoperiodic responses in eye-patched, pinealectomized quail. Thus, Opsin 5 appears to be one of the deep brain photoreceptive molecules that regulates seasonal reproduction in birds.


Food-borne norovirus-outbreak at a military base, Germany, 2009.
Norovirus is often transmitted from person-to-person. Transmission may also be food-borne, but only few norovirus outbreak investigations have identified food items as likely vehicles of norovirus transmission through an analytical epidemiological study.During 7-9 January, 2009, 36 persons at a military base in Germany fell ill with acute gastroenteritis. Food from the military base's canteen was suspected as vehicle of infection, norovirus as the pathogen causing the illnesses. An investigation was initiated to describe the outbreak's extent, to verify the pathogen, and to identify modes of transmission and source of infection to prevent further cases. For descriptive analysis, ill persons were defined as members of the military base with acute onset of diarrhoea or vomiting between 24 December 2008, and 3 February 2009, without detection of a pathogen other than norovirus in stools. We conducted a retrospective cohort study within the headquarters company. Cases were military base members with onset of diarrhoea or vomiting during 5-9 January. We collected information on demographics, food items eaten at the canteen and contact to ill persons or vomit, using a self-administered questionnaire. We compared attack rates (AR) in exposed and unexposed persons, using bivariable and multivariable logistic regression modelling. Stool specimens of ill persons and canteen employees, canteen food served during 5-7 January and environmental swabs were investigated by laboratory analysis. Overall, 101/815 (AR 12.4%) persons fell ill between 24 December 2008 and 3 February 2009. None were canteen employees. Most persons (n = 49) had disease onset during 7-9 January. Ill persons were a median of 22 years old, 92.9% were male. The response for the cohort study was 178/274 (72.1%). Of 27 cases (AR 15.2%), 25 had eaten at the canteen and 21 had consumed salad. Salad consumption on 6 January (aOR: 8.1; 95%CI: 1.5-45.4) and 7 January (aOR: 15.7; 95%CI: 2.2-74.1) were independently associated with increased risk of disease.Norovirus was detected in 8/28 ill persons' and 4/25 canteen employees' stools, 6/55 environmental swabs and 0/33 food items. Sequences were identical in environmental and stool samples (subtype II.4 2006b), except for those of canteen employees. Control measures comprised cohort isolation of symptomatic persons, exclusion of norovirus-positive canteen employees from work and disinfection of the canteen's kitchen. Our investigation indicated that consumption of norovirus-contaminated salad caused the peak of the outbreak on 7-9 January. Strict personal hygiene and proper disinfection of environmental surfaces remain crucial to prevent norovirus transmission.


Attitude and knowledge of Iranian female nurses about human papilomavirus infection and cervical cancer: a cross sectional survey.
Human Papilomavirus (HPV) is one of the most widespread sexually transmitted diseases is highly related to cervical cancer in women. Cervical cancer's crude incidence rate in Iran is 6-8 per 100,000. The HPV vaccine provides a chance to considerably decrease the transmission of most types of HPV. The aim of this study was to evaluate awareness and knowledge of HPV infection and vaccines and to assess the attitude and approach toward these vaccines among female nurses at Shahid Sadoughi University of Medical Sciences, Yazd, Iran. This cross-sectional, descriptive study was performed among 380 female nurses. Data were collected using a questionnaire was consisted in demographic variables and questions on knowledge of participants about HPV infection, HPV vaccine and cervical cancer and also questions on attitude of ourses towards HPV vaccination. The validity and internal consistency of questionnaire was confirmed during experts consents and pilot testing (alpha = 0.79). Data analysis was performed using SPSS15 using chi2-test or Fisher's exact test. Three hundred and eighty questionnaires were distributed and 357 female nurses completed and returned their questionnaires: Only one hundred and thirty-one of the nurses (36.7%) knew about HPV infection and how it can cause abnormal pap Smear results. about 147 (41.2%) of the nurses stated they would want to be vaccinated. About 146 (40.9%) of respondents supported vaccination of preadolescent girls. The results of this study confirm the lack of knowledge about HPV vaccine and its relation to cervical cancer and also the ways of this cancer prevention. Our study shows an urgent need to design similar studies in other regions of Iran and draw a broad estimation on knowledge of different target groups to make a national program to increase the knowledge of women on this matter and help to decrease the rate of cervical cancer in Iranian population.


Differential prevalence of transporter polymorphisms in symptomatic and asymptomatic falciparum malaria infections in Uganda.
We explored associations between Plasmodium falciparum drug resistance-mediating polymorphisms and clinical presentations in parasitemic children enrolled in a cross-sectional survey in Tororo, Uganda, using a retrospective case-control design. All 243 febrile children (cases) and 243 randomly selected asymptomatic children (controls) were included. In a multivariate analysis adjusting for age, complexity of infection, and parasite density, the prevalence of wild-type genotypes was significantly higher in febrile children compared to asymptomatic children (pfcrt K76T: odds ratio [OR] 4.41 [95% confidence interval {CI}, 1.28-15.1]; pfmdr1 N86Y: OR 4.08 [95% CI, 2.01-8.31], and pfmdr1 D1246Y: OR 4.90 [95% CI, 1.52-15.8]), suggesting greater virulence for wild-type parasites.


Predictors of lower extremity arterial injury after total knee or total hip arthroplasty.
Lower extremity arterial injury is a rare complication following total knee (TKA) or total hip arthroplasty (THA). To date, no multi-institutional study has identified preoperative factors that may portend increased risk for these injuries. We queried a large clinical database for the incidence and predictors of arterial injury and/or compromise following lower extremity arthroplasty. Prospectively collected preoperative and postoperative data by the National Surgical Quality Improvement Program (NSQIP) of the Veterans Affairs Medical Centers were analyzed. All patients from 1996 to 2003 in the NSQIP database who underwent TKA or THA were identified via CPT codes. NSQIP defined, 30-day, postoperative outcomes were analyzed. Data were compared using bivariable analysis, as well as limited multivariable logistic regression. A total of 41,633 arthroplasties (24,029 TKA, 2077 redo-TKA, 13,494 THA, 2033 redo-THA) were identified in the NSQIP database. A total of 34 (0.08%) lower extremity arterial injuries were recognized (0.08% TKA, 0.19% redo-TKA, 0.04% THA, 0.20% redo-THA). Eighteen injuries were repaired on the same day of surgery (seven intraop, 11 postop), eight between postoperative days 1 and 5, and 8 between days 6 and 30. Only two patients underwent lower extremity amputation (overall limb loss rate of 5.9% of patients who had arterial injury). Statistically significant predictors of lower extremity arterial injury identified on logistic regression analysis included redo procedure (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.2-6.0, P = .013) and African American race (OR 2.5, 95% CI 1.2-5.3, P = .02). Lower extremity arterial injury was exceedingly rare after total knee or total hip arthroplasty. There is an increased incidence in African American patients and those undergoing redo arthroplasty. Among patients who sustain vascular injury, excellent limb salvage rates can be achieved with close postoperative surveillance to achieve early detection and repair of injuries.


Down-regulation of miR-605 promotes the proliferation and invasion of prostate cancer cells by up-regulating EN2.
MicroRNA served as inhibitor for gene expression in various cancers. This study aimed to investigate the role of miR-605 and EN2 in prostate cancer (PCa). In this research, the expression of miR-605 and EN2 protein in PCa tissues and cells were determined by qRT-PCR and western blot, respectively. The cell proliferation was measured by Cell Counting Kit-8 (CCK-8) and the tumor cell invasion assay was accomplished with transwell system. Flow cytometry was used to analyze the cell cycle. The endogenous expression of miR-605 and EN2 was modulated by recombinant plasmids and cell transfection. Dual luciferase reporter assay was performed to determine the interaction between miR-605 and EN2 in PCa cells. The expression of miR-605 was lower in PCa tissue and cells than that in normal tissues and cells, while the expression of EN2 was just the opposite. Down-regulation of the EN2 by siRNA inhibited the proliferation and invasion of PC3 cells, and the cell cycle was arrested in G0/G1 phase. EN2 regulated the expression of E-cadherin and Vimentin through Snail and EN2 regulated the cell cycle and cell proliferation via PI3K/AKT pathway. MiR-605 inhibited the proliferation and invasion of PCa cells through targeting EN2. EN2 is negatively regulated by miR-605, and down-regulation of miR-605 promotes the proliferation and invasion of PCa cells by up-regulating EN2, which leads to PCa development and progression.


Health Economic Analysis of Two-Layer Bandage System for Treatment of Chronic Venous Insufficiency.
Background: Compression therapy is the gold standard for the treatment of chronic venous insufficiency (CVI). Two-layer bandage (2LB) systems have been shown to be a safe and effective treatment option. Objective: To estimate the total cost per response (CPR) for the resolution of edema and wounds in patients with CVI treated with a 2LB system as part of their overall wound healing regimen. Methods: A probabilistic decision tree model was developed to estimate the incremental CPR for a 2LB system. The model simulated 10 000 patients to estimate the CPR for the resolution of edema and wound healing. The analysis was performed using clinical data from a published single-arm, multicenter prospective study of CVI indicated for compression therapy. The response outcomes of interest were resolution of edema and rate of wound healing. The follow-up time was a maximum of 6 weeks, and the perspective of the study was a US outpatient treatment center. Economic data for compression therapy were based on the public prices of a 2LB system. Dressing changes occurred per manufacturer instructions for use. Results: The study comprised 702 patients (56% female), with a total of 414 wounds. The median duration of the wounds was 42 days, and the median size at the initial visit was 3.5 cm2. The average pain reduction fell by 67% using a visual analog score. Bandages were typically changed once or twice a week (51.7%). Wound healing occurred in 128 of the 414 wounds (30.9%). The expected incremental CPR of a 2LB system for the resolution of edema was $65.67 (range, $16.67-$124.32). The expected incremental CPR of a 2LB system for the healing of a wound was $138.71 (range, $35.71-$273.53). Conclusion: This economic evaluation complements previous clinical effectiveness and safety studies of 2LB systems for the treatment of CVI. The results demonstrate that the costs of incorporating 2LB into standard wound-healing protocols are negligible compared with overall treatment costs. Two-layer bandages may be considered a cost-effective first-line system for the treatment of wounds caused by CVI.


The intrinsic structure and stability of out-of-alternation base pairs in Z-DNA.
Alternating pyrimidine-purine sequences typically form Z-DNA, with the pyrimidines in the anti and purines in the syn conformations. The observation that dC and dT nucleotides can also adopt the syn conformation (i.e. the nucleotides are out-of-alternation) extends the range of sequences that can convert to this left-handed form of DNA. Here, we study the effects of placing two adjacent d(G*C) base pairs as opposed to a single d(G*C) base pair or two d(A*T) base pairs out-of-alternation by comparing the structure of d(m5CGGCm5CG)2with the previously published structures of d(m5CGGGm5CG)*d(m5CGCCm5CG) and d(m5CGATm5CG)2. A high buckle and loss of stacking interactions are observed as intrinsic properties of the out-of-alternation base pairs regardless of sequence and the context of the dinucleotide. From solution titrations, we find that the destabilizing effect of out-of-alternation d(G*C) base pairs are identical whether these base pairs are adjacent or isolated. We can therefore conclude that it is these intrinsic distortions in the structure of the base pairs and not neighboring effects that account for the inability of out-of-alternation base pairs to adopt the left-handed Z conformation.


Detection of common viruses using the polymerase chain reaction to assess levels of viral presence in type 1 (insulin-dependent) diabetic patients.
The polymerase chain reaction was used to detect a range of common viruses in the peripheral blood of Type 1 diabetic and non-diabetic control patients in order to identify any abnormal viral presence, with possible roles in the pathogenesis of Type 1 diabetes. Peripheral blood from 17 newly diagnosed Type 1 diabetic patients, 38 Type 1 diabetic patients with disease of longer duration, and 43 age and sex matched non-diabetic controls was obtained. Samples were screened for cytomegalovirus, Epstein-Barr virus, enterovirus (including coxsackie), and mumps virus. Cytomegalovirus was detected in control patients only (5%), Epstein-Barr virus was detected equally in newly diagnosed and control patients (12%), and enterovirus was detected slightly more frequently in diabetic than non-diabetic patients (41% and 31%, respectively). Mumps virus was not detected in any of the samples. It is concluded that Type 1 diabetic individuals are neither more prone to persistence of common viruses nor to more frequent acute infections with the viruses tested for than non-diabetic individuals. If common viruses are involved in the pathogenesis of Type 1 diabetes then they act either as non-specific agents to which the host has abnormal immune responses, or, the diabetogenic viruses are eliminated from the body by the time of disease diagnosis.


Intracellular photodynamic therapy with photosensitizer-nanoparticle conjugates: cancer therapy using a 'Trojan horse'.
Phthalocyanine-nanoparticle conjugates have been designed and synthesised for the delivery of hydrophobic photosensitizers for photodynamic therapy (PDT) of cancer. The phthalocyanine photosensitizer stabilized gold nanoparticles have an average diameter of 2-4 nm. The synthetic strategy interdigitates a phase transfer reagent between phthalocyanine molecules on the particle surface that solubilises the hydrophobic photosensitizer in polar solvents enabling delivery of the nanoparticle conjugates to cells. The phthalocyanine is present in the monomeric form on the nanoparticle surface, absorbs radiation maximally at 695 nm and catalytically produces the cytotoxic species singlet oxygen with high efficiency. These properties suggest that the phthalocyanine-nanoparticle conjugates are ideally suited for PDT. In a process that can be considered as cancer therapy using a 'Trojan horse', when the nanoparticle conjugates are incubated with HeLa cells (a cervical cancer cell line), they are taken up thus delivering the phthalocyanine photosensitizer directly into the cell interior. Irradiation of the nanoparticle conjugates within the HeLa cells induced substantial cell mortality through the photodynamic production of singlet oxygen. The PDT efficiency of the nanoparticle conjugates, determined using colorimetric assay, was twice that obtained using the free phthalocyanine derivative. Following PDT with the nanoparticle conjugates, morphological changes to the HeLa cellular structure were indicative of cell mortality via apoptosis. Further evidence of apoptosis was provided through the bioluminescent assay detection of caspase 3/7. Our results suggest that gold nanoparticle conjugates are an excellent vehicle for the delivery of surface bound hydrophobic photosensitizers for efficacious photodynamic therapy of cultured tumour cells.


Infrared microspectroscopy identifies biomolecular changes associated with chronic oxidative stress in mammary epithelium and stroma of breast tissues from healthy young women: implications for latent stages of breast carcinogenesis.
Studies of the decades-long latent stages of breast carcinogenesis have been limited to when hyperplastic lesions are already present. Investigations of earlier stages of breast cancer (BC) latency have been stymied by the lack of fiducial biomarkers needed to identify where in histologically normal tissues progression toward a BC might be taking place. Recent evidence suggests that a marker of chronic oxidative stress (OxS), protein adducts of 4-hydroxy-2-nonenal (4HNE), can meet this need. Specifically: (1) 4HNE immunopositive (4HNE+) mammary epithelial (ME) cells were found to be prevalent in normal (reduction mammoplasty) tissues of most women (including many teenagers) studied, representative of those living in the United States' high risk-posing environment and: (2) marked (> 1.5-fold) differences were identified between tissues of healthy young women with many vs. few 4HNE+ ME cells in the relative levels of transcripts for 42 of the 84 OxS-associated genes represented in SABioscience Oxidative-Stress/Oxidative-Defense PCR array. Herein we used synchrotron radiation-based Fourier-transform infrared (SR-FTIR) microspectroscopy to identify molecular changes associated with 4HNE adducts in basal and luminal ME cells in terminal ductal units (TDLU), which are the cells of origin of BC, and associated intralobular and interlobular stroma, known contributors to carcinogenesis. Multivariate analysis-derived wavenumbers differentiated 4HNE+ and 4HNE- cells in each of the anatomical compartments. Specifically, principal component and linear discriminant analyses of mid-infrared spectra obtained from these cells revealed unambiguous, statistically highly significant differences in the "biochemical fingerprint" of 4HNE+ vs. 4HNE- luminal and basal ME cells, as well as between associated intralobular and interlobular stroma. These findings demonstrate further SR-FTIR microspectroscopy's ability to identify molecular changes associated with altered physiological and/or pathophysiological states, in this case with a state of chronic OxS that provides a pro-carcinogenic microenvironment.


Bone conductive implants in single-sided deafness.
Bone conduction implants (BCIs) have been shown to partially restore some of the functions lost when binaural hearing is missing, such as in subjects with single-sided deafness (SSD). The use of a single BCI needs to be recommended by a clinician based on thorough counselling with the SSD subject. To perform an overview of the present capabilities of BCIs for SSD and to evaluate the reliability of the audiological evaluation for assessing speech recognition in noise and sound localization cues, which are major problems related to the loss of binaural hearing. Nine subjects with SSD who received BCI implants underwent a preoperative audiological evaluation that included sound field speech audiometry, word recognition score (WRS) testing and sound localization testing in quiet and in noise. They were also tested for the accuracy of their directional word recognition in noise and their subjective perceptions of their hearing difficulties using the APHAB questionnaire. The mean maximum accuracy of word discrimination was 65.5% in the unaided condition and 78.9% in the BCI-aided condition. Sound localization in noise was better with the BCI than in the unaided condition, especially when the stimulus and noise were presented on the same side as the implanted ear. The accuracy of directional word recognition showed an improvement with the BCI with respect to the unaided condition on the BCI side, with either the stimulus in the implanted ear and the noise in the contralateral ear or with both the stimulus and noise presented to the implanted ear.


The Role of Salvage Second Autologous Hematopoietic Cell Transplantation in Relapsed Multiple Myeloma.
Multiple myeloma (MM), a malignant disorder of plasma cells affecting primarily elderly patients, is the second most commonly diagnosed hematologic neoplasm. With the recent influx of effective new agents available, including proteasome inhibitors, immunomodulators, targeted monoclonal antibodies, and now chimeric antigen receptor T cell (CAR-T) therapy, the treatment landscape is evolving rapidly. Although the role of consolidative autologous stem cell transplantation (ASCT) in first remission is well established, in the relapsed setting after upfront ASCT, the role of a second ASCT (SAT) following reinduction is less clear and understudied. Practice patterns vary significantly across institutions, and most of the literature available to guide clinical decisions consists of single-institution experiences, with only 1 randomized study evaluating the role of SAT compared with a nontransplantation approach. SAT is likely underused, because it has not been included in clinical trials examining novel regimens for relapsed disease. Furthermore, outcomes likely can be improved with approaches to intensify the preparative regimen and the use of standard post-transplantation maintenance. In this review, we examine the role of SAT in the current MM treatment landscape in the context of recent data on the efficacy of CAR-T therapy in this disease. We caution the abandonment of SAT, given that CAR-T therapy is in its infancy in MM treatment, and that real-world data in the relapsed setting are consistently inferior to clinical trial outcomes.


Enhancement of intracellular concentration and biological activity of PNA after conjugation with a cell-penetrating synthetic model peptide.
In order to evaluate the ability of the cell-penetrating alpha-helical amphipathic model peptide KLALKLALKALKAALKLA-NH(2) (MAP) to deliver peptide nucleic acids (PNAs) into mammalian cells, MAP was covalently linked to the 12-mer PNA 5'-GGAGCAGGAAAG-3' directed against the mRNA of the nociceptin/orphanin FQ receptor. The cellular uptake of both the naked PNA and its MAP-conjugate was studied by means of capillary electrophoresis combined with laser-induced fluorescence detection, confocal laser scanning microscopy and fluorescence-activated cell sorting. Incubation with the fluorescein-labelled PNA-peptide conjugate led to three- and eightfold higher intracellular concentrations in neonatal rat cardiomyocytes and CHO cells, respectively, than found after exposure of the cells to the naked PNA. Correspondingly, pretreatment of spontaneously-beating neonatal rat cardiomyocytes with the PNA-peptide conjugate and the naked PNA slowed down the positive chronotropic effect elicited by the neuropeptide nociceptin by 10- and twofold, respectively. The main reasons for the higher bioavailability of the PNA-peptide conjugate were found to be a more rapid cellular uptake in combination with a lowered re-export and resistance against influences of serum.


Catecholamine stimulation of hepatic glycogenolysis during anoxia in the turtle Chrysemys picta.
The remarkable tolerance of some species of turtles to anoxia is well documented. The role that hormones play in this anoxia tolerance, however, is poorly understood. This study examined the role of catecholamines in the mobilization of liver glycogen during anoxic submergence in painted turtles (Chrysemys picta). Turtles were subjected to 4 h of submergence anoxia or air (normoxic controls) and received injections of propranolol, a beta-adrenergic receptor antagonist, or saline. The results indicated that the catecholamines function during anoxia to increase blood glucose levels by stimulating hepatic glycogenolysis through an increase in both the total activity of glycogen phosphorylase and the percent a form. Anoxic turtles given propranolol showed a decrease in the percent a form of glycogen phosphorylase compared with control turtles given propranolol, indicating that anoxia per se or a correlate of anoxia may depress hepatic glycogenolysis. Catecholamines may counteract this depressant effect. Hepatic glycogen mobilization during anoxia appeared to be stimulated via beta-adrenergic receptors, as propranolol was effective in blocking the stimulation, whereas phentolamine, an alpha-receptor antagonist, was not.


Caching for where and what: evidence for a mnemonic strategy in a scatter-hoarder.
Scatter-hoarding animals face the task of maximizing retrieval of their scattered food caches while minimizing loss to pilferers. This demand should select for mnemonics, such as chunking, i.e. a hierarchical cognitive representation that is known to improve recall. Spatial chunking, where caches with the same type of content are related to each other in physical location and memory, would be one such mechanism. Here we tested the hypothesis that scatter-hoarding eastern fox squirrels (Sciurus niger) are organizing their caches in spatial patterns consistent with a chunking strategy. We presented 45 individual wild fox squirrels with a series of 16 nuts of four different species, either in runs of four of the same species or 16 nuts offered in a pseudorandom order. Squirrels either collected each nut from a different location or collected all nuts from a single location; we then mapped their subsequent cache distributions using GPS. The chunking hypothesis predicted that squirrels would spatially organize caches by nut species, regardless of presentation order. Our results instead demonstrated that squirrels spatially chunked their caches by nut species but only when caching food that was foraged from a single location. This first demonstration of spatial chunking in a scatter hoarder underscores the cognitive demand of scatter hoarding.


Immunoglobulin gene repertoire diversification and selection in the stomach - from gastritis to gastric lymphomas.
Chronic gastritis is characterized by gastric mucosal inflammation due to autoimmune responses or infection, frequently with Helicobacter pylori. Gastritis with H. pylori background can cause gastric mucosa-associated lymphoid tissue lymphoma (MALT-L), which sometimes further transforms into diffuse large B-cell lymphoma (DLBCL). However, gastric DLBCL can also be initiated de novo. The mechanisms underlying transformation into DLBCL are not completely understood. We analyzed immunoglobulin repertoires and clonal trees to investigate whether and how immunoglobulin gene repertoires, clonal diversification, and selection in gastritis, gastric MALT-L, and DLBCL differ from each other and from normal responses. The two gastritis types (positive or negative for H. pylori) had similarly diverse repertoires. MALT-L dominant clones (defined as the largest clones in each sample) presented higher diversification and longer mutational histories compared with all other conditions. DLBCL dominant clones displayed lower clonal diversification, suggesting the transforming events are triggered by similar responses in different patients. These results are surprising, as we expected to find similarities between the dominant clones of gastritis and MALT-L and between those of MALT-L and DLBCL.


Occupational dental erosion from exposure to acids: a review.
Dental erosion is characterized as a disorder with a multifactorial aetiology including environmental acid exposure. The purpose of this article was to summarize and discuss the available information concerning occupational dental erosion. Information from original scientific papers, case reports and reviews with additional case reports listed in PubMed, Medline or EMBASE [search term: (dental OR enamel OR dentin) AND (erosion OR tooth wear) AND (occupational OR worker)] were included in the review. References from the identified publications were manually searched to identify additional relevant articles. The systematic search resulted in 59 papers, of which 42 were suitable for the present review. Seventeen papers demonstrated evidence that battery, galvanizing and associated workers exposed to sulphuric or hydrochloric acid were at higher risk of dental erosion. For other industrial workers, wine tasters and competitive swimmers, only a few clinical studies exist and these do not allow the drawing of definitive conclusions. Occupational acid exposure might increase the risk of dental erosion. Evidence for occupational dental erosion is limited to battery and galvanizing workers, while data for other occupational groups need to be confirmed by further studies.


Teaching law students in the medical schools.
Traditional efforts in the law schools to improve interprofessional communication between the medical and legal professions have been confined to abstract case studies and other academic materials, sometimes augmented with visits and demonstrations by physicians in the classroom. This paper describes one approach to broaden the prespective of law students during their training by permitting them to experience directly the atmosphere of the teaching hospital and the sociology of surgery practice in that environment. The experiment has proved beneficial to the young members of both professions.