On-Sight and Red-Point Climbing: Changes in Performance and Route-Finding Ability in Male Advanced Climbers.
In lead climbing, the ascent of the route can be defined as on-sight or red-point. On-sight is the more challenging style since it demands greater physiological and psychological commitment. The differences between the two modes in advanced climbers have not been studied much. Two essential skills needed to optimize performance, in both on-sight and in red-point climbing, are route interpretation (RI) ability and movements sequence recall. Therefore, this study aimed to compare performance between on-sight and red-point ascent in advanced climbers and evaluate how a climber's RI ability and movement sequences recall might change before and after on-sight and red-point climbing. Eighteen advanced male climbers (age 29.2 ± 4.7 years, body mass 67.8 ± 3.6 kg, stature 175.2 ± 2.4 cm, best red-point and on-sight grades 7b+/8a and 7a+/7b+, respectively) were video-recorded during the route ascent in on-sight and red-point modes to evaluate performance and to measure static and dynamic action times. RI ability and movement sequence recall were assessed before and after each climb. Level of anxiety was evaluated via a self-report questionnaire. Heart rate (f H), lactate concentration, ([La-]), and rating of perceived exertion (RPE) were detected during and after each climb. Compared to on-sight, an improvement in performance was observed in a red-point climb: the ascent was faster (148.7 ± 13.6 s and 179.5 ± 12.5 s, respectively, P < 0.05), smoother (significant reduction in exploratory moves and in stops times, P < 0.05), less demanding physiologically (lower f H peak and [La-]peak, P < 0.05), and psychologically (lower RPE, cognitive and somatic anxiety and higher self-confidence, P < 0.05). The RI ability was improved in red-point versus on-sight and, in the same mode, between pre and post ascent. Red-point climbing was found to be less demanding than on-sight, both physiologically and psychologically, under the conditions investigated by this study. Our findings suggest that RI is a trainable skill and underscore the importance of including specific techniques in training programs designed to improve interaction between perceptual, psychological, and physiological factors.


The dimensions of mandibular lingual tissues relative to the placement of a lingual bar major connector.
The purpose of this investigation was to measure and describe the lingual tissues of the anterior mandible to determine the acceptable boundaries of the zone of nonmovable tissue for placement of a lingual bar and to compare these to existing numerical guidelines. Eighty subjects, grouped by age and gender, with clinically normal mandibular lingual gingival tissues from second premolar to second premolar were examined. The lingual sulcular depths (AB) and the distance from the gingival crest to movable tissue of the floor of the mouth (AC) were recorded. The zone of lingual nonmovable tissue was calculated (AC - AB) for each tooth. For all subjects, the mean value of the probing depth (AB) ranged from 1.22 mm (+/-0.33 mm) for central incisors to 1.66 mm (+/-0.43 mm) for second premolars. The mean distance from the gingival crest to movable tissue of the floor of the mouth (AC) ranged from 7.44 mm (+/-1.59 mm) for central incisors to 10.28 mm (+/-2.55 mm) for second premolars. The mean height of the lingual nonmovable tissue (the zone available for the lingual bar; AC - AB) ranged from 6.22 mm (+/-1.59 mm) for central incisors to 8.63 mm (+/-2.57 mm) for second premolars. Most subjects presented with the minimum zone of nonmovable tissue at the central incisors, but with increasing age more subjects presented with minimum values at the posterior teeth. The multifactorial analysis of variance (ANOVA) for males' available nonmovable tissue shows significance for both tooth (p <0.001) and age (p <0.001) factors. The multifactorial ANOVA for females' available nonmovable tissue shows significance for both tooth (p <0.001) and age (p <0.001) factors. Of all subjects, 85% (88% of males, 83% of females) had 4 mm or more of nonmovable tissue, sufficient for a lingual bar. The amount of available room decreased in older females. Within the limits of this study, the use of actual measurements of lingual tissues versus existing numerical guidelines increased the percentage of patients for which the lingual bar can be used from approximately 6% to approximately 85%.


Dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model.
We studied growth factors and their receptors in tumor cells and tumor-associated endothelial cells as the therapeutic targets in colon cancer. Immunohistochemical analysis of 13 surgical specimens of human colon adenocarcinoma revealed that both tumor cells and tumor-associated endothelial cells in 11 of the 13 specimens expressed the epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), EGF receptor (EGFR), phosphorylated EGFR (pEGFR), vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and phosphorylated VEGFR (pVEGFR). HT29 human colon cancer cells growing orthotopically in the cecum of nude mice expressed a high level of EGF, EGFR, pEGFR, VEGF, VEGFR, and pVEGFR. Double-immunofluorescence staining found that tumor-associated mouse endothelial cells also expressed pEGFR and pVEGFR. Tumors in mice treated for 5 weeks with oral AEE788 (an inhibitor of EGFR and VEGFR tyrosine kinase) as a single agent or with CPT-11 alone were smaller (>50%) than those in control mice. Mice treated with the combination of AEE788 and CPT-11 had significantly smaller tumors (P < 0.01) and complete inhibition of lymph node metastasis. AEE788 alone or in combination with CPT-11 inhibited pEGFR, pVEGFR, and phosphorylated Akt expression on tumor-associated endothelial cells as well as on tumor cells. The combination therapy also significantly decreased microvessel density and tumor cell proliferation and increased the level of apoptosis in both tumor cells and tumor-associated endothelial cells. Collectively, these data suggest that the dual inhibition of EGFR and VEGFR signaling pathways in tumor cells and tumor-associated endothelial cells in combination with chemotherapy can provide a new approach to the treatment of colon cancer.


Micromachined silicon grisms for infrared optics.
We demonstrate the successful fabrication of large format (approximately 50 mm × 50 mm) gratings in monolithic silicon for use as high-efficiency grisms at infrared wavelengths. The substrates for the grisms were thick (8-16 mm) disks of precisely oriented single-crystal silicon (refractive index, n ~ 3.42). We used microlithography and chemical wet etching techniques to produce the diffraction gratings on one side of these substrates. These techniques permitted the manufacture of coarse grooves (as few as 7 grooves/mm) with precise control of the blaze angle and groove profile and resulted in excellent groove surface quality. Profilometric measurements of the groove structure of the gratings confirm that the physical dimensions of the final devices closely match their design values. Optical performance of these devices exceeds the specifications required for diffraction-limited performance (RMS wave surface error <λ/20) in the near- and mid-infrared (1-40 μm). Peak diffraction efficiencies measured in the reflection range from 70-95% of the theoretical maximum. Tests of our grisms in the near infrared indicate transmission efficiencies of 30-48% uncorrected for Fresnel losses and confirm excellent performance. In infrared wavelength regions where silicon transmits well, the blaze control and high index permit high-resolution, high-order dispersion in a compact space. The first application of these grisms is to provide FORCAST, a mid-infrared camera on NASA's airborne observatory, with a moderate resolution (R=100-1000) spectroscopic capability.


Resources, roadblocks and turning points: a qualitative study of American Indian/Alaska Native adults with type 2 diabetes.
Type 2 diabetes is a worldwide health problem that has reached epidemic proportions in some communities. Alaska Native and American Indian (AN/AI) people are disproportionately diagnosed with type 2 diabetes and incidence is increasing in many Alaska communities. Developing effective interventions requires understanding the social and psychological factors that impact effective management of diabetes, yet little is known about these factors in AN/AI communities. The objective of this study was to explore perceived psychosocial needs and barriers to management of diabetes among AN/AI adults with type 2 diabetes receiving care at the Alaska Native Primary Care Center (ANPCC) to inform programmatic efforts and potential future research. We conducted three focus groups and five interviews with 13 AN/AI adults with type 2 diabetes. Interview and focus group questions elicited perceived factors that affect management of diabetes, with a focus on the psychological, social and spiritual impacts of diabetes. Data were transcribed, coded and analyzed using thematic analysis. Key themes that emerged from these data included resources and roadblocks, as well as turning points in the trajectory of diabetes. Resources are factors with a perceived positive impact on management of diabetes, including: (1) knowledge and education about diabetes, (2) social support from other people with diabetes, (3) spirituality, and (4) self-efficacy. Roadblocks are factors with a perceived negative impact on management of diabetes and include: (1) self-reported lack of knowledge about nutrition and diet, (2) social difficulties caused by dietary restrictions, and (3) co-morbid medical conditions. Finally, turning points are experiences described by participants as having transformed roadblocks in resources and thus facilitating improvement in the management of diabetes. Future programmatic interventions to improve management of diabetes with this population should focus on improving dietary education and social support opportunities for newly-diagnosed individuals. Also, educational and support opportunities for family members and friends of individuals with diabetes should also be offered to facilitate understanding and support of their loved ones' management of diabetes, especially with regard to dietary restrictions in social settings. Efforts should also focus on strengthening newly-diagnosed individuals' self-efficacy and providing ongoing support as individuals progressively adjust to the illness over time and make behavioral changes. Future research with this population should explore the effects of family support groups and the possibility of Web-based or other alternative interventions for improving psychosocial health and management of diabetes efforts.


Clinical analysis of incidentally discovered unruptured aneurysms.
We analyzed the risk factors for rupture of an intracranial aneurysm based on a retrospective angiographic study of ruptured and unruptured aneurysms. The 44 cases of asymptomatic aneurysms were selected from 1612 patients whose lesions had been discovered fortuitously by angiography (2.7%) during the period from 1980 to 1989. All these patients were free from any sign of intracranial aneurysm. The variations in age, sex, and location of the aneurysms were analyzed compared with 638 ruptured aneurysms that had been treated in our institute during the same period. The size, shape, and arterial geometry of the unruptured aneurysms were examined angiographically. Unruptured aneurysm was discovered fortuitously in 44 (2.7%) of 1612 patients, with greater incidence in women aged older than 60 years. Unruptured aneurysms were less likely to occur in the anterior communicating artery (12.8%) and the middle cerebral artery (6.4%). However, they were frequently found in the internal carotid artery, with an incidence of 10.6% in cavernous portion of the internal carotid artery, 19.1% in the internal carotid-ophthalmic artery, 19.1% in the internal carotid-posterior communicating artery, and 12.8% in the internal carotid-anterior choroidal artery. Seven of the nine internal carotid-posterior communicating artery aneurysms showed a hypoplastic or aplastic posterior communicating artery. The mean diameter of the unruptured aneurysms was 4.8 mm, and 80% were smaller than 6 mm. Intracranial aneurysms are formed not only at the bifurcation of an artery but also at its branching and bending points. However, an aneurysm located at the bifurcation, such as the anterior communicating artery and the middle cerebral artery, bleeds easily in contrast with lateral aneurysms such as those found at the branching and bending points on the internal carotid artery.


Pacemaker activity and inhibitory neurotransmission in the colon of Ws/Ws mutant rats.
The aim of this study was to characterize the pacemaker activity and inhibitory neurotransmission in the colon of Ws/Ws mutant rats, which harbor a mutation in the c-kit gene that affects development of interstitial cells of Cajal (ICC). In Ws/Ws rats, the density of KIT-positive cells was markedly reduced. Wild-type, but not Ws/Ws, rats showed low- and high-frequency cyclic depolarization that were associated with highly regular myogenic motor patterns at the same frequencies. In Ws/Ws rats, irregular patterns of action potentials triggered irregular muscle contractions occurring within a bandwidth of 10-20 cycles/min. Spontaneous activity of nitrergic nerves caused sustained inhibition of muscle activity in both wild-type (+/+) and Ws/Ws rats. Electrical field stimulation of enteric nerves, after blockade of cholinergic and adrenergic activity, elicited inhibition of mechanical activity and biphasic inhibitory junction potentials both in wild-type and Ws/Ws rats. Apamin-sensitive, likely purinergic, inhibitory innervation was not affected by loss of ICC. Variable presence of nitrergic innervation likely reflects the presence of direct nitrergic innervation to smooth muscle cells as well as indirect innervation via ICC. In summary, loss of ICC markedly affects pacemaker and motor activities of the rat colon. Inhibitory innervation is largely maintained but nitrergic innervation is reduced possibly related to the loss of ICC-mediated relaxation.


Radiolabeled Oligonucleotides Targeting the RNA Subunit of Telomerase Inhibit Telomerase and Induce DNA Damage in Telomerase-Positive Cancer Cells.
Telomerase is expressed in the majority (>85%) of tumors, but has restricted expression in normal tissues. Long-term telomerase inhibition in malignant cells results in progressive telomere shortening and reduction in cell proliferation. Here we report the synthesis and characterization of radiolabeled oligonucleotides that target the RNA subunit of telomerase, hTR, simultaneously inhibiting enzymatic activity and delivering radiation intracellularly. Oligonucleotides complementary (Match) and noncomplementary (Scramble or Mismatch) to hTR were conjugated to diethylenetriaminepentaacetic dianhydride (DTPA), allowing radiolabeling with the Auger electron-emitting radionuclide indium-111 (111In). Match oligonucleotides inhibited telomerase activity with high potency, which was not observed with Scramble or Mismatch oligonucleotides. DTPA-conjugation and 111In-labeling did not change telomerase inhibition. In telomerase-positive cancer cells, unlabeled Match oligonucleotides had no effect on survival, however, 111In-labeled Match oligonucleotides significantly reduced clonogenic survival and upregulated the DNA damage marker γH2AX. Minimal radiotoxicity and DNA damage was observed in telomerase-negative cells exposed to 111In-Match oligonucleotides. Match oligonucleotides localized in close proximity to nuclear Cajal bodies in telomerase-positive cells. In comparison with Match oligonucleotides, 111In-Scramble or 111In-Mismatch oligonucleotides demonstrated reduced retention and negligible impact on cell survival. This study indicates the therapeutic activity of radiolabeled oligonucleotides that specifically target hTR through potent telomerase inhibition and DNA damage induction in telomerase-expressing cancer cells and paves the way for the development of novel oligonucleotide radiotherapeutics targeting telomerase-positive cancers. SIGNIFICANCE: These findings present a novel radiolabeled oligonucleotide for targeting telomerase-positive cancer cells that exhibits dual activity by simultaneously inhibiting telomerase and promoting radiation-induced genomic DNA damage.


A modeling study by response surface methodology and artificial neural network on culture parameters optimization for thermostable lipase production from a newly isolated thermophilic Geobacillus sp. strain ARM.
Thermostable bacterial lipases occupy a place of prominence among biocatalysts owing to their novel, multifold applications and resistance to high temperature and other operational conditions. The capability of lipases to catalyze a variety of novel reactions in both aqueous and nonaqueous media presents a fascinating field for research, creating interest to isolate novel lipase producers and optimize lipase production. The most important stages in a biological process are modeling and optimization to improve a system and increase the efficiency of the process without increasing the cost. Different production media were tested for lipase production by a newly isolated thermophilic Geobacillus sp. strain ARM (DSM 21496 = NCIMB 41583). The maximum production was obtained in the presence of peptone and yeast extract as organic nitrogen sources, olive oil as carbon source and lipase production inducer, sodium and calcium as metal ions, and gum arabic as emulsifier and lipase production inducer. The best models for optimization of culture parameters were achieved by multilayer full feedforward incremental back propagation network and modified response surface model using backward elimination, where the optimum condition was: growth temperature (52.3 degrees C), medium volume (50 ml), inoculum size (1%), agitation rate (static condition), incubation period (24 h) and initial pH (5.8). The experimental lipase activity was 0.47 Uml(-1) at optimum condition (4.7-fold increase), which compared well to the maximum predicted values by ANN (0.47 Uml(-1)) and RSM (0.476 Uml(-1)), whereas R2 and AAD were determined as 0.989 and 0.059% for ANN, and 0.95 and 0.078% for RSM respectively. Lipase production is the result of a synergistic combination of effective parameters interactions. These parameters are in equilibrium and the change of one parameter can be compensated by changes of other parameters to give the same results. Though both RSM and ANN models provided good quality predictions in this study, yet the ANN showed a clear superiority over RSM for both data fitting and estimation capabilities. On the other hand, ANN has the disadvantage of requiring large amounts of training data in comparison with RSM. This problem was solved by using statistical experimental design, to reduce the number of experiments.


Calmodulin structure refined at 1.7 A resolution.
We have determined and refined the crystal structure of a recombinant calmodulin at 1.7 A resolution. The structure was determined by molecular replacement, using the 2.2 A published native bovine brain structure as the starting model. The final crystallographic R-factor, using 14,469 reflections in the 10.0 to 1.7 A range with structure factors exceeding 0.5 sigma, is 0.216. Bond lengths and bond angle distances have root-mean-square deviations from ideal values of 0.009 A and 0.032 A, respectively. The final model consists of 1279 non-hydrogen atoms, including four calcium ions, 1130 protein atoms, including three Asp118 side-chain atoms in double conformation, 139 water molecules and one ethanol molecule. The electron densities for residues 1 to 4 and 148 of calmodulin are poorly defined, and not included in our model, except for main-chain atoms of residue 4. The calmodulin structure from our crystals is very similar to the earlier 2.2 A structure described by Babu and coworkers with a root-mean-square deviation of 0.36 A. Calmodulin remains a dumb-bell-shaped molecule, with similar lobes and connected by a central alpha-helix. Each lobe contains three alpha-helices and two Ca2+ binding EF hand loops, with a short antiparallel beta-sheet between adjacent EF hand loops and one non-EF hand loop. There are some differences in the structure of the central helix. The crystal packing is extensively studied, and facile crystal growth along the z-axis of the triclinic crystals is explained. Herein, we describe hydrogen bonding in the various secondary structure elements and hydration of calmodulin.


Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations.
Mutations in the PLA2G6 gene, which encodes group VIA calcium-independent phospholipase A2 (iPLA(2)beta), were recently identified in patients with infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation. A pathological hallmark of these childhood neurodegenerative diseases is the presence of distinctive spheroids in distal axons that contain accumulated membranes. We used iPLA(2)beta-KO mice generated by homologous recombination to investigate neurodegenerative consequences of PLA2G6 mutations. iPLA(2)beta-KO mice developed age-dependent neurological impairment that was evident in rotarod, balance, and climbing tests by 13 months of age. The primary abnormality underlying this neurological impairment was the formation of spheroids containing tubulovesicular membranes remarkably similar to human INAD. Spheroids were strongly labeled with anti-ubiquitin antibodies. Accumulation of ubiquitinated protein in spheroids was evident in some brain regions as early as 4 months of age, and the onset of motor impairment correlated with a dramatic increase in ubiquitin-positive spheroids throughout the neuropil in nearly all brain regions. Furthermore accumulating ubiquitinated proteins were observed primarily in insoluble fractions of brain tissue, implicating protein aggregation in this pathogenic process. These results indicate that loss of iPLA(2)beta causes age-dependent impairment of axonal membrane homeostasis and protein degradation pathways, leading to age-dependent neurological impairment. iPLA(2)beta-KO mice will be useful for further studies of pathogenesis and experimental interventions in INAD and neurodegeneration with brain iron accumulation.


Genome-wide association studies in multiple sclerosis: lessons and future prospects.
Multiple sclerosis (MS) is an inflammatory neurodegenerative disease with complex aetiology. A haplotype within the major histocompatibility region is the major risk factor for MS, but despite clear evidence for a genetic component additional risk variants were not identified until the recent advent of genome-wide association studies (GWAS). At present, 10 GWAS have been conducted in MS, and together with follow-up studies these have confirmed 16 loci with genome-wide significance. Many of these common risk variants are located at or near genes with central immunological functions and the majority are associated with other autoimmune diseases. However, evidence from pathway analyses on more modestly associated variants also supports the involvement of neurological genes. Although the mechanisms by which the associated variants exert their effects are still poorly understood, some have been shown to correlate with expression of nearby genes. Further studies are required to define the functionally relevant variants in the identified regions and to investigate their effects at the molecular and cellular level. Finally, many genetic risk variants for MS remain to be identified. In order to expose some of the loci with more modest effects, a GWAS in nearly 10,000 MS patients has recently been completed.


T-cell proliferative response to antigens secreted by Mycobacterium tuberculosis.
An infection model of human tuberculosis was established with C57BL/6J mice. The lymphocyte proliferative responses to antigens from Mycobacterium tuberculosis were investigated during the course of infection and compared with results obtained with a group of mice immunized with large amounts of killed bacteria. The two groups responded similarly to a number of mycobacterial antigens, but marked differences in responses against secreted antigens were found; only infected mice responded vigorously to these. The responding lymphocyte subpopulation was made up of L3T4+ T lymphocytes under restriction of the Ia molecule.


A new familial glomerulonephropathy in Bernese mountain dogs.
Between 1989 and 1992, 22 Bernese mountain dogs (18 females and four males) aged between two and seven years, which had been suffering for some weeks from weight loss, anorexia, apathy, vomiting, polydipsia and polyuria, were examined. All of them had high blood urea nitrogen and serum creatinine concentrations, and many had hyperphosphataemia, hypercholesterolaemia, hypoproteinaemia and nonregenerative anaemia. All the dogs had very high protein: creatinine ratios in the urine, and macroproteinuria was identified by sodium dodecyl sulphate gel electrophoresis. The immunofluorescent titres against Borrelia burgdorferi, measured in 19 of the dogs, ranged between 256 and 32,768. In all cases, membrano-proliferative glomerulonephritis with concomitant interstitial nephritis was diagnosed. From an analysis of the dogs' pedigree it was concluded that the glomerulonephritis of these Bernese mountain dogs was inherited as an autosomal recessive trait and that its expression was influenced by a second gene locus with a sex-linked dominance exchange.


Oral antifungal-exacerbated inflammatory flare-up reactions of dermatomycosis : case reports and review of the literature.
Inflammatory flare-up reactions of some dermatomycoses, particularly those caused by zoophilic fungi, are typical and potentially severe adverse effects following the intake of some oral antifungals. However, this condition has not previously been reported with the most frequently used antifungals in dermatology, namely fluconazole, itraconazole, and terbinafine. In this report, we describe five patients, observed over a 10-year period, who presented with inflammatory exacerbations following oral antifungal therapy for dermatomycoses. We also review the literature on inflammatory reactions exacerbated by oral antifungal agents. Details of the patients' age, sex, occupation, and atopic background; the site of the lesion, its clinical and histologic features, and any systemic signs; the identity of the fungal pathogen; the antifungal agent taken by the patient; the time between drug intake and occurrence of the flare-up; the approach to management; and the outcome were documented for each patient. A PubMed literature search was also conducted, focusing on inflammatory exacerbations induced by griseofulvin, ketoconazole, itraconazole, fluconazole, and terbinafine. The patients were four farmers and one veterinarian (all male). All primary lesions were inflammatory dermatophytoses, including one kerion. Inflammatory exacerbation of the skin lesions started 12-24 hours after the intake of oral antifungals. Mild systemic changes, including slight fever and malaise, occurred in two cases. Itraconazole 400 mg/day was implicated as the causative agent in four cases and terbinafine 250 mg/day in one case. Mycologic cultures grew Trichophytonverrucosum in four cases. Antifungal treatment was discontinued in all patients. Oral and topical corticosteroids were administered to the two patients with systemic changes; the other three patients were treated with topical corticosteroids only. Two days after the onset of corticosteroids, lower doses of itraconazole (100 mg/day) and terbinafine (125 mg/day) were reintroduced. All lesions healed after 4-5 weeks. The PubMed search did not identify any articles that described inflammatory exacerbations of dermatomycoses induced by oral antifungals. Inflammatory flare-up of dermatomycoses is a rare but potentially severe cutaneous complication of oral antifungal use. Occupational contact with animals, inflammatory dermatomycoses, and zoophilic fungi represent common features in these patients. Although evidence-based data are not available, clinical experience shows that, in addition to antifungal therapy, topical and/or systemic corticosteroids are helpful to reduce the inflammatory reactions. The cases described in this article represent the first published report of oral antifungal-exacerbated inflammatory flare-up reactions of dermatomycosis in patients taking itraconazole or terbinafine.


Reduced dynamic functional connectivity between salience and executive brain networks in insomnia disorder.
Research into insomnia disorder has pointed to large-scale brain network dysfunctions. Dynamic functional connectivity is instrumental to cognitive functions but has not been investigated in insomnia disorder. This study assessed between-network functional connectivity strength and variability in patients with insomnia disorder as compared with matched controls without sleep complaints. Twelve-minute resting-state functional magnetic resonance images and T1-weighed images were acquired in 65 people diagnosed with insomnia disorder (21-69 years, 48 female) and 65 matched controls without sleep complaints (22-70 years, 42 female). Pairwise correlations between the activity time series of 14 resting-state networks and temporal variability of the correlations were compared between cases and controls. After false discovery rate correction for multiple comparisons, people with insomnia disorder and controls did not differ significantly in terms of mean between-network functional connectivity strength; people with insomnia disorder did, however, show less functional connectivity variability between the anterior salience network and the left executive-control network. The finding suggests less flexible interactions between the networks during the resting state in people with insomnia disorder.


Hyperventilation in patients with recurrent functional symptoms.
In view of the similarity between the reported effects of hyperventilation and recurrent functional symptom presented in primary care, a study was undertaken to establish whether such symptoms are attributable to hyperventilation. Twenty patients with two or more recurrent functional symptoms which their doctors found difficult to diagnose or treat, and 30 controls, were studied using symptom questionnaires and a series of hyperventilation provocation tests during which the partial pressure of carbon dioxide (PCO2) and symptoms were recorded. Sixteen cases (80%) had unexplained breathlessness compared with two of the controls (7%). All of the cases recognized familiar functional symptoms during provoked hyperventilation, and in 16 (80%), these included primary physical symptoms; only 23% of the controls recognized any previously experienced symptom. Considerable overlap of PCO2 values between groups meant that absolute values of PCO2 were not useful in differentiating between groups, but cases were more likely than controls to have a PCO2 of less than 4 kPa at rest, three minutes after hyperventilation, or during mental stress (75% of cases fulfilled one or more of these criteria versus 40% of controls). This is the first study in primary care to examine the effect of hyperventilation in a group of patients with multiple somatic symptoms. The findings have implications for the recognition and management of such patients.


Sensitization of head and neck cancer to cisplatin through the use of a novel curcumin analog.
To determine whether a novel small molecule inhibitor derived from curcumin (FLLL32) that targets signal transducer and activator of transcription (STAT) 3 would induce cytotoxic effects in STAT3-dependent head and neck squamous cell cancer (HNSCC) cells and would sensitize tumors to cisplatin. Basic science. Two HNSCC cell lines, UM-SCC-29 and UM-SCC-74B, were characterized for cisplatin [cis-diammineplatinum(II) dichloride] sensitivity. Baseline expression of STAT3 and other apoptosis proteins was determined. The FLLL32 50% inhibitory concentration (IC(50)) dose was determined for each cell line, and the effect of FLLL32 treatment on the expression of phosphorylated STAT3 and other key proteins was elucidated. The antitumor efficacy of cisplatin, FLLL32, and combination treatment was measured. The proportion of apoptotic cells after cisplatin, FLLL32, or combination therapy was determined. The UM-SCC-29 cell line is cisplatin resistant, and the UM-SCC-74B cell line is cisplatin sensitive. Both cell lines express STAT3, phosphorylated STAT3 (pSTAT3), and key apoptotic proteins. FLLL32 downregulates the active form of STAT3, pSTAT3, in HNSCC cells and induces a potent antitumor effect. FLLL32, alone or with cisplatin, increases the proportion of apoptotic cells. FLLL32 sensitized cisplatin-resistant cancer cells, achieving an equivalent tumor kill with a 4-fold lower dose of cisplatin. FLLL32 monotherapy induces a potent antitumor effect and sensitizes cancer cells to cisplatin, permitting an equivalent or improved antitumor effect at lower doses of cisplatin. Our results suggest that FLLL32 acts by inhibiting STAT3 phosphorylation, reduced survival signaling, increased susceptibility to apoptosis, and sensitization to cisplatin.


Lung volumes after antigen infusion in the guinea pig in vivo: effects of vagal section.
The effects of intravenous antigen infusion on lung volumes and quasi-static deflationary pulmonary compliance in guinea pigs previously sensitized to ovalbumin were studied in vivo. Ovalbumin infusion significantly increased minimal gas volume to a similar extent in animals with intact or cut vagi. Total lung capacity fell only in animals with intact vagi. Quasi-static compliance fell in both groups of animals, but the fall was significantly greater in animals with intact vagi. These data demonstrate that immediate hypersensitivity reactions alter lung volumes and the elastic properties of the lung by both vagal dependent and vagal independent mechanisms.


The quantitation of Trypanosoma congolense in calves. 1. Hematological changes.
Anemia due to Trypanosoma congolense infection in neonatal and 6-month-old calves was hemolytic and moderately responsive. The red cells were macrocytic and normochromic in both groups of calves and the anemia was milder in infected neonatal calves compared to the 6-month-old calves. The neonatal calves maintained normal white blood cell counts and developed a lymphocytosis at two weeks of infection. The six-month-old calves developed mild neutropenic leukopenia at one week post-infection without lymphocytosis. Plasma iron turnover rates were not different between infected and control calves in either age group at the second week of infection but both groups of infected calves had higher turnover rates at the sixth week of infection. The mean percent of radioiron uptake into peripheral blood red cells was similar in the controls and infected calves, but the rate of appearance of labelled red cells in the peripheral blood was more rapid in the infected calves. Radioiron uptake was depressed in the infected six-month-old calves during second week of infection but not in the sixth week. Apparent plasma volumes were increased in both groups of calves at both time periods.


Ultrasonography as a complementary diagnostic method for evaluating the skin of healthy cats.
Ultrasonography is not often used in feline dermatology. The purpose of this study was to assess the usefulness and applicability of ultrasonography for skin evaluation in 21 clinically healthy cats. Ultrasonographic examination was conducted in 4 cutaneous regions (frontal, dorsal neck, sacral, and abdominal) using an 18-MHz linear-sequential-array transducer. Findings were assessed using histomorphometric analysis of skin samples set as reference standards. Morphologic evaluation, thickness measurements, measurement variability, and comparison between regions and genders were carried out. The ultrasonographic pattern of feline skin was characterized by 3 distinct layers of different echogenicity and echostructure. Skin was thickest at the dorsal neck region and thinnest at the abdominal region. Skin at the frontal region and dorsal neck region was thicker in males. Variability was < 10% in all regions. No apparent correspondence was found between ultrasonographic and histometric measurements of skin thickness. Collectively, these findings suggest that ultrasonography is a simple, noninvasive, and reproducible technique that allows cutaneous layers to be identified and accurately measures skin thickness in cats.


Predental students' attitudes toward and perceptions of the dental profession.
The purpose of this study was to assess reasons students seek a career in dentistry, their perceptions of the dental school admissions process, and their expectations of the profession. Of 155 predental students participating in a dental school simulation course offered at a Nevada dental school, 152 participated in this study (68.4 percent [n=104] male, and 31.6 percent [n=48] female). When asked when they made the decision to pursue a career in dentistry, 52 percent (n=79) said they decided in college, while 33.6 percent (n=51) made the decision in high school. A slight majority of the respondents (52.6 percent; n=80) identified their family dentist as having the greatest influence in their decision. Nearly half (47.8 percent; n=64) expected to pursue a career in general dentistry, while the next largest subgroup expected to pursue orthodontics (16.4 percent; n=22). A significant majority of the respondents (72.8 percent; n=110) perceived the dental school admissions process to be fair. Males were significantly more likely to identify themselves as competitive applicants than did females (chi(2)=9.644; p<.01). Approximately half (47.4 percent; n=72) anticipate earning between $100,000 and $199,999 within five years after graduation, with 50.7 percent (n=77) anticipating working between thirty-five and forty hours a week. By understanding the applicant pool and their perceptions, admissions committees can better prepare to attract the applicants they desire.


Comparison of laparoscopic-guided abomasopexy versus omentopexy via right flank laparotomy for the treatment of left abomasal displacement in dairy cows.
To compare results obtained by use of laparoscopyassisted abomasopexy versus omentopexy via right flank laparotomy for the treatment of dairy cows with left displaced abomasum (LDA). 120 dairy cows with an LDA. In a prospective clinical trial, cows were randomly allocated to the abomasopexy group (laparoscopy-assisted abomasopexy) or to the control group (omentopexy via right flank). Data were obtained during the first 5 days after surgery and 6 weeks and 6 months after surgery. 59 of 60 cows in the abomasopexy group and all 60 cows in the control group were treated successfully. Median duration was shorter for the laparoscopic procedure (27.5 minutes), compared with that for the control group (38 minutes). Five cows in the abomasopexy group had wound complications and 2 had LDA relapses, compared with 2 wound complications and no relapses in the control group. During the 5 days after surgery, the abomasopexy group had a significantly higher increase in rate of energy intake and milk yield and a more rapid return to reference range for serum glutamic dehydrogenase activity and total bilirubin concentration, compared with results for the control group. Success rates were almost equal for both methods. Advantages of the laparoscopic abomasopexy procedure include practicality, low risk of complications, and rapid postoperative recovery. Contraindications are cardiopulmonary diseases. Other disadvantages include the cost of the instruments and inability to perform the procedure in cows with abomasal adhesions.


An algorithm recommendation for the management of knee osteoarthritis in Europe and internationally: a report from a task force of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).
Existing practice guidelines for osteoarthritis (OA) analyze the evidence behind each proposed treatment but do not prioritize the interventions in a given sequence. The objective was to develop a treatment algorithm recommendation that is easier to interpret for the prescribing physician based on the available evidence and that is applicable in Europe and internationally. The knee was used as the model OA joint. ESCEO assembled a task force of 13 international experts (rheumatologists, clinical epidemiologists, and clinical scientists). Existing guidelines were reviewed; all interventions listed and recent evidence were retrieved using established databases. A first schematic flow chart with treatment prioritization was discussed in a 1-day meeting and shaped to the treatment algorithm. Fine-tuning occurred by electronic communication and three consultation rounds until consensus. Basic principles consist of the need for a combined pharmacological and non-pharmacological treatment with a core set of initial measures, including information access/education, weight loss if overweight, and an appropriate exercise program. Four multimodal steps are then established. Step 1 consists of background therapy, either non-pharmacological (referral to a physical therapist for re-alignment treatment if needed and sequential introduction of further physical interventions initially and at any time thereafter) or pharmacological. The latter consists of chronic Symptomatic Slow-Acting Drugs for OA (e.g., prescription glucosamine sulfate and/or chondroitin sulfate) with paracetamol at-need; topical NSAIDs are added in the still symptomatic patient. Step 2 consists of the advanced pharmacological management in the persistent symptomatic patient and is centered on the use of oral COX-2 selective or non-selective NSAIDs, chosen based on concomitant risk factors, with intra-articular corticosteroids or hyaluronate for further symptom relief if insufficient. In Step 3, the last pharmacological attempts before surgery are represented by weak opioids and other central analgesics. Finally, Step 4 consists of end-stage disease management and surgery, with classical opioids as a difficult-to-manage alternative when surgery is contraindicated. The proposed treatment algorithm may represent a new framework for the development of future guidelines for the management of OA, more easily accessible to physicians.


An unusual ryanodine receptor 1 (RYR1) phenotype: Mild calf-predominant myopathy.
To identify the genetic defect causing a distal calf myopathy with cores. Families with a genetically undetermined calf-predominant myopathy underwent detailed clinical evaluation, including EMG/nerve conduction studies, muscle biopsy, laboratory investigations, and muscle MRI. Next-generation sequencing and targeted Sanger sequencing were used to identify the causative genetic defect in each family. A novel deletion-insertion mutation in ryanodine receptor 1 (RYR1) was found in the proband of the index family and segregated with the disease in 6 affected relatives. Subsequently, we found 2 more families with a similar calf-predominant myopathy segregating with unique RYR1-mutated alleles. All patients showed a very slowly progressive myopathy without episodes of malignant hyperthermia or rhabdomyolysis. Muscle biopsy showed cores or core-like changes in all families. Our findings expand the spectrum of RYR1-related disorders to include a calf-predominant myopathy with core pathology and autosomal dominant inheritance. Two families had unique and previously unreported RYR1 mutations, while affected persons in the third family carried 2 previously known mutations in the same dominant allele.


Salivary gland enlargement and sialorrhoea in dogs with spirocercosis: a retrospective and prospective study of 298 cases.
This longitudinal cross-sectional clinical study investigated the incidence of sialorrhoea in dogs with spirocercosis and determined whether breed, body weight and the extent of the oesophageal involvement was associated with this presentation. A retrospective analysis was performed on the medical records of 233 dogs and information pertaining to 65 dogs was collected as part of a prospective study. All the animals were client-owned. Patients from the retrospective study underwent thoracic radiography or oesophageal endoscopy to diagnose and characterise the infection and were placed on therapy with a macrocyclic lactone, whereas the patients in the prospective study had both radiography and endoscopy routinely performed and biopsies of the oesophageal nodules collected where possible. Tru-cut biopsies of affected salivary glands were taken in 10 of 13 patients demonstrating clinical signs of sialorrhoea and salivary gland enlargement. The entire salivary gland was sectioned in an additional three dogs with spirocercosis and no sialorrhoea that were presented for post mortem examination. Sialorrhoea was present in 33/298 cases (11%). Fox terrier breeds were over-represented in the patients with sialorrhoea, comprising 36% of cases, whereas they only comprised 1.5% of the patients without sialorrhoea (p < 0.001, chi squared test) and 5% of the combined group. Dogs weighing 12 kg or less were significantly over-represented in the sialorrhoea group, 69% versus 19.5% (p < 0.001, chi square test). Age was not significantly different between the two groups (p < 0.08, Mann-Whitney test). The number of oesophageal nodules per case was significantly higher in the non-sialorrhoea cases (p = 0.048, Mann-Whitney test). The prevalence of distal oesophageal and lower oesophageal sphincter involvement, and neoplastic transformation of the nodules were not statistically different between the two groups. None of the fox terriers in either group showed neoplastic transformation of the parasitic nodules even though they were over-represented as a breed. Mandibular salivary glands were affected in 86% of cases showing sialorrhoea. Histopathology revealed acinar hyperplasia in all cases with concurrent necrosis detected in only two cases.Sialorrhoea and salivary gland enlargement has an incidence of 11% (33/298 cases) in canine spirocercosis. Small breeds (≤ 12 kg) and particularly fox terrier breeds are over-represented in the group demonstrating sialorrhoea and this appeared to be the only risk factor.The conclusion was that sialorrhoea secondary to canine spirocercosis occurs frequently and its presence should prompt further investigation for oesophageal and gastro-intestinal disease. Severely affected patients can be managed with phenobarbitone to control the dysphagia in addition to the routine macrocyclic lactones treatment.


Medicare Advantage's private fee-for-service plans: paying for coordinated care without the coordination.
Like the private managed care plans offered under Medicare Advantage, private fee-for-service (PFFS) plans are paid more per beneficiary than those individuals would be expected to cost if they were enrolled in traditional fee-for-service Medicare. However, PFFS plans are not required to provide the same type of coordinated care required of Medicare Advantage plans. Payments to PFFS plans in 2008 average 16.6 percent more than costs in traditional Medicare, or $1,248 for each of the 2 million enrollees in PFFS plans-a total of nearly $2.5 billion in extra payments. Recently, Congress has made significant revisions to policies that will affect how PFFS plans will operate in 2011 and thereafter, as well as their prospects for continued growth. This issue brief examines the development of PFFS plans, the policies underlying the rapid increase in the plans and their enrollment, the payments they receive, and the potential impact of the new legislation.


Prevalence of a vertically transmitted single-stranded DNA virus in spinybacked orbweavers (Gasteracantha cancriformis) from Florida, USA.
Spiders (order Araneae, class Arachnida) are an important group of predatory arthropods in terrestrial ecosystems that have been recently identified as an untapped reservoir of single-stranded (ss)DNA viruses. Specifically, spiders harbour a diversity of ssDNA viruses encoding a replication-associated protein (Rep) within a circular genome. However, little is known about the ecology of novel circular Rep-encoding ssDNA (CRESS DNA) viruses. Here we investigated two CRESS DNA viruses recently identified in spinybacked orbweavers (Gasteracantha cancriformis), namely spinybacked orbweaver circular virus (SpOrbCV) 1 and 2. SpOrbCV-1 was detected in the majority (> 65 %) of spider specimens from all life stages, including eggs, spiderlings and adults, demonstrating that this virus is active within spinybacked orbweavers. In contrast, SpOrbCV-2 was only detected in adults at a lower (36 %) prevalence. Since we also detected SpOrbCV-2 in other spider species and this virus has been reported from a dragonfly, we suggest that SpOrbCV-2 is accumulated in these predators through common insect prey. The prevalence of SpOrbCV-1 in collected specimens allowed us to design assays to characterize this virus, which represents a new group of CRESS DNA viruses, the 'circularisviruses'. To our knowledge, SpOrbCV-1 is the first example of a vertically transmitted virus in spiders, which may explain its high prevalence in spinybacked orbweavers. Since vertically transmitted viruses infecting insects (class Insecta) can manipulate their host's behaviour and physiology, future studies should investigate the ecological role of vertically transmitted viruses in spiders.


Refractive index measurement of acute rat brain tissue slices using optical coherence tomography.
An optical coherence tomography (OCT) system employing a microelectromechanical system (MEMS) mirror was used to measure the refractive index (RI) of anatomically different regions in acute brain tissue slices, in which viability was maintained. RI was measured in white-matter and grey-matter regions, including the cerebral cortex, putamen, hippocampus, thalamus and corpus callosum. The RI in the corpus callosum was found to be ~4% higher than the RIs in other regions. Changes in RI with tissue deformation were also measured in the cerebral cortex and corpus callosum under uniform compression (20-80% strain). For 80% strain, measured RIs increased nonlinearly by up to 70% and 90% in the cerebral cortex and corpus callosum respectively. Knowledge of RI in heterogeneous tissues can be used to correct distorted optical images caused by RI variations between different regions. Also deformation-dependent changes in RI can be applied to OCT elastography or to mechanical tests based on optical imaging such as indentation tests.


Physics, Astrophysics and Cosmology with Gravitational Waves.
Gravitational wave detectors are already operating at interesting sensitivity levels, and they have an upgrade path that should result in secure detections by 2014. We review the physics of gravitational waves, how they interact with detectors (bars and interferometers), and how these detectors operate. We study the most likely sources of gravitational waves and review the data analysis methods that are used to extract their signals from detector noise. Then we consider the consequences of gravitational wave detections and observations for physics, astrophysics, and cosmology.


The occurrence of cardiac abnormalities in canine steroid-responsive meningitis arteritis.
To document the prevalence of cardiac abnormalities in dogs with steroid-responsive meningitis arteritis and to assess resolution of these abnormalities following corticosteroid therapy. Steroid-responsive meningitis arteritis was diagnosed based on signalment, physical examination findings, complete blood count, biochemistry and CSF analysis. Echocardiography, C-reactive protein and cardiac troponin I were measured in all cases before and 10 to 14 days after commencing corticosteroid therapy. Fibrinogen was also measured in a proportion of dogs. Fourteen dogs were prospectively enrolled. Increased cardiac troponin I was identified in five of 14 dogs and echocardiographic abnormalities were detected in 12 of 14 dogs, including spontaneous echo contrast (12 of 14), mild pericardial effusion (five of 14) and mildly decreased fractional shortening (five of 14). All dogs had increased C-reactive protein and fibrinogen was increased in 11 of 12. Corticosteroid treatment was associated with clinical improvement and normalisation of C-reactive protein in all dogs. The cardiac troponin I levels normalised in four of five and fibrinogen had normalised in all five dogs which were retested. Spontaneous echo contrast improved or completely resolved in 12 of 12 and pericardial effusion resolved in five of five dogs. Fractional shortening normalised in two of five dogs. Cardiac changes are common in dogs with steroid-responsive meningitis arteritis and most resolve with therapy. Further investigation into the cause and significance of these changes is necessary in determining whether antithrombotic therapy or positive inotropic therapy is indicated.


Modified phase-generated carrier demodulation compensated for the propagation delay of the fiber.
In general applications, the output signals of the fiber-optic interferometric sensor (FOIS) need some demodulation techniques to linearly demodulate the sensing phase signal. The common signal demodulation circuit of the FOIS is passive homodyne demodulation using phase-generated carrier [(PGC) demodulation]. Preliminary analysis of the research demonstrates that a variation in the output demodulated signal is related to the length of the fiber, and the output demodulated signal will approach zero at some certain lengths of the fiber. To improve the performance of the FOIS, it is necessary to develop the modified PGC demodulation to compensate for the propagation delay of the fiber.


Cortical blindness after contrast-enhanced CT scan in a patient of sarcoidosis - Is it related to posterior reversible encephalopathy syndrome?
Transient cortical blindness (TCB) is a well known but rare complication of administration of contrast agent. In this case report, we present a 53-year-old woman who is a follow-up case of sarcoidosis and developed TCB with focal neurological symptoms following contrast-enhanced computed tomography scan. Magnetic resonance imaging revealed bilateral T2/Flair hyperintensities in parieto-occipital, high frontal, and cerebellar hemispheres with involvement of corpus callosum. Clinically and radiologically patient improved significantly in 4 days. The exact mechanism is still speculative and its possible relationship with posterior reversible encephalopathy syndrome is briefly discussed. The patient's symptoms were presumed to be exacerbated by presence of hypertension, underlying autoimmune disorder, sepsis, and high osmolality of contrast agent. Though there is no definite evidence to suggest that a certain treatment regimen improves the natural history of this disease but control of risk factors can possibly prevent this rare but devastating complication.


Handling preference heterogeneity for river services' adaptation to climate change.
Climate projection models for the Southern Mediterranean basin indicate a strong drought trend. This pattern is anticipated to affect a range of services derived from river ecosystems and consecutively deteriorate the sectoral outputs and household welfare. This paper aims to evaluate local residents' adaptation preferences for the Piave River basin in Italy. A Discrete Choice Experiment accounting for adaptation scenarios of the Piave River services was conducted and the collected data were econometrically analyzed using Random Parameters Logit, Latent Class and Covariance Heterogeneity models. In terms of policy-relevant outcomes, the analysis indicates that respondents are willing to pay for adaptation plans. This attitude is reflected on the compensating surplus to sustain the current state of the Piave, which corresponds to a monthly contribution of 80€ per household. From an econometric point of view, the results show that it is not sufficient to take solely into account general heterogeneity, provided that distinct treatment of the heterogeneity produces rather different welfare estimates. This implies that analysts should examine a set of criteria when deciding on how to better approach heterogeneity for each empirical data set. Overall, non-market values of environmental services should be considered when formulating cost-effective adaptation measures for river systems undergoing climate change effects and appropriate heterogeneity approximation could render these values unbiased and accurate.


Cell cycle activation contributes to isoflurane-induced neurotoxicity in the developing brain and the protective effect of CR8.
It is well established that exposure of common anesthetic isoflurane in early life can induce neuronal apoptosis and long-lasting cognitive deficit, but the underlying mechanisms were not well understood. The cell cycle protein Cyclin B1 plays an important role in the survival of postmitotic neurons. In the present study, we investigated whether cyclin B1-mediated cell cycle activation pathway is a contributing factor in developmental isoflurane neurotoxicity. Postnatal day 7 mice were exposed to 1.2% isoflurane for 6 hours. CR8 (a selective inhibitor of cyclin-dependent kinases) was applied before isoflurane treatment. Brain samples were collected 6 hours after discontinuation of isoflurane, for determination of neurodegenerative biomarkers and cell cycle biomarkers. We found that isoflurane exposure leads to upregulated expression of cell cycle-related biomarkers Cyclin B1, Phospho-CDK1(Thr-161), Phospho-n-myc and downregulated Phospho-CDK1 (Tyr-15). In addition, isoflurane induced increase in Bcl-xL phosphorylation, cytochrome c release, and caspase-3 activation that resulted in neuronal cell death. Systemic administration of CR8 attenuated isoflurane-induced cell cycle activation and neurodegeneration. These findings suggest the role of cell cycle activation to be a pathophysiological mechanism for isoflurane-induced apoptotic cell death and that treatment with cell cycle inhibitors may provide a possible therapeutic target for prevention of developmental anesthetic neurotoxicity.


Watching pornography: gender differences, violence and victimization. An exploratory study in Italy.
The aims of this article are to analyze exposure to pornography, its content, and the associations between victimization and pornography in a sample of 303 students (49.2% female). The questionnaire included questions on pornography exposure, psychological and physical family violence, and sexual violence. Almost all male students and 67% of female students had ever watched pornography; 42% and 32%, respectively, had watched violence against women. Female students exposed to family psychological violence and to sexual violence were significantly more likely to watch pornography, especially violent pornography than those who had not been exposed. No such association was found among male students.


Distribution of protein poly(ADP-ribosyl)ation systems across all domains of life.
Poly(ADP-ribosyl)ation is a post-translational modification of proteins involved in regulation of many cellular pathways. Poly(ADP-ribose) (PAR) consists of chains of repeating ADP-ribose nucleotide units and is synthesized by the family of enzymes called poly(ADP-ribose) polymerases (PARPs). This modification can be removed by the hydrolytic action of poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3 (ARH3). Hydrolytic activity of macrodomain proteins (MacroD1, MacroD2 and TARG1) is responsible for the removal of terminal ADP-ribose unit and for complete reversion of protein ADP-ribosylation. Poly(ADP-ribosyl)ation is widely utilized in eukaryotes and PARPs are present in representatives from all six major eukaryotic supergroups, with only a small number of eukaryotic species that do not possess PARP genes. The last common ancestor of all eukaryotes possessed at least five types of PARP proteins that include both mono and poly(ADP-ribosyl) transferases. Distribution of PARGs strictly follows the distribution of PARP proteins in eukaryotic species. At least one of the macrodomain proteins that hydrolyse terminal ADP-ribose is also always present. Therefore, we can presume that the last common ancestor of all eukaryotes possessed a fully functional and reversible PAR metabolism and that PAR signalling provided the conditions essential for survival of the ancestral eukaryote in its ancient environment. PARP proteins are far less prevalent in bacteria and were probably gained through horizontal gene transfer. Only eleven bacterial species possess all proteins essential for a functional PAR metabolism, although it is not known whether PAR metabolism is truly functional in bacteria. Several dsDNA viruses also possess PARP homologues, while no PARP proteins have been identified in any archaeal genome. Our analysis of the distribution of enzymes involved in PAR metabolism provides insight into the evolution of these important signalling systems, as well as providing the basis for selection of the appropriate genetic model organisms to study the physiology of the specific human PARP proteins.


The requirement for Vif of SIVmac is cell-type dependent.
The vif gene (viral infectivity factor) of the human and simian immunodeficiency viruses (HIV and SIV) is present in almost all members of the lentivirus group of retroviruses. This gene is highly conserved among different HIV and SIV isolates and is therefore presumed to play an important role in pathogenesis. To analyse the role of Vif in SIV, three SIVmac mutants have been constructed by introducing site-specific mutations or deletions into vif of the pathogenic molecular clone SIVmac239. The effect of Vif on viral replication in T cells was examined by transfecting equal amounts of either vif-positive or vif-negative viral DNA into SupT1, CEM-SS and H9 cells. Reverse transcriptase assay of supernatants from transfected cultures revealed that both SupT1 and CEM-SS cell lines supported replication of all three vif mutants to a level comparable to the parental vif-positive virus, whereas vif mutants did not replicate in H9 cells. Our results demonstrate that the requirement for Vif in SIVmac replication is cell-type dependent and that sequences near both the N and C termini are required for its function. Vif-defective SIVmac239, produced in transfected SupT1 and CEM-SS cells, failed to infect primary T lymphocytes, whereas both vif-positive and vif-defective viruses established productive infection in CEMx174 cells. These findings in primary cells suggest that Vif plays an important role in viral replication in vivo.


Trophic complexity enhances ecosystem functioning in an aquatic detritus-based model system.
1. Understanding the functional significance of species interactions in ecosystems has become a major challenge as biodiversity declines rapidly worldwide. Ecosystem consequences arising from the loss of diversity either within trophic levels (horizontal diversity) or across trophic levels (vertical diversity) are well documented. However, simultaneous losses of species at different trophic levels may also result in interactive effects, with potentially complex outcomes for ecosystem functioning. 2. Because of logistical constraints, the outcomes of such interactions have been difficult to assess in experiments involving large metazoan species. Here, we take advantage of a detritus-based model system to experimentally assess the consequences of biodiversity change within both horizontal and vertical food-web components on leaf-litter decomposition, a fundamental process in a wide range of ecosystems. 3. Our concurrent manipulation of fungal decomposer diversity (0, 1 or 5 species), detritivore diversity (0, 1 or 3 species), and the presence of predatory fish scent showed that trophic complexity is key to eliciting diversity effects on ecosystem functioning. Specifically, although fungi and detritivores tended to promote decomposition individually, rates were highest in the most complete community where all trophic levels were represented at the highest possible species richness. In part, the effects were trait-mediated, reflected in the contrasting foraging responses of the detritivore species to predator scent. 4. Our results thus highlight the importance of interactive effects of simultaneous species loss within multiple trophic levels on ecosystem functioning. If a common phenomenon, this outcome suggests that functional ecosystem impairment resulting from widespread biodiversity loss could be more severe than inferred from previous experiments confined to varying diversity within single trophic levels.


Association Between Pioglitazone Use and Prostate Cancer: A Population-Based Case-Control Study in the Han Population.
To date, few epidemiologic studies have investigated the relationship between pioglitazone use and prostate cancer. The available studies show conflicting findings. This case-control study explored the association between prior pioglitazone usage and prostate cancer using a large, population-based data set. Data were derived from the Longitudinal Health Insurance Database 2005 in Taiwan, a population-based sample of National Health Insurance enrollees with longitudinal claims data since 1995. Cases were 3513 patients with prostate cancer aged over 40 years, and the controls were 3513 patients without prostate cancer, matched with prostate cancer cases on age, and having a medical care utilization episode in the year of the index prostate cancer (1 control per case). We performed conditional logistic regression to examine the odds ratio and 95% confidence intervals for prior pioglitazone use between cases and controls. Analysis showed that 178 of the total sample patients (2.53%) had used pioglitazone prior to the index date. Prior pioglitazone use was found in 72 (2.05%) cases and 106 (3.02%) controls. The crude odds ratio of prior pioglitazone usage for cases was 0.67 (95% confidence interval, 0.50-0.91) compared to controls. After adjusting for demographic characteristics and comorbidities, the negative association of prior pioglitazone with prostate cancer persisted (adjusted odds ratio, 0.59; 95% confidence interval, 0.43-0.80). We concluded that there was an inverse association between prior pioglitazone usage and prostate cancer in this study.


Resistant starches protect against colonic DNA damage and alter microbiota and gene expression in rats fed a Western diet.
Resistant starch (RS), fed as high amylose maize starch (HAMS) or butyrylated HAMS (HAMSB), opposes dietary protein-induced colonocyte DNA damage in rats. In this study, rats were fed Western-type diets moderate in fat (19%) and protein (20%) containing digestible starches [low amylose maize starch (LAMS) or low amylose whole wheat (LAW)] or RS [HAMS, HAMSB, or a whole high amylose wheat (HAW) generated by RNA interference] for 11 wk (n = 10/group). A control diet included 7% fat, 13% protein, and LAMS. Colonocyte DNA single-strand breaks (SSB) were significantly higher (by 70%) in rats fed the Western diet containing LAMS relative to controls. Dietary HAW, HAMS, and HAMSB opposed this effect while raising digesta levels of SCFA and lowering ammonia and phenol levels. SSB correlated inversely with total large bowel SCFA, including colonic butyrate concentration (R(2) = 0.40; P = 0.009), and positively with colonic ammonia concentration (R(2) = 0.40; P = 0.014). Analysis of gut microbiota populations using a phylogenetic microarray revealed profiles that fell into 3 distinct groups: control and LAMS; HAMS and HAMSB; and LAW and HAW. The expression of colonic genes associated with the maintenance of genomic integrity (notably Mdm2, Top1, Msh3, Ung, Rere, Cebpa, Gmnn, and Parg) was altered and varied with RS source. HAW is as effective as HAMS and HAMSB in opposing diet-induced colonic DNA damage in rats, but their effects on the large bowel microbiota and colonocyte gene expression differ, possibly due to the presence of other fiber components in HAW.


Personally relevant intrusions outside the laboratory: long-term suppression increases intrusion.
It has been suggested that the suppression of unwanted thoughts may increase their frequency and that this effect may contribute to some psychological problems. Previous studies have examined this over a period of minutes, in an artificial setting. Suppression over a four day period was evaluated in the present study. Each S was asked to identify a negative intrusive thought which he or she experienced and to record each occurrence of it in conditions designed to maximise the similarity to those experienced by obsessional patients. Ss were randomly allocated to one of three groups. One group was asked to suppress their thoughts whenever they occurred, another group was asked to think about their thoughts whenever they occurred and the third group just recorded the thoughts whenever they occurred. This design allowed experimental control of both attention to and manipulation of the target thoughts in contrast to attention and active suppression. It was found that Ss who suppressed their thoughts experienced more thoughts and found them more uncomfortable than Ss in the other two groups. This is consistent with the theory that suppression increases thought frequency and may be important in the development and maintenance of some disorders.


Critical skin cancer in organ transplant recipients--a dermatopathological view.
Organ transplant recipients (OTR) are at significantly increased risk to develop a wide variety of skin cancers, particularly epithelial skin cancer, Merkel cell carcinoma and Kaposi's sarcoma. In addition, melanoma, skin adnexal neoplasm and cutaneous lymphomas are more common in OTR and may differ in their clinicopathological presentation from tumors in immunocompetent patients. The accuracy of clinical diagnosis of suspected premalignant and malignant skin lesions in OTR is modest. Therefore, histopathological diagnosis is an essential element for the diagnostic workup of skin cancers, and additionally provides important information on prognosis. This review discusses the histopathological aspects of skin cancers in OTR, the impact of dermatopathological analysis on prognosis and understanding of the pathogenesis of these neoplasms.


Developmental origins of pregnancy loss in the adult female common marmoset monkey (Callithrix jacchus).
The impact of the intrauterine environment on the developmental programming of adult female reproductive success is still poorly understood and potentially underestimated. Litter size variation in a nonhuman primate, the common marmoset monkey (Callithrix jacchus), allows us to model the effects of varying intrauterine environments (e.g. nutrient restriction, exposure to male womb-mates) on the risk of losing fetuses in adulthood. Our previous work has characterized the fetuses of triplet pregnancies as experiencing intrauterine nutritional restriction. We used over a decade of demographic data from the Southwest National Primate Research Center common marmoset colony. We evaluated differences between twin and triplet females in the number of pregnancies they produce and the proportion of those pregnancies that ended in fetal loss. We found that triplet females produced the same number of total offspring as twin females, but lost offspring during pregnancy at a significantly higher rate than did twins (38% vs. 13%, p = 0.02). Regardless of their own birth weight or the sex ratio of the litter the experienced as fetuses, triplet females lost more fetuses than did twins. Females with a male littermate experienced a significant increase in the proportion of stillbirths. These striking findings anchor pregnancy loss in the mother's own fetal environment and development, underscoring a "Womb to Womb" view of the lifecourse and the intergenerational consequences of development. This has important translational implications for understanding the large proportion of human stillbirths that are unexplained. Our findings provide strong evidence that a full understanding of mammalian life history and reproductive biology requires a developmental foundation.


Bone strength is maintained after 8 months of inactivity in hibernating golden-mantled ground squirrels, Spermophilus lateralis.
Prolonged inactivity leads to disuse atrophy, a loss of muscle and bone mass. Hibernating mammals are inactive for 6-9 months per year but must return to full activity immediately after completing hibernation. This necessity for immediate recovery presents an intriguing conundrum, as many mammals require two to three times the period of inactivity to recover full bone strength. Therefore, if hibernators experience typical levels of bone disuse atrophy during hibernation, there would be inadequate time available to recover during the summer active season. We examined whether there were mechanical consequences as a result of the extended inactivity of hibernation. We dissected femur and tibia bones from squirrels in various stages of the annual hibernation cycle and measured the amount of force required to fracture these bones. Three groups were investigated; summer active animals were captured during the summer and immediately killed, animals in the 1 month detraining group were captured in the summer and killed following a 1-month period of restricted mobility, hibernating animals were killed after 8 months of inactivity. A three-point bend test was employed to measure the force required to break the bones. Apparent flexural strength and apparent flexural modulus (material stiffness) were calculated for femurs. There were no differences between groups for femur fracture force, tibia fracture force, or femur flexural strength. Femur flexural modulus was significantly less for the 1 month detraining group than for the hibernation and summer active groups. Thus, hibernators seem resistant to the deleterious effects of prolonged inactivity during the winter. However, they may be susceptible to immobilization-induced bone loss during the summer.


The hypermorphic PLCγ2 S707Y variant dysregulates microglial cell function - Insight into PLCγ2 activation in brain health and disease, and opportunities for therapeutic modulation.
Phospholipase C-gamma 2 (PLCγ2) is highly expressed in hematopoietic and immune cells, where it is a key signalling node enabling diverse cellular functions. Within the periphery, gain-of-function (GOF) PLCγ2 variants, such as the strongly hypermorphic S707Y, cause severe immune dysregulation. The milder hypermorphic mutation PLCγ2 P522R increases longevity and confers protection in central nervous system (CNS) neurodegenerative disorders, implicating PLCγ2 as a novel therapeutic target for treating these CNS indications. Currently, nothing is known about what consequences strong PLCγ2 GOF has on CNS functionality, and more precisely on the specific biological functions of microglia. Using the PLCγ2 S707Y variant as a model of chronic activation we investigated the functional consequences of strong PLCγ2 GOF on human microglia. PLCγ2 S707Y expressing human inducible pluripotent stem cells (hiPSC)-derived microglia exhibited hypermorphic enzymatic activity under both basal and stimulated conditions, compared to PLCγ2 wild type. Despite the increase in PLCγ2 enzymatic activity, the PLCγ2 S707Y hiPSC-derived microglia display diminished functionality for key microglial processes including phagocytosis and cytokine secretion upon inflammatory challenge. RNA sequencing revealed a downregulation of genes related to innate immunity and response, providing molecular support for the phenotype observed. Our data suggests that chronic activation of PLCγ2 elicits a detrimental phenotype that is contributing to unfavourable CNS functions, and informs on the therapeutic window for targeting PLCγ2 in the CNS. Drug candidates targeting PLCγ2 will need to precisely mimic the effects of the PLCγ2 P522R variant on microglial function, but not those of the PLCγ2 S707Y variant.


Kinetics of fluorescence expression in nonhuman primates transplanted with GFP retrovirus-modified CD34 cells.
Downregulation and loss of proviral expression have been demonstrated to occur in a variety of in vitro studies and in mouse models. Here we evaluated the kinetics of proviral expression after transplantation in a competitive repopulating model in the baboon. Transgene persistence and green fluorescent protein (GFP) expression in peripheral blood leukocytes (PBL) were analyzed in four animals by semiquantitative PCR and flow cytometry for up to 80 weeks (range 17-80). All animals were transplanted with cells transduced with EGFP or EYFP reporters driven by Moloney murine leukemia virus (MoMuLV) or a modified promoter/enhancer, (MND) respectively. Simultaneous dual-color analysis of fluorescence levels in granulocyte and lymphocyte subsets following hematopoietic reconstitution demonstrated progressive loss of fluorescence intensity occurring predominantly early after transplant in cells transduced with both retrovirus backbones and at serial time points. In addition, we carried out PCR analysis of DNA extracted from sorted EGFP(-)/EYFP(-) cells and confirmed the presence of cells genetically marked by either vector in this population, indicating the persistence of cells that have downregulated or lost retroviral gene expression. In comparison to mouse studies, however, we did not detect substantial differences between MND and MoMuLV backbones.


Improving nutrition through biofortification: A review of evidence from HarvestPlus, 2003 through 2016.
Biofortification is a feasible and cost-effective means of delivering micronutrients to populations that may have limited access to diverse diets and other micronutrient interventions. Since 2003, HarvestPlus and its partners have demonstrated that this agriculture-based method of addressing micronutrient deficiency through plant breeding works. More than 20 million people in farm households in developing countries are now growing and consuming biofortified crops. This review summarizes key evidence and discusses delivery experiences, as well as farmer and consumer adoption. Given the strength of the evidence, attention should now shift to an action-oriented agenda for scaling biofortification to improve nutrition globally. To reach one billion people by 2030, there are three key challenges: 1) mainstreaming biofortified traits into public plant breeding programs; 2) building consumer demand; and 3) integrating biofortification into public and private policies, programs, and investments. While many building blocks are in place, institutional leadership is needed to continue to drive towards this ambitious goal.


On the origin of high-temperature phenomena in Pt/Al2O3.
Treatments of Pt/γ-Al2O3 with H2 under harsh conditions have long been known to strongly influence the properties of this important catalytic system, but the true causes of the high-temperature effects still remain unclear. We have performed a more detailed study of this issue, having used H2-TPD as a sensitive probe of metal-support interactions. The experimental results are in accordance with previous studies and demonstrate strong changes in adsorption and catalytic properties of Pt/γ-Al2O3 after high-temperature H2 treatments, as well as the possibility to reverse the changes, completely or in part, through O2 and H2O treatments. Thorough examination has shown that such behaviour is an intrinsic property of Pt/γ-Al2O3 and cannot be attributed to impurities or experimental artifacts. Moreover, there is no abrupt transition to a high-temperature state, but the system undergoes smooth and gradual changes upon increasing the H2-treatment temperature (TTR), with the changes being already apparent at a TTR of ∼ 300 °C. The results suggest that hydrogen can generate oxygen vacancies on the surface of the support in close vicinity to the Pt particles, and the system appears under equilibrium to be kinetically driven by temperature and thermodynamically driven by the PH2/PH2O ratio or local concentration of surface hydroxyls near Pt particles. The generated vacancies change the properties of contacting particles, and the changes are most pronounced for sub-nanometric Pt clusters and single atoms. Implications of the phenomena for the synthesis, study, and use of Pt/γ-Al2O3 and its related nanosystems are discussed.


Epstein-Barr virus-associated B-cell lymphoproliferative disorders in angloimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified.
Various patterns of Epstein-Barr virus (EBV)-associated B-cell lymphoproliferation occur in patients with immunodeficiency. We studied 17 cases of T-cell lymphoma displaying extensive EBV-driven B-cell lymphoproliferation or simultaneous/subsequent EBV-associated B-cell lymphoma. In 10 cases of angioimmunoblastic T-cell lymphoma, an uncommonly prominent population of EBV+ atypical, activated, focally confluent large transformed B cells was found in the background of T-cell lymphoma. In 4 cases, an EBV-associated B-cell neoplasm (3 diffuse large B-cell lymphomas, 1 plasmacytoma) occurred in patients with T-cell lymphoma. Three cases were composite lymphomas of a peripheral T-cell lymphoma, unspecified, combined with EBV-associated diffuse large B-cell lymphoma. The transformed B-cell population displayed EBV latency types 2 and 3. Monoclonal and oligoclonal B-cell populations were detected in 5 and 6 cases, respectively. Similar to other states of immunodeficiency, disease-related and therapy-induced immunosuppression in T-cell lymphoma may lead to a prominent EBV-associated B-cell lymphoproliferation and to EBV+ B-cell neoplasms.


Halbach arrays consisting of cubic elements optimised for high field gradients in magnetic drug targeting applications.
A key challenge in the development of magnetic drug targeting (MDT) as a clinically relevant technique is designing systems that can apply sufficient magnetic force to actuate magnetic drug carriers at useful tissue depths. In this study an optimisation routine was developed to generate designs of Halbach arrays consisting of multiple layers of high grade, cubic, permanent magnet elements, configured to deliver the maximum pull or push force at a position of interest between 5 and 50 mm from the array, resulting in arrays capable of delivering useful magnetic forces to depths past 20 mm. The optimisation routine utilises a numerical model of the magnetic field and force generated by an arbitrary configuration of magnetic elements. Simulated field and force profiles of optimised arrays were evaluated, also taking into account the forces required for assembling the array in practice. The resultant selection for the array, consisting of two layers, was then constructed and characterised to verify the simulations. Finally the array was utilised in a set of in vitro experiments to demonstrate its capacity to separate and retain microbubbles loaded with magnetic nanoparticles against a constant flow. The optimised designs are presented as light-weight, inexpensive options for applying high-gradient, external magnetic fields in MDT applications.


Phenotypic profile linked to inhibition of the major Zn influx system in Salmonella enterica: proteomics and ionomics investigations.
Zinc is required for a wide variety of cellular functions and plays a key role in bacterial metabolism and virulence. However, Zn can also be toxic and, therefore, its influx is tightly regulated. The high affinity zinc uptake transporter ZnuABC is the main Zn influx system in Salmonella enterica under conditions of Zn starvation. It has been shown that deletion of the gene encoding for its periplasmic subunit ZnuA significantly affects S. Typhimurium growth rate and virulence, highlighting the importance of this system in the host-pathogen interaction. To gain further insight into the mechanisms involved in Zn influx regulation, we characterized the main alterations in the ionome and proteome of S. Typhimurium wild type and znuA mutant strains grown either under Zn starvation or under Zn-replete conditions. We found significant differences in the element profile and protein expression that were reversed by Zn supplementation. In particular, several of the differentially regulated proteins are predicted to be metal-binding proteins. Interestingly, their over-expression in the znuA mutant strain strictly depends on Zn starvation and correlates with the differences found at the ionome level. In conclusion, our data demonstrate that inhibition of Zn influx has relevant effects either on the bacterial ionome or proteome and shed new light on the role of the ZnuABC system and Zn influx in S. Typhimurium pathogenicity.


Cannabinoids and endocannabinoids as therapeutics for nervous system disorders: preclinical models and clinical studies.
Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body. They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases. Some of these include central nervous system (CNS) diseases and dysfunctions such as forms of epilepsy, multiple sclerosis, Parkinson's disease, pain and neuropsychiatric disorders. In addition, the endogenously produced cannabinoid lipids, endocannabinoids, are critical for normal CNS function, and if controlled or modified, may represent an additional therapeutic avenue for CNS diseases. This review discusses in vitro cellular, ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies. In addition, the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases. Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.


A concise evidence-based physical examination for diagnosis of acromioclavicular joint pathology: a systematic review.
The clinical examination of the shoulder joint is an undervalued diagnostic tool for evaluating acromioclavicular (AC) joint pathology. Applying evidence-based clinical tests enables providers to make an accurate diagnosis and minimize costly imaging procedures and potential delays in care. The purpose of this study was to create a decision tree analysis enabling simple and accurate diagnosis of AC joint pathology. A systematic review of the Medline, Ovid and Cochrane Review databases was performed to identify level one and two diagnostic studies evaluating clinical tests for AC joint pathology. Individual test characteristics were combined in series and in parallel to improve sensitivities and specificities. A secondary analysis utilized subjective pre-test probabilities to create a clinical decision tree algorithm with post-test probabilities. The optimal special test combination to screen and confirm AC joint pathology combined Paxinos sign and O'Brien's Test, with a specificity of 95.8% when performed in series; whereas, Paxinos sign and Hawkins-Kennedy Test demonstrated a sensitivity of 93.7% when performed in parallel. Paxinos sign and O'Brien's Test demonstrated the greatest positive likelihood ratio (2.71); whereas, Paxinos sign and Hawkins-Kennedy Test reported the lowest negative likelihood ratio (0.35). No combination of special tests performed in series or in parallel creates more than a small impact on post-test probabilities to screen or confirm AC joint pathology. Paxinos sign and O'Brien's Test is the only special test combination that has a small and sometimes important impact when used both in series and in parallel. Physical examination testing is not beneficial for diagnosis of AC joint pathology when pretest probability is unequivocal. In these instances, it is of benefit to proceed with procedural tests to evaluate AC joint pathology. Ultrasound-guided corticosteroid injections are diagnostic and therapeutic. An ultrasound-guided AC joint corticosteroid injection may be an appropriate new standard for treatment and surgical decision-making. II - Systematic Review.


Neural-network prediction with noisy predictors.
Very often the input variables for neural-network predictions contain measurement errors. In particular, this may happen because the original input variables are often not available at the time of prediction and have to be replaced by predicted values themselves. This issue is usually ignored and results in nonoptimal predictions. This paper shows that under some general conditions, the optimal prediction using noisy input variables can be represented by a neural network with the same structure and the same weights as the optimal prediction using exact input variables. Only the activation functions have to be adjusted. Therefore we can achieve optimal prediction without costly retraining of the neural network. We explicitly provide an exact formula for adjusting the activation functions in a logistic network with Gaussian measurement errors in input variables. This approach is illustrated by an application to short-term load forecasting.


Screening for and surveillance of high-risk patients with HBV-related chronic liver disease: promoting the early detection of hepatocellular carcinoma in China.
In China, hepatocellular carcinoma (HCC) is the second most common cancer in urban areas and first most common in rural areas. It ranks as the second leading cause of cancer-related deaths in males and the third leading cause of cancer-related deaths in females, with the total mortality rate of 26.26 per 100,000. Currently, people with hepatitis B virus (HBV) infection are a major population at risk of developing HCC in China. In fact, there are 93 million Chinese who are HBV carriers, and about 20 million of them have chronic HBV infection. Several cohort studies have shown that screening high-risk patients with HBV-or HCV-related chronic liver disease may improve the rate of early HCC detection and the rate of curative treatment. However, a government-funded national program to screen for high-risk patients with HBV-related chronic liver disease has yet to be established in China. Although several remarkable advances in HCC management have been made during the past few decades, most patients with HCC still present with advanced-stage disease, thus reducing the chance of curative treatment. Based on firsthand experience in Japan and other countries or areas, this work examined the current status, challenges, and prospects for the future of early detection of HCC in China. Findings suggested the need for a systematic guideline for the standardized management of HCC, a government-funded nationwide screening and surveillance program for high-risk patients with HBV-related chronic liver disease, and extensive use of des-γ-carboxyprothrombin (DCP) as a screening tool in China in order to facilitate the early detection of HCC in China.


Working memory training in congenitally blind individuals results in an integration of occipital cortex in functional networks.
The functional relevance of crossmodal activation (e.g. auditory activation of occipital brain regions) in congenitally blind individuals is still not fully understood. The present study tested whether the occipital cortex of blind individuals is integrated into a challenged functional network. A working memory (WM) training over four sessions was implemented. Congenitally blind and matched sighted participants were adaptively trained with an n-back task employing either voices (auditory training) or tactile stimuli (tactile training). In addition, a minimally demanding 1-back task served as an active control condition. Power and functional connectivity of EEG activity evolving during the maintenance period of an auditory 2-back task were analyzed, run prior to and after the WM training. Modality-specific (following auditory training) and modality-independent WM training effects (following both auditory and tactile training) were assessed. Improvements in auditory WM were observed in all groups, and blind and sighted individuals did not differ in training gains. Auditory and tactile training of sighted participants led, relative to the active control group, to an increase in fronto-parietal theta-band power, suggesting a training-induced strengthening of the existing modality-independent WM network. No power effects were observed in the blind. Rather, after auditory training the blind showed a decrease in theta-band connectivity between central, parietal, and occipital electrodes compared to the blind tactile training and active control groups. Furthermore, in the blind auditory training increased beta-band connectivity between fronto-parietal, central and occipital electrodes. In the congenitally blind, these findings suggest a stronger integration of occipital areas into the auditory WM network.


β-catenin and Her2/neu expression in rectal cancer: association with histomorphological response to neoadjuvant therapy and prognosis.
Neoadjuvant treatment strategies have been developed to improve survival of patients with advanced rectal cancer. Since mainly patients with major histopathological response benefit from this therapy, predictive and prognostic markers are needed. We examined the association of β-catenin and Her2/neu protein expression with histopathologic response to neoadjuvant radiochemotherapy and prognosis in patients with locally advanced rectal cancer. Fifty-four patients (33 male; 21 female; median age 60.4 years) with locally advanced rectal cancer were included in this study. All patients received a neoadjuvant radiochemotherapy (50.4 Gy, 5-FU) followed by surgical resection. Histomorphologic regression was evaluated by Dworak and Cologne staging system. Major response was defined by Dworak classification when resected specimens contained less than 50% vital tumor cells (n = 14) and by Cologne grading system when resected specimens contained less than 10% vital tumor cells (n = 15). Intratumoral β-catenin (nuclear/membranous) and Her2/neu (cytoplasmatic/membranous) expression was determined by immunohistochemistry in pre- and post-therapeutic specimens and correlated with clinicopathologic parameters. A significant association was detected between pre-therapeutic membranous β-catenin levels and response: patients with a lower β-catenin protein expression showed significantly more often a major response compared with patients having high intratumoral protein levels (p = 0.011). In addition, patients with a higher Her2/neu protein expression showed a significant survival benefit compared with patients having low intratumoral protein levels (5-year survival rate: 81% vs. low 41%; p = 0.023). The pre-therapeutic β-catenin and Her2/neu protein expression seem to be valuable predictive and prognostic markers in the multimodality treatment of advanced rectal cancer.


Isolated thoracic perfusion with chemofiltration for progressive malignant pleural mesothelioma.
Therapy of malignant pleural mesothelioma and especially the adequate role of surgery in this context remain the subject of controversial discussions. Radical surgery in particular, which is associated with substantial morbidity, failed to translate into a definite survival advantage. We report on interim results of an ongoing Phase II study of regional chemotherapy in terms of isolated thoracic perfusion with chemofiltration (ITP-F). Twenty-eight patients (25 male, 3 female, mean age 63.4 years) with advanced pleural mesothelioma were included in this study. Isolation of the chest was achieved by insertion of a venous and arterial stop-flow balloon catheter via a femoral access. The aorta and inferior vena cava were blocked at the level of the diaphragm and the upper arms were blocked by pneumatic cuffs. Chemotherapy, consisting of 60 mg/m2 cisplatin and 15 mg/m2 mitoxantrone, was administered directly into the aorta. The isolated circuit was maintained for 15 minutes followed bŷ45 minutes of chemofiltration with a hemoprocessor until 5 L of filtrate were reached. The endpoints of the study were overall survival and quality of life (QoL). Out of 28 patients enrolled in the study, 5 had prior surgeries, 10 patients had systemic chemotherapy, and 5 patients additional irradiation. In all patients in restaging, clinical progress was noted. In all, 162 cycles were administered. Due to chemofiltration, toxicity was within tolerable limits, revealing World Health Organization grade I leucopenia and thrombocytopenia in 9 patients and mucositis grade I in 6 patients. The major surgical complication was inguinal lymphatic fistula in 40% of the cases. Gastrointestinal toxicity and/or neurotoxicity were never observed. One-year survival was 49%, 2-year and 3-year survival was 31%, and 5-year survival was 18%. Median overall survival was 12 months and progression-free survival 9 months. ITP-F for patients with advanced pleural mesothelioma, progressive after standard therapies, is an effective and well-tolerated treatment modality, offering comparably long survival data at a good QoL.


Normal values for pancreatic stone protein in different age groups.
Pancreatic stone protein (PSP) has been identified as a promising sepsis marker in adults, children and neonates. However, data on population-based reference values are lacking. This study aimed to establish age-specific reference values for PSP. PSP was determined using a specific ELISA. PSP serum concentrations were determined in 372 healthy subjects including 217 neonates, 94 infants and children up to 16 years, and 61 adults. The adjacent categories method was used to determine which age categories had significantly different PSP concentrations. PSP circulating levels were not gender-dependent and ranged from 1.0 to 99.4 ng/ml with a median of 9.2 ng/ml. PSP increased significantly between the age categories, from a median of 2.6 ng/ml in very preterm newborns, to 6.3 ng/ml in term newborns, to 16.1 ng/ml in older children (p < 0.001). PSP levels were higher on postnatal day three compared to levels measured immediately post delivery (p < 0.001). Paired umbilical artery and umbilical vein samples were strongly correlated (p < 0.001). Simultaneously obtained capillary heel-prick versus venous samples showed a good level of agreement for PSP (Rho 0.89, bias 19 %). This study provides age-specific normal values that may be used to define cut-offs for future trials on PSP. We demonstrate an age-dependent increase of PSP from birth to childhood.