Release of tumor necrosis factor alpha in response to Vibrio vulnificus capsular polysaccharide in in vivo and in vitro models.
Vibrio vulnificus produces a severe septic shock syndrome in susceptible individuals. Virulence of the bacterium has been closely linked to the presence of a surface-exposed acidic capsular polysaccharide (CPS). To investigate whether CPS plays an additional role in pathogenesis by modulating inflammatory-associated cytokine production, studies were initiated in a mouse model and followed by investigations of cytokine release from human peripheral blood mononuclear cells (PBMCs). Mouse tumor necrosis factor alpha (TNF-alpha) could be detected in serum up to 12 h postinoculation in animals challenged with the encapsulated parent strain MO6-24/O. The unencapsulated strain CVD752 was quickly eliminated by the animals, thus preventing a direct association between serum TNF-alpha levels and the presence or absence of the CPS. Purified CPS from MO6-24/O when injected into D-galactosamine-sensitized mice was a more immediate inducer of TNF-alpha than an equivalent quantity of MO6-24/O lipopolysaccharide (LPS). Both V. vulnificus CPS and V. vulnificus LPS induced inflammation-associated cytokine responses from primary human PBMCs in vitro. CPS elicited TNF-alpha from PBMCs in a dose-dependent manner, with maximal induction at 6 to 10 h, and was not inhibited by polymyxin B. Expression of interleukin-6 (IL-6) mRNAs was also induced in the presence of CPS. Interestingly, while adherent PBMCs secreted high levels of TNF-alpha after stimulation with LPS, they secreted little TNF-alpha in response to CPS. These studies provide evidence that V. vulnificus CPS directly stimulates the expression and secretion of proinflammatory cytokines by murine and human cells and suggest that CPS activation of PBMCs operates through a cellular mechanism distinct from that of LPS.


Two mouse early embryonic beta-globin gene sequences. Evolution of the nonadult beta-globins.
We have determined the complete nucleotide sequence of two early embryonic beta-globin genes of the BALB/c mouse: beta h0 and beta h1 X beta h1 codes for the embryonic z protein, while the beta h0 gene may be a minor early embryonic beta-globin gene. The general sequence organization of both genes is entirely analogous to other functional globin genes. There is, however, a 220-base pair insertion of unique sequence within the first intron of beta h0 X beta h0 and beta h1 are 96% homologous for 260 base pairs 5' to the AUG initiation codon, and 93% homologous throughout their coding regions. Analysis of the 5'-flanking sequence demonstrates that these genes are more nonadult-like than adult-like. The sequences show evidence for gene conversions among the mouse nonadult beta-globin genes that were limited to individual exons, presumably by the presence of non-homologous introns. We propose that this arrangement has the beneficial evolutionary effect of allowing gene conversion to act independently on regions of the protein with different structural or functional responsibilities. beta h0 and beta h1 are evolutionary homologs to the human fetal and rabbit beta 3 genes, while their manner of expression is similar to rabbit beta 3 and dissimilar to human fetal expression. The evolutionary history of the human beta-globin genes, therefore, includes the recruitment of an embryonic gene to fetal developmental control.


Nup50, a nucleoplasmically oriented nucleoporin with a role in nuclear protein export.
We present here a detailed analysis of a rat polypeptide termed Nup50 (formerly NPAP60) that was previously found to be associated with the nuclear pore complex (F. Fan et al., Genomics 40:444-453, 1997). We have found that Nup50 (and/or a related 70-kDa polypeptide) is present in numerous rat cells and tissues. By immunofluorescence microscopy, Nup50 was found to be highly concentrated at the nuclear envelope of rat liver nuclei, whereas in cultured NRK cells it also is abundant in intranuclear regions. On the basis of immunogold electron microscopy of both rat liver nuclear envelopes and NRK cells, we determined that Nup50 is specifically localized in the nucleoplasmic fibrils of the pore complex. Microinjection of anti-Nup50 antibodies into the nucleus of NRK cells resulted in strong inhibition of nuclear export of a protein containing a leucine-rich nuclear export sequence, whereas nuclear import of a protein containing a classical nuclear localization sequence was unaffected. Correspondingly, CRM1, the export receptor for leucine-rich export sequences, directly bound to a fragment of Nup50 in vitro, whereas several other import and export receptors did not significantly interact with this fragment. Taken together, our data indicate that Nup50 has a direct role in nuclear protein export and probably serves as a binding site on the nuclear side of the pore complex for export receptor-cargo complexes.


Tissue size and cell number in the olive (Olea europaea) ovary determine tissue growth and partitioning in the fruit.
The relationship between tissue size and cell number in the ovary and tissue size in the fruit, was studied in eight olive (Olea europaea L.) cultivars with different fruit and ovary size. All tissues in the ovary increased in size with increasing ovary size. Tissue size in the fruits correlated with tissue size in the ovary for both mesocarp and endocarp, but with different correlations: the mesocarp grew about twice as much per unit of initial volume in the ovary. Tissue size in the fruit also correlated with tissue cell number in the ovary. In this case, a single regression fitted all data pooled for both endocarp and mesocarp, implying that a similar tissue mass was obtained in the fruit per initial cell in the ovary, independent of tissues and cultivars. Tissue relative growth from bloom to harvest (i.e. the ratio between final and initial tissue size) differed among cultivars and tissues, but correlated with tissue cell size at bloom, across cultivars and tissues. These results suggest that in olive, tissue growth and partitioning in the fruit is largely determined by the characteristics of the ovary tissues at bloom, providing important information for plant breeding and crop management.


Randomised study of HPV prevalence and detection of CIN2+ in vaginal self-sampling compared to cervical specimens collected by medical personnel.
We conducted a randomised study to compare vaginal self-sampling with assisted sampling by medical personnel on the cervix for HPV testing in primary screening. The first aim was to determine if the HPV prevalence is independent of sampling location (vagina versus cervix) and the person performing the sampling. The second aim was to evaluate if the two sampling strategies differed in the detection rate of CIN2+. In total, 19,523 women were randomised into two groups, with 9926 invited to perform self-sampling (SS arm) using the Rover VIBA-brush and 9597 offered assisted sampling using the cytobrush (AS arm). All samples were applied to the indicating FTA elute card and analysed for high-risk HPV using the hpVIR real-time PCR assay. The outcome for the first aim was HPV prevalence and for the second aim the number of CIN2+ based on histology. In the SS arm, 52.7% of invited women participated in the study, as compared to 34.2% in the AS arm. All samples contained sufficient amount of nuclear DNA for a valid HPV result, with vaginal samples having a higher DNA amount than cervical samples (p < 4.62 × 10-11 ). HPV prevalence was 4.6% in the SS arm and 4.1% in the AS arm (p = 5.5 × 10-2 ), and the distribution of HPV types similar between arms. There was no difference in the prevalence of CIN2+ per 1000 women screened between arms (p = 0.86). The results show that vaginal self-sampling is an equivalent alternative to sampling by medical personnel for HPV typing and identification of CIN2+.


Regulation of endogenous neural stem/progenitor cells for neural repair-factors that promote neurogenesis and gliogenesis in the normal and damaged brain.
Neural stem/precursor cells in the adult brain reside in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. These cells primarily generate neuroblasts that normally migrate to the olfactory bulb (OB) and the dentate granule cell layer respectively. Following brain damage, such as traumatic brain injury, ischemic stroke or in degenerative disease models, neural precursor cells from the SVZ in particular, can migrate from their normal route along the rostral migratory stream (RMS) to the site of neural damage. This neural precursor cell response to neural damage is mediated by release of endogenous factors, including cytokines and chemokines produced by the inflammatory response at the injury site, and by the production of growth and neurotrophic factors. Endogenous hippocampal neurogenesis is frequently also directly or indirectly affected by neural damage. Administration of a variety of factors that regulate different aspects of neural stem/precursor biology often leads to improved functional motor and/or behavioral outcomes. Such factors can target neural stem/precursor proliferation, survival, migration and differentiation into appropriate neuronal or glial lineages. Newborn cells also need to subsequently survive and functionally integrate into extant neural circuitry, which may be the major bottleneck to the current therapeutic potential of neural stem/precursor cells. This review will cover the effects of a range of intrinsic and extrinsic factors that regulate neural stem/precursor cell functions. In particular it focuses on factors that may be harnessed to enhance the endogenous neural stem/precursor cell response to neural damage, highlighting those that have already shown evidence of preclinical effectiveness and discussing others that warrant further preclinical investigation.


Prevention of local tumor recurrence following surgery using low-dose chemotherapeutic polymer films.
To evaluate the efficacy of a polymer film designed for prolonged paclitaxel release at surgical margins to prevent local recurrence in non-small-cell lung cancer (NSCLC) following complete surgical resection in a murine model. Poly(glycerol monostearate co-epsilon-caprolactone) polymer films were prepared with or without 10% (w/w) paclitaxel and characterized for prolonged tumor cytotoxicity in vitro against several NSCLC cell lines including LLC, NCI-H460, and NCI-H292. Films were implanted following complete LLC tumor resection and assessed in vivo for prevention of local tumor recurrence, impact on wound healing, and extent of local drug delivery. Plasma and local tissue concentrations of paclitaxel were compared following systemic administration and film implantation. The flexible polymeric films eluted paclitaxel over several weeks and remained cytotoxic to LLC, NCI-H460, and NCI-H292 cells in vitro for 50 days, while unloaded films did not impair tumor cell growth. Implanted paclitaxel films prevented local tumor recurrence in vivo in 83.3% of animals, compared with unloaded films (12.5%), systemic (22.2%) or locally administered paclitaxel (0%) (P < 0.005). Although minimal paclitaxel remained in either plasma or tissue 10 days after systemic injection, local paclitaxel concentration at the site of surgical resection was significantly greater (3,000-fold) at 10 days when paclitaxel was locally delivered via films (P = 0.024). Local application of paclitaxel-loaded polymer films following surgical resection can prevent local tumor recurrence without impairing wound healing.


The effect of light on outer segment calcium in salamander rods.
Calcium acts as a second messenger in vertebrate rods, regulating the recovery phase of the light response and modulating sensitivity during light-adaptation. Since light not only decreases the outer segment calcium concentration ([Ca2+]i) by closing cyclic nucleotide-gated channels but can also increase [Ca2+]i by releasing Ca2+ from buffer sites or intracellular stores, we examined in detail the effect of light and circulating current on [Ca2+]i by making simultaneous measurements of suction pipette current and [Ca2+]i from isolated rods of the salamander Ambystoma tigrinum after incorporation of the fluorescent dye fluo-5F. When the release of Ca2+ is measured in 0 Ca2+-0 Na+ solution, minimising fluxes of Ca2+ across the plasma membrane, it is substantial only for light bright enough to bleach a significant fraction of the photopigment and is restricted to the part of the outer segment in which the bleach occurred. It is unlikely, therefore, to make a large contribution to [Ca2+]i for most of the physiological operating range of the rod. Nevertheless, since release is half-maximal for a bleach of less than 10 %, it cannot be produced by a simple mechanism such as a change in the affinity of a binding site on rhodopsin itself but must instead require some more complex interaction. In Ringer solution, the Ca2+ in the light-releasable pool can be discharged merely by the decrease in [Ca2+]i that occurs as the outer segment channels close. In steady background light or after exposure to saturating illumination, the fraction of Ca2+ in the pool decreases essentially in proportion to [Ca2+]i as if Ca2+ were being removed from a buffer site within the cytoplasm. Furthermore, [Ca2+]i itself changes in proportion to the circulating current, with little evidence for a contribution from Ca2+ release or other mechanisms of Ca2+ homeostasis. This indicates that flux of Ca2+ across the plasma membrane is the major determinant of outer segment Ca2+ concentration within the rod's normal operating light intensity range. Once Ca2+ has been discharged from the releasable pool, it is restored following dim illumination apparently as the simple result of the subsequent restoration of dark [Ca2+]i and the rebinding of Ca2+ to its release site, but after brighter light perhaps also as a consequence of regeneration of the photopigment.


Human aortic fibrolipid lesions. Progenitor lesions for fibrous plaques, exhibiting early formation of the cholesterol-rich core.
The early development of the lipid-rich core and other features of atherosclerotic fibrous plaques has been elucidated by examining discrete, small regions of raised intima in human aorta, which often bear a resemblance to both fatty streaks and fibrous plaques. Approximately one-fourth of small raised lesions (less than 16 sq mm of surface area) contained little or no stainable lipid, while three-fourths had a characteristic appearance, which included a superficial layer of foam cells, a core of noncrystalline and/or crystalline lipid, and a developed or developing collagenous cap. Total intimal volumes of the lipid-containing lesions, termed "fibrolipid lesions," ranged from 3 to 43 microliters, with the majority less than 16 microliters. Core lipid in the smallest lesions was located in the musculoelastic layer of the intima. In larger lesions the core extended luminally into the elastic hyperplastic layer, and cholesterol crystals were found more frequently. Total cholesterol concentration in fibrolipid lesions was similar to that in fatty streaks; however, the ratio of unesterified to total cholesterol was relatively high, similar to that found in fibrous plaques. It is concluded that 1) the formation of a lipid-rich core and cholesterol crystallization are early events in the development of many raised lesions; 2) the consistent association between the superficial layer of foam cells and the deep-lying lipid-rich core raises the possibility of an influence, possibly indirect, of foam-cell lipid metabolism on core formation; and 3) the fibrolipid lesion may represent one stage in a potential transitional morphologic sequence between fatty streak and fibrous plaque.


State-of-the-art in design rules for drug delivery platforms: lessons learned from FDA-approved nanomedicines.
The ability to efficiently deliver a drug to a tumor site is dependent on a wide range of physiologically imposed design constraints. Nanotechnology provides the possibility of creating delivery vehicles where these design constraints can be decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing targeting efficiency and efficacy. Here we review the design strategies of the two FDA-approved antibody-drug conjugates (Brentuximab vedotin and Trastuzumab emtansine) and the four FDA-approved nanoparticle-based drug delivery platforms (Doxil, DaunoXome, Marqibo, and Abraxane) in the context of the challenges associated with systemic targeted delivery of a drug to a solid tumor. The lessons learned from these nanomedicines provide an important insight into the key challenges associated with the development of new platforms for systemic delivery of anti-cancer drugs.


Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET.
The histamine H(3) receptor is implicated in the pathophysiology of several central nervous system disorders. N-methyl-6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-nicotamide (GSK189254) is a highly potent, selective, and brain-penetrant H(3) receptor antagonist. Previous studies in the pig using PET have shown that (11)C-GSK189254 uptake in H(3)-rich regions of the brain can be blocked by the selective H(3) antagonist ciproxifan. The purpose of the present study was to evaluate (11)C-GSK189254 as a PET radioligand for human studies and to determine the dose-receptor occupancy relationship of GSK189254 in the human brain. Dynamic PET scans were obtained in healthy subjects over 90 min after intravenous administration of approximately 370 MBq of (11)C-GSK189254. Blood samples were taken throughout the scans to derive the arterial plasma parent input function. Each subject was scanned twice, either with tracer alone (test-retest) or before and after a single oral dose of GSK189254 (10-100 microg). Data were analyzed by compartmental analysis, and regional receptor-occupancy estimates were obtained by graphical analysis of changes in the total volumes of distribution (V(T)) of the radioligand. (11)C-GSK189254 readily entered the brain; its regional brain distribution reflected the known distribution of H(3) receptors, with high binding in the caudate and putamen, intermediate binding in cortical regions, and low binding in the cerebellum. GSK189254 displayed a high receptor affinity, and a marked reduction in V(T) was apparent at all the doses tested. The oral dose equaling 50% occupancy of the available receptor sites (ED(50)) was estimated as 4.33 microg. Additional data on plasma pharmacokinetics after oral dosing and the plasma free fraction gave a corresponding estimate of the free concentration of GSK189254 required to occupy 50% of the available receptor sites (EC(50)) (0.011 nM). The test-retest data showed reductions in regional V(T) on the second scan in all subjects. A nonlinear compartmental analysis of this effect demonstrated that this reduction was consistent with carryover of a tracer mass dose effect with an estimated in vivo apparent dissociation constant of 0.010 nM, close to the independent estimate of the plasma EC(50). (11)C-GSK189254 can be used to quantify H(3) receptor availability in humans in vivo using PET but requires high specific activity; the possibility of tracer mass dose effects should be carefully analyzed.


The benefits of exercise training in interstitial lung disease: protocol for a multicentre randomised controlled trial.
Interstitial lung disease encompasses a diverse group of chronic lung conditions characterised by distressing dyspnoea, fatigue, reduced exercise tolerance and poor health-related quality of life. Exercise training is one of the few treatments to induce positive changes in exercise tolerance and symptoms, however there is marked variability in response. The aetiology and severity of interstitial lung disease may influence the response to treatment. The aims of this project are to establish the impact of exercise training across the range of disease severity and to identify whether there is an optimal time for patients with interstitial lung disease to receive exercise training. One hundred and sixteen participants with interstitial lung disease recruited from three tertiary institutions will be randomised to either an exercise training group (supervised exercise training twice weekly for eight weeks) or a usual care group (weekly telephone support). The 6-minute walk distance, peripheral muscle strength, health-related quality of life, dyspnoea, anxiety and depression will be measured by a blinded assessor at baseline, immediately following the intervention and at six months following the intervention. The primary outcome will be change in 6-minute walk distance following the intervention, with planned subgroup analyses for participants with idiopathic pulmonary fibrosis, dust-related interstitial lung disease and connective-tissue related interstitial lung disease. The effects of disease severity on outcomes will be evaluated using important markers of disease severity and survival, such as forced vital capacity, carbon monoxide transfer factor and pulmonary hypertension. This trial will provide certainty regarding the role of exercise training in interstitial lung disease and will identify at what time point within the disease process this treatment is most effective. The results from this study will inform and optimise the clinical management of people with interstitial lung disease. Australian New Zealand Clinical Trials Registry ACTRN12611000416998.


The relationship between intelligence and training gains is moderated by training strategy.
We examined the relationship between training regimen and fluid intelligence in the learning of a complex video game. Fifty non-game-playing young adults were trained on a game called Space Fortress for 30 hours with one of two training regimens: (1) Hybrid Variable-Priority Training (HVT), with part-task training and a focus on improving specific skills and managing task priorities, and (2) Full Emphasis Training (FET) in which participants practiced the whole game to obtain the highest overall score. Fluid intelligence was measured with the Raven's Progressive Matrix task before training. With FET, fluid intelligence was positively associated with learning, suggesting that intellectual ability played a substantial role in determining individual differences in training success. In contrast, with HVT, fluid intelligence was not associated with learning, suggesting that individual differences in fluid intelligence do not factor into training success in a regimen that emphasizes component tasks and flexible task coordination. By analyzing training effects in terms of individual differences and training regimens, the current study offers a training approach that minimizes the potentially limiting effect of individual differences.


Phase II trial of S-1 and concurrent radiotherapy in patients with locally advanced pancreatic cancer.
S-1 has a favorable effect in unresectable pancreatic cancer and a potential radiosensitizer. In addition, daily oral administration of S-1 is more convenient than continuous infusion of 5-fluorouracil. This study was designed to evaluate the efficacy and safety of S-1 and concurrent radiotherapy in patients with locally advanced pancreatic cancer. Eligibility criteria were histologically proven pancreatic adenocarcinoma, locally advanced disease, and no previous treatment. S-1 was administered orally at a dose of 40 mg/m(2) twice daily from day 1 to 14 and from day 22 to 35, and concurrent radiotherapy (a total dose of 50.4 Gy) was delivered in 28 fractions. One month after treatment completion, tumor response was evaluated by computed tomography (CT). A total of 25 patients were evaluable for efficacy and toxicity on the basis of the intention-to-treat analysis. The response rate and disease control rate were 24.0 and 68.0%, respectively. There was no treatment-related death or grade 4 toxicity. The most common grade 3 hematologic and non-hematologic toxicities were thrombocytopenia (4.0%) and anorexia (20%), respectively. All toxicities were tolerable and transient. The median time-to-progression and median overall survival were 6.5 months (95% confidence interval, 4.1-9.0 months) and 12.9 months (95% confidence interval, 6.7-19.0 months), respectively, and the 1-year survival rate was estimated to be 43%. S-1 and concurrent radiotherapy shows favorable efficacy for disease control against locally advanced pancreatic cancer and was well tolerated with no severe toxicities.


Immunohistochemical and biogenetic features of diffuse-type tenosynovial giant cell tumors: the potential roles of cyclin A, P53, and deletion of 15q in sarcomatous transformation.
Diffuse-type tenosynovial giant cell tumor (D-TSGCT) is an aggressive proliferation of synovial-like mononuclear cells with inflammatory infiltrates. Despite the COL6A3-CSF1 gene fusion discovered in benign lesions, molecular aberrations of malignant D-TSGCTs remain unidentified. We used fluorescent in situ hybridization and in situ hybridization to evaluate CSF1 translocation and mRNA expression in six malignant D-TSGCTs, which were further immunohistochemically compared with 24 benign cases for cell cycle regulators involving G(1) phase and G(1)-S transition. Comparative genomic hybridization, real-time reverse transcription-PCR, and a combination of laser microdissection and sequencing were adopted to assess chromosomal imbalances, cyclin A expression, and TP53 gene, respectively. Five of six malignant D-TSGCTs displayed CSF1 mRNA expression by in situ hybridization, despite only one having CSF1 translocation. Cyclin A (P = 0.008) and P53 (P < 0.001) could distinguish malignant from benign lesions without overlaps in labeling indices. Cyclin A transcripts were more abundant in malignant D-TSGCTs (P < 0.001). All malignant cases revealed a wild-type TP53 gene, which was validated by an antibody specifically against wild-type P53 protein. Chromosomal imbalances were only detected in malignant D-TSGCTs, with DNA losses predominating over gains. Notably, -15q was recurrently identified in five malignant D-TSGCTs, four of which showed a minimal overlapping deletion at 15q22-24. Deregulated CFS1 overexpression is frequent in malignant D-TSGCTs. The sarcomatous transformation involves aberrations of cyclin A, P53, and chromosome arm 15q. Cyclin A mRNA is up-regulated in malignant D-TSGCTs. Non-random losses at 15q22-24 suggest candidate tumor suppressor gene(s) in this region. However, P53 overexpression is likely caused by alternative mechanisms rather than mutations in hotspot exons.


Effectiveness of tyrosine kinase inhibitors on "uncommon" epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer.
Clinical features of epidermal growth factor receptor (EGFR) mutations, L858R, deletions in exon 19, T790M, and insertions in exon 20, in non-small cell lung cancer (NSCLC) are well known. The clinical significance of other uncommon EGFR mutations, such as their association with the effectiveness of EGFR tyrosine kinase inhibitors (TKI), is not well understood. This study aimed to improve the understanding of these uncommon EGFR mutations of unknown clinical significance. Specimens from 1,261 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of gefitinib and erlotinib in NSCLC patients with uncommon EGFR mutations. Of the 1,261 patients, 627 (49.8%) had EGFR mutations. This included 258 patients with deletions in exon 19, 260 patients with L858R, 25 patients with insertions or duplications in exon 20, 6 patients with de novo T790M, and 78 (12.4%) patients with uncommon mutations. Of the 78 patients, 62 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 48.4%, and the median progression-free survival (PFS) was 5.0 months. Mutations on G719 and L861 composed a major part (28 of 62) of uncommon mutations, and were associated with a favorable effectiveness of EGFR TKIs (response rate, 57.1%; median PFS, 6.0 months). Mutations other than G719 and L861 led to a worse response to EGFR TKIs (response rate, 20.0%; median PFS, 1.6 months). Uncommon EGFR mutations constituted a distinct part of the whole group of EGFR mutations. Their composition was heterogeneous, and their associations with EGFR TKIs differed.


[SEXUALITY IN PSYCHIATRIC HOSPITALIZATION: REALITY VERSUS POLICY].
Psychiatric hospitalization might be a necessity for certain groups of patients with mental illness, involving acute symptoms and substantial disability which do not allow independent living in the community. In such situations, it is crucial to enable inpatients to enjoy the best possible quality of life, including the right for sexual autonomy as a basic human right. Satisfying sexual life is part of meaningful life and plays an important role in personal and social recovery. On the other hand, sexual relations in psychiatric wards raise many dilemmas, including the need to protect inpatients from sexual abuse and victimization, particularly when mental illness involves judgment deficits and decreased ability to express autonomous will. In spite of its' importance, this subject receives little attention in policy guidelines and clinical practice and is largely ignored. The article reviews literature examining various aspects of sexual behavior in psychiatric facilities, revealing ethical dilemmas, risks and the role of policy guidelines to address this subject. We present viewpoints of practitioners, consumers and family members concerning sexual behavior in psychiatric hospitalization. We conclude with implications that emerge from accumulated knowledge with regard to policy making and proposed frameworks for change.


[Discovery of monoamine oxidase forms A and B].
During the 1960's, reports suggesting the existence of multiple forms of monoamine oxidase (MAO) appeared with increasing frequency. In July 1968, two reports appeared in the same issue of Biochemical Pharmacology that established the existence of MAO-A and MAO-B. This terminology was unanimously accepted at an international meeting on MAO in 1971. MAO-A preferentially deaminates serotonin (5HT) and is selectively inhibited by harmine and clorgyline, while MAO-B preferentially deaminates phenethylamine and benzylamine, and is selectively inhibited by (-)deprenyl as well as low concentrations of pargyline. It was later found that MAO-A and MAO-B are encoded by separate genes. The two genes have identical exon-intron organizations, but differ with respect to their promoters. In humans both genes are located very close together on the short arm of the X chromosome (Xp21-p11). In mice, the MAO-A gene is also located on the X chromosome, but the chromosomal locations of the MAO-A and -B genes for other species appear to be unknown at present. Some degree of polymorphism seem to exist in both genes. Both forms probably occur naturally as homodimers in the mitochondrial outer membrane, raising the possibility of 3 variants of both MAO-A and -B in human females that are heterozygous for alleles at each locus. Highly specific antibodies for MAO-A and -B, respectively, have been produced, and immunohistochemical studies show that the two forms are differentially expressed in different cell types. In rat and primate brain MAO-A is restricted to catecholamine neurons, while MAO-B is largely restricted to serotonin neurons and astrocytes. Congenital lack of MAO-A is associated with mental retardation, impulsive aggressive behavior and other behavioral/neurological disorders. These results support the conclusion that both MAO-A and -B play predominantly protective roles in the organism.


Che-1 sustains hypoxic response of colorectal cancer cells by affecting Hif-1α stabilization.
Solid tumours are less oxygenated than normal tissues. Consequently, cancer cells acquire to be adapted to a hypoxic environment. The poor oxygenation of solid tumours is also a major indicator of an adverse cancer prognosis and leads to resistance to conventional anticancer treatments. We previously showed the involvement of Che-1/AATF (Che-1) in cancer cell survival under stress conditions. Herein we hypothesized that Che-1 plays a role in the response of cancer cells to hypoxia. The human colon adenocarcinoma HCT116 and HT29 cell lines undepleted or depleted for Che-1 expression by siRNA, were treated under normoxic and hypoxic conditions to perform studies regarding the role of this protein in metabolic adaptation and cell proliferation. Che-1 expression was detected using western blot assays; cell metabolism was assessed by NMR spectroscopy and functional assays. Additional molecular studies were performed by RNA seq, qRT-PCR and ChIP analyses. Here we report that Che-1 expression is required for the adaptation of cells to hypoxia, playing an important role in metabolic modulation. Indeed, Che-1 depletion impacted on HIF-1α stabilization, thus downregulating the expression of several genes involved in the response to hypoxia and affecting glucose metabolism. We show that Che-1 a novel player in the regulation of HIF-1α in response to hypoxia. Notably, we found that Che-1 is required for SIAH-2 expression, a member of E3 ubiquitin ligase family that is involved in the degradation of the hydroxylase PHD3, the master regulator of HIF-1α stability.


Different effects of simvastatin and interferon beta on the proteolytic activity of matrix metalloproteinases.
Interferon beta and statins are known to exert immunomodulatory actions by inhibiting gene transcription and translation of various proinflammatory molecules. Although interferon beta represents a mainstay in therapy for multiple sclerosis (MS), statins are considered a potential new approach in treating MS. To investigate the effect of interferon beta and statins on the posttranslational activity of matrix metalloproteinases (MMPs) released from mononuclear cells in vitro that were obtained from patients with MS and healthy donors. Blood samples from 10 patients with a relapsing-remitting course of MS and 5 matched healthy individuals were studied. Peripheral blood mononuclear cells were isolated and stimulated with an antibody to CD3, phytohemagglutinin, or medium alone as a negative control. Proteolytic activity was investigated in the supernatants by means of sodium dodecyl sulfate-polyacrylamide gel electrophoresis zymography in which gels were incubated with interferon beta or simvastatin during development. Zones of gelatin digestion were visualized and quantified. Incubation with interferon beta resulted in an inhibition of the gelatinolytic activity of MMP-9 and MMP-2. In contrast, simvastatin enhanced the proteolytic capacity of MMP-2 and MMP-9, with a statistically significant increase of MMP-2 activity when compared with findings in controls. There were no differences in the enzymatic response between patients with MS and healthy individuals. Interferon beta exhibits inhibitory effects at the posttranslational level of MMP activity, whereas simvastatin augments the proteolytic activity of MMP-2 and MMP-9, suggesting that statins exert anti-inflammatory and proinflammatory effects. This dual mechanism of action should be considered, given the recent interest in developing these drugs for treatment of MS.


Infections with Sarcocystis wenzeli are prevalent in the chickens of Yunnan Province, China, but not in the flocks of domesticated pigeons or ducks.
The distribution and prevalence of infections with species of Sarcocystis in domestic fowl in Asia are poorly known. Here, ducks, pigeons, and chickens from Yunnan Province, China were examined for evidence of parasitic infection with Sarcocystis spp. One hundred and ninety one chickens, 514 ducks, and nine pigeons were investigated. Whereas the ducks and pigeons lacked tissue cysts in their muscle, brain or peripheral nervous system, cysts of Sarcocystis wenzeli were identified in 17 of 191 chickens (8.9%). Morphologically, the cysts were thread-like, ranging in size from 334-3169 × 41-117 μm (mean 1093 × 65 μm). Cysts were septate with dense, short finger-like protrusions which appeared radially striated. The cyst wall was 1.4-3.5 μm (mean 2.4 μm) thick. The bradyzoites were lancet shaped and measured 12.2-17.7 × 1.8-2.9 μm (mean 14.6 × 2.5 μm). Ultrastucturally, the primary sarcocyst wall had stubby villar protrusions, corresponding to the 'type 9' class previously designated. The protrusions measured 0.87-1.89 × 0.47-0.91 μm (mean 1.27 × 0.59 μm; n = 57). These findings confirm previous work from the vicinity of Kunming concerning the occurrence of S. wenzeli in chickens, and its use of both cats and dogs as definitive hosts, but indicate that corresponding infections may not occur in the regional domestic flocks of other types of fowl.


Immune mediated shaping of microflora community composition depends on barrier site.
Barrier surfaces, such as the intestinal lining and the skin, are colonized by a diverse community of commensal microorganisms. Although commensal microorganisms clearly impact the host immune system, whether the immune system also shapes the commensal community is poorly understood. We used 16S rDNA deep sequencing to test whether mice with specific immune defects have an altered commensal microflora. Initially, skin swabs were obtained from wild-type and Langerhans Cell (LC) deficient mice. Despite the intimate contacts that LC make with the upper epidermis, no significant differences were observed in microbial community composition. Similarly, the skin of MyD88/TRIF(-/-), Rag1(-/-) and heterozygous littermate controls showed no alteration in their commensal communities. Next we examined mouth swabs and feces. We did not find a difference in the MyD88/TRIF(-/-) mice. However, we did observe a significant shift in the microbial composition in the feces and mouths of Rag1(-/-) mice. Thus, we conclude that the adaptive immune system modulates the microbial composition at mucosal surfaces in the steady-state but LC, adaptive immunity, and MyD88-dependent innate responses do not affect the skin microbiome revealing a major distinction between barrier sites.


Genetic and Histological Alterations Reveal Key Role of Prostaglandin Synthase and Cyclooxygenase 1 and 2 in Traumatic Brain Injury-Induced Neuroinflammation in the Cerebral Cortex of Rats Exposed to Moderate Fluid Percussion Injury.
After the initial insult in traumatic brain injury (TBI), secondary neurodegeneration occurs that is intimately associated with neuroinflammation. Prostaglandin (PG) synthases and cyclooxygenase (COX) 1 and 2 may contribute to inflammation in the brain. Temporal and spatial expression features of PG and COX1 and 2 following trauma may guide the development of antineuroinflammation strategies. Here, we examined PG synthase signaling and COX1 and 2 gene expression levels and COX-1- and 2-positive cell types and their temporal localization in TBI-induced brain in an effort to reveal their participation in the disease's evolving neuroinflammation. Using brain samples from the cerebral cortex of rats subjected to TBI model of lateral moderate fluid percussion injury (FPI), we sought to characterize the temporal (subacute TBI) and spatial (lateral cortical lesion) brain alterations accompanying the disease progression. Temporal gene expression changes of PG synthase signaling were compared between sham-operated and TBI-treated rats using microarray pathway analysis. Moreover, we examined COX1 and 2 expression patterns and their intracellular distribution in sham-operated and TBI-treated rats by immunohistochemistry. After FPI, COX1 and 2 gene expression levels, and PGE2 synthase increased while PGD2 synthase decreased, suggesting that PGE2 and PGD2 afforded contraindicative effects of inflammation and anti-inflammation, respectively. Immunohistochemical analyses showed that both COX1 and COX2 increased in a time-dependent manner in the brain, specifically in degenerating neurons of the cortex. Interestingly, the expression of COX cell type was cell-specific, in that COX1 was particularly increased in degenerating neurons while COX2 was expressed in macrophages. In view of the dynamic temporal and spatial expression of PG, COX1 and 2 gene expression and localization in the injured brain regulating PG synthase and COX1 and 2 activity will require a careful disease-specific tailoring of treatments to abrogate the neuroinflammation-plagued secondary cell death due to TBI.


Recognising out-of-hospital cardiac arrest during emergency calls increases bystander cardiopulmonary resuscitation and survival.
Initiation of early bystander cardiopulmonary resuscitation (CPR) depends on bystanders' or medical dispatchers' recognition of out-of-hospital cardiac arrest (OHCA). The primary aim of our study was to investigate if OHCA recognition during the emergency call was associated with bystander CPR, return of spontaneous circulation (ROSC), and 30-day survival. Our secondary aim was to identify patient-, setting-, and dispatcher-related predictors of OHCA recognition. We performed an observational study of all OHCA patients' emergency calls in the Capital Region of Denmark from 01/01/2013-31/12/2013. OHCAs were collected from the Danish Cardiac Arrest Registry and the Mobile Critical Care Unit database. Emergency call recordings were identified and evaluated. Multivariable logistic regression analyses were applied to all OHCAs and witnessed OHCAs only to analyse the association between OHCA recognition and bystander CPR, ROSC, and 30-day survival. Univariable logistic regression analyses were applied to identify predictors of OHCA recognition. We included 779 emergency calls in the analyses. During the emergency calls, 70.1% (n=534) of OHCAs were recognised; OHCA recognition was positively associated with bystander CPR (odds ratio [OR]=7.84, 95% confidence interval [CI]: 5.10-12.05) in all OHCAs; and ROSC (OR=1.86, 95% CI: 1.13-3.06) and 30-day survival (OR=2.80, 95% CI: 1.58-4.96) in witnessed OHCA. Predictors of OHCA recognition were addressing breathing (OR=1.76, 95% CI: 1.17-2.66) and callers located by the patient's side (OR=2.16, 95% CI: 1.46-3.19). Recognition of OHCA during emergency calls was positively associated with the provision of bystander CPR, ROSC, and 30-day survival in witnessed OHCA.


Topical flurbiprofen pretreatment does not block apraclonidine's effect on aqueous flow in humans.
Flurbiprofen's effect on the ability of apraclonidine hydrochloride (para-aminoclonidine) to reduce aqueous humor flow was studied in 20 healthy human volunteers. Flurbiprofen sodium, in a 0.03% concentration, was administered topically to one eye and a placebo to the contralateral eye of each subject in a random, double-masked fashion. A total of four drops was administered to each eye during a 30-minute period beginning at 7 AM. Thirty minutes later, one drop of 1% apraclonidine was instilled into each eye. Flow rates were measured with fluorophotometry from 7 AM to noon. The mean (+/- SD) rate of flow after administration of flurbiprofen and apraclonidine at the peak of apraclonidine's effect was 1.56 +/- 0.50 microL/min, and after administration of placebo and apraclonidine was 1.53 +/- 0.43 microL/min. With a sample size of 20 and a coefficient of variation of flow measurement of 15%, there is a 95% chance of detecting a difference in flow rate of 15% or greater using the techniques employed in this study. Since there was no statistically significant difference between the rates of flow under the two conditions, we conclude that flurbiprofen has no appreciable effect on apraclonidine's ability to suppress aqueous flow.


Vocal cord paralysis following orthognathic surgery intubation.
The incidence of recurrent laryngeal nerve paralysis following short-term oro-endotracheal intubation for any surgical procedure is very rare. The diagnosis becomes very difficult if the surgical procedure may alter the vocal characteristics following surgery. We report a case of a 24 year-old healthy male patient who developed prolonged hoarseness which developed after having undergone a bimaxillary orthognathic surgical procedure. Following surgery, the patient's complaints of hoarseness and mild coughing on taking thin liquids were investigated with the assistance of the otolarynology voice department. A flexible fiberoptic laryngoscopy and videostroboscopy showed a partial paralysis of the left vocal cord suggesting damage to the left recurrent laryngeal nerve. The recovery was gradual and resolved without any intervention in approximately 6 weeks. Prolonged change or loss of voice quality following an orthognathic surgical procedure, as discussed in this case, when associated with difficulty in swallowing thin or thick liquids warrants a thorough investigation and can be managed at times with observation alone.


Effects of ribose on cardiac metabolism and function in isoproterenol-treated rats.
Continuous iv infusion of ribose for 5 h in unanesthetized and unrestrained rats treated with isoproterenol (25 mg/kg sc) further enhanced the available pool of 5-phosphoribosyl-1-pyrophosphate and the biosynthesis of adenine nucleotides in the myocardium. The increase in adenine nucleotide biosynthesis was of such an extent that the isoproterenol-induced decline of the ATP level (mumol/g) was attenuated after 5 h (isoproterenol + ribose infusion 4.0 +/- 0.2, n = 10; isoproterenol + NaCl infusion 3.5 +/- 0.1, n = 23; control 4.5 + 0.1, n = 38) and prevented after 24 h (isoproterenol + ribose infusion 4.6 +/- 0.3, n = 5; isoproterenol + NaCl infusion 3.2 +/- 0.1, n = 9). Ribose, however, did not affect the isoproterenol-elicited elevation of the adenosine 3',5'-cyclic monophosphate (cAMP) and glucose 6-phosphate content nor did it influence the decline in glycogen. Thus ribose acts primarily via elevation of the cardiac 5-phosphoribosyl-1-pyrophosphate pool. Measurements of hemodynamic parameters with an ultraminiature catheter pressure transducer in intact rats anesthetized with thiobutabarbital sodium revealed that ribose infusion for at least 3 h further enhanced the isoproterenol-elicited increase in left ventricular dP/dtmax by about 20% but did not influence appreciably the rise in heart rate and the fall in left ventricular systolic pressure. Since ribose did not affect the immediate hemodynamic alterations induced by isoproterenol, it appears that it exerts its hemodynamic effects via the pronounced influence on cardiac adenine nucleotide metabolism.


A comparison of the gastric emptying characteristics of selected sports drinks.
The purpose of this study was to determine the effects of repeated ingestion of drinks containing varying concentrations of carbohydrate on gastric emptying rate during steady-state exercise. On five separate occasions, 14 subjects cycled for 90 min at an average power output of 151 +/- 2 W. At 15-min intervals, subjects ingested 227 +/- 3 ml of either water, 4% carbohydrate (CHO), 6% CHO, or 8% CHO. Gastric volume was determined prior to each drink and at 90 min using the modified double-sampling technique. Gross gastric volumes were significantly greater and mean gastric emptying rates and the percentage of ingested beverage emptied from the stomach were significantly less for 8% CHO. These data indicate that repeated ingestion of an 8% CHO beverage during exercise significantly reduces gastric emptying rate, whereas lower concentrations of carbohydrate do not. In addition, beverage osmolality is not as important as beverage energy content in influencing gastric emptying rate at these carbohydrate concentrations.


Tumor necrosis factor-alpha and interferon-gamma induce expression of functional Fas ligand on HT29 and MCF7 adenocarcinoma cells.
Tumor cells develop diverse mechanisms to escape from immune surveillance, including expression of Fas ligand (FasL), a 40-kDa type II transmembrane protein that mediates apoptosis by binding to its cognate receptor Fas (APO-1/CD95). Upon activation, T lymphocytes and natural killer (NK) cells express Fas and thus become sensitive to FasL-mediated apoptosis. Here we show that tumor necrosis factor-alpha (TNF-alpha) in addition to interferon-gamma (IFN-gamma) induces cell surface expression of functional FasL in human HT29 colon and MCF7 breast adenocarcinoma cells that constitutively lack cell surface expression of FasL. These cells, expressing FasL, are capable of inducing apoptosis in Fas-positive Jurkat T cells mediated by plasma membrane-bound FasL and soluble forms of FasL. By contrast, mutational deletion of Fas cell surface expression as well as inhibition of caspase family proteases involved in Fas signaling and monoclonal antibodies neutralizing FasL protect Jurkat T cells from apoptosis caused by the FasL-expressing HT29 or MCF7 cells. These results demonstrate that TNF-alpha and IFN-gamma induce expression of functional FasL in adenocarcinoma cells which thereby can kill T lymphocytes by the FasL/Fas pathway.


Influenza-like illness surveillance on Twitter through automated learning of naïve language.
Twitter has the potential to be a timely and cost-effective source of data for syndromic surveillance. When speaking of an illness, Twitter users often report a combination of symptoms, rather than a suspected or final diagnosis, using naïve, everyday language. We developed a minimally trained algorithm that exploits the abundance of health-related web pages to identify all jargon expressions related to a specific technical term. We then translated an influenza case definition into a Boolean query, each symptom being described by a technical term and all related jargon expressions, as identified by the algorithm. Subsequently, we monitored all tweets that reported a combination of symptoms satisfying the case definition query. In order to geolocalize messages, we defined 3 localization strategies based on codes associated with each tweet. We found a high correlation coefficient between the trend of our influenza-positive tweets and ILI trends identified by US traditional surveillance systems.


Oxidation-Mediated, Zwitterionic Polydopamine Coatings for Marine Antifouling Applications.
We synthesized a zwitterionic dopamine derivative ( ZW-DOPA) containing both catechol and amine groups, and we demonstrated an excellent marine antifouling surface by controlling the oxidation of ZW-DOPA. The oxidation was mediated by the deprotonation of catechol or the addition of an oxidant (ammonium persulfate (AP) or sodium periodate (NaIO4)). The oxidation and subsequent molecular transformation of ZW-DOPA was investigated over time by UV-vis spectroscopy. Among the different oxidation conditions tested, NaIO4-induced ZW-DOPA coating was the most efficient and successfully formed on various substrates, such as titanium dioxide, stainless steel, and nylon. Compared with uncoated substrates, ZW-DOPA-coated substrates showed high resistance to marine diatom adhesion. Considering the ease of use and substrate independence of the ZW-DOPA coating, this method shows promise as a basis for inhibiting marine fouling on a variety of substrates used in the marine industry and aquatic environments.


Improving Myoelectric Control for Amputees through Transcranial Direct Current Stimulation.
Most prosthetic myoelectric control studies have shown good performance for unimpaired subjects. However, performance is generally unacceptable for amputees. The primary problem is the poor quality of electromyography (EMG) signals of amputees compared with healthy individuals. To improve clinical performance of myoelectric control, this study explored transcranial direct current stimulation (tDCS) to modulate brain activity and enhance EMG quality. We tested six unilateral transradial amputees by applying active and sham anodal tDCS separately on two different days. Surface EMG signals were acquired from the affected and intact sides for 11 hand and wrist motions in the pre-tDCS and post-tDCS sessions. Autoregression coefficients and linear discriminant analysis classifiers were used to process the EMG data for pattern recognition of the 11 motions. For the affected side, active anodal tDCS significantly reduced the average classification error rate (CER) by 10.1%, while sham tDCS had no such effect. For the intact side, the average CER did not change on the day of sham tDCS but increased on the day of active tDCS. These results demonstrated that tDCS could modulate brain function and improve EMG-based classification performance for amputees. It has great potential in dramatically reducing the length of learning process of amputees for effectively using myoelectrically controlled multifunctional prostheses.


Study on different surgical approaches for acute Lumber disk protrusion combined with Cauda Equina Syndrome.
To compare the long and short term effectiveness and complications of different surgical approaches for Lumber disk protrusion combined with Cauda Equina Syndrome and find a better surgical method for the disease. In this study, follow up records of 144 patients received conventional laminectomy and minimally invasive decompression and fenestration 48 hours within acute injury of lumber disk protrusion combined with Cauda Equina Syndrome were analyzed. Surgical outcome immediately and 3, 6, 12, 36 months after the surgery were compared to evaluate the effectiveness two different approaches. The results indicated that there are no significant differences regarding age, sexual proportion, body mass index (BMI), visual analogue scale of pain (VAS) score as well as Frankel scores before the surgery, and significant differences VAS score as well as Frankel scores immediately after the surgery. In conclusion, minimally invasive decompression and fenestration can be of the same effectiveness and less complications comparing with the conventional laminectomy.


Application of Dynamic Mode Decomposition to Study Temporal Flow Behavior in a Saccular Aneurysm.
Aneurysms are abnormal expansion of weakened blood vessels which can cause mortality or long-term disability upon rupture. Several studies have shown that inflow conditions spatially and temporally influence aneurysm flow behavior. The objective of this investigation is to identify impact of inflow conditions on spatio-temporal flow behavior in an aneurysm using dynamic mode decomposition (DMD). For this purpose, low-frame rate velocity field measurements are performed in an idealized aneurysm model using particle image velocimetry (PIV). The inflow conditions are precisely controlled using a ViVitro SuperPump system where nondimensional fluid parameters such as peak Reynolds number (Rep) and Womersely number (α) are varied from 50-270 and 2-5, respectively. The results show the ability of DMD to identify the spatial flow structures and their frequency content. Furthermore, DMD captured the impact of inflow conditions, and change in mode shapes, amplitudes, frequency, and growth rate information is observed. The DMD low-order flow reconstruction also showed the complex interplay of flow features for each inflow scenario. Furthermore, the low-order reconstruction results provided a mathematical description of the flow behavior in the aneurysm which captured the vortex formation, evolution, and convection in detail. These results indicated that the vortical structure behavior varied with the change in α while its strength and presence of secondary structures are influenced by the change in Rep.


Atherosclerosis of carotid and intracranial arteries.
The role of diagnostic imaging in the study of atherosclerosis of carotid and intracranial vessels is analyzed, after the illustration of the main characteristics of the disease. Atherosclerosis should be considered a systemic disease, however it tends to be segmental. The commonest sites are the coronary artery, the superficial femoral artery, the subrenal aorta and the carotid arteries at the level of the bifurcation. Traditionally, the percentage of intraluminal stenosis has represented the standard measurement of the severity of atheromatosis. However, the grade of stenosis is not the only sign predictive of clinical complications. The most vulnerable plaques show predominant core necrosis or hemorrhage, separated from the vascular lumen by a thin unstable fibrous cap. The two major aspects of lesions at high risk of rupture are the presence of a large soft core and the status of the fibrous cap that can be intact, ruptured or infiltrated by inflammatory cells. Imaging procedures should be addressed to the identification of these pathologic conditions predisposing to the embolic-thrombotic complication. However, additional information on blood flow dynamics, vascular collateral compensation and brain perfusion is useful for decision-making about the therapeutic approach. This is the reason why in diagnostic imaging of atheromatosis, digital angiography should be combined with color Doppler-US, CT and MRI.


Lyme arthritis in a 12-year-old patient after a latency period of 5 years.
Lyme arthritis (LA) may be confused with other rheumatic diseases, particularly in the absence of a history of erythema migrans (EM). We report the case of a 12-year-old patient who developed a large effusion of the right knee joint. The titer for antinuclear antibodies was 1:80 and the test for rheumatoid factor was negative. Investigations for antibody response to Borrelia burgdorferi demonstrated remarkable elevation of IgG antibody and no specific IgM response. These results were confirmed by immunoblotting reactivity with the bands p83/100, p58, p43, p41, p39, OspA, p30, OspC, p21, and p17. We subsequently learned that the child had suffered a tick bite followed by an EM 5 years earlier and had been treated with trimethoprim/sulfamethoxazole at that time. The patient now was given intravenous ceftriaxone, 2 g daily for 14 days. In the absence of clinical improvement 3 weeks later a knee joint aspiration was performed which resulted in a positive polymerase chain reaction (PCR) test for B. burgdorferi DNA (OspA) in the synovial fluid. The patient fully recovered 2 months later without further treatment. The case indicates that the latency period between EM and onset of LA may last up to 5 years. In addition to serologic test methods, analysis of synovial fluid using PCR may be decisive for making the final diagnosis of LA.


A poly(ε-caprolactone)-poly(glycerol)-poly(ε-caprolactone) triblock copolymer for designing a polymeric micelle as a tumor targeted magnetic resonance imaging contrast agent.
Gadolinium-based macromolecular contrast agents (CAs) with favorable biocompatibility, targeting specificity, and high relaxivity properties are desired for magnetic resonance imaging (MRI) of tumors. Herein, a novel triblock polymeric micelle based on poly(glycerol) (PG) and poly(ε-caprolactone) (PCL) was designed as a nanocarrier to fabricate a tumor targeted contrast agent (CA). Through conjugating gadolinium chelates and folic acid (FA) molecules to the PG block, a triblock-micelle contrast agent (T-micelle) formed from self-assembly demonstrated a low critical micelle concentration (CMC) of 6 mg L-1 and a hydrodynamic diameter of about 250 nm. Compared with small-molecule CAs, the T-micelle exhibited a higher longitudinal relaxivity (r1) of 14.71 mM-1 s-1. Moreover, the cellular viability assay revealed negligible cytotoxicity, and estimation of targeting capacity showed significant targeting specificity to tumor cells. In addition, MRI on tumor-bearing mice confirmed that the T-micelle could efficiently accumulate at the tumor region through targeting specificity and provide obvious contrast enhancement. Consequently, the T-micelle is a promising gadolinium-based macromolecular CA for tumor diagnosis.


The COVID-19: macroeconomics scenarii and role of containment in Morocco.
In the present paper we are interested in the epidemiological evolution of Covid19 in Morocco and we try to simulate the possible trajectories of the contagion. The objective of this research is to model the economic consequences of the epidemic and also to highlight the importance of the containment policy in facilitating economic recovery in Morocco. The results obtained using a combination of Ramsey's model and the epidemiological propagation model affirm that the choice of the containment policy made it possible to reduce the negative repercussions of the pandemic on Morocco, despite the economic consequences of the latter. The comparisons made between the two situations confirm that the economic repercussions remain moderate and Morocco will be able to face this disaster with even stricter or even more intelligent containment.


The natural inhibitor of DNA topoisomerase I, camptothecin, modulates HIF-1α activity by changing miR expression patterns in human cancer cells.
DNA topoisomerase I (Top1) inhibition by camptothecin derivatives can impair the hypoxia-induced cell transcriptional response. In the present work, we determined molecular aspects of the mechanism of camptothecin's effects on hypoxia-inducible factor-1α (HIF-1α) activity in human cancer cells. In particular, we provide evidence that low concentrations of camptothecin, without interfering with HIF-1α mRNA levels, can reduce HIF-1α protein expression and activity. As luciferase assays demonstrated the involvement of the HIF-1α mRNA 3' untranslated region in camptothecin-induced impairment of HIF-1α protein regulation, we performed microarray analysis to identify camptothecin-induced modification of microRNAs (miRNA) targeting HIF-1α mRNA under hypoxic-mimetic conditions. The selected miRNAs were then further analyzed, demonstrating a role for miR-17-5p and miR-155 in HIF-1α protein expression after camptothecin treatments. The present findings establish miRNAs as key factors in a molecular pathway connecting Top1 inhibition and human HIF-1α protein regulation and activity, widening the biologic and molecular activity of camptothecin derivatives and the perspective for novel clinical interventions.


CXCR-4 desensitization is associated with tissue localization of hemopoietic progenitor cells.
The chemokine stroma-derived factor (SDF)-1, and its receptor, CXCR-4, have been shown to be essential for the translocation of hemopoietic stem cells from the fetal liver to the bone marrow (BM). We hypothesized that if CXCR-4 plays a crucial role in the localization of human hemopoiesis, stem cells from distinct tissue sources should demonstrate distinct CXCR-4 expression or signaling profiles. CD34(+) cells from BM were compared with blood: either mobilized peripheral blood or umbilical cord blood. Unexpectedly, significantly higher levels of CXCR-4 surface expression on CD34(+) cells from blood sources, mobilized peripheral blood, or cord blood were observed compared with BM (p = 0.0005 and p = 0.002, respectively). However, despite lower levels of CXCR-4, responsiveness of the cells to SDF-1 as measured by either calcium flux or transmigration was proportionally greatest in cells derived from BM. Further, internalization of CXCR-4 in response to ligand, associated with receptor desensitization, was significantly lower on BM-derived cells. Therefore, preserved chemokine receptor signaling was highly associated with marrow rather than blood localization. To test the functional effects of perturbing CXCR-4 signaling, adult mice were exposed to the methionine-SDF-1beta analog that induces prolonged down-regulation/desensitization of CXCR-4 and observed mobilization of Lin(-), Sca-1(+), Thy-1(low), and c-kit(+) hemopoietic progenitor cells to the peripheral blood with a >30-fold increase compared with PBS control (p = 0.0007 day 1 and p = 0.004 day 2). These data demonstrate that CXCR-4 expression and function can be dissociated in progenitor cells and that desensitization of CXCR-4 induces stem cell entry into the circulation.


How eukaryotic genes are transcribed.
Regulation of eukaryotic gene expression is far more complex than one might have imagined 30 years ago. However, progress towards understanding gene regulatory mechanisms has been rapid and comprehensive, which has made the integration of detailed observations into broadly connected concepts a challenge. This review attempts to integrate the following concepts: (1) a well-defined organization of nucleosomes and modification states at most genes; (2) regulatory networks of sequence-specific transcription factors; (3) chromatin remodeling coupled to promoter assembly of the general transcription factors and RNA polymerase II; and (4) phosphorylation states of RNA polymerase II coupled to chromatin modification states during transcription. The wealth of new insights arising from the tools of biochemistry, genomics, cell biology, and genetics is providing a remarkable view into the mechanics of gene regulation.


Microbiological and genetic analysis of probiotic products licensed for medicinal purposes.
The purpose of our study was to investigate both qualitatively and quantitatively the microbial content of probiotic products licensed for medicinal purposes. Microbiological analysis was performed on five different brands of probiotic products that claimed to contain lactobacilli and/or bifidobacteria. The species were determined based on phenotypic characters, using API 50CH, API 20A, and API rapid ID 32A kits. Bacterial strains belonging to the Bifidobacterium genus were further identified using genotypic methods (amplification of specific DNA fragments by PCR and analysis of their nucleotide sequences). The products were also analyzed for pathogenic bacteria. The number of microorganisms contained in four of the products was determined using the plate-count method and the most-probable-number method. The actual and claimed content of probiotic products was analyzed statistically. Microbiological and genetic analysis showed that, in terms of quality, only three of the five products contained the bacterial strains claimed on the label. None of the tested products contained pathogens. Quantitative analysis demonstrated that 57 of 64 samples (89% [95% CI: 81-97]) contained bacterial counts at the cell densities (doses) claimed on the label. Our study demonstrates unsatisfactory qualitative microbiological specification in the tested products. However, there was good quantitative agreement with the labeling. Our findings indicate that regulations governing the labeling of probiotic products are urgently required.


Activity energy expenditure is a major determinant of dietary fat oxidation and trafficking, but the deleterious effect of detraining is more marked than the beneficial effect of training at current recommendations.
Previous studies suggested that physical activity energy expenditure (AEE) is a major determinant of dietary fat oxidation, which is a central component of fat metabolism and body weight regulation. We tested this hypothesis by investigating the effect of contrasted physical activity levels on dietary saturated and monounsaturated fatty acid oxidation in relation to insulin sensitivity while controlling energy balance. Sedentary lean men (n = 10) trained for 2 mo according to the current guidelines on physical activity, and active lean men (n = 9) detrained for 1 mo by reducing structured and spontaneous activity. Dietary [d31]palmitate and [1-¹³C]oleate oxidation and incorporation into triglyceride-rich lipoproteins and nonesterified fatty acid, AEE, and muscle markers were studied before and after interventions. Training increased palmitate and oleate oxidation by 27% and 20%, respectively, whereas detraining reduced them by 31% and 13%, respectively (P < 0.05 for all). Changes in AEE were positively correlated with changes in oleate (R² = 0.62, P < 0.001) and palmitate (R² = 0.66, P < 0.0001) oxidation. The d31-palmitate appearance in nonesterified fatty acid and very-low-density lipoprotein pools was negatively associated with changes in fatty acid translocase CD36 (R² = 0.30), fatty acid transport protein 1 (R² = 0.24), and AcylCoA synthetase long chain family member 1 (ACSL1) (R² = 0.25) expressions and with changes in fatty acid binding protein expression (R² = 0.33). The d31-palmitate oxidation correlated with changes in ACSL1 (R² = 0.39) and carnitine palmitoyltransferase 1 (R² = 0.30) expressions (P < 0.05 for all). Similar relations were observed with oleate. Insulin response was associated with AEE (R² = 0.34, P = 0.02) and oleate (R² = 0.52, P < 0.01) and palmitate (R² = 0.62, P < 001) oxidation. Training and detraining modified the oxidation of the 2 most common dietary fats, likely through a better trafficking and uptake by the muscle, which was negatively associated with whole-body insulin sensitivity.


Exploring Semi-Supervised Methods for Labeling Support in Multimodal Datasets.
Working with multimodal datasets is a challenging task as it requires annotations which often are time consuming and difficult to acquire. This includes in particular video recordings which often need to be watched as a whole before they can be labeled. Additionally, other modalities like acceleration data are often recorded alongside a video. For that purpose, we created an annotation tool that enables to annotate datasets of video and inertial sensor data. In contrast to most existing approaches, we focus on semi-supervised labeling support to infer labels for the whole dataset. This means, after labeling a small set of instances our system is able to provide labeling recommendations. We aim to rely on the acceleration data of a wrist-worn sensor to support the labeling of a video recording. For that purpose, we apply template matching to identify time intervals of certain activities. We test our approach on three datasets, one containing warehouse picking activities, one consisting of activities of daily living and one about meal preparations. Our results show that the presented method is able to give hints to annotators about possible label candidates.


Equine CTNNB1 and PECAM1 nucleotide structure and expression analyses in an experimental model of normal and pathological wound repair.
Wound healing in horses is fraught with complications. Specifically, wounds on horse limbs often develop exuberant granulation tissue which behaves clinically like a benign tumor and resembles the human keloid in that the evolving scar is trapped in the proliferative phase of repair, leading to fibrosis. Clues gained from the study of over-scarring in horses should eventually lead to new insights into how to prevent unwanted scar formation in humans. cDNA fragments corresponding to CTNNB1 (coding for beta-catenin) and PECAM1, genes potentially contributing to the proliferative phase of repair, were previously identified in a mRNA expression study as being up-regulated in 7 day wound biopsies from horses. The aim of the present study was to clone full-length equine CTNNB1 and PECAM1 cDNAs and to study the spatio-temporal expression of mRNAs and corresponding proteins during repair of body and limb wounds in a horse model. The temporal pattern of the two genes was similar; except for CTNNB1 in limb wounds, wounding caused up-regulation of mRNA which did not return to baseline by the end of the study. Relative over-expression of both CTNNB1 and PECAM1 mRNA was noted in body wounds compared to limb wounds. Immunostaining for both beta-catenin and PECAM1 was principally observed in endothelial cells and fibroblasts and was especially pronounced in wounds having developed exuberant granulation tissue. This study is the first to characterize equine cDNA for CTNNB1 and PECAM1 and to document that these genes are expressed during wound repair in horses. It appears that beta-catenin may be regulated in a post-transcriptional manner while PECAM1 might help thoracic wounds mount an efficient inflammatory response in contrast to what is observed in limb wounds. Furthermore, data from this study suggest that beta-catenin and PECAM1 might interact to modulate endothelial cell and fibroblast proliferation during wound repair in the horse.


The differential expression of EphB2 and EphB4 receptor kinases in normal bladder and in transitional cell carcinoma of the bladder.
Effective treatment of transitional cell carcinoma (TCC) of the bladder requires early diagnosis. Identifying novel molecular markers in TCC would guide the development of diagnostic and therapeutic targets. Ephrins mediate signals via tyrosine kinase activity that modulates diverse physiologic and developmental processes, and ephrins are increasingly implicated in carcinogenesis. The aim of our study was to examine the differential regulation of EphB4 and EphB2 in normal bladder and in TCC of the bladder in 40 patients undergoing radical cystectomy for curative intent. Immunostaining and Western blotting revealed that normal urothelium expresses EphB2 (20 of 24 cases, 83% of the time) not EphB4 (0 of 24 cases, 0%). In sharp contrast, TCC specimens show loss of EphB2 expression (0 of 34 cases, 0%) and gain of EphB4 expression (32 of 34, 94%). Furthermore, EphB4 signal strength statistically correlated with higher tumor stage, and trended toward the presence of carcinoma in situ (CIS). These results are confirmed by analysis of normal urothelial and tumor cell lines. EphB2 is not a survival factor in normal urothelium, while EphB4 is a survival factor in TCC. Treatment of bladder tumor xenograft with an EphB4 inhibitor sEphB4-HSA leads to 62% tumor regression and complete remission when combined with Bevacizumab. Furthermore, tissue analysis revealed that sEphB4-HSA led to increased apoptosis, decreased proliferation, and reduced vessel density, implicating direct tumor cell targeting as well as anti-angiogenesis effect. In summary loss of EphB2 and gain of EphB4 expression represents an inflection point in the development, growth and possibly progression of TCC. Therapeutic compounds targeting EphB4 have potential for diagnosing and treating TCC.


Associations between metal concentrations in whole blood and placenta previa and placenta accreta: the Japan Environment and Children's Study (JECS).
Placenta previa and placenta accreta associate with high morbidity and mortality for both mothers and fetus. Metal exposure may have relationships with placenta previa and placenta accreta. This study analyzed the associations between maternal metal (cadmium [Cd], lead [Pb], mercury [Hg], selenium [Se], and manganese [Mn]) concentrations and placenta previa and placenta accreta. We recruited 17,414 women with singleton pregnancies. Data from a self-administered questionnaire regarding the first trimester and medical records after delivery were analyzed. Maternal blood samples were collected to measure metal concentrations. The subjects were classified into four quartiles (Q1, Q2, Q3, and Q4) according to metal concentrations. The odds ratio for placenta previa was significantly higher among subjects with Q4 Cd than those with Q1 Cd. The odds ratio for placenta previa was significantly higher for subjects with Q2 Pb than those with Q1 Pb. Participants with placenta previa had higher Cd concentrations. However, this study was cross-sectional and lacked important information related to Cd concentration, such as detailed smoking habits and sources of Cd intake. In addition, the subjects in this study comprised ordinary pregnant Japanese women, and it was impossible to observe the relationship between a wide range of Cd exposure and placenta previa. Therefore, epidemiological and experimental studies are warranted to verify the relationship between Cd exposure and pregnancy abnormalities.


Tobacco/nicotine use among individuals using cannabis for therapeutic purposes.
While the relationship between recreational cannabis and nicotine use is well established, little is known about nicotine use among users of cannabis for therapeutic purposes (CTP). Patients attending a medical marijuana dispensary (N = 697; 75.3% White; 60.0% male) completed a survey examining nicotine use, motivation to quit cigarette smoking, routes of administration of nicotine and cannabis, and CTP qualifying conditions. More than one-third (39.3%) of participants reported current nicotine use. Compared to exclusive cigarette smokers, e-cigarette users and non-users of nicotine were approximately four times more likely to vape, rather than to smoke, cannabis. Furthermore, 46.8% of cigarette smokers reported plans to quit smoking in the next 6 months (but not in the next month) and an additional 31.6% planned to quit in the next month. Having a psychiatric condition was associated with nicotine use and higher motivation to quit smoking. Users of CTP are more likely to use nicotine products than the general population and the route of administration of nicotine products is related to the route of administration of CTP. If aerosolized CTP is a less harmful route of administration than smoked CTP, dispensary staff should be aware of this relationship and take this into account when recommending a noncombustible route. This study further characterizes nicotine use behaviors and motivation to quit smoking among users of CTP and may be among the first to examine nicotine use among patients of a medical marijuana dispensary.


Hypocalcemia, hypoparathyroidism, and organic anxiety syndrome.
The author describes a case of functional hypoparathyroidism with hypocalcemia that developed in a patient after ablation of a parathyroid adenoma. The patient's clinical presentation was characterized by a severe anxiety state. The literature on the neuropsychiatric manifestations of hypoparathyroidism indicates that anxiety states are not uncommon in this condition and suggests that hypoparathyroidism should be considered in the differential diagnosis of organic anxiety syndrome.


Randomised study of the influence of non-steroidal anti-inflammatory drugs on the treatment of peptic ulcer in patients with rheumatic disease.
Sixty-seven patients with rheumatic disease, treated with non-steroidal anti-inflammatory drugs (NSAIDs), entered a controlled trial with a diagnosis of duodenal (n = 51), gastric (n = 14), or gastric and duodenal (n = 2) ulcers. The main objectives of the study were a comparison of ranitidine and sucralfate in ulcer treatment, and to observe the influence of continued NSAID administration during peptic ulcer therapy. Ulcers healed within nine weeks in 52 patients. The mean healing time was similar in 27 patients given ranitidine 150 mg bd (4.9 weeks) and 25 patients given sucralfate 1 g qid (4.6 weeks). In patients with unhealed ulcers after nine weeks of treatment, healing was obtained in seven after further therapy for 3-9 weeks. Of the 30 patients who continued NSAIDs during treatment with either ranitidine or sucralfate, 23 ulcers healed (mean healing time: 5.0 weeks). Of 32 patients in whom NSAIDs were stopped, ulcer healing was documented in 29 (mean healing time: 4.6 weeks). The difference in healing rates was not statistically significant (p greater than 0.10). The outcome of ulcer treatment did not differ in patients with rheumatoid arthritis and patients suffering from osteoarthritis. During a 12 month follow up 14 symptomatic ulcer recurrences were recorded.


Development of a physiologically based pharmacokinetic model of actinomycin D in children with cancer.
Use of the anti-tumour antibiotic actinomycin D is associated with development of hepatotoxicity, particularly in young children. A paucity of actinomycin D pharmacokinetic data make it challenging to develop a sound rationale for defining dosing regimens in younger patients. The study aim was to develop a physiologically based pharmacokinetic (PBPK) model using a combination of data from the literature and generated from experimental analyses. Assays to determine actinomycin D Log P, blood:plasma partition ratio and ABCB1 kinetics were conducted. These data were combined with physiochemical properties sourced from the literature to generate a compound file for use within the modelling-simulation software Simcyp (version 14 release 1). For simulation, information was taken from two datasets, one from 117 patients under the age of 21 and one from 20 patients aged 16-48. The final model incorporated clinical renal and biliary clearance data and an additional systemic clearance value. The mean AUC0-26h of simulated subjects was within 1.25-fold of the observed AUC0-26h (84 ng h ml(-1) simulated vs. 93 ng h ml(-1) observed). For the younger age ranges, AUC predictions were within two-fold of observed values, with simulated data from six of the eight age/dose ranges falling within 15% of observed data. Simulated values for actinomycin D AUC0-26h and clearance in infants aged 0-12 months ranged from 104 to 115 ng h ml(-1) and 3.5-3.8 l h(-1) , respectively. The model has potential utility for prediction of actinomycin D exposure in younger patients and may help guide future dosing. However, additional independent data from neonates and infants is needed for further validation. Physiological differences between paediatric cancer patients and healthy children also need to be further characterized and incorporated into PBPK models.


Leukocyte esterase analysis in the diagnosis of joint infection: can we make a diagnosis using a simple urine dipstick?
Analysis of joint fluid remains a key factor in the diagnosis of periprosthetic infection. Recent reports have shown that neutrophils in infected joint fluid release esterase, an enzyme that is a reliable marker for infection. Testing for leukocyte esterase is routinely done in the analysis of urine for the presence of urinary tract infection, by a simple "dipstick" method. We report our experience with this technique in the evaluation of patients suspected of having septic arthritis or periprosthetic joint infection (PJI) by comparing results of leukocyte esterase positivity with confirmed joint infection as defined by the American Academy of Orthopaedic Surgeons (AAOS). We retrospectively reviewed leukocyte esterase test results performed on synovial fluid aspirated from 57 patients with prosthetic (52) and native (5) joints. Patients either presented with unexplained painful arthroplasties, routine testing of PROSTALAC (PROSthesis with Antibiotic-Loaded Acrylic Cement) orthopedic implants, or clinical suspicion of periprosthetic infection or septic arthritis. Synovial fluid was percutaneously aspirated using a standard technique. The patient age range was 31-91 years with a mean age of 69.1 years, consisting of 30 women (52.6 %) and 27 men (47.4 %). The "gold standard" for the presence or absence of infection at our institution and in the study group was based on the most recent recommendations of the AAOS. Positive culture remained the "gold standard" for native joint infection. Of the total 57 joints aspirated and included in the study, 20 (35.1 %) were read as positive (2+) on the leukocyte test strip and 37 (64.9 %) were read as negative (negative, trace, or 1+). PJI was diagnosed in 19 patients and native joint septic arthritis was identified in one patient. Sensitivities were excellent at 100 % with no false negatives in the entire cohort. There was one false positive in the periprosthetic group yielding a specificity, positive predictive value and negative predictive value of 97, 95, and 100 %, respectively. The results for the native joints showed markedly less specificity and positive predictive value at 50 and 33 %; however, its negative predictive value remained at 100 %. Our test results confirm that the leukocyte esterase test can accurately detect PJI and that it can be used as a part of the traditional PJI workup. In the assessment of native joints, its high negative predictive value suggests that it is a valuable tool in excluding native joint septic arthritis.


Personality disorders from a phenomenological perspective.
Different studies have questioned the capacity of the categorical diagnostics to establish a clear distinction between the existence or not of a determined personality disorder. The dimensional perspective would approach more to reality, in the measure that it tries to measure the different intensity degrees in which these disorders are present in the patients. But its application is very laborious and besides, presupposes that those categories whose nuances it pretends to measure really exist. The foresaid leads us to appeal to phenomenological perspective, which seems to be more adequate for the study of complex realities, as it is the case of the personality and its disorders. The essential features of the phenomenological method in the sense of Husserl are described, as well as his contribution to the study of personality disorders. This can be summarized in three fundamental points: the ideal types, introduced in psychiatry by Karl Jaspers, the existential types, by Ludwig Binswanger, and the dialectic typologies and polarities, by Wolfgang Blankenburg and the undersigned. This author defines and develops each one of these concepts, aiming to show their advantages with respect to the categorical and dimensional systems.


An observational study to assess changes in arterial blood gas values during untreated porcine ventricular fibrillation.
Cardiocerebral resuscitation (CCR) is reportedly superior to cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest (OHCA) even though active ventilation is not initially provided. Understandably, concerns have been raised regarding the withholding of positive pressure ventilation (PPV) during CCR because of the longstanding belief that respiratory gas exchange is a critical action during resuscitation. In this observational study, we sought to quantify the effect of prolonged untreated ventricular fibrillation (VF) on arterial pH, partial pressure of carbon dioxide (pCO(2)), and partial pressure of oxygen (pO(2)) values in a swine model of witnessed cardiac arrest to begin exploring the validity of these concerns. Both included studies were approved by the institutional animal care and use committee (IACUC). Eighty-three animals (25-35 kg) were instrumented under general anesthesia. Baseline characteristics were recorded. An arterial blood gas (ABG) sample was drawn from each animal via femoral catheter just prior to electrical induction of VF. After 8 minutes of untreated VF in one study (study 1 [n = 30]) and 10 minutes of untreated VF in the other study (study 2 [n = 53]), a second ABG sample was drawn. All samples were processed immediately using an i-STAT portable whole blood analyzer. Baseline characteristics of animals in the two studies were assessed using descriptive statistics. For the second ABG sample in each study, the mean pH, pCO(2), and pO(2) values, with 95% confidence intervals (95% CIs), were determined. The paired ABG results for each animal were then compared and the average pH, pCO(2), and pO(2) proportions, with 95% CIs, for each study were calculated. The baseline characteristics of the animals in the two studies were similar. After 8 and 10 minutes of untreated VF cardiac arrest, the pH values were 7.35 (95% CI = 7.32, 7.37) and 7.37 (95% CI = 7.36, 7.38), the pCO(2) increased to 44.1 mmHg (95% CI = 41.1, 47.1) and 52.7 mmHg (95% CI = 51.0, 54.4), and the pO(2) decreased to 44.8 mmHg (95% CI = 42.2, 47.4) and 45.5 mmHg (95% CI = 43.3, 47.6), respectively. Using our swine model of witnessed cardiac arrest with prolonged untreated VF, the arterial pH remained essentially unchanged and the pCO(2) increased to 1.42 times baseline after 10 minutes, while almost half of the initial O(2) concentration in the blood at the beginning of resuscitation remained.


HIV-1 therapeutic vaccine: a ray of hope.
The human immunodeficiency virus (HIV) epidemic is still in its early stages, and a marked increase in global prevalence is projected for the next coming years. Neither behavioural therapies nor current antiretroviral drugs are likely to have an impact on this silent epidemic. Current antiretroviral drugs are too expensive for the developing countries, and there are major problems of adherence, resistance and toxicity, which limit their application and efficacy. The main problem facing us, as inhabitants of a single world, is to prevent further infections regardless of where they occur, and this requires a vaccine programme. A successful immunotherapeutic HIV vaccine has the potential to overcome these problems, and would be a valuable advance. To accelerate the development of an HIV vaccine, additional candidate vaccines must be evaluated in parallel in both industrialized and developing countries. This will require international collaboration and coordination and critical ethical issues will need to be addressed. The probable triple cocktail of the future for global HIV prevention will be vaccination, anti-retroviral therapy, and not the least, behavioural therapy.


What is backward disequilibrium and how do i treat it? A complex patient case study.
Postural vertical refers to a component of an individual's perception of verticality that is derived from information about the direction of gravitational forces. Backward disequilibrium (BD) is a postural disorder observed in some older adults who have a distortion in their perception of postural vertical. Individuals with BD sustain their center of mass (COM) posterior to their base of support and resist correction of COM alignment. The purposes of this case study are to describe a patient with BD and propose a physical therapy management program for this condition. The patient was an 83-year-old woman admitted for home care services 4 months after falling and sustaining a displaced right femoral neck fracture and subsequent hemiarthroplasty. Details of the clinical examination, diagnosis, and intervention are provided and a treatment protocol for physical therapy management is suggested. During the episode of care, the patient (1) decreased her dependence on caregivers, (2) surpassed minimal detectable change or minimal clinically important improvements in gait speed and on the Short Physical Performance Battery and Performance-Oriented Mobility Assessment, and (3) achieved her primary goal of staying in her own apartment at an assisted living facility. Knowledge of BD coupled with a thorough clinical examination may assist physical therapists in identifying this condition and employing the specific intervention we have proposed. We believe that failure to recognize and manage our patient's condition appropriately would have led to nursing home placement.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A94).


Highly efficient 10 cm long fiber laser.
We investigate an innovative multipass-pumping technique in a short photonic crystal fiber laser. The technique is based on simple optical elements and shows, in a power oscillator configuration, highly efficient CW and Q-switched operation of an extremely short fiber laser. We report significantly higher absorption of the pump light, compared to a single-pass configuration, which results in an impressive fourfold increase in slope efficiency, up to 60%. Moreover, we show pulse energy of 1.22 mJ and pulse duration shorter than 12 ns, corresponding to a peak power of more than 100 kW.


The alloreactive and self-restricted CD4+ T cell response directed against a single MHC class II/peptide combination.
The cellular basis for allograft rejection derives from the strong T cell response to cells bearing foreign MHC. While it was originally assumed that alloreactive T cells focus their recognition on the polymorphic residues that differ between syngeneic and allogeneic MHC molecules, studies with MHC class I-restricted CTL have shown that MHC-bound peptides play a critical role in allorecognition. It has been suggested that alloreactive T cells depend more strongly on interactions with the MHC molecule than with the associated peptide, but there is little evidence to support this idea. Here we have studied the alloreactive and self-restricted response directed against the class II H2-Ab molecule bound with a single peptide, Ep, derived from the H2-Ealpha chain. This MHC class II-peptide combination was a poor target and stimulator of alloreactive CD4+ T cell responses, indicating that MHC-bound peptides are as important for alloreactive CD4+ T cells as they are for alloreactive CTL. We also generated alloreactive T cells with exquisite specificity for the Ab/Ep complex, and compared their reactivity with self-restricted T cells specific for the same Ab/Ep complex. Our results showed that peptide-specific alloreactive T cells, as compared with self-restricted T cells, were more sensitive to peptide stimulation, but equally sensitive to amino acid substitutions in the peptide. These findings indicate that alloreactive and self-restricted T cells interact similarly with their MHC/peptide ligand.


Children's meals in restaurants: families need more help to make healthy choices.
Helping families make healthier choices when eating out is important because eating out is a growing and significant part of Americans' diets and eating out is associated with obesity. Although a number of restaurants have announced improvements recently, many restaurant children's meals remain high in calories, saturated fat, and sodium, and default options are often fries and sugary drinks. Behavioral economic interventions that make default options healthy make healthy choices easier and mean that individuals must actively work to engage in less desirable behaviors. Providing healthier default options for children's meals supports parents by reducing barriers to feeding their children healthfully. This article outlines a number of ways to help families make the healthy choice the easy and the default choice for children when eating out.


Optimized CRISPR guide RNA design for two high-fidelity Cas9 variants by deep learning.
Highly specific Cas9 nucleases derived from SpCas9 are valuable tools for genome editing, but their wide applications are hampered by a lack of knowledge governing guide RNA (gRNA) activity. Here, we perform a genome-scale screen to measure gRNA activity for two highly specific SpCas9 variants (eSpCas9(1.1) and SpCas9-HF1) and wild-type SpCas9 (WT-SpCas9) in human cells, and obtain indel rates of over 50,000 gRNAs for each nuclease, covering ~20,000 genes. We evaluate the contribution of 1,031 features to gRNA activity and develope models for activity prediction. Our data reveals that a combination of RNN with important biological features outperforms other models for activity prediction. We further demonstrate that our model outperforms other popular gRNA design tools. Finally, we develop an online design tool DeepHF for the three Cas9 nucleases. The database, as well as the designer tool, is freely accessible via a web server, http://www.DeepHF.com/ .


Internal anal sphincter augmentation and substitution.
There is an increasing recognition of the importance of internal anal sphincter (IAS) dysfunction presenting as passive faecal incontinence. This problem may manifest after anal sphincterotomy or following the more minimally invasive operations for haemorrhoids, as well as with advancing age. Because of the poor results of IAS plication and the beneficial outcomes with peri-urethral bulking agents in urology, these materials have been developed for use in IAS dysfunction. This review outlines the basic purported mechanisms of action, defining the materials in clinical use, their methods of deployment, complications and reported outcomes. There is still much that is unknown concerning the ideal agent or the volume and the technique of deployment, which will only be answered by powerful, prospective, randomized, controlled trials. The specific role of autologous stem cells designed to regenerate the sphincters in cases of functional impairment or muscle loss is yet to be seen.


Translatome analysis of an NB-LRR immune response identifies important contributors to plant immunity in Arabidopsis.
An important branch of plant immunity involves the recognition of pathogens by nucleotide-binding, leucine-rich repeat (NB-LRR) proteins. However, signaling events downstream of NB-LRR activation are poorly understood. We have analysed the Arabidopsis translatome using ribosome affinity purification and RNA sequencing. Our results show that the translational status of hundreds of transcripts is differentially affected upon activation of the NB-LRR protein RPM1, showing an overall pattern of a switch away from growth-related activities to defense. Among these is the central translational regulator and growth promoter, Target of Rapamycin (TOR) kinase. Suppression of TOR expression leads to increased resistance to pathogens while overexpression of TOR results in increased susceptibility, indicating an important role for translational control in the switch from growth to defense. Furthermore, we show that several additional genes whose mRNAs are translationally regulated, including BIG, CCT2, and CIPK5, are required for both NB-LRR-mediated and basal plant innate immunity, identifying novel actors in plant defense.


Pattern of vital staining and its correlation with aqueous tear deficiency and meibomian gland dropout.
To assess the relationship between the degree and anatomic location of ocular surface vital staining and the degree of aqueous tear deficiency in patients with dry eye, as measured by the Schirmer test, and the presence of meibomian gland dropout. Twenty-two patients with dry eye (nine men and 13 women; mean age, 60 years) were prospectively enrolled in the study. Eleven subjects with no ocular disease were considered control subjects. Lissamine green vital staining, Schirmer test, and meibomian gland dropout were evaluated. Patients were stratified based on their vital staining pattern (presence or absence of corneal staining). A progressive decrease in the Schirmer test result was found when the vital staining score increased (r = -0.655; P<0.0001). Patients with dry eye showed an increase in meibomian gland dropout when compared to control subjects (P<or=0.001). The presence of corneal vital staining correlates with a more severe dry eye as shown by the Schirmer test. Patients with dry eye have an increased meibomian gland dropout. The degree and pattern of vital staining correlate with the severity of dry eye.