Caring for the suicidal person: A Delphi study of what characterizes a recovery-oriented caring approach.
More research is needed for supporting mental health nurses in their caring for suicidal individuals. This study aimed to describe what characterizes a recovery-oriented caring approach, and how this can be expressed through caring acts involving suicidal patients and their relatives. Delphi methodology was used, and research participants were recruited as experts by experience to explore a recovery-oriented caring approach in a dialogical process between the experts and the researchers. The results highlight that it is important to acknowledge the view of the uniqueness of each person and reflected understanding of each individual person and experience. The results also reveal that a recovery-oriented caring approach is characterized by a 'communicative togetherness'. This communicative togetherness is associated with enabling a nurturing and caring space for suicidal patients to really express themselves and to reach for their own resources. The recovery-oriented caring approach has thereby potential to facilitate a mutual understanding of the complexities of the patient's situation, and supports patients in influencing their care and regaining authority over their own lives. Accordingly, mental health nurses need to listen sensitively to what suicidal patients really say by acknowledging their lifeworlds and being open to individual variations of their recovery processes. This includes recognizing available and supportive relatives as capable of contributing to the patient's life project to continue living.


Prostaglandins and parturition.
It seems likely that prostaglandins play a significant part in the mechanisms of parturition both at term and preterm. Concentrations of prostaglandins are increased in the blood, urine and amniotic fluid during labour. There are differences in the concentrations of prostaglandins in amniotic fluid from the forebag and hindbag. Nevertheless, if liquor is sampled only from the hindbag a highly significant increase in prostaglandin concentrations occurs throughout labour. Furthermore, we now have evidence that prostaglandin concentrations in amniotic fluid increase before the onset of labour. Prostaglandins are synthesized by uterine tissues and increased rates of production occur during labour. The amnion, chorion and decidua all contain mRNA for the newly-discovered inducible form of prostaglandin H synthase (PGHS-2) as well as mRNA for the constitutive form (PGHS-1). Using the reverse transcription polymerase chain reaction (RT-PCR) both mRNAs can be detected during late pregnancy whether women are in labour or not. PGHS-2 protein is detected by Western blot analysis in cells derived from all three tissues. There is regulation of PGHS-2 protein amounts by cytokines, phorbol esters and growth factors. For example, in amnion cells interleukin-1 beta induces a rapid increase in PGHS-2 mRNA levels followed by a decrease to undetectable levels within 4 h of treatment; PGHS-2 protein amounts are also elevated by this treatment. Administration of prostaglandins will induce labour and delivery, whereas inhibition of prostaglandin biosynthesis will delay labour and delivery. Hence, increased prostaglandin production is likely to be a key determinant of the onset and progression of the parturient process.


Toward a Combinatorial Approach for the Prediction of IgG Half-Life and Clearance.
The serum half-life and clearance of therapeutic monoclonal antibodies (mAbs) are critical factors that impact their efficacy and optimal dosing regimen. The pH-dependent binding of an mAb to the neonatal Fc receptor (FcRn) has long been recognized as an important determinant of its pharmacokinetics. However, FcRn affinity alone is not a reliable predictor of mAb half-life, suggesting that other biologic or biophysical mechanisms must be accounted for. mAb thermal stability, which reflects its unfolding and aggregation propensities, may also relate to its pharmacokinetic properties. However, no rigorous statistical regression methods have been used to identify combinations of physical parameters that best predict biologic properties. In this work, a panel of eight mAbs with published human pharmacokinetic data were selected for biophysical analyses of FcRn binding and thermal stability. Biolayer interferometry was used to characterize FcRn/mAb binding at acidic and neutral pH, while differential scanning calorimetry was used to determine thermodynamic unfolding parameters. Individual binding or stability parameters were generally weakly correlated with half-life and clearance values. Least absolute shrinkage and selection operator regression was used to identify the combination of two parameters with the best correlation to half-life and clearance as being the FcRn binding response at pH 7.0 and the change in heat capacity. Leave-one-out subsampling yielded a root mean square difference between observed and predicted half-life of just 2.7 days (16%). Thus, the incorporation of multiple biophysical parameters into a cohesive model may facilitate early-stage prediction of in vivo half-life and clearance based on simple in vitro experiments.


Validation of microdialysis probes for studying nitrosative chemistry within localized regions of the human upper gastrointestinal tract.
We have examined the suitability of microdialysis probes for examining nitrosative chemistry within localized regions of the lumen of the gastrointestinal tract. Chemical nitrosation occurs maximally at pH 2.5 in the presence of nitrite and thiocyanate and absence of ascorbic acid. Nitrite and thiocyanate are delivered into the stomach in saliva and ascorbic acid is secreted in gastric juice. We used a benchtop model to reproduce the nitrosative chemistry occurring in the human upper GI tract and assessed the ability of the microdialysis probes to measure it. The microdialysis probes were reliable at measuring nitrite ascorbic acid, total vitamin C and thiocyanate in both aqueous solutions and human gastric juice over the full range of intragastric pH, i.e. 1.5, 2.5, 3.5, 5.0 and 7.0. The probes were also reliable at measuring these chemicals under conditions simulating the active interaction between nitrite and ascorbic acid. Under such conditions with ascorbic acid in excess the probes gave a more accurate assessment of the nitrite level than that obtained by directly sampling the gastric juice. This was due to the probes not being subject to artefactual measurement of nitric oxide as nitrite. This was prevented by the rapid diffusion of nitric oxide through the probe collecting tube. Microdialysis probes provide a reliable means of examining nitrosative chemistry within the lumen of the upper GI tract. In addition, they have the advantage of measuring this chemistry in very local regions and of simultaneously comparing the chemistry in different regions of the upper GI tract.


Lipopolysaccharide initiates a bypass feedback loop of epidermal growth factor receptor signaling by HPS70-induced COX-2 in H22 hepatocarcinoma cells.
LPS can induce TACE upregulation via signaling from TLR4-derived EGFR activation in tumor cells. The regulation and activity of TACE have been investigated with the observation that gene expression is upregulated in response to LPS followed by EGFR activation, however, the process remains poorly understood. In this study, we examined the effects of LPS on H22 hepatocarcinoma cells that displayed constitutively active TLR4 expression. Upon TLR4 shRNA transfection into H22 cells, HSP70 expression significantly increased. However, LPS induced early phosphorylation of EGFR in H22 cells, which reached maximum levels within 30 min. Inhibition of TLR4 in H22 cells resulted in a significant rise in both EGFR phosphorylation and TACE upregulation 24 h after exposure to LPS. Exogenous HSP70 also induced rapid phosphorylation of EGFR, upregulated the expression of COX-2 via a signaling pathway that involved TACE-dependent TGF-α release. Furthermore, inhibition of EGFR activation and reduction of COX-2 expression by COX-2 inhibitor prevented HSP70-induced cell invasion in vitro. These findings demonstrate that the biological importance of HSP70/COX-2 is crucial to the second, but not the first, phase of EGFR phosphorylation in tumor cells. The growth of tumor cells by inserting shRNA plasmid TLR4 combination with COX-2 inhibitor could be effectively reduced in LPS stimulation. We concluded that LPS triggered a bypass feedback loop of EGFR activation and involved HSP70/COX-2 in H22 cells by inhibition of TLR4 and that EGFR phosphorylation is implicated in tumor growth by LPS stimulation.


Flexible sigmoidoscopy or colonoscopy as a screening modality for colorectal adenomas in older age groups? Findings in a cohort of the normal population aged 63-72 years.
Most cases of colorectal cancer originate from adenomas. Removing adenomas has been shown to reduce the incidence of colorectal cancer. The design of cost effective endoscopic screening programmes requires a knowledge of the distribution of adenomas in different age groups. To investigate the distribution of colorectal adenomas in older age groups in the normal population. A total of 356 men and women selected randomly from the population register were offered a colonoscopic screening examination to detect and remove polyps. In all, 241(68%) subjects, mean age 67.4 years (range 62-73), attended. The caecum was intubated in 193 (80%), and in this group 32 (38%) women and 51 (47%) men had adenomas. One hundred and ten (54%) of the adenomas and 11 (39%) of the "high risk adenomas" (adenomas larger than 10 mm in diameter, adenomas containing villous components, and adenomas with severe dysplasia) were found proximal to the sigmoid colon. In 36 (43%) of the subjects with adenomas, the adenomas were only found proximal to the sigmoid colon. Twenty two (11%) subjects had more than two adenomas. Of 203 adenomas discovered, 189 (93%) were less than 10 mm in diameter. More than half of the adenomas were localised proximal to the sigmoid colon, and, in nearly half of the adenoma bearing subjects examined, the adenoma was proximal to the descending colon. This indicates that a sigmoidoscopic screening examination in this age group would miss a substantial number of adenomas, but this may be acceptable as the vast majority of proximal adenomas do not progress to clinical cancer within the life expectancy of this age group.


Obesity and reproductive function: a review of the evidence.
Over the last decade, the evidence linking obesity to impaired reproductive function has grown. In this article, we review this evidence and discuss the underlying pathophysiology. Obese women are less likely than normal-weight women to achieve pregnancy. Female obesity adversely affects reproductive function through alterations in the hypothalamic-pituitary-ovarian axis, oocyte quality, and endometrial receptivity. It is unclear which mechanism contributes the most to subfecundity, and it is likely a cumulative process. Emerging data highlight the contribution of male obesity to impaired reproductive function and that couple obesity has synergistic adverse effects. Once pregnant, obese women are at higher risk for adverse pregnancy outcomes. Weight loss improves reproductive potential in obese patients. As obese women surpass 35 years of age, age may be more important than body mass index in determining reproductive potential. Obstetrician gynecologists need to be aware of the negative impact of obesity on reproductive function so that they appropriately counsel their patients. Further work is needed to clarify the underlying pathophysiology responsible for adverse effects of obesity on reproduction so that novel treatment approaches may be developed.


[The comparative study of the medical action of lyuteolin, rosmarinic acid and echinochrom A at experimental stress-induced cardiopathology].
The method of the physical load in condition of the coronary circulation of the blood disturbance, caused mesaton injection, induced development rat cardiopathology, bring about of the heart function decompensation and 40% death of experimenthal animals. Under electronic-microscopic study of rat cardiomyocytes are discovered signs to disorganizations of mitochondrial apparatus of these cells. Administration to therapeutic mode of luteolin and echinochrome A preparations has provided to 100% animal probability of survival. At the same time, mitochondrial apparatus of cardiomyocytes was characterized by the normal parameter i.e. given preparations have provided of defensive adative effect at cardiomyocytes level. Similar activities for rosmarinic acid have not shown. Study some metabolic parameter and endocrine status animal has also allowed revealing of therapeutic effect of luteolin and echinochrome A. Findings be evidence of that echinochrome A and luteolin capable to play the important positive role in metabolism of cardiomyocytes by stimulating of mitochondrial biogenesis and by changing of adaptative mechanisms of the organism cardiovascular system protection.


Effect of vitamin D sterols and dietary magnesium on calcium and phosphorous homeostasis.
Calcium (Ca) and phosphorus (P) metabolism were studied in vitamin D-deficient rats as vitamin D status and dietary magnesium (Mg) were varied. Rats given normal (0.03%) or high (0.2%) Mg diets received either vehicle, vitamin D3 (1,650 pmol/day), or 1,25-dihydroxyvitamin D3 (60 pmol/day) for 9 days. In vitamin D-deficient rats, high dietary Mg lowered intestinal Ca absorption from 40 +/- 5 to 11 +/- 5%; P absorption decreased 50%. Treatment with 1,25-dihydroxyvitamin D3 prevented the Mg-induced fall in absorption; vitamin D3 did so only for the first 6 days. The total Ca and Mg (Ca + Mg) absorbed (mM/day) decreased from 0.85 +/- 0.050 mM/day to 0.14 +/- 0.10 with the high dietary Mg; 1,25-dihydroxyvitamin D3 treatment raised Ca + Mg absorption regardless of diet Mg; high dietary Mg raised serum Ca despite a decreased intestinal Ca absorption and urinary Ca; treatment with either sterol had no added calcemic effect. These results are consistent with two processes for intestinal Ca and P transport: one vitamin D-dependent and the other non-vitsamin D-dependent and inhibited by high dietary Mg. Also high dietary Mg increases serum Ca, perhaps by affecting bone resorption.


Semaphorin 4D Induces Vasculogenic Differentiation of Dental Pulp Stem Cells.
This work aimed to evaluate the effect of Semaphorin 4D (SEMA4D) signaling through Plexin B1 on the vasculogenic differentiation of dental pulp stem cells. We assessed the protein expression of SEMA4D and Plexin B1 in dental pulp stem cells (DPSC) from permanent human teeth and stem cells from human exfoliated deciduous (SHED) teeth using Western blots. Their expression in human dental pulp tissues and DPSC-engineered dental pulps was determined using immunofluorescence. We then exposed dental pulp stem cells to recombinant human SEMA4D (rhSEMA4D), evaluated the expression of endothelial cell differentiation markers, and assessed the vasculogenic potential of rhSEMA4D using an in vitro sprouting assay. Lastly, Plexin B1 was silenced to ascertain its role in SEMA4D-mediated vasculogenic differentiation. We found that SEMA4D and Plexin B1 are expressed in DPSC, SHED, and human dental pulp tissues. rhSEMA4D (25-100 ng/mL) induced the expression of endothelial markers, i.e., vascular endothelial growth factor receptor (VEGFR)-2, cluster of differentiation (CD)-31, and tyrosine kinase with immunoglobulin-like and EGF-like domains (Tie)-2, in dental pulp stem cells and promoted capillary-like sprouting in vitro (p < 0.05). Furthermore, Plexin B1 silencing abrogated the vasculogenic differentiation of dental pulp stem cells and significantly inhibited capillary sprouting upon exposure to rhSEMA4D. Collectively, these data provide evidence that SEMA4D induces vasculogenic differentiation of dental pulp stem cells through Plexin B1 signaling.


Effects of repeated sensory stimulation sessions (electro-acupuncture) on skin temperature in chronic pain patients.
Changes in skin temperature and haemodynamics were studied during experimentally administered electro-acupuncture before and after a 4-week period of electro-acupuncture (EA) treatments. Subjective pain intensity was evaluated using a pain questionnaire. Twelve patients with long-lasting nociceptive pain were included. Before clinical treatment, skin temperature tended to decrease after 30 minutes' stimulation. In contrast, a significant increase was seen after the clinical treatment. No significant changes were seen for blood pressure, heart rate or pain intensity before and after the clinical treatment. The data indicate that an increased skin vasoconstrictor sympathetic activity may be responsible for the decreased skin temperature during the electro-acupuncture in the initial test sessions, whereas an inhibition of skin sympathetic activity and/or a release of vasodilatory substances may be responsible for the increase in temperature after completed clinical treatment. Despite a small number of subjects and correction for multiple inference, the difference in temperature effects before and up to 3 months after acupuncture treatment was significant.


Hearing rehabilitation in congenital canal atresia.
The purpose of this study was to review the results of our patients with congenital canal atresia after implantation of bone-anchored hearing aids (BAHA). The occurrence of complications was also reviewed. This was a retrospective analysis of the first 16 patients who had BAHA implantation at Universiti Kebangsaan Malaysia Medical Centre, Malaysia. Audiometric assessment was done preoperatively and postoperatively for each patient using the standard procedure. The surgical procedure was described and its complications discussed. The 16 patients consisted of 11 male and five female patients. Their mean age was 8.9 years at the time of the surgery. The main indication was bilateral canal atresia. 11 patients had implantation of BAHA performed in two stages, while the other five patients had it as a single-staged procedure. The complications that occurred were failure of osseointegration (one patient), granulation tissue overgrowth into the abutment (two patients) and cellulitis surrounding the abutment (three patients). The average preoperative unaided air conduction threshold was 64.9 dB and the average postoperative aided hearing threshold was 29.7 dB. The overall mean functional gain was 35.2 dB. BAHA has many advantages over the conventional hearing aid in the form of cosmesis, discomfort and hearing gain. It is a reliable hearing rehabilitation tool with good predictable hearing outcome in patients with bilateral canal atresia, especially those unsuitable for canalplasty. Despite its higher cost and the need for surgical implantation, its use is justifiable in properly selected patients.


Hemilingual spasm: defining a new entity, its electrophysiological correlates and surgical treatment through microvascular decompression.
We report on vascular compression syndrome of the 12th cranial nerve (hypoglossal), an occurrence not previously reported, and demonstrate, through corresponding objective electrophysiological evidence, that microvascular decompression of the hypoglossal nerve root can cure hemilingual spasm. A 52-year-old man had lower face muscle twitching and tongue spasms, which worsened with talking, chewing, or emotional stress. Carbamazepine offered only temporary relief, and relief from injections of botulinum toxin was insignificant. He was referred for surgical treatment. High-resolution magnetic resonance imaging of his posterior fossa contents revealed no obvious evidence of any compressive vessel along the facial nerve, but a compressive vessel along the hypoglossal nerve was apparent. The presence of preoperative tongue spasms encouraged interoperative monitoring of tongue motor responses. The facial nerve exit zone was explored, but microsurgical inspection of the seventh/eighth cranial nerve complex did not reveal any compressive vessel. However, at the anterolateral aspect of the medulla oblongata, the hypoglossal nerve was clearly compressed and distorted laterally by a large tortuous vertebral artery. When the artery was mobilized away from the nerve, the abnormal late electromyographic response to transcranial electrical stimulation disappeared; immediately after shredded Teflon was interpositioned between the artery and the nerve, the abnormal spontaneous tongue fasciculation also disappeared. The patient has remained spasm free 6 months after surgery. Hemilingual spasm may be caused by vascular contact/compression along cranial nerve XII at the lower brainstem and belong to the same family of cranial nerve hyperactivity disorders as hemifacial spasm.


The Effects of Interleukin-33 (IL-33) on Osteosarcoma Cell Viability, Apoptosis, and Epithelial-Mesenchymal Transition are Mediated Through the PI3K/AKT Pathway.
BACKGROUND Osteosarcoma is the most common primary tumor of bone. Interleukin-33 (IL-33) is a pro-inflammatory cytokine that also participates in tumor progression. This study aimed to investigate the role of IL-33 in human osteosarcoma cell viability, proliferation, apoptosis, and epithelial-mesenchymal transition (EMT) in vitro and the molecular mechanisms involved. MATERIAL AND METHODS The normal osteoblast cell line, hFOB 1.19, and the human osteosarcoma cell lines SOSP-9607, SAOS2, MG63, and U2OS were studied. The expression of IL-33 mRNA and protein in human osteosarcoma cell lines were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. The effects of IL-33 on human osteosarcoma cell viability, apoptosis, EMT, and the signaling pathways were studied using the MTT assay, flow cytometry, qRT-PCR, and Western blot. RESULTS IL-33 was upregulated in human osteosarcoma cell lines, including U2OS cells. The use of an IL-33 gene plasmid promoted osteosarcoma cell viability, inhibited cell apoptosis, increased the expression of Bcl-2, and reduced the expression of Bax. IL-33 reduced the level of E-cadherin and increased the levels of N-cadherin and matrix metalloproteinase-9 (MMP-9) in osteosarcoma cells at the mRNA and protein level. The use of the IL-33 plasmid increased the protein expression levels of p-AKT and the p-AKT/AKT ratio in osteosarcoma cells, and IL-33 siRNA reversed these findings. CONCLUSIONS IL-33 was highly expressed in human osteosarcoma cells. Down-regulation of IL-33 reduced cell viability and EMT of osteosarcoma cells, and induced cell apoptosis through activation of the PI3K/AKT signaling pathway.


ATP-dependent regulation of flagellar adenylylcyclase in gametes of Chlamydomonas reinhardtii.
Adenylylcyclase activity in the flagella of gametes of Chlamydomonas reinhardtii was inhibited by prior incubation at or below 30 degrees C in the presence of ATP. This decrease did not occur in the absence of ATP, in the presence of the ATP analog 5'-adenylylimidodiphosphate (App(NH)p), or in the presence of ATP plus the protein kinase inhibitor staurosporine (2 microM). If ATP treatment was performed in the absence of an ATP-regenerating system, activity initially declined and subsequently recovered. Incubation of flagella at 45 degrees C in the absence of ATP or incubation at lower temperatures in the presence of either App(NH)p or staurosporine both increased adenylylcyclase activity (over 10-fold) and blocked subsequent ATP-dependent loss of activity at 30 degrees C. This heat-induced activation was prevented by the presence of ATP plus an ATP-regenerating system. Incubation of flagella with [gamma-32P]ATP followed by gel electrophoresis in sodium dodecyl sulfate indicated the presence of endogenous protein kinase and protein phosphatase activities. These data suggest that the flagellar adenylylcyclase in Chlamydomonas gametes is inhibited by phosphorylation and stimulated by dephosphorylation. This mechanism for regulating adenylylcyclase may underlie the rapid increase in cyclic AMP that is induced by flagellar adhesion during fertilization in Chlamydomonas.


Implementing evidence-based practices for youth in an HMO: the roles of external ratings and market share.
A qualitative study of child clinicians in a non-profit HMO examined implementation of evidence-based practices (EBPs) for anxiety and oppositional defiant disorders using interviews and focus groups with 33 clinicians (97% of participants), and ethnography of emails and meetings. Analysis showed statistical measures of access and service-key elements of rating organizations' "report cards"- were central in creating "pressure" making transition to EBPs difficult. EBPs were secondary to access and service targets. "Research" and "statistics" were perceived as unrealistic, "literature" as lacking authority. Rating organizations should include outcome and fidelity metrics to align market share pressures with children's health.


An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection.
The gene for the most common and severe form of autosomal dominant polycystic kidney disease, PKD1, encodes a 14 kb mRNA that is predicted to result in an integral membrane protein of 4302 amino acids. The major challenge faced by researchers attempting to complete mutation analysis of the PKD1 gene has been the presence of several homologous loci also located on chromosome 16. Because the sequence of PKD1 and its homologs is nearly identical in the 5' region of the gene, most traditional approaches to mutation analysis cannot distinguish sequence variants occurring uniquely in PKD1. Therefore, only a small number of mutations have been identified to date and these have all been found in the 3', unique portion of the gene. In order to begin analysis of the duplicated region of PKD1, we have devised a novel strategy that depends on long-range PCR and a single gene-specific primer from the unique region of the gene to amplify a PKD1-specific template that spans exons 23-34. This 10 kb template, amplified from genomic DNA, can be employed for mutation analysis using a wide variety of sequence-based approaches. We have used our long-range PCR strategy to begin screening for sequence variants with heteroduplex analysis, and several affected individuals were discovered to have clusters of base pair substitutions in exons 23 and 25. In two patients, these changes, identified in exon 23, would be predicted to result in multiple amino acid substitutions in a short stretch of the protein. This clustering of base pair substitutions is unusual and suggests that mutation may result from unique structural features of the PKD1 gene.


Challenges in Clinical Management of Radiation-Induced Illnesses During Exploration Spaceflight.
INTRODUCTION: Analysis of historical solar particle events (SPEs) provides context for some understanding of acute radiation exposure risk to astronauts who will travel outside of low-Earth orbit. Predicted levels of radiation exposures to exploration crewmembers could produce some health impacts, including nausea, emesis, and fatigue, though more severe clinical manifestations are unlikely. Using current models of anticipated physiological sequelae, we evaluated the clinical challenges of managing radiation-related clinical concerns during exploration spaceflight.METHODS: A literature review was conducted to identify terrestrial management standards for radiation-induced illnesses, focusing on prodromal symptom treatment. Terrestrial management was compared to current spaceflight medical capabilities to identify gaps and highlight challenges involved in expanding capabilities for future exploration spaceflight.RESULTS: Current spaceflight medical resources, such as those found on the International Space Station, may be sufficient to manage some aspects of radiation-induced illness, although effective treatment of all potential manifestations would require substantial expansion of capabilities. Terrestrial adjunctive therapies or more experimental treatments are unavailable in current spaceflight medical capabilities but may have a role in future management of acute radiation exposure.DISCUSSION: Expanded medical capabilities for managing radiation-induced illnesses could be included onboard future exploration vehicles. However, this would require substantial research, time, and funding to reach flight readiness, and vehicle limitations may restrict such capabilities for exploration missions. The benefits of including expanded capabilities should be weighed against the likelihood of significant radiation exposure and extensive mission design constraints.Blue RS, Chancellor JC, Suresh R, Carnell LS, Reyes DP, Nowadly CD, Antonsen EL. Challenges in clinical management of radiation-induced illnesses during exploration spaceflight. Aerosp Med Hum Perform. 2019; 90(11):966-977.


Current approach to prevention and treatment of Pseudomonas aeruginosa infections in burned patients.
The extensively burned or severely injured patient is at increased risk of wound infection as well as of infection of other organs as a result of various degrees of impairment of host defense mechanisms. The incidence of burn wound and other infections increases as the severity of injury increases. The ease with which gram-negative, opportunistic organisms, especially Pseudomonas aeruginosa of either endogenous or exogenous origin, can colonize and invade the immunosuppressed patient demands an active infection-surveillance program. Topical therapy for burn wounds with any of three available agents has significantly reduced the occurrence of invasive pseudomonas burn-wound sepsis, but none of the agents sterilize the burn wound, and the microbial flora of the burns of any given patient may escape from control and invade viable tissue. Clinical identification and biopsy confirmation of invasive burn-wound sepsis necessitates changes in both wound and general care, with surgical and antibiotic treatment guided by the extent and depth of wound invasion. Immunologic prophylaxis and treatment of pseudomonas infections, although attractive, remain of unverified clinical effectiveness. Effective treatment of pseudomonas septicemia secondary to invasive burn-wound sepsis and of pseudomonas infections in other organs is dependent on early diagnosis, appropriate antibiotic therapy guided by sensitivity testing, and adequate surgical intervention when required.


Electrocortical evidence for rapid allocation of attention to threat in the dot-probe task.
Threatening stimuli have been shown to preferentially capture attention using a range of tasks and measures. However, attentional bias to threat has not typically been found in unselected individuals using behavioral measures in the dot-probe task, one of the most common ways of examining attention to threat. The present study leveraged event-related potentials (ERPs) in conjunction with behavioral measures in the dot-probe task to examine whether more direct measures of attention might reveal an attentional bias to threat in unselected individuals. As in previous dot-probe studies, we found no evidence of an attentional bias to threat using reaction time; additionally, this measure exhibited poor internal reliability. In contrast, ERPs revealed an initial shift of attention to threat-related stimuli, reflected by the N2pc, which showed moderate internal reliability. However, there was no evidence of sustained engagement with the threat-related stimuli, as measured by the late positive potential (LPP). Together, these results demonstrate that unselected individuals do initially allocate attention to threat in the dot-probe task, and further, that this bias is better characterized by neural measures of attention than traditional behavioral measures. These results have implications for the study of attention to threat in both unselected and anxious populations.


iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition.
The most frequently mutated protein in human cancer is p53, a transcription factor (TF) that regulates myriad genes instrumental in diverse cellular outcomes including growth arrest and cell death. Cell context-dependent p53 modulation is critical for this life-or-death balance, yet remains incompletely understood. Here we identify sequence signatures enriched in genomic p53-binding sites modulated by the transcription cofactor iASPP. Moreover, our p53-iASPP crystal structure reveals that iASPP displaces the p53 L1 loop-which mediates sequence-specific interactions with the signature-corresponding base-without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. A TF commonly uses multiple structural modules to recognize its cognate DNA, and thus this mechanism of a cofactor fine-tuning TF-DNA interactions through targeting a particular module is likely widespread. Previously, all tumor suppressors and oncoproteins that associate with the p53 DNA-binding domain-except the oncogenic E6 from human papillomaviruses (HPVs)-structurally cluster at the DNA-binding site of p53, complicating drug design. By contrast, iASPP inhibits p53 through a distinct surface overlapping the E6 footprint, opening prospects for p53-targeting precision medicine to improve cancer therapy.


The European Organisation for Research and Treatment of Cancer, State of Science in radiation oncology and priorities for clinical trials meeting report.
New technologies and techniques in radiation oncology and imaging offer opportunities to enhance the benefit of loco-regional treatments, expand treatment to new patient populations such as those with oligometastatic disease and decrease normal tissue toxicity. Furthermore, novel agents have become available which may be combined with radiation therapy, and identification of radiation-related biomarkers can be studied to refine treatment prescriptions. Finally, the use of artificial intelligence (AI) capabilities may also improve treatment quality assurance or the ease with which radiation dosing is prescribed. All of these potential advances present both opportunities and challenges for academic clinical researchers. Recently, the European Organisation for Research and Treatment of Cancer addressed these topics in a meeting of multiple stakeholders from Europe and North America. The following five themes radiobiology-based biomarkers, new technologies - particularly proton beam therapy, combination systemic and radiation therapy, management of oligometastatic disease and AI opportunities in radiation oncology were discussed in a State of Science format to define key controversies, unanswered questions and propose clinical trial priorities for development. Priorities for clinical trials implementing new science and technologies have been defined. Solutions to integrate the multidimensional complexity of data have been explored. New types of platforms and partnerships can support innovative approaches for clinical research in radiation oncology.


Human cloning, stem cell research. An Islamic perspective.
The rapidly changing technologies that involve human subjects raise complex ethical, legal, social, and religious issues. Recent advances in the field of cloning and stem cell research have introduced new hopes for the treatment of serious diseases. But this promise has raised many complex questions. This field causes debate and challenge, not only among scientists but also among ethicists, religious scholars, governments, and politicians. There is no consensus on the morality of human cloning, even within specific religious traditions. In countries in which religion has a strong influence on political decision making, the moral status of the human embryo is at the center of the debate. Because of the inevitable consequences of reproductive cloning, it is prohibited in Islam. However, stem cell research for therapeutic purposes is permissible with full consideration, and all possible precautions in the pre-ensoulment stages of early fetus development, if the source is legitimate.


Threat of Antimicrobial Resistance among Pilgrims with Infectious Diseases during Hajj: Lessons Learnt from COVID-19 Pandemic.
Hajj pilgrimage is a large mass gathering global event that may facilitate the spread and emergence of various infectious diseases as well as antimicrobial resistance (AMR) in a local and global scenario. Planning and preparing for these public health issues is a challenging and complex process for the Kingdom of Saudi Arabia (KSA) health authorities. Despite multiple efforts for the prevention and treatment of infectious diseases through longtime funding in education and medical care, the prevalence of infectious disease is still high among Hajj pilgrims. The commonly observed infectious diseases during Hajj include respiratory tract infections (influenza and pneumonia), urinary tract infections and skin infections that may necessitate the use of antimicrobials. Beta-lactams are used as a first-line treatment for hospital acquired infections as well as community acquired infections due to their broad-spectrum activity. However, most of the bacterial isolates such as Staphylococcus spp., Pseudomonas spp. and E. coli are resistant to beta-lactams. Irrational use of antimicrobials, lack of infection prevention practices and suboptimal healthcare access further exacerbate the risk of spreading AMR among Hajj pilgrims. Enhanced collaboration between countries, sharing of best practices and international cooperation are crucial in addressing AMR threats among pilgrims. Consequently, robust surveillance systems for early detection and monitoring of AMR, collaboration with national as well as international healthcare agencies, effective infection prevention and control measures, public awareness and rational use of antimicrobials via antimicrobial stewardship programs are required to mitigate the risk of AMR and ensure the health and well-being of pilgrims during Hajj.


Impairment of glucose tolerance in hyperthyroid cats.
Intravenous glucose tolerance tests were performed in eight adult cats before and after a 4-week treatment with thyroxine. The untreated cats had a mean fasting blood glucose concentration of 7.7 +/- 0.3 mmol/l and a mean fasting insulin concentration of 88 +/- 31 pmol/l which were not significantly different from mean fasting glucose and insulin concentrations after 4 weeks of thyroxine administration (6.9 +/- 0.2 mmol/l and 101 +/- 28 pmol/l respectively). At 120 min after glucose injection, the glucose concentration in untreated cats returned to baseline concentrations as did the insulin concentration. However, in the hyperthyroid cats both glucose and insulin concentrations were significantly (P less than 0.001) higher (13.6 +/- 0.8 mmol/l and 245 +/- 17 pmol/l respectively) in comparison with the baseline and untreated cats. The t1/2 for glucose disappearance was significantly higher in the cats rendered hyperthyroid, and the glucose disposal rate constant (K) was significantly lower in this group. It is concluded that hyperthyroidism in cats leads to impairment of glucose tolerance possibly due to peripheral insulin resistance.


Agenesis of the Corpus Callosum Due to Defective Glial Wedge Formation in Lhx2 Mutant Mice.
Establishment of the corpus callosum involves coordination between callosal projection neurons and multiple midline structures, including the glial wedge (GW) rostrally and hippocampal commissure caudally. GW defects have been associated with agenesis of the corpus callosum (ACC). Here we show that conditional Lhx2 inactivation in cortical radial glia using Emx1-Cre or Nestin-Cre drivers results in ACC. The ACC phenotype was characterized by aberrant ventrally projecting callosal axons rather than Probst bundles, and was 100% penetrant on 2 different mouse strain backgrounds. Lhx2 inactivation in postmitotic cortical neurons using Nex-Cre mice did not result in ACC, suggesting that the mutant phenotype was not autonomous to the callosal projection neurons. Instead, ACC was associated with an absent hippocampal commissure and a markedly reduced to absent GW. Expression studies demonstrated strong Lhx2 expression in the normal GW and in its radial glial progenitors, with absence of Lhx2 resulting in normal Emx1 and Sox2 expression, but premature exit from the cell cycle based on EdU-Ki67 double labeling. These studies define essential roles for Lhx2 in GW, hippocampal commissure, and corpus callosum formation, and suggest that defects in radial GW progenitors can give rise to ACC.


Association between the occurrence of falls and the performance on the Incremental Shuttle Walk Test in elderly women.
Because the incremental shuttle walk test (ISWT) requires agility in its performance, we hypothesized that the test may be associated with balance and risk of falls in the elderly. To evaluate and compare the association between the performance on the ISWT, the timed up and go (TUG) and the occurrence of falls in the elderly. Thirty-three elderly individuals (68±7 years) performed the TUG and the ISWT. Balance was assessed using the Berg Scale (BBS). Participants who fell at least twice in the last 12 months were placed in the "falls" group (FG) and all other participants comprised the control group (CG). There were seventeen elderly women in the FG and 16 in the CG. Participants from the FG had a significant worse performance (p<0.05) on the TUG (8.01±0.22 vs. 6.22±0.21 s), BBS (51±3 vs. 55±1 points) and ISWT [313±79 (92±15%pred.) vs. 395±75 m (113±19%pred.)] than participants from the CG. The ISWT significantly correlated with the TUG (r=-0.75, p<0.001), BBS (r=0.50, p=0.002) and number of falls (r=0.36, p=0.031). After logistic regression, the TUG was determinant (p=0.03) and the ISWT showed a tendency to determine the occurrence of falls (p=0.05). The ISWT was a valid measure to assess the risk of falls and balance and therefore, may be useful for the simultaneous assessment of cardiorespiratory fitness and balance in older women.


[Alternative type of fuel--biobutanol].
Butanol--an alternative fuel that on amid dwindling global (accessible) oil reserves can serve as a source of energy. In the industrial-scale butanol is produced by chemical synthesis, although initially butanol production was due to microbiological synthesis. For cost-efficient production, a strain of microorganisms must have over production of butanol. In the review of butanol synthesis pathway with the help of microorganisms, their regulation, the principles and techniques of increasing the productivity of the most promising strains and producer strains for industrial production.


Novel kinetic and structural properties of the class-I D-fructose 1,6-bisphosphate aldolase from Escherichia coli (Crookes' strain).
Investigation of aldolase 1, the class-I D-fructose 1,6-bisphosphate aldolase (EC220.127.116.11) from Escherichia coli (Crookes' strain), showed it to have unusual kinetic and structural properties. The enzyme appeared to be larger than was previously supposed and may be a decamer with a mol. wt. of approx. 340000. Its fructose 1,6-bisphosphate-cleavage activity was unaffected by these compounds. The enhancement exhibited a strong dependence on pH. These novel kinetic properties do not seem to be shared by any other fructose 1,6-bisphosphate aldolase, but recall the activation by polycarboxylic acids of the deoxyribose 3-phosphate aldolases from some other organisms. In view of its unusual properties, it is unlikely that aldolase 1 from E. coli is closely related to the class-1 aldolases that have been detected in several other prokaryotes, or to the typical class-1 enzymes from eukaryotes.


Canine distemper virus persistence in demyelinating encephalitis by swift intracellular cell-to-cell spread in astrocytes is controlled by the viral attachment protein.
The mechanism of viral persistence, the driving force behind the chronic progression of inflammatory demyelination in canine distemper virus (CDV) infection, is associated with non-cytolytic viral cell-to-cell spread. Here, we studied the molecular mechanisms of viral spread of a recombinant fluorescent protein-expressing virulent CDV in primary canine astrocyte cultures. Time-lapse video microscopy documented that CDV spread was very efficient using cell processes contacting remote target cells. Strikingly, CDV transmission to remote cells could occur in less than 6 h, suggesting that a complete viral cycle with production of extracellular free particles was not essential in enabling CDV to spread in glial cells. Titration experiments and electron microscopy confirmed a very low CDV particle production despite higher titers of membrane-associated viruses. Interestingly, confocal laser microscopy and lentivirus transduction indicated expression and functionality of the viral fusion machinery, consisting of the viral fusion (F) and attachment (H) glycoproteins, at the cell surface. Importantly, using a single-cycle infectious recombinant H-knockout, H-complemented virus, we demonstrated that H, and thus potentially the viral fusion complex, was necessary to enable CDV spread. Furthermore, since we could not detect CD150/SLAM expression in brain cells, the presence of a yet non-identified glial receptor for CDV was suggested. Altogether, our findings indicate that persistence in CDV infection results from intracellular cell-to-cell transmission requiring the CDV-H protein. Viral transfer, happening selectively at the tip of astrocytic processes, may help the virus to cover long distances in the astroglial network, "outrunning" the host's immune response in demyelinating plaques, thus continuously eliciting new lesions.


Local peroperative treatment with a bisphosphonate improves the fixation of total knee prostheses: a randomized, double-blind radiostereometric study of 50 patients.
Postoperative migration of a joint prosthesis is related to the risk of late loosening. We have previously reported that oral treatment with clodronate reduced migration of the cemented NexGen total knee prosthesis during the first postoperative year, as measured by radiostereometry (RSA). Oral bisphosphonate treatment is sometimes unpleasant, and local treatment will enable higher local concentrations. We now report the results of local peroperative treatment with another bisphosphonate, ibandronate, with the same prosthesis. This is a double-blind, randomized study of 50 patients using RSA with maximal total point motion (MTPM) as primary effect variable. 1 mg ibandronate (1 mL) or 1 mL saline was applied to the tibial bone surface 1 min before cementation. RSA examination was done on the first postoperative day, and at 6, 12, and 24 months. One ibandronate-treated patient died of unrelated causes, and 1 control patient refused to come for follow-up, leaving 24 patients in each group for analysis. There were no cases of aseptic loosening. By repeated measures ANOVA, migration (MTPM) was reduced by local application of ibandronate (p=0.006). The effect was most pronounced at 6 months, with a reduction from 0.45 to 0.32 mm (95% CI for reduction: 0.04-0.21 mm). At 12 months, the migration from the postoperative examination was reduced from 0.47 to 0.36 mm (95% CI for reduction: 0.02-0.20 mm). At 24 months, the reduction was from 0.47 to 0.40 mm (95% CI: -0.01-0.16 mm). This is the first study to show improvement of prosthesis fixation by local pharmacological treatment in humans. The treatment appears to be safe, cheap, and easy to perform. However, the improvement in postoperative stability was not greater than with systemic clodronate treatment.


"Endoscopy Salon" for Controlling Respiratory Droplet Spreading During Endoscopic Procedure.
Introduction Preventing droplet dispersal is an important issue for decreasing the coronavirus 2019 (COVID-19) transmission rate; numerous personal protective equipment (PPE) devices have been recently developed for this. Objective To evaluate the effectiveness of a novel PPE device to prevent droplet spread during nasal endoscopic and fiber optic laryngoscopic examination and postuse equipment cleaning technique. Methods The "endoscopy salon" was created with a hooded salon hair dryer, plastic sheath, and silicone nipple. Comparison fluorescence dye dispersal from simulating forceful coughing with and without using the "endoscopy salon" was conducted to assess the droplet spread control. The effects of heat produced in the "endoscopy salon" and disinfection cleaning were also evaluated. Results Fluorescent dye droplet spread from a mannequin's mouth without using the "endoscopy salon" to care providers' clothes and the floor surrounding mannequin, whereas no dye droplets spread out when using the "endoscopy salon". The maximal temperature observed in the hair dryer was 56.3°C. During the cleaning process, when a plastic bag was attached to the hair dryer's hood to create a closed system, the temperature increased to 79.8 ± 3.1 °C. These temperatures eliminated four test organism cultures during equipment disinfection. Conclusion This novel "endoscopy salon" device prevented respiratory droplet spread and eliminated infectious organisms during postuse equipment cleaning.


Seroprevalence of anti-HCV and hepatitis B surface antigen in HIV infected patients.
Human immunodeficiency virus (HIV) is known to influence the natural history of infections with certain hepatitis viruses and interactions between HIV and hepatitis viruses may potentiate HIV replication. There is high degree of epidemiological similarity between hepatitis B virus and HIV as regard to high-risk group and route of transmission. Transmission of hepatitis C virus (HCV) through blood transfusion and intravenous drug abuse is well documented. Present study deals with the study of concurrent infection of HBV and HCV with HIV infection. In the study of 110 HIV seropositive patients, 34(30.4%) were positive for HBV and 8(7.27%) for HCV. The difference of concomitant infection was highly significant compared to controls. (p value < 0.0001). Heterosexual high risk behaviour was observed in 89(80.91%) of 110 HIV positive patients, out of which 23(25.8%) and 5(5.62%) were HBsAg and anti-HCV positive respectively. History of transmission was unclear in remaining patients. Concomitant infection of HIV and HBV was found to be significantly more in the symptomatic group (40.68%) compared to asymptomatic group (19.6%). As HIV infection is known to affect the natural history of both HBV and HCV infection, screening of their concurrent association is necessary.


Testing a new platform to screen disease-modifying therapy in type 1 diabetes.
Studies of new therapies to preserve insulin secretion in early type 1 diabetes require several years to recruit eligible subjects and to see a treatment effect; thus, there is interest in alternative study designs to speed this process. Most people with longstanding type 1 diabetes no longer secrete insulin. However, studies from pancreata of those with longstanding T1D show that beta cells staining for insulin can persist for decades after diagnosis, and this is paralleled in work showing proinsulin secretion in individuals with longstanding disease; collectively this suggests that there is a reserve of alive but "sleeping" beta cells. Here, we designed a novel clinical trial platform to test whether a short course of therapy with an agent known to have effects in type 1 diabetes with residual endogenous insulin could transiently induce insulin secretion in those who no longer produce insulin. A therapy that transiently "wakes up" sleeping beta cells might be tested next in a fully powered trial in those with endogenous insulin secretion. In this three-arm non-randomized pilot study, we tested three therapies known to impact disease: two beta-cell supportive agents, liraglutide and verapamil, and an immunomodulatory agent, golimumab. The golimumab treated arm was not fully enrolled due to uncertainties about immunotherapy during the COVID-19 pandemic. Participants had mixed-meal tolerance test (MMTT)-stimulated C-peptide below the quantitation limit (<0.02 ng/mL) at enrollment and received 8 to 12 weeks of therapy. At the completion of therapy, none of the individuals achieved the primary outcome of MMTT-stimulated C-peptide ≥ 0.02 ng/mL. An exploratory outcome of the verapamil arm was MRI-assessed pancreas size, diffusion, and longitudinal relaxation time, which showed repeatability of these measures but no treatment effect. The liraglutide and golimumab arms were registered on clinicaltrials.gov under accession number NCT03632759 and the verapamil arm under accession number NCT05847413. Trail registration: Protocols are registered in ClinicalTrials.gov under accession numbers NCT03632759 and NCT05847413.


Combined subretinal and sub-retinal pigment epithelium neovascular membranes in age-related macular degeneration: a clinicopathologic study of six cases.
Subfoveal neovascular membranes are usually located either in the subsensory retinal space or below the retinal pigment epithelium (RPE). This article describes the clinical and histopathologic features of subfoveal membranes with both subretinal and sub-RPE components (combined membranes). Six surgically excised subfoveal neovascular membranes from six patients were examined histopathologically. Preoperative and postoperative clinical information was obtained from each patient. Clinically, the combined membranes had no special characteristic features. The most common fluorescein angiographic finding postoperatively was a window defect of the RPE. Visual acuity improved in three patients and became worse in the other three patients. All patients with combined subfoveal neovascular membranes had age-related macular degeneration. In this disease, a single subfoveal membrane may extend into both the subretinal and the sub-RPE spaces. Patients may benefit from surgical removal of the membrane.


Mitonuclear Interactions Mediate Transcriptional Responses to Hypoxia in Drosophila.
Among the major challenges in quantitative genetics and personalized medicine is to understand how gene × gene interactions (G × G: epistasis) and gene × environment interactions (G × E) underlie phenotypic variation. Here, we use the intimate relationship between mitochondria and oxygen availability to dissect the roles of nuclear DNA (nDNA) variation, mitochondrial DNA (mtDNA) variation, hypoxia, and their interactions on gene expression in Drosophila melanogaster. Mitochondria provide an important evolutionary and medical context for understanding G × G and G × E given their central role in integrating cellular signals. We hypothesized that hypoxia would alter mitonuclear communication and gene expression patterns. We show that first order nDNA, mtDNA, and hypoxia effects vary between the sexes, along with mitonuclear epistasis and G × G × E effects. Females were generally more sensitive to genetic and environmental perturbation. While dozens to hundreds of genes are altered by hypoxia in individual genotypes, we found very little overlap among mitonuclear genotypes for genes that were significantly differentially expressed as a consequence of hypoxia; excluding the gene hairy. Oxidative phosphorylation genes were among the most influenced by hypoxia and mtDNA, and exposure to hypoxia increased the signature of mtDNA effects, suggesting retrograde signaling between mtDNA and nDNA. We identified nDNA-encoded genes in the electron transport chain (succinate dehydrogenase) that exhibit female-specific mtDNA effects. Our findings have important implications for personalized medicine, the sex-specific nature of mitonuclear communication, and gene × gene coevolution under variable or changing environments.


Association of the Recurrent Rare Variant c.415T>C p.Phe139Leu in CLN5 With a Recessively Inherited Macular Dystrophy.
Homozygous variants in the neuronal ceroid lipofuscinosis type 5 (CLN5) gene are associated with neuronal ceroid lipofuscinosis, a progressive neurologic disorder that leads to ataxia, seizures, and early death. The association between a homozygous variant in this gene and a macular dystrophy is described here. To describe an autosomal recessive macular dystrophy associated with a recurrent variant in CLN5. This cohort study took place at a national referral center and had a follow-up duration ranging between 1 and 5 years. All patients who were identified to carry a specific homozygous missense variant in CLN5, among more than 2000 patients who were diagnosed with or suspected to have retinal dystrophies, who did not carry this variant, were included. Data were collected between June 2014 and September 2020. All patients who were sampled for DNA analysis due to molecularly unconfirmed retinal dystrophy and who were subsequently identified to carry the homozygous missense variant c.415T>C (p.Phe139Leu) in CLN5 were included, while patients who did not carry the variant were excluded. Retinal phenotype associated with this specific homozygous missense variant in CLN5. Seven affected patients (mean [SD] age, 43 [18] years; age range, 33-52 years; 5 male) carried the homozygous missense in CLN5. All patients were diagnosed as having a macular dystrophy. Four patients had mild electroretinographic alterations. All patients had hypoautofluorescent maculas with retinal thinning (central subfield thickness, 80 µm). Visual acuity ranged between 2/200 and 20/100. Neurologic symptoms were mild (dizziness) in 5 patients and absent in 2 patients. Neuroimaging demonstrated cerebellar atrophy and white matter lesions, respectively, in 2 patients. These results suggest that CLN5, similar to CLN7, may be associated with isolated macular dystrophy as well as neuronal ceroid lipofuscinosis. The variant c.415T>C p.Phe139Leu does not seem to be associated with any prominent neurologic disease at least until the fourth to sixth decades of life. These findings may imply a specific role of CLN5 in macular neurons. Additional study is suggested, such as molecular screening for this variant in cohorts of patients with undiagnosed macular dystrophies and biological studies of its molecular effects.


Older people's preferences for prognostic information in a situation of serious illness with less than a year to live.
This study aimed to determine the preferences of community-dwelling older people about information disclosure regarding poor prognosis, the likely symptoms and problems, and the care options available in a situation of serious illness with less than a year to live; and to identify factors associated with a preference for information disclosure regarding poor prognosis. The Brazilian version of the Preferences and Priorities for End of Life Care (PRISMA) questionnaire was administered face-to-face to 400 older people, living in the city of Belo Horizonte, Minas Gerais, Brazil. The main results indicated that 74.0% preferred to be informed that they had limited time left, 89.3% wished to be informed about symptoms and problems, and 96.3% about available care options. The factors associated with preferences for information about poor prognosis were: gender (women: OR = 0.446, 95% CI: 0.269-0.738) and choosing the least preferred place to die (home of a relative or friend: OR = 2.423, 95% CI: 1.130-5.198. These results show that most older people want to be informed in an advanced illness situation with less than a year to live. Health care professionals need to be prepared to anticipate news about poor prognosis and the disease.


Identification of genomic regions associated with soybean responses to off-target dicamba exposure.
The widespread adoption of genetically modified (GM) dicamba-tolerant (DT) soybean was followed by numerous reports of off-target dicamba damage and yield losses across most soybean-producing states. In this study, a subset of the USDA Soybean Germplasm Collection consisting of 382 genetically diverse soybean accessions originating from 15 countries was used to identify genomic regions associated with soybean response to off-target dicamba exposure. Accessions were genotyped with the SoySNP50K BeadChip and visually screened for damage in environments with prolonged exposure to off-target dicamba. Two models were implemented to detect significant marker-trait associations: the Bayesian-information and Linkage-disequilibrium Iteratively Nested Keyway (BLINK) and a model that allows the inclusion of population structure in interaction with the environment (G×E) to account for variable patterns of genotype responses in different environments. Most accessions (84%) showed a moderate response, either moderately tolerant or moderately susceptible, with approximately 8% showing tolerance and susceptibility. No differences in off-target dicamba damage were observed across maturity groups and centers of origin. Both models identified significant associations in regions of chromosomes 10 and 19. The BLINK model identified additional significant marker-trait associations on chromosomes 11, 14, and 18, while the G×E model identified another significant marker-trait association on chromosome 15. The significant SNPs identified by both models are located within candidate genes possessing annotated functions involving different phases of herbicide detoxification in plants. These results entertain the possibility of developing non-GM soybean cultivars with improved tolerance to off-target dicamba exposure and potentially other synthetic auxin herbicides. Identification of genetic sources of tolerance and genomic regions conferring higher tolerance to off-target dicamba may sustain and improve the production of other non-DT herbicide soybean production systems, including the growing niche markets of organic and conventional soybean.


Effects of elevated temperature and CO2 on aboveground-belowground systems: a case study with plants, their mutualistic bacteria and root/shoot herbivores.
Interactions between above- and belowground herbivores have been prominent in the field of aboveground-belowground ecology from the outset, although little is known about how climate change affects these organisms when they share the same plant. Additionally, the interactive effects of multiple factors associated with climate change such as elevated temperature (eT) and elevated atmospheric carbon dioxide (eCO2) are untested. We investigated how eT and eCO2 affected larval development of the lucerne weevil (Sitona discoideus) and colonization by the pea aphid (Acyrthosiphon pisum), on three cultivars of a common host plant, lucerne (Medicago sativa). Sitona discoideus larvae feed on root nodules housing N2-fixing rhizobial bacteria, allowing us to test the effects of eT and eCO2 across trophic levels. Moreover, we assessed the influence of these factors on plant growth. eT increased plant growth rate initially (6, 8 and 10 weeks after sowing), with cultivar "Sequel" achieving the greatest height. Inoculation with aphids, however, reduced plant growth at week 14. eT severely reduced root nodulation by 43%, whereas eCO2 promoted nodulation by 56%, but only at ambient temperatures. Weevil presence increased net root biomass and nodulation, by 31 and 45%, respectively, showing an overcompensatory plant growth response. Effects of eT and eCO2 on root nodulation were mirrored by weevil larval development; eT and eCO2 reduced and increased larval development, respectively. Contrary to expectations, aphid colonization was unaffected by eT or eCO2, but there was a near-significant 10% reduction in colonization rates on plants with weevils present belowground. The contrasting effects of eT and eCO2 on weevils potentially occurred through changes in root nodulation patterns.


Internet use and social support in women with breast cancer.
Many Web sites offer information to breast cancer patients, who are increasingly using these sites. The authors investigated the potential psychological benefits of Internet use for medical information by breast cancer patients. Of the 251 women approached, 188 were successfully interviewed (74.9%). Forty-two percent used the Internet for medical information related to breast health issues and did so for an average of 0.80 hr per week. The Interpersonal Support Evaluation List and the UCLA Loneliness Scale, with results controlled for covariates, showed that Internet use for breast health issues was associated with greater social support and less loneliness than Internet use for other purposes or nonuse. Breast cancer patients may obtain these psychological benefits with only a minimal weekly time commitment.


Novel antigen design for the generation of antibodies to G-protein-coupled receptors.
Antibodies are important tools for the study of G-protein-coupled receptors, key proteins in cellular signaling. Due to their large hydrophobic membrane spanning regions and often very short loops exposed on the surface of the cells, generation of antibodies able to recognize the receptors in the endogenous environment has been difficult. Here, we describe an antigen-design method where the extracellular loops and N-terminus are combined to a single antigen for generation of antibodies specific to three selected GPCRs: NPY5R, B2ARN and GLP1R. The design strategy enabled straightforward antigen production and antibody generation. Binding of the antibodies to intact receptors was analyzed using flow cytometry and immunofluorescence based confocal microscopy on A-431 cells overexpressing the respective GPCR. The antibody-antigen interactions were characterized using epitope mapping, and the antibodies were applied in immunohistochemical staining of human tissues. Most of the antibodies showed specific binding to their respective overexpressing cell line but not to the non-transfected cells, thus indicating binding to their respective target receptor. The epitope mapping showed that sub-populations within the purified antibody pool recognized different regions of the antigen. Hence, the genetic combination of several different epitopes enables efficient generation of specific antibodies with potential use in several applications for the study of endogenous receptors.


Adaptive resistance to antibiotics in bacteria: a systems biology perspective.
Despite all the major breakthroughs in antibiotic development and treatment procedures, there is still no long-term solution to the bacterial antibiotic resistance problem. Among all the known types of resistance, adaptive resistance (AdR) is particularly inconvenient. This phenotype is known to emerge as a consequence of concentration gradients, as well as contact with subinhibitory concentrations of antibiotics, both known to occur in human patients and livestock. Moreover, AdR has been repeatedly correlated with the appearance of multidrug resistance, although the biological processes behind its emergence and evolution are not well understood. Epigenetic inheritance, population structure and heterogeneity, high mutation rates, gene amplification, efflux pumps, and biofilm formation have all been reported as possible explanations for its development. Nonetheless, these concepts taken independently have not been sufficient to prevent AdR's fast emergence or to predict its low stability. New strains of resistant pathogens continue to appear, and none of the new approaches used to kill them (mixed antibiotics, sequential treatments, and efflux inhibitors) are completely efficient. With the advent of systems biology and its toolsets, integrative models that combine experimentally known features with computational simulations have significantly improved our understanding of the emergence and evolution of the adaptive-resistant phenotype. Apart from outlining these findings, we propose that one of the main cornerstones of AdR in bacteria, is the conjunction of two types of mechanisms: one rapidly responding to transient environmental challenges but not very efficient, and another much more effective and specific, but developing on longer time scales. WIREs Syst Biol Med 2016, 8:253-267. doi: 10.1002/wsbm.1335 For further resources related to this article, please visit the WIREs website.


Ultradian rhythms of autonomic, cardiovascular, and neuroendocrine systems are related in humans.
Autonomic, cardiovascular, and neuroendocrine activities were monitored for 5-6 h in 10 normal adult resting humans (8 males, 2 females). The nasal cycle, a measure of lateralized autonomic tone, was measured at 4 Hz. Impedance cardiography (BoMed NCCOM3) was used to measure cardiac output, thoracic fluid index, heart rate, ejection velocity index, stroke volume, and ventricular ejection time (averages of 12 heart beats). Systolic, diastolic, and mean arterial pressures were measured with an automated cuff at 7.5-min intervals. Separate blood samples were taken every 7.5 min simultaneously from both arms with the use of indwelling venous catheters. Assays for adrenocorticotropic hormone, luteinizing hormone, norepinephrine, epinephrine, and dopamine were performed on samples from each arm. Time-series analysis, using the fast orthogonal search method of Korenberg, was used to detect variance structure. Significant spectral periods were observed in five windows at 220-340, 170-215, 115-145, 70-100, and 40-65 min. The greatest spectral power was observed in the lower frequencies, but periods at 115-145, 70-100, and 40-65 min were common across variables. Significant correlation coefficients for linear regressions of all paired variables in each subject were observed in 38.87% of the comparisons (subject range, 18.05-48-9.70%) with r > 0.30. These results suggest that either a common oscillator (the hypothalamus) or mutually entrained oscillators regulate these systems.


How organizational factors interact to influence the quality of care of older people in the care home sector.
To examine how organizational factors affect good care and mistreatment of older people in care homes. Eight residential care homes for older people (including private sector, local authority and NHS providers) took part in a participatory observation-based study of organizational factors affecting care quality. Grouping organizational factors into infrastructure, management and procedures, staffing, resident population characteristics and culture, we show the context-sensitive nature of interactions between these factors. These interactions could enhance care quality where factors combined positively. Conversely, they could amplify difficulties where one factor came to undermine another, thereby limiting care quality. This analysis provides empirical insights into how and why similar sector-wide changes to care provision have differential effects at the care home level. It indicates the situated and unpredictable ways in which organizational factors interact, implying the need for locally contextualized quality assessment and improvement actions.


The glucose-6-phosphatase catalytic subunit gene promoter contains both positive and negative glucocorticoid response elements.
Glucose-6-phosphatase catalyzes the final step in the gluconeogenic and glycogenolytic pathways. Glucocorticoids stimulate glucose-6-phosphatase catalytic subunit (G6Pase) gene transcription and studies performed in H4IIE hepatoma cells demonstrate the presence of a glucocorticoid response unit (GRU) in the proximal G6Pase promoter. In vitro deoxyribonuclease I footprinting analyses show that the glucocorticoid receptor binds to three glucocorticoid response elements (GREs) in the -231 to -129 promoter region and transfection results indicate all three contribute to glucocorticoid induction of G6Pase gene transcription. Furthermore, binding sites for hepatocyte nuclear factor-1 and -4, CRE binding factors, and FKHR (FOXO1a) are required for the full glucocorticoid response. Chromatin immunoprecipitation assays show that dexamethasone treatment stimulates glucocorticoid receptor and FKHR binding to the endogenous G6Pase promoter. Surprisingly, although glucocorticoids stimulate G6Pase gene transcription, deoxyribonuclease I footprinting and transfection analyses demonstrate the presence of a negative GRE and an associated negative accessory factor element in the -271 to -225 promoter region, which inhibit the glucocorticoid response. This appears to be the first report of a promoter that contains both positive and negative GREs, which function within the same cellular environment. We hypothesize that targeted signaling to the negative accessory element within the GRU may provide tight regulation of the glucocorticoid stimulation.


Carriage of GB virus C/hepatitis G virus RNA is associated with a slower immunologic, virologic, and clinical progression of human immunodeficiency virus disease in coinfected persons.
The prevalence of GB virus C (GBV-C) infection is high in human immunodeficiency virus (HIV)-infected persons. However, the long-term consequences of coinfection are unknown. HIV-positive persons with a well-defined duration of infection were screened on the basis of their GBV-C/hepatitis G virus (HGV) RNA status and studied. GBV-C/HGV viremia was observed in 23, who carried the virus over a mean of 7.7 years. All parameters (survival, CDC stage B/C, HIV RNA load, CD4 T cell count) showed significant differences in terms of the cumulative progression rate between persons positive and negative for GBV-C/HGV RNA. When GBV-C/HGV RNA-positive and -unexposed subjects were matched by age, sex, baseline HIV RNA load, and baseline CD4 T cell count, HIV disease progression appeared worse in GBV-C/HGV RNA-negative subjects. The carriage of GBV-C/HGV RNA is associated with a slower progression of HIV disease in coinfected persons.


Parent/caregiver stress during pediatric hospitalization for chronic feeding problems.
This study examined changes in stress in 37 mothers/caregivers of children with chronic feeding problems. Stress was measured by the Parenting Stress Index-Short Form at three specific stages during pediatric hospitalization for treatment of chronic feeding problems. The relationship between caregiver stress and stage of hospitalization as well as that between stress and various child and family variables were investigated. Repeated-measures analyses of variance and t tests found that stress related to social isolation and self-perception and total parenting stress changed significantly in relation to the stage of hospitalization. Correlational analyses indicated that caregiver stress was positively related to the presence of mental retardation, oral-motor dysfunction, tonal abnormalities, or a pervasive developmental disorder in the hospitalized child. Caregiver stress was negatively related to coping strategies that involved understanding the child's medical situation. These results provide a more comprehensive picture of families of children with chronic feeding problems, a population that has received little attention in the research literature. Information regarding parent/caregiver stress during a child's hospitalization can enhance nurses' understanding of the experiences of these families, thereby contributing to more effective treatment planning. In addition, the results emphasize the need to examine a variety of child and family factors that may influence parenting stress as well as family involvement in intervention services.


Hemodilution mediates changes in renal hemodynamics after acute volume expansion in rats.
The present study examined the factors responsible for triggering renal hemodynamic adjustments during acute volume expansion. The renal hemodynamic effects of graded volume expansion with 0.9% saline (Sal; 1, 2, and 4% of body wt), 7% BSA solution (0.35, 0.70, and 1.4% body wt), or whole blood from a donor rat (WBL; 0.35, 0.70, and 1.4% body wt) were compared in rats anesthetized with pentobarbital sodium. Neural influences on the kidney were eliminated by vagus nerves, baro/chemoreceptor afferents, and renal nerves section, and renal perfusion pressure was controlled at constant level (approximately 120 mmHg) throughout the experiments. In Sal- and BSA-expanded rats, renal blood flow (RBF) increased (Sal: 15, 40, 71%; BSA 17, 49, 107%) and renal vascular resistance (RVR) decreased in parallel with the degree of volume expansion (RVR: Sal 17, 31, 44%; and BSA: 15, 35, 54%). Renal hemodynamics remained unaltered after expansion with WBL. In rats expanded with Sal or BSA, correction of the fall of hematocrit restored RBF and RVR to control levels. Interference with tubuloglomerular feedback by uretheral obstruction had no effect on the decrease in RVR with Sal or BSA. Inhibition of the vascular tone by intrarenal papaverine infusion also did not alter the renal hemodynamic response to volume expansion with Sal or BSA. These findings suggest that the changes in renal hemodynamics after acute expansion are likely mediated by changes in rheologic properties of the blood rather than by changes in active vascular tone.


Faster title and abstract screening? Evaluating Abstrackr, a semi-automated online screening program for systematic reviewers.
Citation screening is time consuming and inefficient. We sought to evaluate the performance of Abstrackr, a semi-automated online tool for predictive title and abstract screening. Four systematic reviews (aHUS, dietary fibre, ECHO, rituximab) were used to evaluate Abstrackr. Citations from electronic searches of biomedical databases were imported into Abstrackr, and titles and abstracts were screened and included or excluded according to the entry criteria. This process was continued until Abstrackr predicted and classified the remaining unscreened citations as relevant or irrelevant. These classification predictions were checked for accuracy against the original review decisions. Sensitivity analyses were performed to assess the effects of including case reports in the aHUS dataset whilst screening and the effects of using larger imbalanced datasets with the ECHO dataset. The performance of Abstrackr was calculated according to the number of relevant studies missed, the workload saving, the false negative rate, and the precision of the algorithm to correctly predict relevant studies for inclusion, i.e. further full text inspection. Of the unscreened citations, Abstrackr's prediction algorithm correctly identified all relevant citations for the rituximab and dietary fibre reviews. However, one relevant citation in both the aHUS and ECHO reviews was incorrectly predicted as not relevant. The workload saving achieved with Abstrackr varied depending on the complexity and size of the reviews (9 % rituximab, 40 % dietary fibre, 67 % aHUS, and 57 % ECHO). The proportion of citations predicted as relevant, and therefore, warranting further full text inspection (i.e. the precision of the prediction) ranged from 16 % (aHUS) to 45 % (rituximab) and was affected by the complexity of the reviews. The false negative rate ranged from 2.4 to 21.7 %. Sensitivity analysis performed on the aHUS dataset increased the precision from 16 to 25 % and increased the workload saving by 10 % but increased the number of relevant studies missed. Sensitivity analysis performed with the larger ECHO dataset increased the workload saving (80 %) but reduced the precision (6.8 %) and increased the number of missed citations. Semi-automated title and abstract screening with Abstrackr has the potential to save time and reduce research waste.


Deficient interleukin-10 production by neonatal T cells does not explain their ineffectiveness at promoting neonatal B cell differentiation.
Neonatal T cells are poor promoters of Ig secretion by neonatal B cells. Since IL-10 has been shown to play a role in B cell differentiation, we investigated the relationship of IL-10 production by neonatal T cells and their ability to provide B cell help. Neonatal CD4+(CD8-) T cells and adult naive CD4+ (CD8-/CD45RO-) T cells activated with immobilized anti-CD3 produced consistently less IL-10 than adult memory CD4+(CD8-/CD45RA-) T cells. Production of IL-10 by adult and neonatal T cells was dependent on IL-2, but was unaffected by supplemental IL-4. Despite diminished IL-10 production, supplemental IL-10 increased neonatal T cell-dependent Ig secretion only modestly, but did not increase Ig heavy chain isotype switching. This contrasted with the ability of IL-10 to enhance the secretion of all Ig isotypes by adult B cells stimulated in the presence of either IL-2 or IL-4. These results suggest that IL-10 can promote T cell-dependent Ig secretion but not Ig heavy chain isotype switching by neonatal B cells. However, deficient IL-10 production alone does not account for the poor ability of neonatal T cells to support neonatal B cell Ig production.


Rat primary embryo fibroblast cells suppress transformation by the E6 and E7 genes of human papillomavirus type 16 in somatic hybrid cells.
The E6 and E7 genes of human papillomavirus type 16 (HPV-16) transform established lines of rat cells but not rat cells in primary culture irrespective of the expression of the two genes. The reason for this difference between the susceptibilities of cell lines and primary cells was examined by using hybrid cells obtained by somatic cell fusion of rat cell lines transformed by the E6 and E7 genes of HPV-16 and freshly isolated rat embryo fibroblast cells. In these hybrid cells, transformed phenotypes, including colony formation in soft agar, saturation density, and tumorigenicity in nude mice, were suppressed, whereas hybrid cells between E6/E7-transformed cell lines and normal rat cell lines retained these transformed phenotypes. RNA analysis showed that the E6 and E7 genes were transcribed in both types of hybrid cells. These results suggest that primary rat cells possess intracellular functions that cause posttranscriptional suppression of induction of the transformed phenotypes by the E6 and E7 genes of HPV-16.


Latent structure of quantitative dermatoglyphic traits of middle Dalmatia (Croatia).
The latent structure of quantitative dermatoglyphic traits has been analyzed from the population in Middle Dalmatia: islands of Brac, Hvar and Korcula, peninsula of Peljesac and Makarska coastal region. We analyzed 18 variables from fingers and palms, and principal component analysis was performed. In males, we extracted 4 factors for the islands Brac and Korcula, 5 factors for the island of Hvar and Peljesac peninsula and 6 factors for Makarska coastal region. In females we extracted 4 factors for the island of Korcula, 5 factors for the island of Brac, Hvar and Peljesac peninsula, 6 factors for the Makarska region. The total variance in males varies for 4 factors, from 64.19% to 70.71% (for all factors from 68.88% to 75.80%). In females, for 4 factors the total variance was from 57.03% to 66.87% (for all factors from 66.87% to 76.13%). In all population groups on the first factor all finger dermatoglyphics were extracted, while on the other factors there is evident variability of a number of factors extracted and variable explanations. The analysis of variables from extracted factors might give us information about similarities and differences between the groups concerning the latent structure, and also the differences and inter-individual variability in females in comparison to the males. This study provides an insight into the effects of population structure and microevolution on quantitative variation.


A qualitative study of speaking out about patient safety concerns in intensive care units.
Much policy focus has been afforded to the role of "whistleblowers" in raising concerns about quality and safety of patient care in healthcare settings. However, most opportunities for personnel to identify and act on these concerns are likely to occur much further upstream, in the day-to-day mundane interactions of everyday work. Using qualitative data from over 900 h of ethnographic observation and 98 interviews across 19 English intensive care units (ICUs), we studied how personnel gave voice to concerns about patient safety or poor practice. We observed much low-level social control occurring as part of day-to-day functioning on the wards, with challenges and sanctions routinely used in an effort to prevent or address mistakes and norm violations. Pre-emptions were used to intervene when patients were at immediate risk, and included strategies such as gentle reminders, use of humour, and sharp words. Corrective interventions included education and evidence-based arguments, while sanctions that were applied when it appeared that a breach of safety had occurred included "quiet words", bantering, public exposure or humiliation, scoldings and brutal reprimands. These forms of social control generally functioned effectively to maintain safe practice. But they were not consistently effective, and sometimes risked reinforcing norms and idiosyncratic behaviours that were not necessarily aligned with goals of patient safety and high-quality healthcare. Further, making challenges across professional boundaries or hierarchies was sometimes problematic. Our findings suggest that an emphasis on formal reporting or communication training as the solution to giving voice to safety concerns is simplistic; a more sophisticated understanding of social control is needed.


Combinations of trabecular and cortical bone properties distinguish various loading modalities between athletes and controls.
Variation in trabecular and cortical bone properties is often used to infer habitual behavior in the past. However, the structures of both types of bone are rarely considered together and may even contradict each other in functional interpretations. We examine trabecular and cortical bone properties in various athletes and sedentary controls to clarify the associations between combinations of cortical and trabecular bone properties and various loading modalities. We compare trabecular and cortical bone properties using peripheral quantitative computed tomography scans of the tibia between groups of 83 male athletes (running, hockey, swimming, cricket) and sedentary controls using Bayesian multilevel models. We quantify midshaft cortical bone rigidity and area (J, CA), midshaft shape index (Imax/Imin), and mean trabecular bone mineral density (BMD) in the distal tibia. All groups show unique combinations of biomechanical properties. Cortical bone rigidity is high in sports that involve impact loading (cricket, running, hockey) and low in nonimpact loaded swimmers and controls. Runners have more anteroposteriorly elliptical midshafts compared to other groups. Interestingly, all athletes have greater trabecular BMD compared to controls, but do not differ credibly among each other. Results suggest that cortical midshaft hypertrophy is associated with impact loading while trabecular BMD is positively associated with both impact and nonimpact loading. Midshaft shape is associated with directionality of loading. Individuals from the different categories overlap substantially, but group means differ credibly, suggesting that nuanced group-level inferences of habitual behavior are possible when combinations of trabecular and cortical bone are analyzed.


A Brief Dermatology Curriculum in Skin Cancer Detection and Prevention to Improve Medical Student Knowledge and Confidence.
While the incidence of skin cancers continues to rise, there remains a disproportionate lack of introductory training on skin cancer screening and identification of modifiable behaviors in medical curricula. Trainees and students have cited low confidence in their ability to counsel patients and lack of instruction as barriers. To address this need, we created a 1-hour didactic lecture based on a cognitive teaching framework for third-year medical students during their core primary care clerkship. The session highlighted visual identification of different skin cancers, factors increasing individual risk, and photoprotective behaviors. Session content was based on American Academy of Dermatology recommendations for skin cancer prevention. An assessment of knowledge, behaviors, and attitudes given before, immediately following, and at 6 months after the session was used to determine efficacy. One hundred eight students before and immediately after the session demonstrated significantly improved knowledge (mean correct: 71% presession vs. 99% postintervention, p < .0001). Based on 39 participants completing 6-month follow-up, knowledge remained improved (mean answered correctly: 80%, p < .0001). Confidence in patient counseling on preventive behaviors, risk assessment, and reported likelihood of counseling significantly increased across the three time points (p < .0001 for all attitude questions). Specific topics included appropriate referral to a dermatologist, sunscreen application, and dangers of indoor tanning bed usage. Our session on skin cancer screening and prevention demonstrated improvements in medical student knowledge, confidence, and patient counseling likelihood. This introductory curriculum could be adapted for multiple core clerkships or specialties.


In vivo effect of uncoupling agents on the incorporation of calcium and strontium into mitochondria and other subcellular fractions of rat liver.
After injection of (45)Ca(++) or (89)Sr(++) into rats, the largest part of the radioactivity in the liver cell is associated with the subcellular structures, only negligible amounts of it being found in the soluble hyaloplasm. 50 % or more of the (45)Ca(++) and (89)Sr(++) in the liver cell is recovered in the mitochondrial fraction. The specific activity of Ca(++) after injection of (45)Ca(++) is far greater in mitochondria than in microsomes. Pretreatment of the rats with uncouplers of oxidative phosphorylation markedly decreases the amount of radioactivity associated with the mitochondrial fraction. The amount of radioactivity recovered in the microsomes and in the final supernatant on the contrary increases. These effects are present only when mitochondrial oxidative phosphorylation is completely uncoupled. The Ca(++) content of mitochondria from the livers of rats pretreated with uncouplers is sharply decreased with respect to the controls. It is concluded that in the liver cells of the intact animal energy-linked movements of Ca(++) and Sr(++) take place in mitochondria.


Campylobacter sputorum subsp mucosalis and Campylobacter hyointestinalis infections in the intestine of gnotobiotic pigs.
At 4 days of age, 7 gnotobiotic pigs were orally inoculated with broth cultures of both Campylobacter sputorum subsp mucosalis (CSM) and Campylobacter hyointestinalis (CH). One pig was killed and evaluated each week for 7 weeks. Forty-eight hours after inoculation, CH and CSM were recovered from the feces of the pigs; thereafter, only CH was recovered. Organisms morphologically typical of Campylobacter sp were observed on the mucosal surface and on the crypt epithelial cells of the ileum, cecum, and colon from post-inoculation weeks (PIW) 2 through 7. Bacteria were clustered around the surface opening of goblet cells in pigs at PIW 6 and 7. Crypt epithelial cell proliferation and intracellular bacteria were not seen, except in 1 pig (killed at PIW 7) in which intracellular bacteria were seen only in the cecum. Therefore, CSM and CH did not induce porcine proliferative enteritis in gnotobiotic pigs.


Exercise dependence among customers from a Parisian sport shop.
We assessed exercise dependence (ED), alcohol and nicotine use disorders, eating disorders, hypochondria and compulsive buying and in a population of customers of a Parisian sport shop. Five hundred consecutive customers of a sport shop were invited to participate. Diagnostic of exercise dependence was made with the Exercise Addiction Inventory and a specific questionnaire checking all diagnostic criteria. The DSM-IV-TR criteria for bulimia, alcohol and nicotine use disorders were checked and all subjects answered the CAGE and Fagerström questionnaires. Hypochondria was assessed with the DSM-IV-TR criteria and the Whiteley Index of Health Anxiety. For all parameters, customers with (ED+) and without (ED-) exercise dependence were compared. The prevalence of exercise dependence was 29.6%. Subjects from the ED+ group were younger than in the ED-group (27.1 vs 29.8 years) and there were more women. They were more dependent on alcohol, had higher scores at the CAGE questionnaire. ED+ subjects more often presented hypochondria (23 vs 15%), bulimia and binge eating and they more often made gifts to themselves and to others. Exercise dependence appears as a frequent and almost always unrecognized form of behavioral dependence in non clinical population frequenting sport shops. It is frequently associated to chemical dependence and eating disorders.


Description of technique and lower reference limit for magnetic resonance imaging of hippocampal volumetry in dogs.
To evaluate the use of high-resolution MRI for hippocampal volumetry in dogs and to define a lower reference limit for hippocampal formation (HF) volume. 20 dogs (with no history of seizures and no underlying structural brain disease) that underwent MRI of the brain. The MRI protocol included a high-resolution T1-weighted 3-D ultrafast gradient-echo sequence aligned in a dorsal plane perpendicular to the long axis of the HF. Images obtained with MRI were retrospectively analyzed by 2 observers (A and B). Intraobserver and interobserver agreement were calculated with the Lin concordance correlation coefficient. Volume measurements of the HF were adjusted for intracranial volume, and a lower 95% reference limit for adjusted HF volume was calculated. There was substantial intraobserver agreement (Lin concordance correlation coefficient, 0.97 [95% confidence interval {CI}, 0.94 to 0.99]) but poor interobserver agreement (Lin concordance correlation coefficient, 0.63 [95% CI, 0.37 to 0.79]). The lower 95% reference limit for adjusted HF volume was 0.56 cm(3) (90% CI, 0.52 to 0.60 cm(3)) for the right HF and 0.55 cm(3) (90% CI, 0.52 to 0.58 cm(3)) for the left HF. HF volumes should be adjusted for intracranial volume to account for the large variation in canine skull size. The amount of time required to perform HF volumetry and low interobserver agreement may restrict this technique to research applications, such as the investigation of epileptic patients for hippocampal sclerosis or other cognitive disorders.


RNA polymerase I catalysed transcription of insert viral cDNA.
RNA polymerase I has been used for transcription of influenza hemagglutinin (HA) cDNA precisely linked in the anti-sense configuration to both mouse rDNA promoter and terminator segments. In transcription reactions based on Ehrlich ascites cell nuclear extracts, specific uniform RNA products are synthesized in high rates that are comparable to original rDNA template transcriptions. Primer extension reactions show the 5' ends of these RNA transcripts to be located exactly at position +1, corresponding to the 5' end of negative strand HA viral RNA. RNA 3' ends in a first series of constructs were found extended beyond the accepted location of pre-rRNA 3' ends, in using both hybrid cDNA and original rDNA templates. But upon deletion of six basepairs from the rDNA termination region RNA polymerase I transcription has been adapted to yield correctly terminated influenza viral RNA in vitro. This result has been confirmed in an in vivo experiment via synthesis of an anti-sense viral RNA molecule containing the chloramphenicol acetyltransferase (CAT) gene, which in turn is recognized at its terminal sequence by viral RNA dependent RNA polymerase for plus strand mRNA synthesis and expression of CAT activity.


Pesticide methoxychlor promotes the epigenetic transgenerational inheritance of adult-onset disease through the female germline.
Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures.


Revisiting the use of web search data for stock market movements.
Advances in Big Data make it possible to make short-term forecasts for market trends from previously unexplored sources. Trading strategies were recently developed by exploiting a link between the online search activity of certain terms semantically related to finance and market movements. Here we build on these earlier results by exploring a data-driven strategy which adaptively leverages the Google Correlate service and automatically chooses a new set of search terms for every trading decision. In a backtesting experiment run from 2008 to 2017 we obtained a 499% cumulative return which compares favourably with benchmark strategies. A crowdsourcing exercise reveals that the term selection process preferentially selects highly specific terms semantically related to finance (e.g. Wells Fargo Bank), which may capture the transient interests of investors, but at the cost of a shorter span of validity. The adaptive strategy quickly updates the set of search terms when a better combination is found, leading to more consistent predictability. We anticipate that this adaptive decision framework can be of value not only for financial applications, but also in other areas of computational social science, where linkages between facets of collective human behavior and online searches can be inferred from digital footprint data.