Activation of mitogen activated protein (MAP) kinases by vanadate is independent of insulin receptor autophosphorylation.
Treatment of Chinese hamster ovary (CHO) cells over-expressing the human insulin receptor (CHO-HIRc) with the insulin mimetic agent, vanadate, resulted in a dose- and time-dependent tyrosine phosphorylation of two proteins with apparent molecular sizes of 42 kDa (p42) and 44 kDa (p44). However, vanadate was unable to stimulate the tyrosyl phosphorylation of the beta-subunit of the insulin receptor. By using myelin basic protein (MBP) as the substrate to measure mitogen-activated protein (MAP) kinase activity in whole cell lysates, vanadate-stimulated tyrosyl phosphorylation of p42 and p44 was associated with a dose- and time-dependent activation of MAP kinase activity. Furthermore, affinity purification of cell lysates on anti-phosphotyrosine agarose column followed by immunoblotting with a specific antibody to MAP kinases demonstrated that vanadate treatment increased the tyrosyl phosphorylation of both p44mapk and p42mapk by several folds, as compared to controls, in concert with MAP kinase activation. In addition, retardation in gel mobility further confirmed that vanadate treatment increased the phosphorylation of p44mapk and p42mapk in CHO-HIRc. A similar effect of vanadate on MAP kinase tyrosyl phosphorylation and activation was also observed in CHO cells over-expressing a protein tyrosine kinase-deficient insulin receptor (CHO-1018). These results demonstrate that the protein tyrosine kinase activity of the insulin receptor may not be required in the signaling pathways leading to the vanadate-mediated tyrosyl phosphorylation and activation of MAP kinases.


The global landscape of availability, accessibility and affordability of essential diagnostics and therapeutics for the management of HER2-positive breast cancer: The ONCOLLEGE-001 survey.
Barriers in access to essential care are key determinants of disparities in cancer survival. Breast cancer (BC) is the most common cancer and lead cause of mortality among women, 60 % occurring in low- and middle-income countries (LMs). A quarter of BC are characterized by an over-expression of the epidermal growth factor receptor 2 (HER2). Valuable strategies to diagnose and manage patients with HER2-positive BC have been determined and some considered essential health interventions. ONCOLLEGE-001 is a global survey of availability, accessibility, and affordability of essential HER2 diagnostics and therapeutics. A self-administered questionnaire was shared electronically to oncologists, identified from oncology networks. Data were analyzed using descriptive statistics, per income areas and geographic regions. We received 191 responses (84 % response rate). The majority of the responders were from LMs (n = 153) and were physician providers. Immunohistochemistry was the most common HER2 diagnostics available (n = 185). A third of the responders from low/lower-middle and a half of upper-middle income countries had HER2 testing only in the private sector. Trastuzumab was not available for 8 %: when available, 15%-21% reported accessibility only as out-of-pocket expenditure; when not reimbursed, only 10 % of the providers could significantly offer this intervention. Availability of trastuzumab biosimilars was reported in more than a half of the responders (n = 107). Stark disparities are reported, with high out-of-pocket expenses for HER2 testing and significant financial barriers to access trastuzumab treatments. Policy solutions are urgently warranted for the selection, prioritization, and reimbursement of essential health interventions, to result in improved population health. POLICY SUMMARY STATEMENT: the inclusion of essential services for cancer management should be assured and financed in the benefit packages of healthcare to all. Prioritizing high-value health interventions, including medicines and medical devices, is critical to deliver impactful programs on population health.


Estimating the Direct Medical Outpatient Costs of Diagnosis and Treatment of Trichomoniasis Among Commercially Insured Patients in the United States, 2016 to 2018.
We used 2016-2018 outpatient claims data to calculate direct outpatient medical costs per case of trichomoniasis in 2019 US dollars. The outpatient, drug, and total costs per treated case of trichomoniasis were $174, $39, and $213, respectively. Total costs were higher for female patients ($220) than for male patients ($158).


Examining the impact of larval source management and insecticide-treated nets using a spatial agent-based model of Anopheles gambiae and a landscape generator tool.
Agent-based models (ABMs) have been used to estimate the effects of malaria-control interventions. Early studies have shown the efficacy of larval source management (LSM) and insecticide-treated nets (ITNs) as vector-control interventions, applied both in isolation and in combination. However, the robustness of results can be affected by several important modelling assumptions, including the type of boundary used for landscapes, and the number of replicated simulation runs reported in results. Selection of the ITN coverage definition may also affect the predictive findings. Hence, by replication, independent verification of prior findings of published models bears special importance. A spatially-explicit entomological ABM of Anopheles gambiae is used to simulate the resource-seeking process of mosquitoes in grid-based landscapes. To explore LSM and replicate results of an earlier LSM study, the original landscapes and scenarios are replicated by using a landscape generator tool, and 1,800 replicated simulations are run using absorbing and non-absorbing boundaries. To explore ITNs and evaluate the relative impacts of the different ITN coverage schemes, the settings of an earlier ITN study are replicated, the coverage schemes are defined and simulated, and 9,000 replicated simulations for three ITN parameters (coverage, repellence and mortality) are run. To evaluate LSM and ITNs in combination, landscapes with varying densities of houses and human populations are generated, and 12,000 simulations are run. General agreement with an earlier LSM study is observed when an absorbing boundary is used. However, using a non-absorbing boundary produces significantly different results, which may be attributed to the unrealistic killing effect of an absorbing boundary. Abundance cannot be completely suppressed by removing aquatic habitats within 300 m of houses. Also, with density-dependent oviposition, removal of insufficient number of aquatic habitats may prove counter-productive. The importance of performing large number of simulation runs is also demonstrated. For ITNs, the choice of coverage scheme has important implications, and too high repellence yields detrimental effects. When LSM and ITNs are applied in combination, ITNs' mortality can play more important roles with higher densities of houses. With partial mortality, increasing ITN coverage is more effective than increasing LSM coverage, and integrating both interventions yields more synergy as the densities of houses increase. Using a non-absorbing boundary and reporting average results from sufficiently large number of simulation runs are strongly recommended for malaria ABMs. Several guidelines (code and data sharing, relevant documentation, and standardized models) for future modellers are also recommended.


Aluminum chloride induces neuroinflammation, loss of neuronal dendritic spine and cognition impairment in developing rat.
Aluminum (Al) is present in the daily life of humans, and the incidence of Al contamination increased in recent years. Long-term excessive Al intake induces neuroinflammation and cognition impairment. Neuroinflammation alter density of dendritic spine, which, in turn, influence cognition function. However, it is unknown whether increased neuroinflammation is associated with altered density of dendritic spine in Al-treated rats. In the present study, AlCl3 was orally administrated to rat at 50, 150 and 450 mg/kg for 90d. We examined the effects of AlCl3 on the cognition function, density of dendritic spine in hippocampus of CA1 and DG region and the mRNA levels of IL-1β, IL-6, TNF-α, MHC II, CX3CL1 and BNDF in developing rat. These results showed exposure to AlCl3 lead to increased mRNA levels of IL-1β, IL-6, TNF-α and MCH II, decreased mRNA levels of CX3CL1 and BDNF, decreased density of dendritic spine and impaired learning and memory in developing rat. Our results suggest AlCl3 can induce neuroinflammation that may result in loss of spine, and thereby leads to learning and memory deficits.


Vesiculated alpha-tocopheryl succinate enhances the anti-tumor effect of dendritic cell vaccines.
Alpha tocopheryl succinate (alpha-TOS) is a non-toxic vitamin E analog under study for its anti-cancer properties. In an earlier study, we showed that alpha-TOS, when used in combination with non-matured dendritic cells (nmDC) to treat pre-established tumors, acts as an effective adjuvant. In this study, we have used vesiculated alpha-TOS (Valpha-TOS), a more soluble form of alpha-TOS that is relevant for clinical use, in combination with dendritic cells to treat pre-established murine tumors. We demonstrate that Valpha-TOS kills tumor cells in vitro and inhibits the growth of pre-established murine lung carcinoma (3LLD122) as effectively as alpha-TOS. The combination of Valpha-TOS plus non-matured or TNF-alpha-matured DC is more effective at inhibiting the growth of established tumors than Valpha-TOS alone. We also observed that Valpha-TOS induces expression of heat shock proteins in tumor cells and that co-incubation of non-matured DC with lysate derived from Valpha-TOS-treated tumor cells leads to DC maturation evidenced by up-regulation of co-stimulatory molecules and secretion of IL-12p70. This study therefore demonstrates the immunomodulatory properties of Valpha-TOS that may account for its adjuvant effect when combined with DC vaccines to treat established tumors.


Effect of 5-Aminolevulinic Acid and Sodium Fluorescein on the Extent of Resection in High-Grade Gliomas and Brain Metastasis.
Surgery is essential in the treatment of high-grade gliomas (HGG) and gross total resection (GTR) is known to increase the overall survival and progression-free survival. Several studies have shown that fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) increases GTR considerably compared to white light surgery (65% vs. 36%). In recent years, sodium fluorescein (SF) has become an increasingly popular agent for fluorescence-guided surgery due to numerous utility benefits compared to 5-ALA, including lower cost, non-toxicity, easy administration during surgery and a wide indication range covering all contrast-enhancing lesions with disruption of the blood-brain barrier in the CNS. However, currently, SF is an off-label agent and the level of evidence for use in HGG surgery is inferior compared to 5-ALA. Here, we give an update and review the latest literature on fluorescence-guided surgery with 5-ALA and SF for brain tumors with emphasis on fluorescence-guided surgery in HGG and brain metastases. Further, we assess the advantages and disadvantages of both fluorophores and discuss their future perspectives.


Anterograde axonal transport of [125I]wheat germ agglutinin by motor neurons innervating the rat lateral rectus muscle.
Despite widespread evidence of the affinity of wheat germ agglutinin (WGA) for sensory, preganglionic autonomic and other CNS neuron cell bodies, evidence of the uptake and anterograde transport of WGA by motor neurons innervating skeletal muscle is lacking. It was hypothesized that these cells might lack plasma membrane moieties with N-acetylglucosamine for selective uptake and transport of WGA. To test this, rats were anesthetized and injected intracisternally with affinity-purified [125I]-WGA in order to label abducens motor neurons. Based on results of light and electron microscopic autoradiography, it can be concluded that abducens motoneurons, and presumably other motoneurons, are capable of uptake and anterograde axonal transport of [125I]WGA.


Effect of ACGT motif in spatiotemporal regulation of AtAVT6D, which improves tolerance to osmotic stress and nitrogen-starvation.
Plasma membrane-localized AtAVT6D importing aspartic acid can be targeted to develop plants with enhanced osmotic and nitrogen-starvation tolerance. AtAVT6D promoter can be exploited as a stress-inducible promoter for genetic improvements to raise stress-resilient crops. The AtAVT6 family of amino acid transporters in Arabidopsis thaliana has been predicted to export amino acids like aspartate and glutamate. However, the functional characterization of these amino acid transporters in plants remains unexplored. The present study investigates the expression patterns of AtAVT6 genes in different tissues and under various abiotic stress conditions using quantitative Real-time PCR. The expression analysis demonstrated that the member AtAVT6D was significantly induced in response to phytohormone ABA and stresses like osmotic and drought. The tissue-specific expression analysis showed that AtAVT6D was strongly expressed in the siliques. Taking together these results, we can speculate that AtAVT6D might play a vital role in silique development and abiotic stress tolerance. Further, subcellular localization study showed AtAVT6D was localized to the plasma membrane. The heterologous expression of AtAVT6D in yeast cells conferred significant tolerance to nitrogen-deficient and osmotic stress conditions. The Xenopus oocyte studies revealed that AtAVT6D is involved in the uptake of Aspartic acid. While overexpression of AtAVT6D resulted in smaller siliques in Arabidopsis thaliana. Additionally, transient expression studies were performed with the full-length AtAVT6D promoter and its deletion constructs to study the effect of ACGT-N24-ACGT motifs on the reporter gene expression in response to abiotic stresses and ABA treatment. The fluorometric GUS analyses revealed that the promoter deletion construct-2 (Pro.C2) possessing a single copy of ACGT-N24-ACGT motif directed the strongest GUS expression under all the abiotic conditions tested. These results suggest that Pro.C2 can be used as a stress-inducible promoter to drive a significant transgene expression.


Management of post-traumatic bone defects of the tibia using vascularised fibular graft combined with Ilizarov external fixator.
Post-traumatic bone defects of the tibia present a difficult reconstructive challenge. Various methods of reconstruction are available, such as allografts, vascularised fibular graft (either free or pedicled) and bone transport technique. Fourteen patients with an average age of 34.1 years at operation (range, 12-65) with post-traumatic bony defects of the tibia were selected for reconstruction with vascularised fibular graft combined with Ilizarov external fixation. There were 12 male and two female. The size of the bony gap was 10.4 cm (range, 7-13) and the average length of the fibula used was 16.4 cm (range, 14-21). The mean follow up period was 20.4 months (range, 10-37). All patients had bony union at both proximal and distal ends of the fibula primarily except one patient that required secondary iliac bone graft at the distal end of the fibula to obtain union. The average time for bone healing was 3.9 months (range, 3-9). The average time spent in Ilizarov frame was 5.9 months (range, 5-11). Unprotected full weight-bearing was achieved within an average of 7.3 months (range, 6-12). Vascularised fibular bone graft combined with an Ilizarov frame is a successful approach to safely and effectively reconstruct bone defects of the tibia. It has the advantages of vascularised fibular bone grafts together with the biomechanical advantages of Ilizarov frame that allows weight bearing to start almost immediately after surgery. This leads to a good outcome regarding the union and function.


Electroactive gold nanoparticles protected by 4-ferrocene thiophenol monolayer.
Numerous reports have focused on ferrocene-terminated electroactive self-assembled monolayers (SAMs) on a flat Au surface but only a few on ferrocene SAMs on Au colloid. In this paper, we employ 4-ferrocene thiophenol as a novel capping agent to produce electroactive gold nanoparticles in consideration of the peculiar pi-conjugated structure. Transmission electron microscopy shows the narrow-dispersed gold core with an average core diameter of ca. 2.5 nm. UV/vis spectra examine the pi-conjugated structure of 4-ferrocene thiophenol and surface plasmon absorbance of the indicated gold nanoparticles. X-ray photoelectron spectroscopy reveals electronic properties of the Au core and thiol ligands. Electrochemical measurement shows that the oxidation peak current is proportional to the scan rate, indicating the electrode process is controlled by adsorbed layer reaction. The formal potential of the Fc-MPCs is compared with that of free ferrocene in MeCN solution and the Fc-SAMs. The shifts are attributed to the phenyl moiety in the 4-ferrocene thiophenol and dielectric constant of the solvation environment.


The changing profile of anorexia nervosa at the Toronto Programme for Eating Disorders.
The present study is a retrospective comparison of anorexic patients of the restricting subtype (AN) with those of the bulimic subtype (AN+BN) over three consecutive 5-year time periods. Subjects consisted of 806 female out-patients diagnosed as either AN or AN+BN between 1978 and 1994 during an assessment of their eating problem at the University of Toronto Programme for Eating Disorders in Toronto, Canada. During each time period an increasing proportion of subjects was diagnosed with AN+BN than with AN. Subjects with AN+BN reported a longer duration of illness prior to being assessed. Over time, subjects in both groups appeared to weigh more, and were less likely to report amenorrhea. Subjects from both groups reported higher frequencies of purging behavior, impulsive behaviors, and associated affective symptoms in the later time periods. Over time, the differences between the two subgroups of patients became less distinct. The results indicate changes in the clinical profile of patients with anorexia nervosa seen at the Toronto Programme for Eating Disorders over the past 16 years. The implications of these changes are explored.


Thoracic aortic occlusion: somatosensory evoked potential monitoring and neurologic outcome in a canine model.
Somatosensory evoked potentials (SEPs) were monitored in 17 canines during spinal cord ischemia induced by balloon occlusion of the thoracic aorta. Graded distal aortic hypotension to 40 mmHg in seven animals had no significant effect upon the evoked potential. A significant alteration in the SEP did result in 21 +/- 9.8 minutes when distal aortic pressures were reduced in a graded fashion below 30 mmHg. Acute occlusion of the thoracic aorta (10 animals, distal pressure 15-25 mmHg) was associated with a change in the SEP in 8.4 +/- 4.3 minutes. Continuation of aortic occlusion for 30 minutes beyond an evoked potential change resulted in a moderate to severe motor deficit in all cases. Somatosensory evoked potentials obtained 72-96 hours after the ischemic injury were closely correlated with sensory deficits, but were not predictive of motor examination. Histologic examination of the spinal cords demonstrated central gray necrosis of the lumbar region in all animals with a severe deficit, and a variable degree of neuronal loss in the intermediate and dorsal gray matter zones in animals with moderate deficits. This balloon occlusion method is relevant as a model of spinal cord injury during aortic occlusion, such as may occur during aortic surgery.


How long does it take for tuberculosis to cause secondary amyloidosis?
It is often believed that secondary amyloidosis occurs months to years after the onset of the predisposing cause. We describe two cases that, to the best of our knowledge, are the earliest described cases of amyloidosis occurring after the diagnosis of active tuberculosis.


Dental anxiety treatment by a dentist in primary care: A 1-year follow-up study.
In an earlier randomized controlled trial of dental anxiety treatments (n = 96) we compared the effects of dentist-administered cognitive behavioural therapy (D-CBT) and dental treatment supplemented with the Four Habits communication model plus midazolam sedation. Both treatments, applied in a general dental practice, were associated with a clinically relevant decrease in dental anxiety. In this follow-up study, 52 of the 82 treatment completers responded to an online questionnaire 1 year post-treatment. Reduction in dental anxiety persisted for both treatment groups. From baseline to 1 year post-treatment the Modified Dental Anxiety Scale was reduced by 7.8 [SD: 4.4; Cohen's d effect size: 1.2 (CI: 0.8-1.7)] and 7.8 [SD: 4.2; Cohen's d: 1.4 (0.9-1.8)] in the D-CBT and Four Habits/midazolam groups, respectively. Most patients (74% for D-CBT, 80% for Four Habits/midazolam) continued with dental treatment. Nine patients in the D-CBT and seven in the Four Habits/midazolam groups received additional CBT treatment from a psychologist/dentist team. Both methods tested should be accessible to interested dentists who receive adequate training. Effective first-line treatments for dental anxiety in general dental practice can generate more accessible care pathways for patients with dental anxiety. Evidence-based dental anxiety treatment programmes should be included in the dental curriculum and established as best practice for dentists.


Cancer patients' experience of oncology services in Assam, India.
Cancer patients' experience is dependent on the complex interaction between the patient, carer, healthcare practitioners and healthcare system. The aim of the study was to assess the experience of cancer patients in Assam in order to identify potential areas for improvement in delivering high quality cancer care. A cross sectional patient experience survey was conducted in 400 patients using structured interviews and pre-tested questionnaires that collected patient-reported outcomes including access to cancer care, experience while availing cancer services across the pathway, waiting times, communication and counselling support, out-of-pocket expenditure and advice regarding available insurance schemes and financial support. The cancer patient's experience of accessing healthcare in Assam is variable with principal challenges being financial constraint and geographical distance to healthcare facilities. Overall, patients' experience during registration, first consultation, pre-treatment and during treatment was good with high satisfaction rates expressed in several of the areas assessed. Areas that were identified for improvement were better explanation of long-term side effects of treatment, enhanced guidance in choosing treatment options and greater support from healthcare professionals to help patients cope with the psychological, emotional and physical aspects of their cancer diagnosis, treatment and recovery. Understanding cancer patient experiences across their journey is critical to delivering accessible and affordable care. Effective, adaptive and responsive communication remains the anchor of excellent patient-centred care especially in resource constraint settings. The paper provides an insight into critical areas focusing on diagnosis, treatment, continuum of care and communication during cancer patients' care in India. Healthcare policy needs to focus on developing a robust, holistic, healthcare system in terms of accessibility, affordability and psychosocial care, including counselling and financial support, to ensure better cancer outcomes.


"The emerging role of capivasertib in breast cancer".
Over 50% of breast tumors harbor alterations in one or more genes of the phosphatidylinositol 3-kinase (PI3K) pathway including PIK3CA mutations (31%), PTEN loss (34%), PTEN mutations (5%) and AKT1 mutations (3%). While PI3K and mTOR inhibitors are already approved in advanced breast cancer, AKT inhibitors have been recently developed as a new therapeutic approach. Capivasertib (AZD5363) is a novel, selective ATP-competitive pan-AKT kinase inhibitor that exerts similar activity against the three AKT isoforms, AKT1, AKT2, and AKT3. Preclinical studies demonstrated efficacy of capivasertib in breast cancer cell lines as a single agent or in combination with anti-HER2 agents and endocrine treatment, especially in tumors with PIK3CA or MTOR alterations. Phase I/II studies demonstrated greater efficacy when capivasertib was co-administered with paclitaxel, fulvestrant in hormone receptor (HR)-positive, HER2-negative breast cancer or olaparib. The recommended phase II dose of capivasertib as monotherapy was 480 mg bid on a 4-days-on, 3-days-off dosing schedule. Toxicity profile proved to be manageable with hyperglycemia (20-24%), diarrhea (14-17%) and maculopapular rash (11-16%) being the most common grade ≥3 adverse events. Ongoing Phase III trials of capivasertib in combination with fulvestrant (CAPItello-291), CDK4/6 inhibitor palbociclib (CAPItello-292) and paclitaxel (CAPItello- 290) will better clarify the therapeutic role of capivasertib in breast cancer.


Aortic and extracranial large vessel giant cell arteritis: a review of 72 cases with histopathologic documentation.
Giant cell arteritis (GCA) is closely identified with the temporal arteritis-polymyalgia rheumatica syndrome of the elderly. It is also a systemic disease that can cripple and kill. Up to 15% of patients with temporal arteritis may have angiographic evidence of extracranial GCA, and aortic insufficiency, ruptured aortic aneurysm, aortic dissection, stroke, or myocardial infarction may be the initial manifestation of systemic GCA. A review of 72 cases of aortic and extracranial GCA, all with histopathologic verification of the disease, revealed that 25% of patients with aortic and extracranial large-vessel GCA had asymptomatic temporal arteritis; the ascending aorta and aortic arch were most frequently involved (39%), followed by the subclavian and axillary arteries (26%), and the femoropopliteal arteries (18%). Nine patients (12.5%) underwent an upper or lower limb amputation. Of the 18 patients whose death was directly attributable to extracranial GCA the causes were ruptured aortic aneurysm (6), aortic dissection (6), stroke (3), and myocardial infarction (3). The findings of these 72 cases caution against attributing all aortic and large-vessel arterial disease in the elderly to atherosclerosis and emphasize that timely surgical intervention may be necessary for life-saving and limb-salvage in patients with aortic and extracranial GCA.


Feedback Methods in an Interprofessional Mock Paging Program.
Many medical schools offer a culminating internship readiness experience. Curricula focus on particular knowledge and skills critical to internship, such as answering urgent nursing pages. Studies have shown student performance improvement with mock paging education programs, but the role of feedback versus self-regulated practice has not been studied. The interprofessional mock paging program included 156 medical students enrolled in a 4th-year internship readiness course and 44 master's level direct entry nursing students. Medical students were randomized to receive verbal feedback immediately after each of the three phone calls (intervention group) or delayed written feedback (control group) after the third phone call only. Specialty-specific case scenarios were developed and a single checklist for all scenarios was developed using the communication tool ISBAR. Medical students and nursing students had separate training sessions before the pages commenced. The nursing students administered the phone calls and evaluated the medical students by ISBAR checklist. An interrater reliability measure was obtained with physician observation of a selection of phone calls. After adjusting for the case effects (different case scenarios for different specialties), students showed no statistically significant differences on checklist scores for case 1 (first case, F = 1.491, df = 1, p = .224), but did show statistically significant differences on checklist scores for case 3 (final case, F = 12.238, df = 1, p = .001). Strong interrater reliability was found between the faculty physician and observed nursing students (ICC = .89). Immediate feedback significantly improves student checklist scores with a mock paging program. This finding suggests that coaching with feedback may have advantages above self-regulated learning.


Left ovarian to left external iliac vein transposition for the treatment of nutcracker syndrome.
Nutcracker syndrome represents the constellation of symptoms caused by extrinsic compression of the left renal vein between the aorta and superior mesenteric artery, producing left renal venous outflow obstruction and, frequently, pelvic venous congestion. When severe, the syndrome is most commonly treated by surgical transposition of the left renal vein onto the inferior vena cava or by renal venous stent placement. Each of these treatment modalities is associated with significant immediate and long-term risks. This report provides the details of a simpler technique for the treatment of nutcracker syndrome by transposing the distal left ovarian to the left external iliac vein.


Inhibitor of 2',5'-oligoadenylate synthetase induced in human T lymphoblastoid cell line treated with deoxyadenosine, deoxycoformycin and interferon.
The effect of deoxyadenosine (dAdo) with deoxycoformycin on the induction of 2',5'-oligoadenylate synthetase by interferon was investigated. After semi-purification through poly(I):poly(C) gel, the activity was similar in control and dAdo-treated cells. However, the activity in the crude extract decreased with rising concentrations of dAdo. On the other hand, the level of 2'-phosphodiesterase, which is also induced by interferon and degrades 2',5'-oligoadenylate, showed no significant change after dAdo treatment. Thus, the crude extract was speculated to contain an inhibitor of 2',5'-oligoadenylate synthetase. Further characterization of the inhibitor revealed that inhibition was not due to dATP accumulation in cells.


Psychological aspects of oncology.
The patient with cancer presents the physician with challenging psychological issues: maintenance of an effective and understanding physician-patient relationship, in the context of optimal medical care, and alertness to signs of significant psychologic symptoms that may occur more commonly in the course of cancer. The closest relative, also under great emotional stress, must be considered in communications about the patient's clinical state and treatment. Psychological aspects of oncology are a demanding component of total care of the cancer patient, yet an integral part of optimal cancer care.


Dampened circumrotation by CH···π interactions in hydrogen bonded [2]rotaxanes.
Establishment of CH···π interactions between the aliphatic axis and the benzylic amide macrocycle of hydrogen-bonded [2]rotaxanes causes a measurable interference in the pirouetting submolecular motion of these interlocked molecules.


When can we choose to forget? An ERP study into item-method directed forgetting of emotional words.
Emotionally arousing information is treated in a specialised manner across a number of different processing stages, and memory for affective events is often found to be heightened by virtue of this. However, in some cases, emotional experiences might be the very ones that we would like to forget. Here, two item-method directed forgetting studies are presented which investigate people's ability to intentionally forget affective words when stimuli and memory instructions are presented simultaneously. In the first experiment an interaction between task instruction and emotional content was evident in a diminished directed forgetting effect for emotional words, suggesting that they may be relatively resistant to deliberate forgetting. The interaction between instruction and emotion appeared both in free recall of words and in a yes-no recognition task. In the second study, an ERP procedure was utilised to investigate whether emotion modulates the effects of instruction during the initial encoding of stimuli. Recognition data again showed a clear interaction between instruction and emotion, with a reduced directed forgetting effect for emotional words. The ERP data demonstrated evidence for individual effects of both emotion and instruction during encoding; however, despite this, no evidence for an interaction between these factors was evident in the ERP data. As such, we conclude that even when study items are presented simultaneously with their associated memory instructions, neither does emotion prevent differential processing of directed forgetting instruction, nor does memory instruction prevent differential processing of emotion during early encoding. Implications are discussed in relation to the directed forgetting literature and more broadly with respect to circumstances under which emotion and cognitive processing work in parallel or in competition with each other.


Dental calculus as a proxy for animal microbiomes.
The field of dental calculus research has exploded in recent years, predominantly due to the multitude of studies related to human genomes and oral pathogens. Despite having a subset of these studies devoted to non-human primates, little progress has been made in the distribution of oral pathogens across domestic and wild animal populations. This overlooked avenue of research is particularly important at present when many animal populations with the potentiality for zoonotic transmission continue to reside in close proximity to human groups due to reasons such as deforestation and climatic impacts on resource availability. Here, we analyze all previously available published oral microbiome data recovered from the skeletal remains of animals, all of which belong to the Mammalia class. Our genus level results emphasize the tremendous diversity of oral ecologies across mammals in spite of the clustering based primarily on host species. We also discuss the caveats and flaws in analyzing ancient animal oral microbiomes at the species level of classification. Lastly, we assess the benefits, challenges, and gaps in the current knowledge of dental calculus research within animals and postulate the future of the field as a whole.


Expression profile analysis of two cathepsin S in channel catfish (Ictalurus punctatus) mucosal tissues following bacterial challenge.
Cathepsin S belongs to the papain family of cysteine protease, and is considered to play key roles in immune responses after bacterial challenge. However, despite the recognized importance of Cathepsin S in immunity, no studies have systematically characterized Cathepsin S in catfish. In this regard, here, we characterized the Cathepsin S gene family in channel catfish, and investigated their expression patterns following two different Gram-negative bacterial challenge. In the present study, two Cathepsin S genes (ctss and ctssa) were captured in channel catfish. In comparison to other species, the catfish Cathepsin S genes are highly conserved in their structural features. Phylogenetic analysis indicated the strongest phylogenetic relationship with zebrafish, which is consistent with their evolutional relationships. Tissue distribution analysis revealed that Cathepsin S genes were ubiquitously expressed in catfish tissues. Following bacterial infection, the Cathepsin S genes were significantly up-regulated at most time-points in mucosal surfaces, with an acute response post Edwardsiella ictaluri infection. Obviously, the expression profiles were quite distinct between two Cathepsin S genes, across the tissues and between pathogens, suggesting that Cathepsin S genes may exert disparate roles in mucosal immune responses. Our findings here, provide early insight into the immune functions of Cathepsin S in catfish; however, further studies are needed to determine the mechanisms of Cathepsin S for antigen presentation during inflammatory processes and innate host defense.


The involvement of copper transporter in lead-induced oxidative stress in astroglia.
Lead (Pb), depositing primarily in astroglia in the brain, is a well-known neurotoxicant and a risk factor for neurologic disorders. Pb has been reported to induce oxidative stress by probably the disturbance of copper (Cu) homeostasis in astroglia. Thus, we hypothesized that Pb-induced oxidative stress is initiated by interfering with Cu transporter in astroglia. In this study, we observed Pb-induced oxidative stress as indicated by reactive oxygen species (ROS) augmentation and GRP78 and GRP94 protein induction, and it was parallel to Cu accumulation intracellularly by Pb. To further address Cu transporter as a potential Pb target, a heavy metal-binding (HMB) domain of Cu-transporting ATPase (Atp7a) was overexpressed and purified. Evidence showed that one molecule of HMB chelated 11 Pb ions or seven Cu ions and that Pb competed with Cu for binding to HMB. These findings suggest that Pb-induced oxidative stress results from the impairment of Cu metabolism by Pb targeting of Atp7a.


(n,2n) cross section calculations for tungsten, tantalum and osmium nuclei.
Tungsten, tantalum and osmium are important alloying elements in the nuclear technology research and development, particularly in nuclear fission/fusion power plant material applications. So, data results of the cross sections and emission spectra of neutron-induced reactions are required to predict nuclear responses in these elements. However, the cross sections measurements of (n,2n) reactions on tungsten, tantalum and osmium isotopes are rather limited in the literature. In this case, theoretical approaches are often used for obtaining the cross section data. In this article, theoretical (n,2n) cross sections on 180,182-184,186W, 181Ta and 186,192Os target nuclei are calculated up to 20 MeV energy, using the simulation codes TALYS 1.95, ALICE/ASH and CEM03.01. Further, the empirical (n,2n) systematics based on the statistical model have been used for predicting the cross section data at ∼14 MeV incident neutrons. The present results from the empirical systematics and model-based calculations are also compared with the literature experimental data, and JENDL-5.0, ENDF/B-VIII, JEFF3.3 and TENDL-2021 libraries. This paper can provide a contribution to complete description of the (n,2n) reactions considering the lack of experimental cross section data.


Long-range heteronuclear J-coupling constants in esters: Implications for 13C metabolic MRI by side-arm parahydrogen-induced polarization.
Side-arm parahydrogen induced polarization (PHIP-SAH) presents a cost-effective method for hyperpolarization of 13C metabolites (e.g. acetate, pyruvate) for metabolic MRI. The timing and efficiency of typical spin order transfer methods including magnetic field cycling and tailored RF pulse sequences crucially depends on the heteronuclear J coupling network between nascent parahydrogen protons and 13C, post-parahydrogenation of the target compound. In this work, heteronuclear nJHC (1 < n ≤ 5) couplings of acetate and pyruvate esters pertinent for PHIP-SAH were investigated experimentally using selective HSQMBC-based pulse sequences and numerically using DFT simulations. The CLIP-HSQMBC technique was used to quantify 2/3-bond JHC couplings, and 4/5-bond JHC ≲ 0.5 Hz were estimated by the sel-HSQMBC-TOCSY approach. Experimental and numerical (DFT-simulated) nJHC couplings were strongly correlated (P < 0.001). Implications for 13C hyperpolarization by magnetic field cycling, and PH-INEPT and ESOTHERIC type spin order transfer methods for PHIP-SAH were assessed, and the influence of direct nascent parahydrogen proton to 13C coupling when compared with indirect homonuclear TOCSY-type transfer through intermediate (non-nascent parahydrogen) protons was studied by the density matrix approach.


Extremity fracture pain after emergency department reduction and casting: predictors of pain after discharge.
The aims of this study are to determine the prevalence of pediatric extremity fracture pain after emergency department (ED) discharge, compare pain severity between fractures requiring simple casting versus sedated reduction and casting, and explore predictors of postdischarge pain. This is a prospective observational study of children aged 4 to younger than 18 years and presenting to the ED with extremity fracture from May 2010 to February 2011. The Parents' Postoperative Pain Measure, which scores pain according to 15 behavior-related questions, was completed 48 to 72 hours after discharge. A score greater than or equal to 6 of 15 indicates clinically meaningful pain. Univariate tests and multivariable regression analyses were used to compare Parents' Postoperative Pain Measure scores between cohorts. Two hundred fifty-seven patients were enrolled; 202 (79%) had Parents' Postoperative Pain Measure scores for analysis. Pain scores greater than or equal to 6 were reported by 37 of 102 (36%) of the simple casted and 44 of 100 (44%) of the reduced casted children. There was no difference in scores between the simple (median 4.0) and reduced casted (median 5.0) cohorts (difference 16.7%; 95% confidence interval [CI] -3.0% to 40%). In the multivariate analysis, ED narcotic administration was associated with 24% higher Parents' Postoperative Pain Measure scores (95% CI 0.95% to 53.6%). Children receiving ED narcotics had more than 2 times increased odds of pain scores greater than or equal to 6 after discharge (95% CI 1.24 to 5.39). Children in both simple casted and reduced casted groups had clinically meaningful pain after ED discharge. Identifying these children is important to improving pain management and discharge care.


Poison queries received during 1985 by the Regional Drug and Poison Information Centre, Durban.
The Regional Drug and Poison Information Centre at Addington Hospital, Durban, received a total of 3,177 requests for information on poisoning during 1985, with the highest incidence in August. The most common substances involved were prescribed medicines (895 calls, 28%) and household products (708 calls, 22%). The most frequent enquirers were hospital doctors (1,468 calls, 46%).


Coenzyme B12-dependent diol dehydratase: regulation of apoenzyme synthesis in Klebsiella pneumoniae (Aerobacter aerogenes) ATCC 8724.
Immunochemical studies demonstrated that Klebsiella pneumoniae (Aerobacter aerogenes) ATCC 8724 produces only a single diol dehydratase whether grown on glycerol or on 1,2-propanediol. The enzyme was subject to induction by 1,2-diols and to catabolite repression reversed by cyclic AMP.


Ectopic expression of LoSVP, a MADS-domain transcription factor from lily, leads to delayed flowering in transgenic Arabidopsis.
A MADS-domain transcription factorLoSVP, which could delay flowering through vernalization pathway, was isolated from lily. MADS-domain transcription factors play important roles in plant growth and development, especially in the transition from vegetative phase to reproductive phase. However, their functions in bulbous flowering plants are largely unknown. In this work, a SHORT VEGETATIVE PHASE (SVP) encoding genes LoSVP from oriental lily was isolated. Bioinformatic analyses demonstrated that LoSVP encodes a type II MADS-box protein containing a conserved MADS-box, as well as a conserved K-box domain. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) revealed ubiquitous expression of LoSVP in various tissues, including petals, stamens, pistils, leaves and scales. Real-time polymerase chain reaction (PCR) analyses demonstrated that LoSVP was predominantly expressed in the early stage of developing flowers. Constitutive expression of LoSVP in Arabidopsis led to significantly delayed flowering of transgenic plants. These results suggest that LoSVP is involved in plant flowering and could be used as a potential candidate gene for the genetic regulation of flowering time in higher plants.


Positive Predictive Value of Prostate Imaging Reporting and Data System Version 2 for the Detection of Clinically Significant Prostate Cancer: A Systematic Review and Meta-analysis.
The variability of the positive predictive value (PPV) represents a significant factor affecting the diagnostic performance of multiparametric magnetic resonance imaging (mpMRI). To analyze published studies reporting mpMRI PPV and the reasons behind the variability of clinically significant prostate cancer (csPCa) detection rates on targeted biopsies (TBx) according to Prostate Imaging Reporting and Data System (PI-RADS) version 2 categories. A search of PubMed, Cochrane library's Central, EMBASE, MEDLINE, and Scopus databases, from January 2015 to June 2020, was conducted. The primary and secondary outcomes were to evaluate the PPV of PI-RADS version 2 in detecting csPCa and any prostate cancer (PCa), respectively. Individual authors' definitions for csPCa and PI-RADS thresholds for positive mpMRI were accepted. Detection rates, used as a surrogate of PPV, were pooled using random-effect models. Preplanned subgroup analyses tested PPV after stratification for PI-RADS scores, previous biopsy status, TBx technique, and number of sampled cores. PPV variation over cancer prevalence was evaluated. Fifty-six studies, with a total of 16 537 participants, were included in the quantitative synthesis. The PPV of suspicious mpMRI for csPCa was 40% (95% confidence interval 36-43%), with large heterogeneity between studies (I2 94%, p < 0.01). PPV increased according to PCa prevalence. In subgroup analyses, PPVs for csPCa were 13%, 40%, and 69% for, respectively, PI-RADS 3, 4, and 5 (p < 0.001). TBx missed 6%, 6%, and 5% of csPCa in PI-RADS 3, 4, and 5 lesions, respectively. In biopsy-naïve and prior negative biopsy groups, PPVs for csPCa were 42% and 32%, respectively (p = 0.005). Study design, TBx technique, and number of sampled cores did not affect PPV. Our meta-analysis underlines that the PPV of mpMRI is strongly dependent on the disease prevalence, and that the main factors affecting PPV are PI-RADS version 2 scores and prior biopsy status. A substantially low PPV for PI-RADS 3 lesions was reported, while it was still suboptimal in PI-RADS 4 and 5 lesions. Lastly, even if the added value of a systematic biopsy for csPCa is relatively low, this rate can improve patient risk assessment and staging. Targeted biopsy of Prostate Imaging Reporting and Data System 3 lesions should be considered carefully in light of additional individual risk assessment corroborating the presence of clinically significant prostate cancer. On the contrary, the positive predictive value of highly suspicious lesions is not high enough to omit systematic prostate sampling.


Prediction of acute kidney injury after cardiac surgery: model development using a Chinese electronic health record dataset.
Acute kidney injury (AKI) is a major complication following cardiac surgery that substantially increases morbidity and mortality. Current diagnostic guidelines based on elevated serum creatinine and/or the presence of oliguria potentially delay its diagnosis. We presented a series of models for predicting AKI after cardiac surgery based on electronic health record data. We enrolled 1457 adult patients who underwent cardiac surgery at Nanjing First Hospital from January 2017 to June 2019. 193 clinical features, including demographic characteristics, comorbidities and hospital evaluation, laboratory test, medication, and surgical information, were available for each patient. The number of important variables was determined using the sliding windows sequential forward feature selection technique (SWSFS). The following model development methods were introduced: extreme gradient boosting (XGBoost), random forest (RF), deep forest (DF), and logistic regression. Model performance was accessed using the area under the receiver operating characteristic curve (AUROC). We additionally applied SHapley Additive exPlanation (SHAP) values to explain the RF model. AKI was defined according to Kidney Disease Improving Global Outcomes guidelines. In the discovery set, SWSFS identified 16 important variables. The top 5 variables in the RF importance matrix plot were central venous pressure, intraoperative urine output, hemoglobin, serum potassium, and lactic dehydrogenase. In the validation set, the DF model exhibited the highest AUROC (0.881, 95% confidence interval [CI] 0.831-0.930), followed by RF (0.872, 95% CI 0.820-0.923) and XGBoost (0.857, 95% CI 0.802-0.912). A nomogram model was constructed based on intraoperative longitudinal features, achieving an AUROC of 0.824 (95% CI 0.763-0.885) in the validation set. The SHAP values successfully illustrated the positive or negative contribution of the 16 variables attributed to the output of the RF model and the individual variable's effect on model prediction. Our study identified 16 important predictors and provided a series of prediction models to enhance risk stratification of AKI after cardiac surgery. These novel predictors might aid in choosing proper preventive and therapeutic strategies in the perioperative management of AKI patients.


The association of cancer-related fatigue on the social, vocational and healthcare-related dimensions of cancer survivorship.
Cancer-related fatigue (CRF) is well documented in cancer survivors, but little is known about the personal and societal impact of CRF. This study aimed to examine the impact of CRF in relation to social and vocational functioning and health care utilization in a large sample of post-treatment cancer survivors. We conducted a cross-sectional descriptive study of early stage breast and colorectal cancer survivors (n = 454) who were within 5 years from treatment completion. Social difficulties (SDI-21), work status, absenteeism and presenteeism (WHO-HPQ) and healthcare utilization (HSUQ) were compared in those with (CFR +) and without (CRF -) clinically significant fatigue (FACT-F ≤ 34). A total of 32% met the cut-off criteria for CRF (≤ 34). Participants with CRF + had significantly higher scores on the SDI-21 across all domains and 55% of CRF + vs. 11% in CRF - was above the SDI cut-off (> 10) for significant social difficulties. Participants with CRF + were 2.74 times more likely to be unemployed or on leave (95% CI 1.62, 4.61, p < 0.001). In the subgroup of participants who were currently working (n = 249), those with CRF + reported working on average 27.4 fewer hours in the previous 4 weeks compared to CRF - (p = 0.05), and absolute presenteeism was on average 13% lower in the CRF + group (95% CI 8.0, 18.2, p < 0.001). Finally, individuals with CRF + reported significantly more physician (p < 0.001), other health care professional (p = 0.03) and psychosocial visits (p = 0.002) in the past month. CRF is associated with substantial disruption in social and work role functioning in the early transitional phase of cancer survivorship. Better management of persistent CRF and funding for the implementation of existing guidelines and recommended evidence-based interventions are urgently needed.


Advances in dissecting endomembrane trafficking with small molecules.
Chemical genomics is relatively new to plant biology in academia; however, the ability of this approach to present novel discoveries is being demonstrated clearly. One particularly suitable application of this approach is plant endomembrane trafficking. The rapid and dynamic nature of vesicular trafficking plus genetic redundancy has hampered effective study of this complex network. The ability of small molecules to act quickly to inhibit or arrest vesicular trafficking should permit the association of specific vesicles, especially endosome compartments, with their cargoes, particularly those destined for the plasma membrane. This approach and the large target space presented by the endomembrane trafficking network require the discovery of many new bioactive molecules. Advances in high-throughput chemical screening in plants are making this a reality. However, successful chemical genomic approaches in plants must be coupled with improvements in automated microscopy, image analysis, and target identification. In addition, the ability to correlate specific molecules with complex phenotypic data will be crucial. The data obtained from these experiments will be composed of a matrix of intracellular markers displaying complex chemically induced phenotypes as well as whole plant and perhaps data generated by genomics, proteomics, and metabolomics. In this manner, it should be possible to view endomembrane trafficking and its interactions as a systems-based network.


Chemical compositions and properties of Schinus areira L. essential oil on airway inflammation and cardiovascular system of mice and rabbits.
The main purpose was to investigate the effects of essential plant-oil of Schinus areira L. on hemodynamic functions in rabbits, as well as myocardial contractile strength and airways inflammation associated to bacterial endotoxin lipopolysaccharide (LPS) in mice. This study shows the important properties of the essential oil (EO) of S. areira studied and these actions on lung with significant inhibition associated to LPS, all of which was assessed in mice bronchoalveolar lavage fluid and evidenced by stability of the percentage of alveolar macrophages, infiltration of polymorphonuclear leukocytes and tumor necrosis factor-α concentration, and without pathway modifications in conjugated dienes activity. Clinical status (morbidity or mortality), macroscopic morphology and lung/body weight index were unaffected by the administration of the EO S. areira. Furthermore, the ex vivo analysis of isolated hearts demonstrated the negative inotropic action of the EO of S. areira in a mice model, and in rabbits changes in the hemodynamic parameters, such as a reduction of systolic blood pressure. We conclude that EO S. areira could be responsible for modifications on the cardiovascular and/or airway parameters.


Changes in fast axonal transport during experimental nerve compression at low pressures.
The minimal pressure for impairment of fast anterograde axonal transport was determined in rabbit vagus nerve. Proteins, transported by fast anterograde axonal transport, were labeled by a microinjection of [3H]leucine into the nodose ganglion, and a small compression chamber was applied around the cervical vagus nerve. In this way the nerve was subjected to acute, graded compression. Compression at 20 mm Hg for 2 h as well as sham compression did not induce accumulation of axonally transported proteins at the level of compression. However, a pressure of 30 mm Hg for 2 h induced a block of axonal transport at the site of compression. The causes of the axonal transport block are discussed as well as the minimal pressure level in relation to pressures found in clinical nerve compression lesions.


PET probe-guided surgery.
Intraoperative localization of PET-positive recurrent/metastatic lesions can be facilitated using a hand-held PET probe. PET probe is a high-energy gamma probe designed to process the 511 keV photons of PET tracers. Intraoperative gamma probe performance is a function of radiopharmaceutical uptake, clearance kinetics, and probe engineering, all determining the target to background ratio (TBR) and detection threshold. A minimum TBR of 1.5:1 is needed in the operative field for the operating surgeon to be comfortable the differences between tumor tissue and normal adjacent tissue are real. Due to high-energy photon fluxes, achieving a satisfactory TBR intraoperatively is challenging and requires development of a clinically feasible PET-probe guided surgery protocol.


Evaluation of metal mobility from copper mine tailings in northern Chile.
This work shows the results obtained on a copper mine tailing in the Antofagasta Region, Chile. The tailing was classified as saline-sodic with high concentrations of metals, especially Cu and Fe, with pH 8.4. Our objectives were to (1) compare the physicochemical properties of the tailing with surrounding soils of the mine under study, and (2) evaluate the effect of two amendments (CaCO3 and compost) and their mixtures on Cu(2+), Mn, Fe, Zn, Mg(2+), and K(+) and Ca(2+), SO4 (2-), NO3 (-), and PO4 (3-) leaching. The data obtained were submitted to variance and covariance analysis. The results from the comparison between both substrates showed that in general, the tailing presented greater content of metals. Regarding tailing leaching, pH, electrical conductivity (EC), and concentration of the elements of interest were measured. The statistical analysis showed that Cu(2+) leaching and immobilization of Fe occurred to the greatest extent with compost. The EC decreased throughout the experiment with irrigation and increased upon treatment with compost. The major interactions found among the chemical parameters were (1) tailings without treatment, Cu(2+)/Fe and NO3 (-)/SO4 (2-); (2) tailings treated with CaCO3, Cu(2+)/K(+); (3) tailings treated with compost, NO3 (-)/SO4 (-2) and EC/Cu(2+); and (4) tailings treated with both amendments, EC/Fe and Cu(2+)/Fe. The ANOVA showed that the number of irrigations and the amendments statistically significantly affected the copper mobility and the organic amendment significantly influenced the iron mobility.


Historical review of the changing pattern of infant feeding in developing countries: the case of Malaysia, the Caribbean, Nigeria and Zaire.
Prolonged lactation and early supplementation have been traditional practices among low-income mothers in Malaysia, the Caribbean, Nigeria and Zaire. Early supplementation is still the norm but there have been some substantial changes in the types of supplement offered. Thus, except in Zaire, there is now widespread use of processed milks as supplements for very young infants. The use of processed milks began in the 1920s in Malaysia and the Caribbean, but not until the 1960s in Nigeria. Processed milks are, as yet, rarely used in Zaire. The use of processed milks has not, however, led to the abandonment of traditional paps. The latter are still given as supplements to young infants in Nigeria and to older infants in Malaysia and the Caribbean. Breast-feeding duration has declined in Malaysia and the Caribbean although initiation is almost universal. In Nigeria and Zaire most low-income mothers continue to breast-feed for at least 12 months. The changes in the types of supplements used and in breast-feeding duration are analogous to the changes observed in industrialised countries from the mid-19th century, and many of the associated factors are similar: urbanisation; female participation in the labour force; increased availability of processed milks and their promotion both by companies and the health sector; and the regimentation of breast-feeding. This review highlights the negative role played by the health sector in the past, and discusses its future role in promoting and supporting breast-feeding.


Evidence for periaqueductal cholecystokinin-substance P neurons projecting to the spinal cord.
Using indirect immunofluorescence techniques combined with retrogradely transported fluorescent dyes, cholecystokinin (CCK)-like and substance P immunoreactive cell bodies in the periaqueductal central grey of the rat brain were studied. Data from both adjacent sections and elution-restaining techniques indicated that some of these central grey cells contain both a CCK-like peptide and substance P. Injection of the fluorescent dye, Fast Blue, into the cervical spinal cord indicated that this CCK-substance P cell group is a descending system. These findings provide evidence for two peptides in a single neuron, and the possible functional significance of such an occurrence is discussed.


Advances in Wearable Photoplethysmography Applications in Health Monitoring.
In the last few years, interest in wearable technology for physiological signal monitoring is rapidly growing, especially during and after the COVID-19 pandemic [...].


Administration of interferon for two or more years decreases early stage hepatocellular carcinoma recurrence rate after radical ablation: A retrospective study of hepatitis C virus-related liver cancer.
Since hepatocellular carcinoma often recurs after surgical resection or radiofrequency ablation, we analyzed a retrospective large cohort of patients with small hepatocellular carcinoma caused by hepatitis C virus (HCV). Among 379 patients with HCV RNA-positive small hepatocellular carcinoma (multiple up to three nodules, 3 cm or less each), 77 received interferon-alpha injection and 302 received no anti-viral therapy. Four patients (5.2%) attained sustained virological response (SVR). Cumulative recurrence rates in the treated and untreated groups were 41.1% and 57.5% at the end of the third year, and 63.0% and 74.5% at the fifth year, respectively (P = 0.013). Fifth year-recurrence rates in treated group were 25.0% in SVR, 85.7% in biochemical response, 71.1% in no response, and 46.7% in patients with continuous administration. When four patients with SVR were excluded, recurrence rates in short-term interferon therapy (<2 years) and long-term therapy (≥2 years) were 46.2% and 39.3% at the third year, and 66.2% and 57.4% at the fifth year, respectively (P = 0.012). Multivariate analysis showed that long-term interferon therapy significantly decreased recurrence rate (hazard ratio for interferon <2 years 0.80, interferon ≥2 years 0.60, P = 0.044), after adjustment with background covariates including indocyanine green retention rate (P = 0.018), alpha-fetoprotein (P = 0.051), and tumor treatment (P = 0.066). A long-term administration of low-dose interferon significantly decreased recurrence of hepatocellular carcinoma after surgical resection or radiofrequency ablation.


Misleading information from pulse oximetry and the usefulness of continuous blood gas monitoring in a post cardiac surgery patient.
We report a case where misleading readings form a pulse oximeter were compared with the results obtained from a continuous multiparameter blood gas sensor (Paratrend 7 - Biomedical Sensors UK). The continuous mode of recording was useful in determining the right clinical course for the patient and serves to show how pulse oximetry may demonstrate misleading results in low flow states.


Biosensor-guided rapid screening for improved recombinant protein secretion in Pichia pastoris.
Pichia pastoris (Komagataella phaffii) is widely used for industrial production of heterologous proteins due to high secretory capabilities but selection of highly productive engineered strains remains a limiting step. Despite availability of a comprehensive molecular toolbox for construct design and gene integration, there is high clonal variability among transformants due to frequent multi-copy and off-target random integration. Therefore, functional screening of several hundreds of transformant clones is essential to identify the best protein production strains. Screening methods are commonly based on deep-well plate cultures with analysis by immunoblotting or enzyme activity assays of post-induction samples, and each heterologous protein produced may require development of bespoke assays with multiple sample processing steps. In this work, we developed a generic system based on a P. pastoris strain that uses a protein-based biosensor to identify highly productive protein secretion clones from a heterogeneous set of transformants. The biosensor uses a split green fluorescent protein where the large GFP fragment (GFP1-10) is fused to a sequence-specific protease from Tobacco Etch Virus (TEV) and is targeted to the endoplasmic reticulum. Recombinant proteins targeted for secretion are tagged with the small fragment of the split GFP (GFP11). Recombinant protein production can be measured by monitoring GFP fluorescence, which is dependent on interaction between the large and small GFP fragments. The reconstituted GFP is cleaved from the target protein by TEV protease, allowing for secretion of the untagged protein of interest and intracellular retention of the mature GFP. We demonstrate this technology with four recombinant proteins (phytase, laccase, β-casein and β-lactoglobulin) and show that the biosensor directly reports protein production levels that correlate with traditional assays. Our results confirm that the split GFP biosensor can be used for facile, generic, and rapid screening of P. pastoris clones to identify those with the highest production levels.


Toxic effects of triphenyltin on the development of zebrafish (Danio rerio) embryos.
Triphenyltin (TPT) is known to be an environmental endocrine disruptor and has adverse effects on aquatic animals. In this study, zebrafish embryos were treated with three different concentrations (12.5, 25, 50 nmol/L) based on the LC50 value at 96 h post fertilization (96 hpf), after TPT exposure. The developmental phenotype and hatchability were observed and recorded. Reactive oxygen species (ROS) levels in zebrafish were detected at 72 hpf and 96 hpf using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) as a probe. The number of neutrophils after exposure was observed using transgenic zebrafish Tg (lyz: DsRed). RNA-seq analysis was used to compare the gene expression changes in zebrafish embryos at 96 hpf in the control group and 50 nmol/L TPT exposure group. The data revealed that TPT caused a delay in hatching of zebrafish embryos in a time- and dose-dependent manner, as well as causing pericardial edema, spinal curvature and melanin reduction. ROS levels in embryos exposed to TPT increased, and the number of neutrophils increased after TPT exposure to Tg (lyz: DsRed) in transgenic zebrafish. RNA-seq results were also analyzed, and KEGG enrichment analysis showed that significant differential genes were enriched in the PPAR signaling pathway (P < 0.05), and the PPAR signaling pathway mainly affected genes related to lipid metabolism. The RNA-seq results were verified using real-time fluorescence quantitative PCR (RT-qPCR). Oil red O and Nile red staining showed increased lipid accumulation after TPT exposure. These findings suggest that TPT affects the development of zebrafish embryos even at relatively low concentrations.


Comparison of Femto-LASIK With Combined Accelerated Cross-linking to Femto-LASIK in High Myopic Eyes: A Prospective Randomized Trial.
To evaluate the safety and efficacy of femtosecond (fs) laser-assisted in situ keratomileusis (LASIK) combined with accelerated corneal cross-linking (LASIK Xtra) compared to conventional fs-LASIK (convLASIK) in high myopic patients. Prospective, randomized, fellow-eye controlled clinical trial. Setting: Department of Ophthalmology, Goethe University, Frankfurt/Germany. StudyPopulation: Twenty-six patients with high myopia and/or myopic astigmatism received randomized treatment with LASIK Xtra (30 mW/cm2, 90 seconds with continuous ultraviolet-A) in 1 eye and convLASIK in the other eye. MainOutcomeMeasures: Uncorrected distance visual acuity (UDVA), best spectacle-corrected VA (BSCVA), manifest refractive spherical equivalent (MRSE), endothelial cell count (ECC), and corneal thickness. The UDVA improved from 1.26 ± 0.13 logMAR preoperative to -0.02 ± 0.15logMAR in LASIK Xtra eyes and from 1.27 ± 0.12 logMAR to 0.01 ± 0.15 logMAR in the convLASIK eyes (P > .05). The MRSE changed from -7.35 ± 1.15 diopters (D) and -7.5 ± 1.12 D to -0.17 ± 0.43 D and -0.25 ± 0.46 D, respectively. There was no significant difference in outcomes between both groups during the 12 months follow-up except for the convLASIK eyes' showing slightly better BSCVA after 1 week (P < .05). ConvLASIK eyes revealed a nonsignificant trend toward myopic regression from 3 to 12 months postoperative with a change in MRSE of -0.15 D compared to -0.1 D in LASIK Xtra eyes. Topography showed stability of corneal curvature with no signs of keratectasia in both groups at 12 months. While apparently safe, LASIK Xtra showed no advantages over conventional LASIK. At 12 months, both groups showed no difference regarding UDVA and refractive stability, and no signs of keratectasia.


Evaluation of diet and growth in children with and without atopic eczema: follow-up study from birth to 4 years.
Current research into dietary factors contributing to the development of allergic diseases is directed towards new active approaches instead of passive elimination diets. The present study aimed to investigate the explanatory role of the diet in a probiotic intervention study on the appearance of atopic eczema (AE) in childhood and the safety of perinatal supplementation with probiotics (Lactobacillus rhamnosus strain GG; ATCC 53 103). A prospective follow-up study from birth to 48 months of children (n 159) with a family history of allergic disease was carried out. Outcome measures included growth, dietary intake assessed with 4 d food diaries and their association with AE by logistic regression models. Increased intakes of retinol, Ca and Zn, with perinatal administration of probiotics, reduced the risk of AE, whilst an increase in intake of ascorbic acid increased the likelihood of AE. Perinatal administration of probiotics was safe, as it did not influence the height (mean difference 0.04 (95 % CI -0.33, 0.40) sd scores, P=0.852) or the weight-for-height (mean difference -3.35 (95 % CI -7.07, 0.37)%, P=0.077) of the children at 48 months with and without perinatal administration of probiotics. Up to 48 months, AE did not affect height (mean difference -0.05 (95 % CI -0.42, 0.33) sd scores, P=0.815), but mean weight-for-height in children with AE was -5.1 % (95 % CI -8.9, -1.2 %) lower compared with children without (P=0.010). The joint effects of nutrients and probiotics need to be considered in active prevention and management schemes for allergic diseases.


The impact of interspecific competition on lineage evolution and a rapid peak shift by interdemic genetic mixing in experimental bacterial populations.
Epistatic interactions between genes in the genome constrain the accessible evolutionary paths of lineages. Two factors involving epistasis that can affect the evolutionary path and fate of lineages were investigated. The first factor concerns the impact of competition with another species lineage that has different epistatic constraints. Five enteric bacterial populations were evolved by point mutation in medium containing a single limiting resource. Single-species and two-species cultures were used to determine whether different asexual lineages have different capacities for producing variants due to epistatic constraints, and whether their survival is determined by local inter-lineage competition with different species. Local inter-lineage competition quickly resulted in one successful lineage, with another lineage becoming extinct before finding a higher peak. The second factor concerns a peak-shifting process, and whether the sexual recombination between different demes can cause peak shifts was investigated. An Escherichia coli population consisting of a male (Hfr) and female strain (F(-)) was evolved in a single limiting resource and compared to evolving populations containing the male or female strain alone. The E. coli sexual lineage was successful due to its ability to escape lower peaks and reach a higher peak, not because of a rapid approach to the nearest local peak the male or female asexual lineage could reach. The data in this study demonstrate that lineage survivability can be determined by the ability to produce beneficial mutations and checked by local competition between lineages of different species. Interspecific competition may prevent a population from evolving through crossing fitness valleys or adaptive ridges if it requires many generations to achieve peak shifts. The data also show that genomic recombination between different conspecific lineages can rapidly carry the combined lineage to a higher peak.


Photochemical conversion of the O-intermediate to 9-cis-retinal-containing products in bacteriorhodopsin films.
The photochemical activity of the O-state was investigated in bacteriorhodopsin (BR) films containing wildtype BR at pH 6.5 in the presence of glycerol. The formation of a photoproduct of O with an absorption maximum at 490 nm and 9-cis-retinal configuration was found. This 490-nm product was named P and shows a slow thermal reaction into a compound with a maximal absorption at 380 nm which was named Q and contains free 9-cis-retinal in the proteins binding site. The photoproducts of O, i.e., P and Q, are very similar, or even identical, to those previously observed in blue membranes. Common to the O-state and blue membrane forms of bacteriorhodopsin is a protonated aspartic acid 85, and we suggest that it is the reduced negative charge around the Schiff base which is responsible for the 9-cis photoisomerization. The release of a proton from aspartic acid 85 is linked to the conversion of the O-state back to the initial state of BR. Therefore the conditions of low proton mobility in BR films containing glycerol favor the accumulation of the O-state. For optical and holographic applications such BR films are very attractive. It is possible to create photoproducts with red light which are thermally stable at room temperature and that can be photochemically erased. Dependent on the light composition both properties can be realized in the same sample material. This feature may bridge the gap between information processing and short-term and long-term storage of information with BR.


Competition between thermal and surfactant-induced Marangoni flow in evaporating sessile droplets.
Thermal Marangoni flow in evaporating sessile water droplets is much weaker in experiments than predicted theoretically. Often this is attributed to surfactant contamination, but there have not been any in-depth analyses that consider the full fluid and surfactant dynamics. It is expected that more insight into this problem can be gained by using numerical models to analyze the interplay between thermal Marangoni flow and surfactant dynamics in terms of dimensionless parameters. Two numerical models are implemented: one dynamic model based on lubrication theory and one quasi-stationary model, that allows for arbitrary contact angles. It is found that insoluble surfactants can suppress the thermal Marangoni flow if their concentration is sufficiently large and evaporation and diffusion are sufficiently slow. Soluble surfactants, however, either reduce or increase the interfacial velocity, depending on their sorption kinetics. Furthermore, insoluble surfactant concentrations that cause an order 0.1% surface tension reduction are sufficient to reduce the spatially averaged tangential flow velocity at the interface by a factor 100. For larger contact angles and smaller droplets this required concentration is larger (typically <1% surface tension reduction). The numerical models are mutually validated by comparing their results in cases where both are valid.


Interaction of adenylic acid with alkaline earth metal ions in the crystalline solid and aqueous solution. Evidence for the sugar C'2-endo/anti, C'3-endo/anti and C'4-exon/anti conformational changes.
The reaction of adenosine 5'-monophosphoric acid (H2-AMP) with the alkaline earth metal ions has been investigated in aqueous solution at neutral pH. The solid salts of Mg-AMP.5H2O, Ca-AMP.6H2O, Sr-AMP.7H2O and Ba-AMP.7H2O were isolated and characterized by Fourier transform infrared, 1H-NMR spectroscopy and X-ray powder diffraction measurements. Spectroscopic and other evidence showed that the Sr-AMP.7H2O and Ba-AMP.7H2O are isomorphous, whereas the Mg-AMP.5H2O and Ca-AMP.6H2O are not similar. The Mg2+ binding is through the N-7 (inner-sphere) and the phosphate group (outer-sphere via H2O), while the Ca2+ binds to the phosphate group (inner-sphere) and to the base N-7 site (outer-sphere through H2O). The Sr2+ and Ba2+ bind to H2O molecules, H-bonding to the N-7, N-1 and the phosphate group (outer-sphere). In aqueous solution, an equilibrium between the inner- and outer-sphere metal ion bindings can be established. The sugar moiety exhibited C'2-endo/anti conformation, in the free H2-AMP acid and the magnesium salt, C'3-endo/anti in the calcium salt and unusual C'4-exo/anti, in the strontium and barium salts.


Gram-negative bacillary infections. Pathogenic and pathophysiologic correlates.
Gram-negative bacillary infections continue to be extremely important. Escherichia coli is the single most frequently encountered pathogen, followed by organisms belonging to the tribe Klebsiella-Enterobacter-Serratia and Proteus-Providencia. Pseudomonas aeruginosa, although it receives considerable (perhaps excessive) attention, is found relatively less frequently, occurring principally in the hospitalized patient who is immunocompromised. Many factors, both host and microbial, are responsible for invasiveness, virulence, and pathogenicity of gram-negative bacilli, but their relative roles, importance, and the pathophysiologic reactions they trigger are yet to be precisely defined. Certain aspects of many (but certainly not all) of the pathogenic correlates considered important in gram-negative bacillary infections, such as microbial flora, local barriers, surface and serum antibodies, complement, cell-mediated immunity, slime production, capsules, pili, endotoxin, cell wall components, extracellular products, and inoculum size are discussed herein. Points at which preventive or therapeutic strategies might be developed are offered. The benefits of antibiotics in managing susceptible gram-negative bacillary infections appear to be plateauing. If further advances are to be made in the therapy of these infections, new approaches to rapidly identifying the responsible etiologic agent and a better understanding of the factors responsible for invasiveness, virulence, and pathogenicity are needed.


New Solvent-Free Melting-Assisted Preparation of Energetic Compound of Nickel with Imidazole for Combustion Synthesis of Ni-Based Materials.
In this work two approaches to the synthesis of energetic complex compound Ni(Im)6(NO3)2 from imidazole and nicklel (II) nitrate were applied: a traditional synthesis from solution and a solvent-free melting-assisted method. According to infrared spectroscopy, X-ray diffraction, elemental and thermal analysis data, it was shown that the solvent-free melt synthesis is a faster, simpler and environmentally friendly method of Ni(Im)6(NO3)2 preparation. The results show that this compound is a promising precursor for the production of nanocrystalline Ni-NiO materials by air-assisted combustion method. The combustion of this complex together with inorganic supports makes it possible to synthesize supported nickel catalysts for different catalytic processes.


Effects of antidepressants on thinking styles in depressed inpatients.
1. Clinical and empirical evidence point to distorted negative thinking during depressive episodes. 2. The present study, utilizing the Cognitions Questionnaire, examined the thinking styles in depressed inpatients prior to antidepressant pharmacotherapy and again 3-4 weeks after treatment. 3. Across the 5 dimensions of thinking assessed, only generalization across situation changed significantly in the drug-respondent group. 4. While clinically, short-term antidepressant treatment was shown to be efficacious, it only changed cognitions in a limited way.


Evaluation of simultaneous multi-slice readout-segmented diffusion-weighted MRI acquisition in human optic nerve measurements.
Diffusion-weighted magnetic resonance imaging (dMRI) is the only available method to measure the tissue properties of white matter tracts in living human brains and has opened avenues for neuroscientific and clinical studies on human white matter. However, dMRI using conventional simultaneous multi-slice (SMS) single-shot echo planar imaging (ssEPI) still presents challenges in the analyses of some specific white matter tracts, such as the optic nerve, which are heavily affected by susceptibility-induced artifacts. In this study, we evaluated dMRI data acquired by using SMS readout-segmented EPI (rsEPI), which aims to reduce susceptibility-induced artifacts by dividing the acquisition space into multiple segments along the readout direction to reduce echo spacing. To this end, we acquired dMRI data from 11 healthy volunteers by using SMS ssEPI and SMS rsEPI, and then compared the dMRI data of the human optic nerve between the SMS ssEPI and SMS rsEPI datasets by visual inspection of the datasets and statistical comparisons of fractional anisotropy (FA) values. In comparison with the SMS ssEPI data, the SMS rsEPI data showed smaller susceptibility-induced distortion and exhibited a significantly higher FA along the optic nerve. In summary, this study demonstrates that despite its prolonged acquisition time, SMS rsEPI is a promising approach for measuring the tissue properties of the optic nerve in living humans and will be useful for future neuroscientific and clinical investigations of this pathway.


Receipt of the C-terminal tail from a neighboring lambda Int protomer allosterically stimulates Holliday junction resolution.
Bacteriophage lambda integrase (Int) catalyzes the integration and excision of the phage lambda chromosome into and out of the Esherichia coli host chromosome. The seven carboxy-terminal residues (C-terminal tail) of Int comprise a context-sensitive regulatory element that links catalytic function with protein multimerization and also coordinates Int functions within the multimeric recombinogenic complex. The experiments reported here show that the beta5-strand of Int is not simply a placeholder for the C-terminal tail but rather exerts its own allosteric effects on Int function in response to the incoming tail. Using a mutant integrase in which the C-terminal tail has been deleted (W350ter), we demonstrate that the C-terminal tail is required for efficient and accurate resolution of Holliday junctions by tetrameric Int. Addition of a free heptameric peptide of the same sequence as the C-terminal tail partially reverses the W350ter defects by stimulating Holliday junction resolution. The peptide also stimulates the topoisomerase function of monomeric W350ter. Single residue alterations in the peptide sequence and a mutant of the beta5 strand indicate that the observed stimulation arises from specific contacts with the beta5 strand (residues 239-243). The peptide does not stimulate binding of W350ter to its cognate DNA sites and therefore appears to recapitulate the effects of the normal C-terminal tail intermolecular contacts in wild-type Int. Models for the allosteric stimulation of Int activity by beta5 strand contacts are discussed.


Evidence of ortho- and paramyxoviruses in fauna from Antarctica.
Serum antibodies to influenza A viruses and paramyxoviruses were detected in Adelie penguin (Pysoscelis adeliae) and Antarctic skua (Stercorarius skua maccormicki) sera in the Ross Sea Dependency. An avian paramyxovirus was isolated from a penguin cloacal swab.


Sub-Saharan Africa and Eurasia Ancestry of Reassortant Highly Pathogenic Avian Influenza A(H5N8) Virus, Europe, December 2019.
We report detection of a highly pathogenic avian influenza A(H5N8) clade 220.127.116.11b virus in Europe. This virus was generated by reassortment between H5N8 subtype virus from sub-Saharan Africa and low pathogenicity avian influenza viruses from Eurasia.


Effect of vitamin A supplementation on plasma and breast milk vitamin A levels in poorly nourished Gambian women.
Plasma and breast milk vitamin A and plasma carotenoids were measured in groups of pregnant and lactating women in two neighbouring rural Gambian villages. One of the groups (Keneba) received a 650 micrograms daily vitamin A supplement. During pregnancy, plasma retinol values were significantly (19 per cent) higher in the supplemented group. During lactation, breast milk values were significantly (23 per cent) higher in the supplemented group. Changes in plasma and breast milk vitamin A levels during the cycle of pregnancy and lactation and with season are also described, and the value of a combined index of plasma retinol and plasma carotenoids is illustrated. The significant effect of a prolonged low level vitamin A supplement to pregnant and lactating women has important implications for nutrition intervention programmes.


Introduction to defensive behavior in vertebrates.
In this introductory chapter we describe the ethological basis of defensive behavior, including tonic immobility (TI). The defensive repertoire activated in response to threatening stimuli, both in natural and experimental conditions, consists of a system of interrelated behaviors influenced by two main dimensions, as distance from the threat and escapable/inescapable context. When the active strategy of escape is not feasible, passive immobility forms are adopted, the latter representing substitutes of actual escape. In an inescapable context, and at very short distance or in contact with the threatening stimulus, TI is adopted, or submissive posture in a social context. Physical restraint represents the strongest stimulus for TI induction. As a result of behavioral flexibility, subsets of animals within a population show a different capacity and modality to cope with aversive stimuli (animal personality). TI can be regarded as a trait of behavioral syndromes in species as mammals and avians.


3D bioprinted drug-resistant breast cancer spheroids for quantitative in situ evaluation of drug resistance.
Drug-resistant cancer spheroids were fabricated by three-dimensional (3D) bioprinting for the quantitative evaluation of drug resistance of cancer cells, which is a very important issue in cancer treatment. Cancer spheroids have received great attention as a powerful in vitro model to replace animal experiments because of their ability to mimic the tumor microenvironment. In this work, the extrusion printing of gelatin-alginate hydrogel containing MCF-7 breast cancer stem cells successfully provided 3D growth of many single drug-resistant breast cancer spheroids in a cost-effective 3D-printed mini-well dish. The drug-resistant MCF-7 breast cancer spheroids were able to maintain their drug-resistant phenotype of CD44high/CD24low/ALDH1high in the gelatin-alginate media during 3D culture and exhibited higher expression levels of drug resistance markers, such as GRP78 chaperon and ABCG2 transporter, than bulk MCF-7 breast cancer spheroids. Furthermore, the effective concentration 50 (EC50) values for apoptotic and necrotic spheroid death could be directly determined from the 3D printed-gelatin-alginate gel matrix based on in situ 3D fluorescence imaging of cancer spheroids located out of the focal point and on the focal point. The EC50 values of anti-tumor agents (camptothecin and paclitaxel) for apoptotic and necrotic drug-resistant cancer spheroid death were higher than those for bulk cancer spheroid death, indicating a greater drug resistance. STATEMENT OF SIGNIFICANCE: This study proposed a novel 3D bioprinting-based drug screening model, to quantitatively evaluate the efficacy of anticancer drugs using drug-resistant MCF-7 breast cancer spheroids formed within a 3D-printed hydrogel. Quantitative determination of anticancer drug efficacy using EC50, which is extremely important in drug discovery, was achieved by 3D printing that enables concurrent growth of many single spheroids efficiently. This study verified whether drug-resistant cancer spheroids grown within 3D-printed gelatin-alginate hydrogel could maintain and present drug resistance. Also, the EC50 values of the apoptotic and necrotic cell deaths were directly acquired in 3D-embedded spheroids based on in situ fluorescence imaging. This platform provides a single-step straightforward strategy to cultivate and characterize drug-resistant spheroids to facilitate anticancer drug screening.


A highly conserved determinant on human rheumatoid factor idiotypes defined by a mouse monoclonal antibody.
Different human IgM rheumatoid factor (IgM RF) idiotypes have been described defined by polyclonal rabbit anti-idiotypic antibodies. These antisera do not allow clear genetic analysis of the idiotypic determinants, be they cross-reactive or private. Therefore, we tried to obtain a set of monoclonal anti-idiotypic antibodies directed against RF idiotypes. Purified IgM RF serum from a patient with classical rheumatoid arthritis was used to immunize BALB/c mice. The spleen cells were fused with Sp 2/0 Ag 14, a nonsecreting mouse myeloma cell line, and a hybrid producing monoclonal anti-idiotypic antibody was selected. The mouse antibody, an IgG1 kappa, reacts with an identical or similar determinant located on (or close to) the binding site of all tested monoclonal or polyclonal IgM RF from totally unrelated patients with Waldenströms's macroglobulinemias or rheumatoid arthritis. The monoclonal antibody also reacts with 2 rheumatoid arthritis patients' IgG RF and with a low proportion of normal polyclonal IgM without detectable RF activity. An hypothesis is proposed to explain the existence of a such highly conserved determinant on RF idiotypes.


History of perinatal loss: A study of psychological outcomes in mothers and fathers after subsequent healthy birth.
The loss of an expected child is a psychologically difficult and potentially traumatic life event. While most women will become pregnant again within a year following the loss, data are limited regarding the mental health of parents with a history of perinatal loss, especially in the period following the birth of a subsequent healthy child. This study, therefore, investigated the relation between perinatal loss and mothers' and fathers' psychological symptoms and parenting stress 6-months after the birth of a healthy child. A community sample of 92 mother-father dyads living in a Canadian city and having a 6-month-old biological infant were asked to complete questionnaires measuring their history of perinatal losses (55 parents reporting at least one loss) and their psychological symptoms and parenting stress. Mothers and fathers who have experienced a perinatal loss reported more psychological symptoms and parenting stress. Mothers were more likely to report psychological symptoms and parenting stress compared to fathers, but the magnitude of the relation between perinatal losses and psychological outcomes were comparable for mothers and fathers. Limitations of the study include the use of a small community sample with low generalizability and low levels of psychological symptoms and stress. The results suggest that the experience of a perinatal loss might have negative consequences on the psychological wellbeing of parents even after the birth of a healthy child.


Does increased stochasticity speed up extinction?
We consider the impact of increased stochastic fluctuations on the extinction date of an unstructured population subject to either environmental or demographical stochasticity (or both). By modelling the population density as a general linear diffusion, we state a set of typically satisfied conditions under which the decreasing minimal r-excessive mapping (and, therefore, the moment generating function) of the considered diffusion process is convex and, consequently, under which the impact of increased stochastic fluctuations on the expected date at which the density becomes arbitrarily small is unambiguously negative. In other words, we establish a set of sufficient conditions under which increased stochasticity speeds up the extinction process independently of whether stochasticity is environmental or demographic. In this way, we are able to confirm that increased stochasticity is detrimental for population growth.


A radiographic method for measuring radiation dose based on beam quality.
To develop a radiographic method for measuring radiation dose based on beam quality for inexpensive postal surveys of general dental practitioners. Different beam qualities were simulated to expose a commercially available film (X-Omat MA 18 x 22.4 cm, Ready Pack, Kodak Pathe, Paris, France). Density and contrast curves were fitted by means of 4th-degree polynomial functions. The curves were used to estimate beam quality (as the first HVL) and radiation dose in air for 22 different dental X-ray machines by means of linear interpolation. These estimations were compared with the measurements obtained with the NERO system and an ionization chamber (paired t-test). No significant differences were found between the radiographic and the conventional methods in determining beam quality and radiation dose. The radiographic method can be used to determine beam quality and radiation dose of dental X-ray machines from a single exposure. The radiographic method is simple and inexpensive and causes a minimum of disruption to the dental practice.


Post-marketing surveillance of the safety profile of iodixanol in the outpatient CT setting: a prospective, multicenter, observational study of patient risk factors, adverse reactions and preventive measures in 9953 patients.
Non-interventional study in outpatient, contrast-enhanced CT; 1. to determine the extent of preventive measures for risk reduction of adverse drug reactions after contrast-enhanced CT examinations. 2. to prospectively determine the incidence and severity of adverse drug reactions occurring after administration of the iso-osmolar contrast medium iodixanol. 3. to determine a possible influence of preventive measures on the incidence/severity of adverse drug reactions.. Evaluable documentation was provided for 9953 patients from 66 radiology centers across Germany. Patient characteristics, aspects of iodixanol administration, and adverse events with an at least "possible" relationship were documented on a standardized case report form (CRF) and were evaluated up to seven days after contrast medium administration. About 55.5 % of patients showed one or more risk factors (e. g. impaired renal function 4.4 %, diabetes mellitus 8.5 %, hypertension 20.6 %). One third of the sites did not implement any preventive measures. Patients with a known risk for an allergy-like reaction were more likely to receive pharmacologic preventive treatment (0.5 - 50.5 %). Oral hydration was the main preventive measure in patients with renal risk factors (< 8 %) followed by intravenous hydration (1 %). Adverse drug reactions, mainly hypersensitivity reactions, occurred in 77 patients (0.74 %), but were classified as serious in only 3 patients (0.03 %). No statistically significant correlation between risk factors, preventive measures, and adverse reactions could be found. The use of preventive measures for CT examinations in this outpatient setting was generally low with risk patients being pre-medicated more often, depending on their history. In the routine outpatient setting, iso-osmolar iodixanol was very well tolerated in almost 10,000 patients undergoing diagnostic CT. The rate of acute and delayed adverse reactions was low. No correlation could be found between risk factors, preventive measures and the incidence of adverse drug reactions. • Rare use of preventive measures for outpatient CT examinations.• Low rate of acute and late adverse drug reactions to iodixanol.• No correlation between risk factors, preventive measures and adverse drug reactions.


Lack of expression of HLA antigens on immature germ cells from ejaculates with antisperm antibodies.
The lack of expression of HLA antigen on immature germ cells from ejaculates with antisperm antibodies has been reported. The expression of human leukocyte antigens on immature germ cells from ejaculates with antisperm antibodies (ASA) was investigated by indirect immunofluorescence using a panel of monoclonal antibodies (MAb) and automated flow cytometry. Patients were divided into two groups: fertile (prevasectomic; N = 10), and ejaculates with ASA (10 samples with IgG and IgA ASA, and five semen samples with only IgG ASA). ASA were detected on sperm using the direct immunobead test. After centrifuging semen samples on a Ficoll-Hypaque gradient, round cells obtained at the gradient interface were gated by a flow cytometer. The "immature germ cell window" was defined in terms of cellular volume and granularity. The percentage of gated round cells from semen samples that reacted with anti-CD45 was always less than 5%, and with anti-CD44 less than 3%. This lack of reactivity of gated round cells with MAb specific for leukocytes and epithelial cells suggests that they were immature germ cells. Immature germ cells were unreactive with W6/32 and anti-beta-2-microglobulin MAb, which suggests that these cells do not express HLA class I molecules. Similarly, no reactivity of the immature germ cells with the MAb that recognize HLA class II molecules was found. No significant differences were observed in the expression of HLA molecules on immature germ cells between the different semen samples studied: fertile, and ejaculates with ASA. The presence of ASA in ejaculate is not associated with abnormal HLA antigen expression on immature germ cells.


19F imaging of cerebral blood oxygenation in experimental middle cerebral artery occlusion: preliminary results.
Fluorine (19F) nuclear magnetic resonance may be used to image cerebral perfusion in cats receiving perfluorocarbon blood substitutes. 19F relaxation times in these blood substitutes are dependent on oxygen tension (PO2) and may be used to calculate and spatially map cerebrovascular PO2 values in vivo. We have applied this noninvasive method to experimental middle cerebral artery (MCA) occlusion. Following MCA occlusion a perfusion defect is evident in the sylvian region, followed by the appearance of collaterals. Signal from the ipsilateral rete mirabilis is increased. Calculated cortical vascular PO2 values indicate a relative reduction in oxygenation in the ischaemic hemisphere. PO2 maps show a perfused hypoxaemic zone adjacent to the perfusion defect. These changes are partly reversed with reperfusion.