Long-term follow-up of patients with atypical facial pain treated with amitriptyline.
The aim of this study was to assess the efficacy of low-dose amitriptyline in patients with atypical facial pain for one-year follow-ups. Sixteen patients, ten females and six males, ranging in age from 15 to 77 years (mean 46.6 +/- 15.95 years), participated in the study. The onset, duration and temporal pattern of pain, events related to pain, drugs used before treatment and side effects of amitriptyline were recorded. The severity of pain was evaluated by using the visual analogue scale (VAS). Patients were followed for up to 12 months. The results showed that the onset of pain was related to dental pain in half of patients; and 10 patients had continuous pain. The mean VAS scores for pretreatment, post treatment, and 1, 3, 6, and 12 months were 9.6, 4.8, 2, 0.8, 0.3 respectively. In 12 patients, pain was reduced at the first month (p<0.05). All patients, except one, were pain-free at 12 months. It was statistically significant in achieving pain relief for 12 months (p<0.05). The common side effects of the drug were dry mouth and drowsiness. Data obtained from this study suggested that amitriptyline may be preferred in patients with atypical facial pain for rapid, satisfying analgesic effects. Long-term follow-up should be conducted to determine the analgesic effects and to prevent recurrence, even if the analgesic effect occurs in a short time.


Building Spatial Synthetic Biology with Compartments, Scaffolds, and Communities.
Traditional views of synthetic biology often treat the cell as an unstructured container in which biological reactions proceed uniformly. In reality, the organization of biological molecules has profound effects on cellular function: not only metabolic, but also physical and mechanical. Here, we discuss a variety of perturbations available to biologists in controlling protein, nucleotide, and membrane localization. These range from simple tags, fusions, and scaffolds to heterologous expression of compartments and other structures that confer unique physical properties to cells. Next, we relate these principles to those guiding the spatial environments outside of cells such as the extracellular matrix. Finally, we discuss new directions in building intercellular organizations to create novel symbioses.


Gut as an emerging organ for the treatment of diabetes: focus on mechanism of action of bariatric and endoscopic interventions.
Increasing worldwide prevalence of type 2 diabetes mellitus and its accompanying pathologies such as obesity, arterial hypertension and dyslipidemia represents one of the most important challenges of current medicine. Despite intensive efforts, high percentage of patients with type 2 diabetes does not achieve treatment goals and struggle with increasing body weight and poor glucose control. While novel classes of antidiabetic medications such as incretin-based therapies and gliflozins have some favorable characteristics compared to older antidiabetics, the only therapeutic option shown to substantially modify the progression of diabetes or to achieve its remission is bariatric surgery. Its efficacy in the treatment of diabetes is well established, but the exact underlying modes of action are still only partially described. They include restriction of food amount, enhanced passage of chymus into distal part of small intestine with subsequent modification of gastrointestinal hormones and bile acids secretion, neural mechanisms, changes in gut microbiota and many other possible mechanisms underscoring the importance of the gut in the regulation of glucose metabolism. In addition to bariatric surgery, less-invasive endoscopic methods based on the principles of bariatric surgery were introduced and showed promising results. This review highlights the role of the intestine in the regulation of glucose homeostasis focusing on the mechanisms of action of bariatric and especially endoscopic methods of the treatment of diabetes. A better understanding of these mechanisms may lead to less invasive endoscopic treatments of diabetes and obesity that may complement and widen current therapeutic options.


Interaction of gold nanoparticles mediated by captopril and S-nitrosocaptopril: the effect of manganese ions in mild acid medium.
We report herein results regarding reactivity and assembly of citrate-capped gold nanoparticles (AuNPs) mediated by captopril (cap) and S-nitrosocaptopril (NOcap), two angiotensin converting enzyme inhibitors and antihypertensive agents. The results were compared with that of cysteine (Cys), a thiol-containing amino acid found in plasma. The interparticle interactions were characterized by monitoring the evolution of the surface plasmon resonance band using the spectrophotometric method. The original gold nanoparticles were efficiently modified by small amounts of Mn(+2) ions, which are adsorbed onto the surface of 15.4 nm citrate-capped gold nanoparticles, giving rise to manganese-gold nanoparticles (Mn-AuNPs) that, in mild acid medium, have proved to be highly sensitive and a rapid colorimetric detection method for thiols. Depending on the concentration of the Mn(+2) ions the aggregation of AuNPs can be rapidly induced. The kinetics of the assembly process has been studied. Good first-order kinetics has been observed, with the exception of captopril-mediated nanoparticle aggregation at low concentration of either cap or acid. The rate of Cys-mediated assembly of gold nanoparticles in aqueous 10 mM acetic acid is more than 20-times faster than pure AuNPs and concentrations of Cys as low as 34 nM can be detected in less than 40 min under conditions of stable Mn-AuNPs. Similar effects were observed with cap or NOcap. The assembly-disassembly reversibility is shown with cap and NOcap and depends highly on pH.


Neurotransmission and cancer: implications for prevention and therapy.
Published evidence compiled in this review supports the hypothesis that the development, progression, and responsiveness to prevention and therapy of the most common human cancers is strongly influenced, if not entirely orchestrated, by an imbalance in stimulatory and inhibitory neurotransmission. The neurotransmitters acetylcholine, adrenaline, and noradrenaline of the autonomic nervous system act as powerful upstream regulators that orchestrate numerous cell and tissue functions, by releasing growth factors, angiogenesis factors and metastasis factors, arachidonic acid, proinflammatory cytokines, and local neurotransmitters from cancer cells and their microenvironment. In addition, they modulate proliferation, apoptosis, angiogenesis, and metastasis of cancer directly by intracellular signaling downstream of neurotransmitter receptors. Nicotine and the tobacco-specific nitrosamines have the documented ability to hyperstimulate neurotransmission by both branches of the autonomic nervous system. The expression and function of these neurotransmitter pathways are cell type specific. Lifestyle, diet, diseases, stress, and pharmacological treatments modulate the expression and responsiveness of neurotransmitter pathways. Current preclinical testing systems fail to incorporate the modulating effects of neurotransmission on the responsiveness to anticancer agents and should be amended accordingly. The neurotransmitter gamma-aminobutyric acid has a strong inhibitory function on sympathicus-driven cancers whereas stimulators of cyclic adenosine monophosphate/protein kinase A signaling have strong inhibitory function on parasympathicus-driven cancers. Marker-guided restoration of the physiological balance in stimulatory and inhibitory neurotransmission represents a promising and hitherto neglected strategy for the prevention and therapy of neurotransmitter-responsive cancers.


Neonatal screening improves sickle cell disease clinical outcome in Belgium.
Objectives To compare the outcomes of sickle cell disease patients diagnosed through neonatal screening with those who were not. Methods In an observational multicenter study in Belgium, 167 screened and 93 unscreened sickle cell disease patients were analyzed for a total of 1116 and 958 patient-years of follow-up, respectively. Both groups were compared with propensity score analysis, with patients matched on three covariates (gender, genotype, and central Africa origin). Bonferroni correction was applied for all comparisons. Results Kaplan-Meier estimates of survival without bacteremia were significantly higher in the screened group than the unscreened group (94.47%; [95% CI, 88.64-97.36%] versus 83.78% [95% CI, 72.27-90.42%]), p = 0.032. Non-significant differences between both groups were reported for survival without acute chest syndrome, acute anemia, cerebral complication, severe infection, and vaso-occlusive crisis. Significantly lower hospitalization rate and days per 100 patient-years were observed in the screened compared with the unscreened group (0.27 vs. 0.63 and 1.25 vs. 2.82, p = 0.0006 and <0.0001). Conclusion These data confirm the benefit of a neonatal screening programme in reducing bacteremia and hospitalization.


Dichhaptic laterality and field dependence.
Relationships among laterality, field dependence, and sex were investigated using right handed subjects. Dichhaptic measures of laterality showed a significant left-hand advantage for the discrimination of irregular shapes. No significant relationships were found between laterality and sex or sex role perceptions nor between laterality and field dependence. A modality of response effect on the laterality task was interpreted in terms of the functional cerebral space principle.


A complicated disease: what can be done to manage thalassemia major more effectively?
Patients with thalassemia major suffer from many complications, but in the last two decades their lives have improved both in length and quality. We report herein the most common complications and the recent advances that have changed the course of this disease. Also, we report in detail some of the new therapeutic strategies already introduced in practice and briefly some that are still being developed.


A specific radioimmunoassay for the growth hormone (GH)-dependent somatomedin-binding protein: its use for diagnosis of GH deficiency.
The acid-stable subunit of the GH-dependent large mol wt somatomedin-binding protein (SmBP) was isolated from human plasma Cohn fraction IV by a three-step procedure, and a specific RIA was developed which allowed measurement in unextracted serum. Although in normal human serum most of immunoreactive material was present as the large mol wt complex (150K), considerable amounts of smaller components were found by high performance liquid exclusion chromatography in the 60K, 42K, and 32K range. Normal serum levels were low at birth, rose sharply during the first weeks of life, and showed a moderate peak at puberty. To assess the diagnostic efficacy of SmBP for GH deficiency (GHD), patients previously diagnosed as GH-deficient by conventional criteria (n = 132) were compared to short statured children without GHD (n = 130). Taking the fifth centile as a limit of normality the majority of patients with GHD had subnormal levels, yielding high sensitivity of the test (0.97). In contrast, most of the non-GH-deficient children had SmBP levels within the normal range, resulting in high specificity (0.95) and, consequently, high accuracy (0.96). These results suggest that the large mol wt SmBP is an excellent screening parameter and is highly informative for GHD.


Electrochemically deposited Pd-Pt and Pd-Au codeposits on graphite electrodes for electrocatalytic H2O2 reduction.
Improved electrocatalytic activity and selectivity for the reduction of H2O2 were obtained by electrodepositing Pd-Pt and Pd-Au on spectrographic graphite from solutions containing salts of the two metals at varying ratio. The electrocatalytic activity of the resulting binary codeposits for H2O2 reduction was evaluated by means of the redox-competition mode of scanning electrochemical microscopy (SECM) and voltammetric methods. In a potential range from 0 to -600 mV (vs. Ag/AgCl/3 M KCl) at pH 7.0 in 0.1 M phosphate citrate buffer, the electrocatalytic activity of both Pd-Pt and Pd-Au codeposits was substantially improved as compared with the identically deposited single metals suggesting an electrocatalytic synergy of the codeposits. Pd-Pt and Pd-Au codeposits were characterized by X-ray diffraction (XRD) analysis and scanning electron microscopy (SEM). Codepositing with Au caused a change of hedgehog-like shaped Pd nanoparticles into cauliflower-like nanoparticles with the particle size decreasing with increasing Au concentration. Codepositing Pd with Pt caused the formation of oblong structures with the size initially increasing with increasing Pt content. However, the particle size decreases with further increase in Pt concentration. The improved electrocatalytic capability for H2O2 reduction of the Pd-Pt electrodeposits on graphite was further demonstrated by immobilizing glucose oxidase as a basis for the development of an interference-free amperometric glucose biosensor.


[Experience in the treatment of difficult diseases by technical combination of acupuncture].
The technical combination of acupuncture is a combination therapy based on the purpose of improving clinical efficacy. After years of clinical practice, the author has gradually summarized the dominant disease spectrum of combination therapy, especially for the treatment of difficult diseases such as male and dermatological. In the treatment of chronic prostatitis, the combination of acupuncture at "Zhibian (BL 54) through Shuidao (ST 28) therapy" is adopted. When urticaria is treated, the embedding, fire needle, needle knife and filiform needle can be combined to ensure better effect. Regarding the evidence-based acupuncture treatment research of chronic prostatitis and urticaria, it is believed that acupuncture treatment has been recommended as grade Ⅱ and Ⅰ, and there is no reliable treatment method in modern medicine. The author enumerates two cases of related diseases and explains the advantages of combination therapy.


AkrinorTM, a Cafedrine/ Theodrenaline Mixture (20:1), Increases Force of Contraction of Human Atrial Myocardium But Does Not Constrict Internal Mammary Artery In Vitro.
Background: Intraoperative hypotension is a common problem and direct or indirect sympathomimetic drugs are frequently needed to stabilize blood pressure. AkrinorTM consists of the direct and the indirect sympathomimetic noradrenaline and norephedrine. Both substances are covalently bound to the phosphodiesterase (PDE) inhibitor theophylline, yielding theodrenaline and cafedrine, respectively. We investigated pharmacodynamic effects of AkrinorTM and its constituents on contractile force and tension in human atrial trabeculae and internal A. mammaria rings. Methods: Isometric contractions were measured in human atrial trabeculae at 1 Hz and 37°C. CGP 20712A and ICI 118,551 were used to elaborate β1- and β2-adrenoceptor (AR) subtypes involved and phenoxybenzamine to estimate indirect sympathomimetic action. PDE-inhibition was measured as a potentiation of force increase upon direct activation of adenylyl cyclase by forskolin. Human A. mammaria preparations were used to estimate intrinsic vasoconstriction and impact on the noradrenaline-induced vasoconstriction. Results: Clinically relevant concentrations of AkrinorTM (4.2-420 mg/l) robustly increased force in human atrial trabeculae (EC50 41 ± 3 mg/l). This direct sympathomimetic action was mediated via β1-AR and the effect size was as large as with high concentrations of calcium. Only the highest and clinically irrelevant concentration of AkrinorTM increased the potency of forskolin to a minor extent. Norephedrine has lost its indirect sympathomimetic effect when bound to theophylline. Increasing concentrations of AkrinorTM (4.2-168 mg/l) alone did not affect the tension of human A. mammaria interna rings, but shifted the noradrenaline curve rightward from -logEC50 6.18 ± 0.08 to 5.23 ± 0.05 M. Conclusion: AkrinorTM increased cardiac contractile force by direct sympathomimetic actions and PDE inhibition, did not constrict A. mammaria preparations, but shifted the concentration-response curve to the right, compatible with an α-AR antagonistic effect or PDE inhibition. The pharmacodynamic profile and potency of AkrinorTM differs from noradrenaline and norephedrine in vitro. We anticipate metabolism of theodrenaline and cafedrine resulting in a different pharmacodynamic profile of AkrinorTMin vivo.


Detoxification from benzodiazepines: schedules and strategies.
Management of benzodiazepine (BZD) tolerance is divided into low- and high-dose withdrawal. Low-dose withdrawal includes patients who have received manufacturer-recommended doses of BZD on a daily basis for longer than 1 month. Gradual tapering of the BZD over 4 weeks on an outpatient basis is suggested. High-dose withdrawal includes patients who have been ingesting doses of BZD greater than the equivalent of diazepam 40 mg/d for longer than 8 months. It is recommended that the patients be tolerance tested with diazepam and, if tolerant, tapered off medication as inpatients at a rate of 10% per day. Triazolobenzodiazepines may be exceptions to these recommendations. Alprazolam should be titrated at a rate of 0.5 mg three times a day regardless of whether the patient is being tapered for low- or high-dose withdrawal.


Prevalence of food allergy in 137 latex-allergic patients.
There have been reports of increased prevalence of certain food allergies in patients with Type I latex allergy (LA). A detailed food allergy history was obtained from 137 patients with LA. Latex allergy was defined by positive history of IgE mediated reactions to contact with latex and positive skin prick test to latex and/or positive in vitro test (AlaSTAT and/or Pharmacia CAP). Food allergy was diagnosed by a convincing history of possible IgE mediated symptoms occurring within 60 minutes of ingestion. We identified 49 potential allergic reactions to foods in 29 (21.1%) patients. Foods responsible for these reactions include banana 9 (18.3%), avocado 8 (16.3%), shellfish 6 (12.2%), fish 4 (8.1%), kiwi 6 (12.2%), tomato 3 (6.1%), watermelon, peach, carrot 2 (4.1%) each, and apple, chestnut, cherry, coconut, apricot, strawberry, loquat, one (2.0%) each. Reactions to foods included local mouth irritation, angioedema, urticaria, asthma, nausea, vomiting, diarrhea, rhinitis, or anaphylaxis. Our study confirms the earlier reports of increased prevalence of food allergies in patients with LA. We also report increased prevalence of shellfish and fish allergy not previously reported. The nature of cross reacting epitopes or independent sensitization between latex and these foods is not clear.


Characterization of selective Calcium-Release Activated Calcium channel blockers in mast cells and T-cells from human, rat, mouse and guinea-pig preparations.
Loss of function mutations in the two key proteins which constitute Calcium-Release Activated Calcium (CRAC) channels demonstrate the critical role of this ion channel in immune cell function. The aim of this study was to demonstrate that inhibition of immune cell activation could be achieved with highly selective inhibitors of CRAC channels in vitro using cell preparations from human, rat, mouse and guinea-pig. Two selective small molecule blockers of CRAC channels; GSK-5498A and GSK-7975A were tested to demonstrate their ability to inhibit mediator release from mast cells, and pro-inflammatory cytokine release from T-cells in a variety of species. Both GSK-5498A and GSK-7975A completely inhibited calcium influx through CRAC channels. This led to inhibition of the release of mast cell mediators and T-cell cytokines from multiple human and rat preparations. Mast cells from guinea-pig and mouse preparations were not inhibited by GSK-5498A or GSK-7975A; however cytokine release was fully blocked from T-cells in a mouse preparation. GSK-5498A and GSK-7975A confirm the critical role of CRAC channels in human mast cell and T-cell function, and that inhibition can be achieved in vitro. The rat displays a similar pharmacology to human, promoting this species for future in vivo research with this series of molecules. Together these observations provide a critical forward step in the identification of CRAC blockers suitable for clinical development in the treatment of inflammatory disorders.


Intrauterine infections - challenges in the perinatal period (literature review).
The purpose of the study is to summarize the literature data on the state of intrauterine infections that cause antenatal fetal abnormalities. This article presents the assessment of 25 world literature sources from 2000 to 2016, which discuss the etiology of infectious agents acting on the fetus and causing a variety of pathological conditions. During gestation many researchers refer to the infection as one of the causes of antenatal fetal abnormalities. The etiology of intrauterine infection is diverse and differs between countries with different economic conditions. Detection of an infectious agent makes it possible to promptly carry out preventive measures, to improve hygiene standards in order to reduce the rate of infection transmission from mother to fetus. Timely detection of the etiology of intrauterine infections promotes the identification of high-risk groups giving a possibility to provide treatment in order to prevent the transmission of an infectious agent having direct economic benefits, especially in resource-poor countries with low and middle income.


Resolving Nonclassical Magnon Composition of a Magnetic Ground State via a Qubit.
Recently gained insights into equilibrium squeezing and entanglement harbored by magnets point toward exciting opportunities for quantum science and technology, while concrete protocols for exploiting these are needed. Here, we theoretically demonstrate that a direct dispersive coupling between a qubit and a noneigenmode magnon enables detecting the magnonic number states' quantum superposition that forms the ground state of the actual eigenmode-squeezed magnon-via qubit excitation spectroscopy. Furthermore, this unique coupling is found to enable control over the equilibrium magnon squeezing and a deterministic generation of squeezed even Fock states via the qubit state and its excitation. Our work demonstrates direct dispersive coupling to noneigenmodes, realizable in spin systems, as a general pathway to exploiting the equilibrium squeezing and related quantum properties thereby motivating a search for similar realizations in other platforms.


Molecular relationships between trimethoprim R plasmids obtained from human and animal sources.
A total of 65 trimethoprim R plasmids (35 obtained from human strains and 30 from animal strains of Escherichia coli) were examined by the technique of restriction endonuclease fingerprinting. Plasmids belonging to incompatibility groups B, FII and I delta obtained from human and animal sources showed close similarities within each group. Plasmids belonging to incompatibility groups I alpha and P were also obtained from both human and animal sources, but there was no conclusive evidence of close relationships within the groups. Restriction endonuclease fingerprinting was found to be useful for obtaining information about the epidemiology of R plasmids. Its main limitation in this study related to broad host range plasmids of the P incompatibility group, some of which contained very few sites susceptible to cleavage by the restriction endonucleases tested.


Circuit-selective properties of glutamatergic inputs to the rat prelimbic cortex and their alterations in neuropathic pain.
Functional deactivation of the prefrontal cortex (PFC) is a critical step in the neuropathic pain phenotype. We performed optogenetic circuit dissection to study the properties of ventral hippocampal (vHipp) and thalamic (MDTh) inputs to L5 pyramidal cells in acute mPFC slices and to test whether alterations in these inputs contribute to mPFC deactivation in neuropathic pain. We found that: (1) both the vHipp and MDTh inputs elicit monosynaptic excitatory and polysynaptic inhibitory currents. (2) The strength of the excitatory MDTh input is uniform, while the vHipp input becomes progressively stronger along the dorsal-ventral axis. (3) Synaptic current kinetics suggests that the MDTh inputs contact distal, while the vHipp inputs contact proximal dendritic sections. (4) The longer delay of inhibitory currents in response to vHipp compared to MDTh inputs suggests that they are activated by feedback and feed-forward circuitries, respectively. (5) One week after a peripheral neuropathic injury, both glutamatergic inputs are modified: MDTh responses are smaller, without evidence of presynaptic changes, while the probability of release at vHipp-mPFC synapses becomes lower, without significant change in current amplitude. Thus, dysregulation of both these inputs likely contributes to the mPFC deactivation in neuropathic pain and may impair PFC-dependent cognitive tasks.


Human large granular lymphocytes: spontaneous and interferon-boosted NK activity against adherent and nonadherent tumor cell lines.
Human natural killer (NK) cells against K-562 tumor cells have been morphologically identified as large granular lymphocytes (LGL). We have investigated whether LGL are also responsible for NK activity against a variety of adherent and nonadherent tumor cell lines. LGL-enriched fractions, obtained by centrifugation of nonadherent mononuclear cells on discontinuous density gradients of Percoll, contained high levels of spontaneous and interferon- (IFN) boosted NK activity against each of the target cells tested. In contrast, the LGL-depleted functions, which contain most of the typical small lymphocytes, were devoid of NK activity and did not develop appreciable activity after treatment with IFN. The ability of the different fractions to exert NK activity correlated with their capacity to form conjugates with nonadherent tumor cells. Reconstitution of the different fractions with macrophages did not increase the NK activity of already cytotoxic fractions and did not induce appreciable activity in the LGL-depleted fractions. On the other hand, mixtures of highly cytotoxic and nonreactive cell fractions did not reveal the presence of suppressor cells for NK in the nonreactive fractions. Taken together, our data demonstrate that both spontaneous and IFN-boosted NK activity is confined to the LGL-enriched fractions and suggest that LGL are the main effector cells exerting NK cytotoxicity against a variety of adherent as well as nonadherent tumor cell lines.


Lithotripsy.
Shock wave lithotripsy (SWL) is the process of fragmentation of renal or ureteric stones by the use of repetitive shock waves generated outside the body and focused onto the stone. Following its introduction in 1980, SWL revolutionized the treatment of kidney stones by offering patients a non-invasive procedure. It is now seen as a mature technology and its use is perceived to be routine. It is noteworthy that, at the time of its introduction, there was a great effort to discover the mechanism(s) by which it works, and the type of sound field that is optimal. Although nearly three decades of subsequent research have increased the knowledge base significantly, the mechanisms are still controversial. Furthermore there is a growing body of evidence that SWL results in injury to the kidney which may have long-term side effects, such as new onset hypertension, although again there is much controversy within the field. Currently, use of lithotripsy is waning, particularly with the advent of minimally invasive ureteroscopic approaches. The goal here is to review the state of the art in SWL and to present the barriers and challenges that need to be addressed for SWL to deliver on its initial promise of a safe, effective, non-invasive treatment for kidney stones.


[Recurrent erythema multiforme triggered by herpes simplex virus].
We describe two cases of recurrent erythema multiforme, both associated to infection with herpes simplex virus. The importance of subclinical herpes is illustrated. Antiviral and additional treatment is described.


On the measurement of reinforcement frequency in the study of preference.
In a two-link, concurrent-chain schedule, pigeons' pecks on each key during the initial link occasionally produced a terminal link, during which only that key was operative. Responses in the terminal link were reinforced with food on either fixed-interval or variable-interval schedules. In one experiment, relative amount of responding in the initial link equaled the relative harmonic rate of reinforcement in the terminal links. In a second experiment, the selection of interreinforcement intervals in variable-interval schedules in the terminal links was such that rates of reinforcement based on the harmonic or on the arithmetic means of the interreinforcement intervals predicted opposite preferences in the initial links. The observed preference was consistent with that predicted by the harmonic rather than by the arithmetic rates of reinforcement.


Relationship between calcium channel antagonists and nocturnal hypotension and autonomic imbalance in patients with a previous myocardial infarction.
The present study was conducted to evaluate the effect of calcium channel antagonists on diurnal changes in blood pressure and on autonomic function in 71 patients who were receiving a calcium channel antagonist because they had previously suffered a myocardial infarction. Ambulatory blood pressures and Holter ECGs were recorded simultaneously for 24 h. Autonomic function was assessed by heart rate variability. Nocturnal systolic pressure was > or = 90 mmHg in 63 patients (group I) and < 90 mmHg in 8 patients (group II). Significant day to night changes in high-frequency power (from 4.3 +/- 1.2 to 4.5 +/- 1.0/m2) as well as in the ratio of low-frequency power to high-frequency power (from 1.3 +/- 0.1 to 1.1 +/- 0.2) were observed in group I. whereas such changes were blunted in group II. When the calcium antagonist was discontinued or the dose was reduced in group II, the autonomic imbalance improved along with elevation of nocturnal systolic blood pressure. Thus, nocturnal blood pressure should be monitored when such drugs are administered for the treatment of ischemic heart disease to a patient with a previous myocardial infarction. If nocturnal hypotension occurs, the dose should be reduced or the drug should be discontinued.


Involvement in research without compromising research quality.
Health research funders in the UK now ask applicants to state how their research will involve patients and members of the public. Such involvement can help with questions that researchers repeatedly face: about improving trial recruitment, response rates and follow-up. Patient and Public Involvement (PPI) in research is usually presented in the form of a ladder, from a low rung where studies are led by researchers with no patient involvement, to a high rung where studies are patient-led. This hierarchy does not sit well with many clinicians and academics whose expertise appears to have been downgraded. This article argues that research quality and relevance are optimised when patient expertise is integrated with researchers' and policy-makers' expertise, and each role acknowledged and valued, illustrated by an alternative model for PPI which places research and expertise at the centre of the involvement enterprise.


Caspase-8 deficiency in T cells leads to a lethal lymphoinfiltrative immune disorder.
Caspase-8 is best known for its cell death function via death receptors. Recent evidence indicates that caspase-8 also has nonapoptotic functions. Caspase-8 deficiency is associated with pathologies that are unexpected for a proapoptotic molecule, such as abrogation of activation-induced lymphocyte proliferation, perturbed immune homeostasis, and immunodeficiency. In this study, we report the long-term physiological consequences of T cell-specific deletion of caspase-8 (tcasp8-/-). We show that tcasp8-/- mice develop an age-dependent lethal lymphoproliferative and lymphoinfiltrative immune disorder characterized by lymphoadenopathy, splenomegaly, and accumulation of T cell infiltrates in the lungs, liver, and kidneys. Peripheral casp8-/- T cells manifest activation marker up-regulation and are proliferating in the absence of any infection or stimulation. We also provide evidence suggesting that this immune disorder is different from the autoimmune lymphoproliferative syndrome. Interestingly, the condition described in tcasp8-/- mice manifests features consistent with the disorder described in humans with Caspase-8 deficiency. These findings suggest that tcasp8-/- mice may serve as an animal model to evaluate Caspase-8-deficient patient prognosis and therapy. Overall, our study uncovers novel in vivo functions for caspase-8 in immune regulation.


Blind Deep S3D Image Quality Evaluation via Local to Global Feature Aggregation.
Previously, no-reference (NR) stereoscopic 3D (S3D) image quality assessment (IQA) algorithms have been limited to the extraction of reliable hand-crafted features based on an understanding of the insufficiently revealed human visual system or natural scene statistics. Furthermore, compared with full-reference (FR) S3D IQA metrics, it is difficult to achieve competitive quality score predictions using the extracted features, which are not optimized with respect to human opinion. To cope with this limitation of the conventional approach, we introduce a novel deep learning scheme for NR S3D IQA in terms of local to global feature aggregation. A deep convolutional neural network (CNN) model is trained in a supervised manner through two-step regression. First, to overcome the lack of training data, local patch-based CNNs are modeled, and the FR S3D IQA metric is used to approximate a reference ground-truth for training the CNNs. The automatically extracted local abstractions are aggregated into global features by inserting an aggregation layer in the deep structure. The locally trained model parameters are then updated iteratively using supervised global labeling, i.e., subjective mean opinion score (MOS). In particular, the proposed deep NR S3D image quality evaluator does not estimate the depth from a pair of S3D images. The S3D image quality scores predicted by the proposed method represent a significant improvement over those of previous NR S3D IQA algorithms. Indeed, the accuracy of the proposed method is competitive with FR S3D IQA metrics, having ~ 91% correlation in terms of MOS.


The renin-angiotensin-aldosterone system in fulminant hepatic failure.
The relationship of the renin-angiotensin-aldosterone system to blood pressure and sodium homeostasis and to renal function was investigated serially in 12 patients with fulminant hepatic failure. The plasma concentrations of renin, angiotensin II, and aldosterone were, in most instances, markedly increased. Systolic blood pressure, which was often very low, showed a significant inverse relationship to the plasma renin concentration, suggesting that the marked stimulation of the system is a homeostatic response to hypotension. However, the plasma renin substrate concentration was markedly decreased, and the conversion of angiotensin II to inactive peptides increased, both of which may have severely limited the full 'expression' of the stimulated system. Renin and angiotensin II levels were both related to creatinine clearance, which was often reduced, but it is not clear as to which was cause and which effect. No relationship between the plasma aldosterone concentration and renal sodium excretion could be detected.


A Patient Specific Biomechanical Analysis of Custom Root Analogue Implant Designs on Alveolar Bone Stress: A Finite Element Study.
Objectives. The aim of this study was to analyse by means of FEA the influence of 5 custom RAI designs on stress distribution of peri-implant bone and to evaluate the impact on microdisplacement for a specific patient case. Materials and Methods. A 3D surface model of a RAI for the upper right canine was constructed from the cone beam computed tomography data of one patient. Subsequently, five (targeted) press-fit design modification FE models with five congruent bone models were designed: "Standard," "Prism," "Fins," "Plug," and "Bulbs," respectively. Preprocessor software was applied to mesh the models. Two loads were applied: an oblique force (300 N) and a vertical force (150 N). Analysis was performed to evaluate stress distributions and deformed contact separation at the peri-implant region. Results. The lowest von Mises stress levels were numerically observed for the Plug design. The lowest levels of contact separation were measured in the Fins model followed by the Bulbs design. Conclusions. Within the limitations of the applied methodology, adding targeted press-fit geometry to the RAI standard design will have a positive effect on stress distribution, lower concentration of bone stress, and will provide a better primary stability for this patient specific case.


Ascending curbs of progressively higher height increases forward trunk flexion along with upper extremity mechanical and muscular demands in manual wheelchair users with a spinal cord injury.
High upper extremity (U/E) demands are required when manual wheelchair users (MWUs) with spinal cord injury (SCI) ascend curbs; this may contribute to the risk of developing U/E musculoskeletal impairments. The aim of this study was to compare movement strategies (kinematics), mechanical loads (kinetics) and muscular demand (EMG) at the non-dominant U/E among 15 MWUs with SCI when ascending curbs of 4 cm (3 trials), 8 cm (3 trials) and 12 cm high (3 trials) from a starting line set 3 m before the curb. Biomechanical data was collected during three trials for each height. The curb ascent task was divided into three adjustment phases: caster pop, rear-wheel ascent and post-ascent. The greatest effort was generated by the shoulder flexors and internal rotators as well as the elbow flexors. A significant difference (p < 0.0167) between the curb heights was found for most outcome measures studied: movement excursion, net joint moments and muscular utilization ratio (MUR) of the main muscles increased with the higher curb heights, mainly around the shoulder joint. These results provide insight that aside from adhering to a highly structured training method for wheelchair curb ascent, rehabilitation professionals need to propose task-specific strength training programs based on the demands documented in this study and continue to advocate for physically accessible environments.


[A study of trabecular bone structure in the mandibular condyle of healthy young people by cone beam computed tomography].
To evaluate the feasibility of cone beam computed tomography (CBCT) for the evaluation of trabecular bone structure in mandibular condyle and to investigate the distribution of the trabecular bone structure within mandibular condyle. Eighty condyles from 40 healthy young volunteers (aged 20-32) were scanned by CBCT. A coronoid image was acquired of each condyle and divided into 8 regions where regions of interest were specified. After CBCT images were binarized, four morphological parameters including bone volume fraction, trabecular thickness, trabecular number and trabecular separation were computed. All parameters were significantly different between the superior zone and middle/inferior zone of the condyle (P < 0.05). Superior zone showed the largest bone volume fraction (52.2%), the highest trabecular number (1.33 mm(-1)), the thinnest trabecular thickness (393.48 microm), and the smallest trabecular separation (361.59 microm). Inferior zone showed the smallest bone volume fraction (49.64%). These results were not significantly different between bilateral sides of the condyles (P > 0.05). Trabecular bone structure was inhomogeneous within the condyle, but symmetrical between bilateral sides of the condyles. CBCT combined with image processing is a feasible tool in evaluating trabecular bone structure of human mandibular condyle.


Remdesivir for pregnancy: A systematic review of antiviral therapy for COVID-19.
The use of remdesivir for pregnant patients with coronavirus disease 2019 (COVID-19) showed conflicting results in prior studies. We aimed to systematically review its efficacy and safety for this population from the existing literature. On July 26, 2021, registries (ClinicalTrials.gov) and databases (MEDLINE, ScienceDirect, Cochrane Library, JSTOR, DOAJ, and medRxiv) were systematically searched for research articles investigating remdesivir use in pregnant people with COVID-19. Clinical outcome, hospitalization duration, laboratory outcome, mortality, and adverse events were investigated. We obtained 13 observation studies with 113 pregnant people. In these studies, remdesivir improved the clinical condition of pregnant patients with COVID-19, especially those who had a better clinical status at baseline and received earlier remdesivir treatment. Most fetuses were delivered via cesarean section, primarily because of emergency causes. No vertical transmissions were noted. The most reported adverse event was transaminitis, in which 10-day remdesivir treatment yielded more incidence than the 5-day treatment. In pregnancy, the use of Remdesivir in combination with other COVID-19 treatments is inconclusive but its use should be followed with careful monitoring of adverse reactions and transaminase enzyme levels. Further studies are required to confirm its finding.


Paraganglioma of the common hepatic duct.
A case of paraganglioma arising in the common hepatic duct is reported. The patient presented with obstructive jaundice. At operation, a soft mass, 5 X 2 X 1.8 cm, was found firmly adherent to the intraluminal surface of the common hepatic duct. At cholecystectomy, exploration of the common hepatic duct was performed and the mass was partially removed. T-tube choledochostomy and operative cholangiography were performed. The final pathological report was paraganglioma of the common hepatic duct. The patient was clinically improved on discharge.


Relationship of intimal flap position to endovascular treatment of malperfusion syndromes in aortic dissection.
To propose a classification system based on the position and extension of the intimal flap to assist in the endovascular repair of aortic dissection complicated by a malperfusion syndrome. Forty-one patients (34 men; mean age 58 years, range 22-78) with 19 type A and 22 type B dissections complicated by a malperfusion syndrome were treated with stenting, fenestration, or both for the peripheral ischemia. A retrospective review of the preprocedural imaging studies (computed tomographic angiography and arteriography) was performed to determine and categorize the position of the aortic intimal flap. In type 1, the flap was either parallel to or perpendicular to the origin of the malperfused collateral artery; type 2 referred to extension of the dissection into the collateral vessel, while type 3 represented the presence or absence of an avulsed branch ostium. Patients treated with stenting (n=19) alone had type 2 or type 3 arterial dissections, whereas the 12 patients who were treated with fenestration alone had type 1 lesions. Ten patients treated with stenting and fenestration had arterial lesions in which a type 1 dissection was associated with types 2 or 3. This appearance-based imaging approach combined with the symptoms of malperfusion syndromes during aortic dissection can help guide the endovascular treatment strategy.


Structural effect of the Asp345a insertion in penicillin-binding protein 2 from penicillin-resistant strains of Neisseria gonorrhoeae.
A hallmark of penicillin-binding protein 2 (PBP2) from penicillin-resistant strains of Neisseria gonorrhoeae is insertion of an aspartate after position 345. The insertion resides on a loop near the active site and is immediately adjacent to an existing aspartate (Asp346) that forms a functionally important hydrogen bond with Ser363 of the SxN conserved motif. Insertion of other amino acids, including Glu and Asn, can also lower the rate of acylation by penicillin, but these insertions abolish transpeptidase function. Although the kinetic consequences of the Asp insertion are well-established, how it impacts the structure of PBP2 is unknown. Here, we report the 2.2 Å resolution crystal structure of a truncated construct of PBP2 containing all five mutations present in PBP2 from the penicillin-resistant strain 6140, including the Asp insertion. Commensurate with the strict specificity for the Asp insertion over similar amino acids, the insertion does not cause disordering of the structure, but rather induces localized flexibility in the β2c-β2d loop. The crystal structure resolves the ambiguity of whether the insertion is Asp345a or Asp346a (due to the adjacent Asp) because the hydrogen bond between Asp346 and Ser362 is preserved and the insertion is therefore Asp346a. The side chain of Asp346a projects directly toward the β-lactam-binding site near Asn364 of the SxN motif. The Asp insertion may lower the rate of acylation by sterically impeding binding of the antibiotic or by hindering breakage of the β-lactam ring during acylation because of the negative charge of its side chain.


Transparent polycrystalline cubic silicon nitride.
Glasses and single crystals have traditionally been used as optical windows. Recently, there has been a high demand for harder and tougher optical windows that are able to endure severe conditions. Transparent polycrystalline ceramics can fulfill this demand because of their superior mechanical properties. It is known that polycrystalline ceramics with a spinel structure in compositions of MgAl2O4 and aluminum oxynitride (γ-AlON) show high optical transparency. Here we report the synthesis of the hardest transparent spinel ceramic, i.e. polycrystalline cubic silicon nitride (c-Si3N4). This material shows an intrinsic optical transparency over a wide range of wavelengths below its band-gap energy (258 nm) and is categorized as one of the third hardest materials next to diamond and cubic boron nitride (cBN). Since the high temperature metastability of c-Si3N4 in air is superior to those of diamond and cBN, the transparent c-Si3N4 ceramic can potentially be used as a window under extremely severe conditions.


Multilocus variable-number tandem-repeat analysis for molecular typing of Shigella sonnei.
A multilocus variable-number tandem-repeat (VNTR) analysis (MLVA) method was developed and evaluated for the subtyping of Shigella sonnei isolates. A total of 26 VNTR loci were identified by exploring the repeat sequence loci in the genomic sequences of S. sonnei strains Ss046 and 53G and by testing 536 isolates that had previously been characterized by pulsed-field gel electrophoresis (PFGE). The discriminatory power of MLVA (Simpson's index of diversity [D], 0.9524; 95% confidence interval [CI], 0.9373 to 0.9564) for the 536 isolates was significantly higher than that of PFGE (D, 0.8882; CI, 0.8667 to 0.9097). MLVA typing with the four and eight most variable loci had D values of 0.9468 and 0.9481, respectively, results approaching that of 26 loci. The usefulness of MLVA for outbreak investigation was evaluated using 151 isolates from 10 shigellosis outbreaks and 22 PFGE-indistinguishable isolates collected from nine epidemiologically unrelated events in five different countries. The evaluations indicated that MLVA was a powerful typing tool to distinguish isolates for outbreak investigation and that it exhibited a good discrimination of the 22 PFGE-indistinguishable isolates. Single-locus variants did occur during the outbreak; therefore, S. sonnei isolates with MLVA profiles differing at no more than a single locus should be considered part of the same outbreak. The present study suggests that MLVA has the potential to replace PFGE as a standard method of typing S. sonnei isolates for disease surveillance and outbreak investigation.


New type of antidrying lens for vitreous surgery with a noncontact wide-angle viewing system.
Drying of the cornea during surgery, which causes poor visibility of the fundus, is one of the more serious problems when using a noncontact type wide-angle viewing system. We developed an antidrying corneal contact lens for use with this type of viewing system. The lens has a very thin meniscus made of polymethyl methacrylate with a large outer diameter. Following application of the viscoelastic material, the lens can be put on the cornea without using a contact lens fixation ring. The larger diameter and lightweight characteristics of our lens contributed to its overall stability. The smooth surface of this prototype lens was able to achieve an intraoperative view of good quality, not only by preventing the cornea from drying, but also by providing a smooth surface over the entire cornea.


Adenosine 5'-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages.
AMP-activated protein kinase (AMPK) is a conserved serine/threonine kinase with a critical function in the regulation of metabolic pathways in eukaryotic cells. Recently, AMPK has been shown to play an additional role as a regulator of inflammatory activity in leukocytes. Treatment of macrophages with chemical AMPK activators, or forced expression of a constitutively active form of AMPK, results in polarization to an anti-inflammatory phenotype. In addition, we reported previously that stimulation of macrophages with anti-inflammatory cytokines such as IL-10, IL-4, and TGF-β results in rapid activation of AMPK, suggesting that AMPK contributes to the suppressive function of these cytokines. In this study, we investigated the role of AMPK in IL-10-induced gene expression and anti-inflammatory function. IL-10-stimulated wild-type macrophages displayed rapid activation of PI3K and its downstream targets Akt and mammalian target of rapamycin complex (mTORC1), an effect that was not seen in macrophages generated from AMPKα1-deficient mice. AMPK activation was not impacted by treatment with either the PI3K inhibitor LY294002 or the JAK inhibitor CP-690550, suggesting that IL-10-mediated activation of AMPK is independent of PI3K and JAK activity. IL-10 induced phosphorylation of both Tyr(705) and Ser(727) residues of STAT3 in an AMPKα1-dependent manner, and these phosphorylation events were blocked by inhibition of Ca(2+)/calmodulin-dependent protein kinase kinase β, an upstream activator of AMPK, and by the mTORC1 inhibitor rapamycin, respectively. The impaired STAT3 phosphorylation in response to IL-10 observed in AMPKα1-deficient macrophages was accompanied by reduced suppressor of cytokine signaling 3 expression and an inadequacy of IL-10 to suppress LPS-induced proinflammatory cytokine production. Overall, our data demonstrate that AMPKα1 is required for IL-10 activation of the PI3K/Akt/mTORC1 and STAT3-mediated anti-inflammatory pathways regulating macrophage functional polarization.


Chemoenzymatic synthesis of amylose-grafted cellulose.
This paper reports the chemoenzymatic synthesis of an amylose-grafted cellulose. A maltoheptaose was chemically introduced to the amine-functionalized cellulose by reductive amination to produce the maltoheptaose-grafted cellulose. Then, the phosphorylase-catalyzed enzymatic polymerization of glucose 1-phosphate from the graft-chain ends on the cellulose derivative was performed, giving the amylose-grafted cellulose. The obtained material is shown to form gels and films. The dry and wet cycles of the materials were repeated.


Ligand effects on rates and regioselectivities of Rh(I)-catalyzed (5 + 2) cycloadditions: a computational study of cyclooctadiene and dinaphthocyclooctatetraene as ligands.
The first theoretical study on the effects of ligands on the mechanism, reactivities, and regioselectivities of Rh(I)-catalyzed (5 + 2) cycloadditions of vinylcyclopropanes (VCPs) and alkynes has been performed using density functional theory (DFT) calculations. Highly efficient and selective intermolecular (5 + 2) cycloadditions of VCPs and alkynes have been achieved recently using two novel rhodium catalysts, [Rh(dnCOT)](+)SbF(6)(-) and [Rh(COD)](+)SbF(6)(-), which provide superior reactivities and regioselectivities relative to that of the previously reported [Rh(CO)(2)Cl](2) catalyst. Computationally, the high reactivities of the dnCOT and COD ligands are attributed to the steric repulsions that destabilize the Rh-product complex, the catalyst resting state in the catalytic cycle. The regioselectivities of reactions with various alkynes and different Rh catalysts are investigated, and a predictive model is provided that describes substrate-substrate and ligand-substrate steric repulsions, electronic effects, and noncovalent π/π and C-H/π interactions. In the reactions with dnCOT or COD ligands, the first new C-C bond is formed proximal to the bulky substituent on the alkyne to avoid ligand-substrate steric repulsions. This regioselectivity is reversed either by employing the smaller [Rh(CO)(2)Cl](2) catalyst to diminish the ligand-substrate repulsions or by using aryl alkynes, for which the ligand-substrate interactions become stabilizing due to π/π and C-H/π dispersion interactions. Electron-withdrawing groups on the alkyne prefer to be proximal to the first new C-C bond to maximize metal-substrate back-bonding interactions. These steric, electronic, and dispersion effects can all be utilized in designing new ligands to provide regiochemical control over product formation with high selectivities. The computational studies reveal the potential of employing the dnCOT family of ligands to achieve unique regiochemical control due to the steric influences and dispersion interactions associated with the rigid aryl substituents on the ligand.


Ventricular tachycardias and dilated cardiomyopathy caused by Fabry disease.
Women with Fabry disease are considered to have a good prognosis. Here we report the clinical history of a female patient with severe Fabry disease before and after referral to our hospital. She was diagnosed to have a cardiac variant of Fabry disease since a left ventricular endomyocardial biopsy revealed specific features of this disease and that cardiac involvement was the sole manifestation. She developed sustained ventricular tachycardia and dilated cardiomyopathy requiring oral administration of amiodarone and a cardiac defibrillator implant.


Psychotherapy of bereavement after homicide.
The author presents guidelines for the assessment and initial treatment of bereavement after a homicide. Early interventions include nonverbal techniques applied in individual and group therapy. Because patients are over-whelmed and reactive, initial treatment strategy is supportive and focuses on reestablishing resiliency rather than on preexisting vulnerabilities (ambivalence, guilt, repression, denial). Adjustment to homicidal dying is lifelong, and therapist and patient should acknowledge that change may be limited.


Improving home-based providers' communication to primary care providers to enhance care coordination.
Health care system fragmentation is a pervasive problem. Research has not delineated concrete behavioral strategies to guide providers to communicate with personnel in other organizations to coordinate care. We addressed this gap within a particular context: home-based providers delivering depression care management (DCM) to older adults requiring coordination with primary care personnel. Our objective was to pilot test a communication protocol ('BRIDGE - BRinging Inter-Disciplinary Guidelines to Elders') in conjunction with DCM. In an open pilot trial (N = 7), home-based providers delivered DCM to participants. Following the BRIDGE protocol, home-based providers made scripted telephone calls and sent structured progress reports to personnel in participants' primary care practices with concise information and requests for assistance. Home-based providers documented visits with participants, contacts to and responses from primary care personnel. A research interviewer assessed participant outcomes [Symptom Checklist-20 (depressive symptoms), World Health Organization Disability Assessment Schedule-12, satisfaction] at baseline, three months, and six months. Over 12 months, home-based providers made 2.4 telephone calls and sent 6.3 faxes to other personnel, on average per participant. Primary care personnel responded to 18 of 22 requests (81.8%; 2 requests dropped, 2 ongoing), with at least one response per participant. Participants' depressive symptoms and disability improved significantly at both post-tests with large effect sizes (d ranged 0.73-2.3). Participants were satisfied. Using BRIDGE, home-based providers expended a small amount of effort to communicate with primary care personnel, who responded to almost all requests. Larger scale research is needed to confirm findings and potentially extend BRIDGE to other client problems, professions, and service sectors.


Anesthetic and Analgesic Efficient of Regional Nerve Blockade in Otoplasty.
The prominent ear is the most common congenital deformity of the external ear. Otoplasty is performed to correct the appearance of the prominent ear. This study was planned to compare the analgesic and anesthetic effects of local nerve blockade and local infiltration anesthesia in the otoplasties. Thirty-two patients who underwent otoplasty in both ears between February 2018 and March 2019 were included in the study. Three patients were excluded because they refused regional anesthesia. In the patients included in the study, only local infiltration anesthesia was applied to 1 ear and regional nerve blockade was applied to the other ear. Regional nerve blockade was applied to the study group; local infiltration anesthesia was applied to the control group. Surgical and anesthetic complications were recorded. The onset time, duration and severity of pain were followed. Numerical evaluation scale scores were used to evaluate pain levels. It was observed that the first pain of the patients On the side where regional nerve block (RNB) anesthesia was applied after an average of 10.5 hours. On the other hand on the side where local infiltration anesthesia was applied; the pain was observed to start after an average of 3.5 hours. At the 6th and 12th hours postoperatively, the scores of the numerical evaluation scale were significantly lower in the study group than the control group (P < 0.05). At the 24th-hour pain score, the values were lower in the study group, but the difference was not significant between the groups (P > 0.05). In the regional anesthesia group, can develop such as difficulty in swallowing, weakness in the neck, weakness in the upper extremity, nausea, Horner syndrome; but all side effects resolve spontaneously within 6 to 12 hours. The application of regional anesthesia in prominent ear surgical procedures can be considered as an alternative method to provide better quality preoperative anesthesia and better quality postoperative analgesia in patients.


The effects of intravenous cimetidine and metoclopramide on gastric volume and pH.
The effects on gastric pH and volume of intravenous administration of cimetidine and metoclopramide before induction of anesthesia were studied. Sixty ASA Class I patients scheduled for elective surgery were randomly divided into four groups of 15 each, and the study was double-blinded. Group I received normal saline only; Group II received 4 mg/kg of cimetidine only; Group III received 0.15 mg/kg of metoclopramide only; and Group IV received 4 mg/kg of cimetidine and 0.15 mg/kg of metoclopramide. All drugs were given intravenously 30 min before induction of anesthesia. Gastric aspirates were collected during anesthesia, 30 min and 60 min after administration of the drugs. Metoclopramide reduced gastric volume significantly when administered alone (P = 0.0001), but cimetidine did not (P = 0.10). Cimetidine increased the gastric fluid pH significantly (P = 0.0001) as did metoclopramide (P = 0.0023). The effects of cimetidine and metoclopramide on gastric fluid pH were additive when administered together. The combination of cimetidine and metoclopramide when given intravenously before anesthesia provides greater protection against aspiration pneumonitis in patients at risk than does either drug alone.


Leukemia-associated antigen-specific T-cell responses following combined PR1 and WT1 peptide vaccination in patients with myeloid malignancies.
We describe the safety and immunogenicity of a combined vaccine of 2 leukemia-associated antigenic peptides, PR1 and WT1. Eight patients with myeloid malignancies received one subcutaneous dose each of PR1 and WT1 vaccines in Montanide adjuvant, with granulocyte-macrophage colony-stimulating factor. Patients were reviewed weekly for 4 weeks to monitor toxicity and immunologic responses. Toxicity was limited to grades 1 to 2. Using peptide/HLA-A 0201 tetramers and intracellular interferon-gamma staining, CD8(+) T cells against PR1 or WT1 were detected in 8 of 8 patients after a single vaccination. To monitor the kinetics of vaccine-induced CD8(+) T-cell responses and disease regression after vaccination, absolute PR1 and WT1(+)CD8(+) T-cell numbers and WT1 expression were studied weekly after vaccination. Responses occurred as early as 1 week after vaccination. After vaccination, the emergence of PR1 or WT1(+)CD8(+) T cells was associated with a decrease in WT1 mRNA expression as a marker of minimal residual disease, suggesting a vaccine-driven antileukemia effect. Conversely, loss of response was associated with reappearance of WT1 transcripts (P < .01). This is the first demonstration that a combined PR1 and WT1 vaccine is immunogenic. These results support further studies of combination immunization strategies in leukemia patients.


Production of metal ion-dependent monoclonal antibodies against peptides in bovine prothrombin fragment 1.
Bovine prothrombin fragment 1 (F-1: the amino-terminal 156 residues of prothrombin) is used as a model to study the Ca(II) and phospholipid binding of prothrombin. The 35-46 segment in F-1 posses an alpha-helical region and three aromatic residues, conserved in several vitamin K-dependent blood coagulation factors. These residues are believed to have a specific function and to be important in the phospholipid binding of F-1. The 47-62 region, a disulfide loop, is believed to stabilize the gamma-carboxyglutamic acid domain of the protein. Goals of this research were to produce monoclonal antibodies against the above two sequences, for later functional studies. Antibodies S9-32.8 and S9-5.5 were produced against the 35-46 sequence; antibody S11-23.4 was raised against the 47-62 region. Both S9-32.8 and S9-5.5 bound to F-1 immobilized on ELISA plates in the presence of 10 mM Ca(II) with higher affinity than to F-1 coated in the presence of 10 mM Mg(II) or in the absence of metal ions. S11-23.4 showed greatest binding to F-1 coated in the presence of 10 mM Mg(II). Thus, the epitopes of the antibodies are metal ion-dependent and are developed by Ca(II) binding to F-1.


Design of Thermally Activated Delayed Fluorescence Materials with High Intersystem Crossing Efficiencies by Machine Learning-Assisted Virtual Screening.
Efficient intersystem crossing (ISC) and reverse ISC (RISC) processes are of vital significance for thermally activated delayed fluorescence (TADF) materials to achieve 100% internal quantum efficiency. However, it is challenging to rapidly predict the ISC/RISC rates of large amounts of TADF materials and screen promising candidates because of their flexible molecular design. Here, we perform virtual screening of 564 candidates constructed from 20 unique building blocks linking in D-A, D-π-A, and D-A-D (D') configurations using the established machine learning models of GBRT and RF-GBRT-KNN with the Pearson's correlation coefficients (r) of 0.89 and 0.82, respectively. Novel descriptors of ΔELL, Polar, and ΔETT for predicting ISC/RISC rates were proposed, and nine TADF molecules with the predicted ISC and RISC rates of >7 × 107 and 2 × 105 s-1, respectively, were revealed. We provide an efficient approach to predicting ISC and RISC rates of TADF molecules on a large scale, elucidating important building blocks and architectures to design high-performance optoelectronic materials for experimental explorations.


Comparison of the Abbott Realtime HIV-1 and HCV viral load assays with commercial competitor assays.
The introduction of commercially available quantitative HIV-1 RNA detection methods at the end of the last century has had a significant impact on the management of patients requiring treatment. Similarly for hepatitis C virus (HCV), clinical decision-making with respect to initiation and prolonging therapy is largely based on data from viral load assays. The methods developed in the early 1990s and further improved since then still have significant drawbacks. For example, they are labor intensive, have a small dynamic range and are contamination sensitive. The development of real-time detection techniques for reverse transcription PCR has in part solved these problems. In the present review the advantages and disadvantages of the recently marketed Abbott Realtime HCV and HIV-1 viral load assays relative to their competitors will be discussed.


Measurement of Hanatoxin-Induced Membrane Thinning with Lamellar X-ray Diffraction.
Membrane perturbation induced by cysteine-rich peptides is a crucial biological phenomenon but scarcely investigated, in particular with effective biophysical-chemical methodologies. Hanatoxin (HaTx), a 35-residue polypeptide from spider venom, works as an inhibitor of drk1 (Kv2.1) channels, most likely by interacting with the voltage-sensor. However, how this water-soluble peptide modifies the gating remains poorly understood, as the voltage sensor was proposed to be deeply embedded within the bilayer. To see how HaTx interacts with phospholipid bilayers, we observe the toxin-induced perturbation on POPC/DOPG-membranes through measurements of the change in membrane thickness. Lamellar X-ray diffraction (LXD) was applied on stacked planar bilayers in the near-fully hydrated state. The results provide quantitative evidence for the membrane thinning in a concentration-dependent manner, leading to novel and direct combinatory approaches by discovering how to investigate such a biologically relevant interaction between gating-modifier toxins and phospholipid bilayers.


Is the early identification and referral of suspected head and neck cancers by community pharmacists feasible? A qualitative interview study exploring the views of patients in North East England.
Head and neck cancer (HNC) is the eighth most common cancer in the United Kingdom. Survival rates improve when the cancer is diagnosed at an early stage, highlighting a key need to identify at-risk patients. This study aimed to explore opportunistic HNC identification and referral by community pharmacists (CPs) using a symptom-based risk assessment calculator, from the perspective of patients with a diagnosis of HNC. Purposive sampling was used to recruit patients from the HNC pathway in three large teaching hospitals in Northern England. Qualitative methodology was used to collect data through an iterative series of semistructured telephone interviews. Framework analysis was utilised to identify key themes. Four main themes were constructed through the analytic process: (1) HNC presentation and seeking help; (2) the role of the CP; (3) public perception of HNC and (4) the role of a symptom-based risk calculator. Participants agreed that CPs could play a role in the identification and referral of suspected HNCs, but there were concerns about access as patients frequently only encounter the medicine counter assistant when they visit the pharmacy. HNC symptoms are frequently attributed to common or minor conditions initially and therefore considered not urgent, leading to delays in seeking help. While there is public promotion for some cancers, there is little known about HNC. Early presentation of HNC can be quite variable, therefore raising awareness would help. The use of a symptom-based risk calculator was considered beneficial if it enabled earlier referral and diagnosis. Participants suggested that it would also be useful if the public were made aware of it and could self-assess their symptoms. In principle, CPs could play a role in the identification and referral of HNC, but there was uncertainty as to how the intervention would work. Future research is needed to develop an intervention that would facilitate earlier identification and referral of HNC while not disrupting CP work and that would promote HNC and the risk calculator more widely. Patient and public involvement and engagement (PPIE) was integrated throughout the project. Initially, the proposal was discussed during a Cancer Head and Neck Group Experience (CHANGE) PPIE meeting. CHANGE was set up to support HNC research in 2018. The group is composed of seven members (four female, three male) with an age range of 50-71 years, who were diagnosed at Sunderland Royal Hospital. A patient representative from the University of Sunderland PPIE group and a trustee of the Northern HNC Charity were recruited as co-applicants. They attended project management group meetings and reviewed patient-facing documentation.


Baricitinib: First Global Approval.
Baricitinib (Olumiant™) is an orally-administered, small-molecule, janus-associated kinase (JAK) inhibitor developed by Eli Lilly and Incyte Corporation for the treatment of rheumatoid arthritis (RA), atopic dermatitis and systemic lupus erythematosus. JAKs transduce intracellular signals from cell surface receptors for various cytokines and growth factors involved in inflammation and immune function, suggesting JAK inhibitors may be of therapeutic benefit in inflammatory conditions. In February 2017, baricitinib was approved in the EU, as monotherapy or in combination with methotrexate, for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). Regulatory approval to market baricitinib as a treatment for RA has also been sought in the USA and Japan. This article summarizes the milestones in the development of baricitinib leading to this first global approval for the treatment for moderate to severe active RA in adult patients who have responded inadequately to, or are intolerant to one or more DMARDs.


NDH-1 Is Important for Photosystem I Function of Synechocystis sp. Strain PCC 6803 under Environmental Stress Conditions.
Cyanobacterial NDH-1 interacts with photosystem I (PSI) to form an NDH-1-PSI supercomplex. Here, we observed that absence of NDH-1 had little, if any, effect on the functional fractions of PSI under growth conditions, but significantly reduced the functional fractions of PSI when cells of Synechocystis sp. strain PCC 6803 were moved to conditions of multiple stresses. The significant reduction in NDH-1-dependent functional fraction of PSI was initiated after PSII activity was impaired. This finding is consistent with our observation that the functional fraction of PSI under growth conditions was rapidly and significantly decreased with increasing concentrations of DCMU, which rapidly and significantly suppressed PSII activity by blocking the transfer of electrons from QA to QB in the PSII reaction center. Furthermore, absence of NDH-1 resulted in the PSI limitation at the functionality of PSI itself but not its donor-side and acceptor-side under conditions of multiple stresses. This was supported by the result of a significant destabilization of the PSI complex in the absence of NDH-1 but the presence of multiple stresses. Based on the above results, we propose that NDH-1 is important for PSI function of Synechocystis sp. strain PCC 6803 mainly via maintaining stabilization of PSI under conditions of environmental stresses.


Acute renal failure caused by polymyxin B containing ointment.
A case is presented in which a 67-year-old man suffering from non-insulin-dependent diabetes mellitus, after being treated with polymyxin B containing ointment for leg ulcers, developed acute renal failure. After a period of 13 days during which the patient was treated with peritoneal dialysis 5 times, renal function returned. At discharge creatinine-clearance was 12 ml/min. Treating large ulcers with polymyxin B may be dangerous.


Relative age effects in professional German soccer: a historical analysis.
Relative age effects (RAEs) refer to the specific selection, participation and attainment (dis)advantages which occur as a result of physical and cognitive differences within annual age-grouped cohorts. The present study tracked the existence of RAEs in professional German soccer by examining RAEs in players, head coaches and referees who represented professional soccer clubs or officiated in the Bundesliga from 1963/64 to 2006/07. An additional objective was to consider the social-cultural mechanisms responsible for RAEs, so for a similar period, population and soccer participation information was also obtained. When players were categorised into half decade groups, chi-square analyses predominantly showed RAEs across the history of the Bundesliga, irrespective of dates used for annual age grouping in junior/youth soccer. RAEs were also apparent for head coaches but not for referees. Participation data indicated consistent and progressive growth from 1950 to 1990. RAEs influence the likelihood of attaining professional player and coaching status in German soccer. With many coaches being former players, inequalities associated with annual age-grouping appear to extend beyond a playing career. Officiating was not affected, with referees suggested to emerge from an alternative development pathway. Increased popularity of soccer may have propagated RAEs over time, through intensification of competition and selection mechanisms.


Subcutaneous insulin therapy in the hospital setting: issues, concerns, and implementation.
To summarize issues and recommendations regarding subcutaneous insulin therapy in various clinical settings in the hospital. The inpatient insulin regimen must be tailored to the specific clinical circumstance of the individual patient. Because nutritional intake is not necessarily provided as discrete meals in the hospital, the insulin dose requirement can be subclassified into "basal" and "nutritional" needs. In addition, the insulin requirement is generally increased in the presence of acute illness and stress. Thus, components of the insulin requirement are divided into basal, nutritional, and correction insulin. When the physician writes insulin orders, the basal and nutritional components are written as programmed or scheduled insulin, and the correction-dose insulin is written as an algorithm to supplement the scheduled insulin. Total insulin requirements may vary widely. Practical guidelines and suggestions are presented for selection of appropriate insulins, the delivery route, and the logical apportionment to programmed and correction insulin doses for hospitalized patients who are eating or not eating. Moreover, the role of bedside blood glucose monitoring in the hospital setting is discussed. Strict glycemic management in hospitalized patients has been shown to improve outcomes. Development and implementation of specific strategies for insulin delivery and improved methods for blood glucose monitoring should help to achieve target blood glucose levels safely.


Pronounced centennial-scale Atlantic Ocean climate variability correlated with Western Hemisphere hydroclimate.
Surface-ocean circulation in the northern Atlantic Ocean influences Northern Hemisphere climate. Century-scale circulation variability in the Atlantic Ocean, however, is poorly constrained due to insufficiently-resolved paleoceanographic records. Here we present a replicated reconstruction of sea-surface temperature and salinity from a site sensitive to North Atlantic circulation in the Gulf of Mexico which reveals pronounced centennial-scale variability over the late Holocene. We find significant correlations on these timescales between salinity changes in the Atlantic, a diagnostic parameter of circulation, and widespread precipitation anomalies using three approaches: multiproxy synthesis, observational datasets, and a transient simulation. Our results demonstrate links between centennial changes in northern Atlantic surface-circulation and hydroclimate changes in the adjacent continents over the late Holocene. Notably, our findings reveal that weakened surface-circulation in the Atlantic Ocean was concomitant with well-documented rainfall anomalies in the Western Hemisphere during the Little Ice Age.


A discussion about the importance of laws and policies for data sharing for public health in the People's Republic of China.
This paper introduces the current status of data sharing in the People's Republic of China. It discusses barriers to data sharing and proposes three key solutions to overcome these barriers in China. The establishment of national laws and policies for data sharing is considered the key prerequisite to ensuring the successful implementation of resource sharing activities in public health. Driven by established laws and policies, the relevant operational models should be developed. It is also important to have strategies in place to ensure the established laws and policies are implemented by various organizations in different jurisdictions. These discussions are supported by relevant local and international evidence.


Antibiofilm Effect of DNase against Single and Mixed Species Biofilm.
Biofilms are aggregates of microorganisms that coexist in socially coordinated micro-niche in a self-produced polymeric matrix on pre-conditioned surfaces. The biofilm matrix reduces the efficacy of antibiofilm strategies. DNase degrades the extracellular DNA (e-DNA) present in the matrix, rendering the matrix weak and susceptible to antimicrobials. In the current study, the effect of DNase I was evaluated during biofilm formation (pre-treatment), on preformed biofilms (post-treatment) and both (dual treatment). The DNase I pre-treatment was optimized for P. aeruginosa PAO1 (model biofilm organism) at 10 µg/mL and post-treatment at 10 µg/mL with 15 min of contact duration. Inclusion of Mg2+ alongside DNase I post-treatment resulted in 90% reduction in biofilm within only 5 min of contact time (irrespective of age of biofilm). On extension of these findings, DNase I was found to be less effective against mixed species biofilm than individual biofilms. DNase I can be used as potent antibiofilm agent and with further optimization can be effectively used for biofilm prevention and reduction in situ.


Effects of a Community Care Station Program With Structured Exercise Intervention on Physical Performance and Balance in Community-Dwelling Older Adults: A Prospective 2-Year Observational Study.
The Taiwanese government has developed community care stations (CCSs) for community-based older adult care. We investigated the effects of a structured exercise intervention, applied at CCS for 6 months, on physical performance and balance in community-dwelling older adults, including a 2-year reassessment. Fifty-eight participants (aged 76.9 ± 6.3 years) participated in the study. The Elderly Mobility Scale, Short Physical Performance Battery (SPPB), Timed Up and Go (TUG), gait speed, functional reach, one-leg-stance (OLS), and flexibility were evaluated at baseline, 6 months, and 2 years. Compared with baseline, the participants improved significantly in the SPPB (0.93 points), TUG (1.94 s), gait speed (0.13 m/s), and right and left OLS (2.56 and 3.12 s) at 6 months. Furthermore, these significant effects, except for OLS, were maintained at the 2-year reassessment according to repeated-measures ANOVA (p < .01). Our preliminary data suggest that adding a structured exercise program can benefit older adults participating in Taiwanese CCSs.


The bimodal distribution of genic GC content is ancestral to monocot species.
In grasses such as rice or maize, the distribution of genic GC content is well known to be bimodal. It is mainly driven by GC content at third codon positions (GC3 for short). This feature is thought to be specific to grasses as closely related species like banana have a unimodal GC3 distribution. GC3 is associated with numerous genomics features and uncovering the origin of this peculiar distribution will help understanding the potential roles and consequences of GC3 variations within and between genomes. Until recently, the origin of the peculiar GC3 distribution in grasses has remained unknown. Thanks to the recent publication of several complete genomes and transcriptomes of nongrass monocots, we studied more than 1,000 groups of one-to-one orthologous genes in seven grasses and three outgroup species (banana, palm tree, and yam). Using a maximum likelihood-based method, we reconstructed GC3 at several ancestral nodes. We found that the bimodal GC3 distribution observed in extant grasses is ancestral to both grasses and most monocot species, and that other species studied here have lost this peculiar structure. We also found that GC3 in grass lineages is globally evolving very slowly and that the decreasing GC3 gradient observed from 5' to 3' along coding sequences is also conserved and ancestral to monocots. This result strongly challenges the previous views on the specificity of grass genomes and we discuss its implications for the possible causes of the evolution of GC content in monocots.


Quantification of Biologically and Chemically Bound Phosphorus in Activated Sludge from Full-Scale Plants with Biological P-Removal.
Phosphorus (P) is present in activated sludge from wastewater treatment plants in the form of metal salt precipitates, extracellular polymeric substances, or bound into the biomass, for example, as intracellular polyphosphate (poly-P). Several methods for a reliable quantification of the different P-fractions have recently been developed, and this study combines them to obtain a comprehensive P mass-balance of activated sludge from four enhanced biological phosphate removal (EBPR) plants. Chemical characterization by ICP-OES and sequential P fractionation showed that chemically bound P constituted 38-69% of total P, most likely in the form of Fe, Mg, or Al minerals. Raman microspectroscopy, solution state 31P NMR, and 31P MAS NMR spectroscopy applied before and after anaerobic P-release experiments, were used to quantify poly-P, which constituted 22-54% of total P and was found in approximately 25% of all bacterial cells. Raman microspectroscopy in combination with fluorescence in situ hybridization was used to quantify poly-P in known polyphosphate-accumulating organisms (PAO) (Tetrasphaera, Candidatus Accumulibacter, and Dechloromonas) and other microorganisms known to possess high level of poly-P, such as the filamentous Ca. Microthrix. Interestingly, only 1-13% of total P was stored by unidentified PAO, highlighting that most PAOs in the full-scale EBPR plants investigated are known.


Use of reoperative sentinel lymph node biopsy in breast cancer patients.
Ipsilateral breast recurrence or second primary breast cancer can develop in patients who have undergone breast conservation and sentinel lymph node biopsy (SLNB). This brings into question the necessity of complete axillary lymph node dissection (CALND) versus a second SLNB (remapping). Our objective is to determine the feasibility of a reoperative SLNB. A review of patients receiving a reoperative SLNB between April 1994 and December 2006 was conducted with IRB approval. Fifty-six patients underwent a second SLNB on the ipsilateral side an average of 42.5 months after their first SLNB. Sentinel lymph nodes were successfully remapped in 45 of 56 (80.4%) patients. Of 45 patients successfully remapped, 36 (80%) were node negative and were spared CALND. There was only 1 patient (2.2%) in whom a sentinel lymph node was identified outside of the ipsilateral axilla. At 26 months mean followup for the second SLNB, there have been no axillary recurrences and 1 death. Our findings demonstrate that remapping sentinel nodes in patients with ipsilateral recurrence or new primary breast cancer after SLNB achieved success in 80.4% of patients. Overall, 80.0% (36 of 45) of the successfully remapped patients were spared a CALND.


Genotype-phenotype correlations of 39 patients with Cornelia De Lange syndrome: the Dutch experience.
Cornelia de Lange syndrome (CdLS) is a multiple congenital anomaly syndrome characterised by a distinctive facial appearance, prenatal and postnatal growth deficiency, psychomotor delay, behavioural problems, and malformations of the upper extremities. Recently mutations in NIPBL, the human homologue of the Drosophila Nipped-B gene, were found to cause CdLS. Mutations have been found in 39% of reported cases. Patients were enrolled in the study and classified into one of four groups based on clinical examination: classic, mild, possible, or definitively not CdLS. Three dimensional photography was taken of 20 subjects, and compared between groups. Behaviour was assessed with specific attention to autism. We searched for mutations in NIPBL and correlated genotype with phenotype. : We found mutations in 56% of cases. Truncating mutations were generally found to cause a more severe phenotype but this correlation was not absolute. Three dimensional facial imaging demonstrated the potential for classifying facial features. Behavioural problems were highly correlated with the level of adaptive functioning, and also included autism. No correlation of behaviour with the type of mutation was found.


Occupational exposures during routine activities in coal-fueled power plants.
Limited information is available on occupational exposures during routine, nonoutage work activities in coal-fueled power plants. This study evaluated occupational exposures to the principal contaminants in the facilities, including respirable dust (coal dust), arsenic, noise, asbestos, and heat stress. The data were collected over a 3-month period, during the summer of 2001, in 5 facilities that were chosen to be representative of the coal-fueled power plants of a large southeastern power-generating company. Each of the facilities was divided into 5 similar exposure groups based on previous exposure assessments and job tasks performed. From 4 of the 5 facilities, 392 air samples and 302 noise samples were collected with approximately 50 respirable coal dust, 32 arsenic, 15 asbestos, and 70 noise samples from each of the 4 plants. One of the previously surveyed facilities was also evaluated for heat stress, and 1 additional coal-fueled power plant was surveyed for a total of 20 personal heat stress samples. Personal monitors and area WBGT monitors were used. Of the nearly 400 air samples collected, only 1 exceeded the allowable occupational exposure value. For the noise samples, 55 (approximately 18%) were equal to or greater than the Occupational Safety and Health Administration (OSHA) 8-hour hearing conservation program level of 85 dBA, and 12 (approximately 4%) were equal to or greater than the OSHA 8-hour permissible exposure level of 90 dBA. Heat stress monitoring at the facilities indicates that 26% of the 1-hour TWAs were exceeded for one or all of the recommended heat stress limits. The data also concluded that some work sites were above the heat stress ceiling values recommended by the National Institute for Occupational Safety and Health (NIOSH). Four of the 20 employees personally monitored exceeded the recommended limits for heart rate or body core temperature. This suggests there is a potential for heat strain if signs and symptoms are ignored. Recommendations are made to better control the heat stress exposure.


Regulation of the anti-alpha(1----3) dextran IgG antibody response of BALB/c mice by idiotype-specific T suppressor lymphocytes.
The immune response of BALB/c mice against the so-called thymus-independent bacterial Ag alpha(1----3) dextran (Dex) is restricted to the expression of few major idiotypes (Id). It is furthermore under the control of T lymphocytes which regulate the isotype expression in such a way that they prevent anti-Dex IgG antibody production upon immunization. At the same time these T cells are part of a regulatory system for Dex-specific B cell memory formation. The underlying Ts cell activity has previously been analyzed by using euthymic and athymic congenic animals. Now we have isolated CD4-positive Id-specific T cell lines and clones which by several criteria are representatives of the above Ts cells. They inhibit in vitro proliferation and antibody secretion of Dex-specific hybridoma B cells. They prevent Id-restricted in vivo IgG anti-Dex antibody formation in T cell-reconstituted BALB/c nu/nu mice. At the same time they enforce, again Id-specific, accumulation of Dex-specific B memory cells. As has been shown previously under the influence of splenic Ts cells, these B memory cells are arrested in the original host but can be expanded and activated for anti-Dex IgG antibody formation upon adoptive transfer into X-irradiated allotype congenic nonresponder BALB.Ighb mice. The data show that the regulatory influence of T cells on the anti-Dex response is Id specific. It can now be studied by means of cloned Ts cells.


End-of-life care ethical decision-making: Shiite scholars' views.
Recent advances in life-sustaining treatments and technologies, have given rise to newly-emerged, critical and sometimes, controversial questions regarding different aspects of end-of-life decision-making and care. Since religious values are among the most influential factors in these decisions, the present study aimed to examine the Islamic scholars' views on end-of-life care. A structured interview based on six main questions on ethical decision-making in end-of-life care was conducted with eight Shiite experts in Islamic studies, and was analyzed through deductive content analysis. Analysis revealed certain points in Islamic views on the definition of death and the persons making decisions about end-of-life care. According to the participants, in addition to conventional criteria ('urf) such as absence of heartbeat and respiration, the irreversible cessation of human voluntary acts (as a sign that the soul has control over the body and the faculty of thinking) are considered to be the criteria in establishing death. The participants also recognized physicians as the main authorities in verifying signs of death. Furthermore, it was emphasized that life preservation and continuation of care must be sensible, and the patient can request not to have death-prolonging procedures started or continued. In the view of participants, patient's autonomy cannot be the sole basis for all measures, but Islamic ethical and jurisprudential principles should be relied upon to make correct and sensible decisions whether to continue or stop terminal patients' care. Final decisions should be made by a team of experts, and physicians must be at the center of such a team. Finally, we suggest that a guideline in keeping with Islamic norms on human life and death, purpose of life, God's will, boundaries of man's authority, and the physician's ethical duties and obligations should be developed.


Acute-on-chronic subdural haematoma: a rare complication after spinal anaesthesia.
An 88-year-old woman with an undiagnosed chronic subdural haematoma underwent emergency repair of a femoral hernia under spinal anaesthesia. The patient complained of headache postoperatively, and a subsequent computed tomography brain scan showed an acute-on-chronic subdural haematoma, with midline shift and impending coning. The patient recovered completely after surgical decompression. The difficulty in diagnosing chronic subdural haematoma in the elderly patient with no history of trauma is discussed, along with the differential diagnosis of headache following spinal anaesthetic in this age-group.


Electrostatic attraction of weak monoacid anions increases probability for protonation and passage through aquaporins.
A positive electrostatic field emanating from the center of the aquaporin (AQP) water and solute channel is responsible for the repulsion of cations. At the same time, however, a positive field will attract anions. In this regard, l-lactate/lactic acid permeability has been shown for various isoforms of the otherwise highly water and neutral substrate selective AQP family. The structural requirements rendering certain AQPs permeable for weak monoacids and the mechanism of conduction have remained unclear. Here, we show by profiling pH-dependent substrate permeability, measurements of media alkalization, and proton decoupling that AQP9 acts as a channel for the protonated, neutral monocarboxylic acid species. Intriguingly, the obtained permeability rates indicate an up to 10 times higher probability of passage via AQP9 than given by the fraction of the protonated acid substrate at a certain pH. We generated AQP9 point mutants showing that this effect is independent from properties of the channel interior but caused by the protein surface electrostatics. Monocarboxylic acid-conducting AQPs thus employ a mechanism similar to the family of formate-nitrite transporters for weak monoacids. On a more general basis, our data illustrate semiquantitatively the contribution of surface electrostatics to the interaction of charged molecule substrates or ligands with target proteins, such as channels, transporters, enzymes, or receptors.


An experimentally robust model of monomeric apolipoprotein A-I created from a chimera of two X-ray structures and molecular dynamics simulations.
High-density lipoprotein (HDL) retards atherosclerosis by accepting cholesterol from the artery wall. However, the structure of the proposed acceptor, monomeric apolipoprotein A-I (apoA-I), the major protein of HDL, is poorly understood. Two published models for monomeric apoA-I used cross-linking distance constraints to derive best fit conformations. This approach has limitations. (i) Cross-linked peptides provide no information about secondary structure. (ii) A protein chain can be folded in multiple ways to create a best fit. (iii) Ad hoc folding of a secondary structure is unlikely to produce a stable orientation of hydrophobic and hydrophilic residues. To address these limitations, we used a different approach. We first noted that the dimeric apoA-I crystal structure, (Δ185-243)apoA-I, is topologically identical to a monomer in which helix 5 forms a helical hairpin, a monomer with a hydrophobic cleft running the length of the molecule. We then realized that a second crystal structure, (Δ1-43)apoA-I, contains a C-terminal structure that fits snuggly via aromatic and hydrophobic interactions into the hydrophobic cleft. Consequently, we combined these crystal structures into an initial model that was subjected to molecular dynamics simulations. We tested the initial and simulated models and the two previously published models in three ways: against two published data sets (domains predicted to be helical by H/D exchange and six spin-coupled residues) and against our own experimentally determined cross-linking distance constraints. We note that the best fit simulation model, superior by all tests to previously published models, has dynamic features of a molten globule with interesting implications for the functions of apoA-I.


A Text Messaging Intervention for Priming the Affective Rewards of Exercise in Adults: Protocol for a Microrandomized Trial.
Physical activity is a critical target for health interventions, but effective interventions remain elusive. A growing body of work suggests that interventions targeting affective attitudes toward physical activity may be more effective for sustaining activity long term than those that rely on cognitive constructs alone, such as goal setting and self-monitoring. Anticipated affective response in particular is a promising target for intervention. We will evaluate the efficacy of an SMS text messaging intervention that manipulates anticipated affective response to exercise to promote physical activity. We hypothesize that reminding users of a positive postexercise affective state before their planned exercise sessions will increase their calories burned during this exercise session. We will deploy 2 forms of affective SMS text messages to explore the design space: low-reflection messages written by participants for themselves and high-reflection prompts that require users to reflect and respond. We will also explore the effect of the intervention on affective attitudes toward exercise. A total of 120 individuals will be enrolled in a 9-week microrandomized trial testing affective messages that remind users about feeling good after exercise (40% probability), control reminders (30% probability), or no message (30% probability). Two types of affective SMS text messages will be deployed: one requiring a response and the other in a read-only format. Participants will write the read-only messages themselves to ensure that the messages accurately reflect the participants' anticipated postexercise affective state. Affective attitudes toward exercise and intrinsic motivation for exercise will be measured at the beginning and end of the study. The weighted and centered least squares method will be used to analyze the effect of delivering the intervention versus not on calories burned over 4 hours around the time of the planned activity, measured by the Apple Watch. Secondary analyses will include the effect of the intervention on step count and active minutes, as well as an investigation of the effects of the intervention on affective attitudes toward exercise and intrinsic motivation for exercise. Participants will be interviewed to gain qualitative insights into intervention impact and acceptability. Enrollment began in May 2023, with 57 participants enrolled at the end of July 2023. We anticipate enrolling 120 participants. This study will provide early evidence about the effect of a repeated manipulation of anticipated affective response to exercise. The use of 2 different types of messages will yield insight into optimal design strategies for improving affective attitudes toward exercise. ClinicalTrials.gov NCT05582369; https://classic.clinicaltrials.gov/ct2/show/NCT05582369. PRR1-10.2196/46560.