Multiple sclerosis: plaques caused by 2-step demyelination?
Selected studies concerning events at the contour of a progressive plaque are reviewed and an explanation of the subtle changes in periplaque white matter which various investigators have observed on autopsy or biopsy is presented. Recurrent exposure to toxic small molecular weight substances carried by arterial blood and capable of diffusing through the walls of blood vessels cause modification of protein or glycoprotein in the myelin sheath. These then act as allergens (modified native tissue considered as 'nonself' tissue by the immune system) which induce antibody formation (termed allo-auto-allergy). Phagocytosis of altered myelin, debris removal and cellular action to maintain homeostasis in the fluid surrounding neurons characterize the premorbid phase of multiple sclerosis. We suggest that the accumulation in the perivascular space of macrophages with large lysosomes digesting myelin debris (visible in electron micrographs) causes bottlenecks in the lymphatic channels serving the extracellular space near nodes of Ranvier. This changes the chemical microclimate and leads to the second step of demyelination and degeneration of the oligodendrocytes, i.e. plaque formation. Reference is made to outstanding problems. Research into the diffusion of small molecular weight substances into the extracellular spaces of white matter would aid in evaluating the hypothesis.


Uptake and Outcomes of Neoadjuvant Chemotherapy Among US Patients With Less Common Epithelial Ovarian Carcinomas.
Randomized clinical trials examining the effectiveness of neoadjuvant chemotherapy (NACT) for advanced ovarian cancer predominantly included patients with high-grade serous carcinomas. The use and outcomes of NACT in less common epithelial carcinomas are understudied. To investigate the uptake and survival outcomes in treatment with NACT for less common histologic subtypes of epithelial ovarian cancer. A retrospective cohort study and systematic literature review with meta-analysis was conducted using the National Cancer Database from 2006 to 2017 and the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2006 to 2019. Data analysis was performed from July 2022 to April 2023. The evaluation included patients with stage III to IV ovarian cancer with clear cell, mucinous, or low-grade serous histologic subtypes who received multimodal treatment with surgery and chemotherapy. Exposure assignment per the sequence of treatment: primary debulking surgery (PDS) followed by chemotherapy (PDS group) or NACT followed by interval surgery (NACT group). Temporal trends and characteristics of NACT use were assessed using multivariable analysis, and overall survival (OS) was assessed with the inverse probability of treatment weighting propensity score. A total of 3880 patients were examined in the National Cancer Database including 1829 women (median age, 56 [IQR, 49-63] years) with clear cell, 1156 women (median age, 53 [IQR, 42-64] years) with low-grade serous, and 895 women (median age, 57 [IQR, 48-66] years) with mucinous carcinomas. NACT use increased in patients with clear cell (from 10.2% to 16.2%, 58.8% relative increase; P < .001 for trend) or low-grade serous (from 7.7% to 14.2%, 84.4% relative increase; P = .007 for trend) carcinoma during the study period. This association remained consistent in multivariable analysis. NACT use also increased, but nonsignificantly, in mucinous carcinomas (from 8.6% to 13.9%, 61.6% relative increase; P = .07 for trend). Across the 3 histologic subtypes, older age and stage IV disease were independently associated with NACT use. In a propensity score-weighted model, the NACT and PDS groups had comparable OS for clear cell (4-year rates, 31.4% vs 37.7%; hazard ratio [HR], 1.12; 95% CI, 0.95-1.33) and mucinous (27.0% vs 26.7%; HR, 0.90; 95% CI, 0.68-1.19) carcinomas. For patients with low-grade serous carcinoma, NACT was associated with decreased OS compared with PDS (4-year rates, 56.4% vs 81.0%; HR, 2.12; 95% CI, 1.55-2.90). Increasing NACT use and histologic subtype-specific survival association were also found in the Surveillance, Epidemiology, and End Results Program cohort (n = 1447). A meta-analysis of 4 studies, including the current study, observed similar OS associations for clear cell (HR, 1.13; 95% CI, 0.96-1.34; 2 studies), mucinous (HR, 0.93; 95% CI, 0.71-1.21; 2 studies), and low-grade serous (HR, 2.11; 95% CI, 1.63-2.74; 3 studies) carcinomas. Despite the lack of data on outcomes of NACT among patients with less common carcinomas, this study noted that NACT use for advanced disease has gradually increased in the US. Primary chemotherapy for advanced-stage, low-grade serous ovarian cancer may be associated with worse survival compared with PDS.


Cibacron blue 3G-A is a novel inhibitor of Otopetrin 1 (OTOP1), a proton channel.
Otopetrin 1 (OTOP1) is a proton (H+) channel which detects acidic stimuli in sour taste receptor cells and plays some sort of role in the formation of otoconia in the inner ear. Although it is known that zinc ion (Zn2+) inhibits OTOP1, Zn2+ requires high concentrations (mM order) to inhibit OTOP1 sufficiently, and no other inhibitors have been found. Therefore, to identify a novel inhibitor, we screened a chemical library (LOPAC1280) by whole-cell patch clamp recordings, measuring proton currents of heterologously-expressed mouse OTOP1. From the screening, we found that reactive blue 2 inhibited OTOP1 currents. Further evaluations of three analogues of reactive blue 2 revealed that cibacron blue 3G-A potently inhibited OTOP1 currents. Cibacron blue 3G-A inhibited OTOP1 currents in a concentration-dependent manner, and its 50% inhibitory concentration (IC50) and the Hill coefficient were 5.0 μM and 1.1, respectively. The inhibition of OTOP1 currents by cibacron blue 3G-A was less affected by extracellular anion compositions, membrane potentials, and low pH than the inhibition by Zn2+. These results suggest that the inhibition of OTOP1 by cibacron blue 3G-A is neither likely to be a pore-blocking inhibition nor a competitive inhibition. Furthermore, our findings revealed that cibacron blue 3G-A can be used as a novel inhibitor of OTOP1 especially under the conditions in which OTOP1 activity is evaluated such as low pH.


Delayed Recanalization-How Late Is Not Too Late?
Stroke has become the second most prevalent cause of mortality in the world. Currently, the treatment of ischemic stroke is based on thrombolytic and thrombectomy therapy shortly after the ischemic event (≤ 4.5 h for thrombolytic strategies; ≤ 6 h for thrombectomy strategies). However, the majority of patients are unable to receive prompt treatment, particularly in undeveloped countries. Alternative solutions are lacking for those patients that miss the optimal window of opportunity for treatment. Recently, new developments in imaging techniques and intravascular interventional devices enable the expansion of the window of opportunity for treating stroke patients. Clinical studies have reported that delayed recanalization at 24 h, or even more than 1 month, was beneficial for some patients. However, the mechanisms of neuroprotection that underly the delayed recanalization in these ischemic stroke patients remain unclear. In this review, we will summarize the clinical studies of delayed recanalization, and organize them according to the duration of occlusion. Additionally, we will discuss the changing guidelines and possible mechanisms based on animal research, and attempt to draw conclusions and future perspectives.


Relationships between the synthesis and breakdown of protein, dietary absorption and turnovers of nitrogen and carbon in the blue mussel, Mytilus edulis L.
Seasonal and nutritionally induced changes of whole body protein metabolism have been studied in 45 to 57 mm shell-length Mytilus edulis from Whitsand Bay, southwest England. The subtraction of measured net protein balances from coincident rates of protein synthesis, determined in vivo by supplying 15N-labelled alga and monitoring the enrichment of excreted ammonia, enabled computation of protein breakdown rates. Over the range of protein absorption from zero to 0.58% of total soft tissue protein 24 h-1, fractional rates of protein breakdown decreased from 0.41 to 0.03%, whereas protein synthesis and net protein balance both increased from 0.25% to 0.39% and from-0.16% to 0.36%, respectively. The progressive reduction in fractional protein degradation with elevated net protein balance represented a "protein sparing" effect, whereby the efficiency of protein synthesis (defined as net synthesis/overall synthesis) confirmed theoretical predictions of as much as 92% during periods of maximal growth. In addition, 38% of breakdown products were recycled directly to synthesis under conditions of zero net balance, with an increasing contribution evident upon further decreases of protein absorption. The overall response was characterized by a consistently conservative elemental turnover of nitrogen relative to carbon, so that as a fraction of each element absorbed, between 1.2 and 1.9 times as much nitrogen was incorporated within structural materials. Such conservation was most pronounced among mussels starved prior to experimentation, indicating nutritionally related efficiencies in the utilization of resources for synthesis. The changing balance between individual processes also effected large alterations in proportional size of the metabolic pool of free amino acids (0.2 to 14.5% of total soft tissue nitrogen). Finally, it is suggested that adjustments of protein synthetic rate may be significant in the regulation of energy expenditure, accounting for at least 16% of basal energy requirements. Results throughout have been compared and contrasted with those for mammals, and whole-body measurements of both protein synthesis and breakdown proposed as a valuable index for environmental effects on instantaneous growth and metabolism.


Pharmacokinetics of oxaliplatin (NSC 266046) alone and in combination with paclitaxel in cancer patients.
Oxaliplatin (OPT), a third-generation platinating agent, is currently being evaluated in a phase II clinical trial in head and neck cancer patients and in a phase I clinical trial in combination with paclitaxel (TXL). The aim of this study was to investigate the pharmacokinetics and biological correlates of OPT alone as well as the potential pharmacokinetic interaction between OPT and TXL. In the phase II study, OPT was given alone as a 2-h i.v. infusion at 60 mg/m(2) weekly for 4 weeks with the cycle repeated after a 2-week rest. In the concurrent phase I combination trial OPT was also given as a 2-h i.v. infusion, but followed by a 1-h i.v. infusion of TXL, weekly for 4 weeks with the cycle repeated after a 2-week rest. The clinical pharmacokinetics of OPT alone and in combination with TXL were investigated in the first cycle of each treatment protocol. The platinum levels in plasma, plasma ultrafiltrate (PUF) and urine were measured by a fully validated inductively coupled plasma mass spectrometry (ICPMS) method. In the ten patients receiving OPT alone, the concentration-time profiles of total platinum exhibited a biexponential decline both in plasma and in PUF. The peak levels of platinum were 2.72+/-0.41 microg/ml in plasma and 1.36+/-0.42 microg/ml in PUF at the end of the OPT infusion, and the platinum levels were still detectable at >10 ng/ml 94 h after the OPT infusion. The mean terminal t(1/2) values of total platinum in plasma and in PUF were 58.9 h and 22.8 h, respectively. The AUC of ultrafilterable platinum represented about 10% of that of the total plasma platinum. The platinum levels in the DNA fraction of peripheral white blood cells (WBC) correlated with the platinum levels in PUF ( r=0.77, P<0.01). In the phase I combination study, the dose level of OPT was escalated from 35 mg/m(2) to 60 mg/m(2). The concentration-time profiles of platinum in the combination trial also showed biexponential decay in plasma and in PUF as exhibited by OPT alone. However, the terminal elimination rate constant (beta) of total plasma platinum increased at all dose levels of OPT when combined with TXL at 45 mg/m(2) ( P<0.05). A concomitant increase in clearance (CL) of total plasma platinum was observed at the OPT dose level of 45 mg/m(2) in combination with TXL at 45 mg/m(2). No statistically significant difference in the 24-h urinary elimination of total platinum was detected between the combination groups and the single-agent group. The AUC values of total platinum in PUF were proportional to OPT doses ranging from 35 to 60 mg/m(2), whether OPT was given alone or in combination with TXL. OPT clearance may be enhanced by TXL when the two agents are used in combination in patients. The Pt-DNA adduct level in peripheral WBC was found to be a good indicator for oxaliplatin exposure in patients, and should be further exploited for potential tumor drug exposure.


Does a clinical guideline change chlamydia testing? Report from the Waikato Chlamydia Project.
Waikato District Health Board was one of three districts chosen to implement a national chlamydia management guideline, with the aim of optimising testing and treatment. Previous New Zealand studies suggest any test increases associated with such an intervention may be short-lived. District-wide chlamydia test volumes were compared for three periods, before (June-Nov 2008), during (June-Nov 2009) and after (June-Nov 2010) guideline implementation by age, gender and ethnicity. Crude estimates of population test uptake were calculated. Azithromycin pharmacy claim volumes were assessed as a measure of treatment. Chlamydia test uptake for women was already high, with 23% of 15- to 24-year-old women tested during the period from June to November 2008. Although tests from under-25-year-olds increased during implementation in 2009, the change was not significant and was not sustained in 2010, p=0.06. Similarly, there were no significant sustained changes by gender or ethnicity following implementation. This includes a continued emphasis on optimal chlamydia case finding and treatment by focusing on those at greater risk of infection. Efforts to improve partner notification should be instigated which may in turn better engage men around sexual health. Local data should be used to identify local issues. There is a need to determine whether <25 years is the optimal age threshold for targeted chlamydia testing in New Zealand and to ensure appropriate resources, training and support are in place for primary care nurses who play a pivotal role in sexual health care delivery.


UPLC-ESI-QTOF-MS assisted targeted metabolomics to study the enrichment of vinca alkaloids and related metabolites in Catharanthus roseus plants grown under controlled LED environment.
Enrichment of pharmaceutically important vinca alkaloids, vinblastine and vincristine, in the leaves of Madagascar periwinkle (Catharanthus roseus) plants through different pre- or postharvest treatments or cultivation conditions, e.g., exposing the plants to UV-irradiation, has been in focus for decades. Controlled LED environment in the visible light range offers the possibility of monitoring the changes in the concentration of metabolites in the vinca alkaloid-related pathway without involving UV-related abiotic stress. In the frame of our targeted metabolomics approach, 64 vinca alkaloids and metabolites were screened with the help of a UPLC-ESI-QTOF-MS instrumental setup from the leaf extracts of C. roseus plants grown in chambers under control (medium light), low light, and high blue / high red/ high far-red conditions. Out of the 14 metabolites that could be assigned either unambiguously with authentic standards or tentatively with high resolution mass spectrometry-based methods, all three dimer vinca alkaloids, that is, 3',4'-anhydrovinblastine, vinblastine and vincristine showed an at least nine-fold enrichment under high blue irradiation when compared with the control conditions: final concentrations of 961 mg kg-1 dry weight, 33.8 mg kg-1 dry weight, and 11.7 mg kg-1 dry weight could be achieved, respectively. As supported by multivariate statistical analysis, the key metabolites of the vinca alkaloid pathway were highly represented among the metabolites that were specifically stimulated by high blue light application.


Holmium laser lithotripsy under direct peroral cholangioscopy by using an ultra-slim upper endoscope for patients with retained bile duct stones (with video).
Direct peroral cholangioscopy (POC) by using an ultra-slim endoscope provides direct visualization of the bile duct and allows for therapeutic intervention. Holmium laser lithotripsy can be effective for retained bile duct stones, but it requires direct visualization during the procedure for safe and effective fragmentation. Direct POC by using an ultra-slim endoscope may facilitate holmium laser lithotripsy. To evaluate the feasibility, success rates, and complications of holmium laser lithotripsy under direct POC by using an ultra-slim endoscope for retained bile duct stones. Observational clinical feasibility study. Tertiary-care referral center. This study involved 13 patients with retained bile duct stones whose treatment failed by a conventional lithotripsy method involving mechanical lithotripsy. Holmium laser lithotripsy under direct POC by using an ultra-slim endoscope. Success rate of complete stone removal and procedure-related complications. Holmium laser lithotripsy under direct POC by using an ultra-slim endoscope was successful in 11 of 13 patients (84.6%). Although direct POC was successful, holmium laser lithotripsy failed in 2 patients because of inaccurate targeting of the laser fiber to stones. There were no procedure-related complications except one case of mild pancreatitis. A small number of patients and no comparison with other lithotripsy systems. Holmium laser lithotripsy under direct POC by using an ultra-slim endoscope was feasible and can be a safe endoscopic management method for retained bile duct stones.


Effects of hypothalamic lesions on temperature regulation in pigeons.
The effect of hypothalamic lesions on temperature regulation was studied in pigeons by recording deep and skin temperatures, shivering, panting and oxygen consumption. Thresholds of shivering and panting were assessed before and after lesions. Survival was 100% when lesions were done in awake animals in a cool environment. Lesions anterior to the anterior commissure which included the preoptic area resulted in an increased threshold of panting or a lack of panting response at body temperatures up to 44.5 degrees C. Shivering response was unchanged in these animals. Lesions posterior to the anterior commissure were followed by a lack of shivering response with no change in panting threshold. This points to a segregation of the hypothalamic structures controlling heat loss and heat gain in the pigeon.


Pharmacology of the brachium conjunctivum: red nucleus synaptic system in the baboon.
Acetylcholine, biogenic amines, and certain amino acids were applied by microiontophoresis to parvicellular and magnocellular red nucleus (RN) neurons of baboon while recording brachium conjunctivum (BC)-evoked and amino acid-evoked unit discharge from these neurons. Glycine, gamma-aminobutyric acid, and beta-alanine were potent depressants of BC-RN synaptic transmission, amino acid-evoked firing, and spontaneous activity of all RN neurons studied. Glycine was clearly more potent than the other 2 depressant amino acids. L-Glutamic and DL-homocysteic acid were strong excitants of all RN neurons tested. Dopamine, noradrenaline, and 5-hydroxytryptamine depressed the excitability of both parvicellular and magnocellular RN neurons; no excitatory effects were observed with these biogenic amines on RN neurons. Acetylcholine increased the rate of firing of spontaneously discharging parvicellular RN neurons and facilitated the amino acid-induced firing of these same neurons. Acetylcholine did not facilitate BC-RN synaptic transmission nor could this transmission be blocked by cholinergic antagonists. Unlike parvicellular RN neurons, the responsiveness of magnocellular neurons was either unaltered by acetylcholine or slightly decreased. These experiments demonstrate a difference in the pharmacologic responsiveness of parvicellular and magnocellular RN neurons to acetylcholine but do not provide evidence for a cholinergic input to RN via the brachium conjunctivum.


Ventricular Arrhythmia Occurrence and Compliance in Patients Treated With the Wearable Cardioverter Defibrillator Following Percutaneous Coronary Intervention.
The wearable cardioverter defibrillator (WCD) is a life-saving therapy in patients with high risk of arrhythmic death. We aimed to evaluate ventricular arrhythmia (VA) occurrence rate and compliance with the WCD during the first 90 days following myocardial revascularisation with percutaneous coronary intervention (PCI) in patients with left ventricular ejection fraction (LVEF) <30%. From September 2015 to November 2016, clinical characteristics, WCD recordings and compliance data of the aforementioned subset of patients were prospectively collected. Twenty-four patients (men=20, 80%) were included in this analysis. Mean age was 56±10 years and mean LVEF at enrolment was 26.6±4.3%. During a mean wearing period of 3.0±1.3 months, two episodes of VA occurred in two patients (8.3%): one successfully treated with WCD shock and one with spontaneous termination. The mean and median daily use of the WCD was 21.5hours and 23.5hours a day, respectively. Eighteen patients (75%) wore the WCD more than 22hours a day. The rate of VA, during the WCD period use after myocardial revascularisation with PCI, was high in our study. Otherwise it underlined that patient compliance is critical during the WCD period use. Remote monitoring and patient education are keys to achieve good compliance.


Hypoxic Postconditioning Promotes Angiogenesis After Ischemic Stroke.
Although hypoxic postconditioning (HPC) has a protective effect on ischemic stroke, its effect on angiogenesis after ischemic stroke is still unclear. This study was designed to investigate the effects of HPC on angiogenesis after ischemic stroke and to preliminarily study the mechanism involved. Oxygen-glucose deprivation (OGD)-intervened bEnd.3 (mouse brain-derived Endothelial cell. 3) was used to simulate cerebral ischemia. Cell counting kit-8 (CCK-8), Cell BrdU proliferation, wound healing, Transwell and tube formation assays were used to evaluate the effect of HPC on the cell viability, proliferation, migration (horizontal and vertical migration), morphogenesis and tube formation of bEnd.3. A middle cerebral artery occlusion (MCAO) model was made in C57 mice to simulate focal cerebral ischemia. Rod rotation test, corner test, modified neurological severity score (mNSS), and balance beam walking test were used to evaluate the effect of HPC on the neurological impairment of mice. Immunofluorescence staining was used to evaluate the effect of HPC on angiogenesis in mice. The angiogenesis-related proteins were evaluated and quantified using western blot. Results showed that HPC significantly promoted proliferation, migration and tube formation of bEnd.3. HPC significantly reversed the neurological deficit of MCAO mice. Moreover, HPC significantly promoted angiogenesis in the peri-infarct area, and angiogenesis was found to be positively correlated with the improvement of neurological impairment. The HPC mice showed higher PLCλ and ALK5 than did MCAO. We conclude that HPC improves the neurological deficit caused by focal cerebral ischemia by promoting angiogenesis. Furthermore, the effect of HPC on improving angiogenesis may be related to PLCλ and ALK5.


Response to treatment with the leukocyte-derived immunomodulator IMREG-1 in immunocompromised patients with AIDS-related complex. A multicenter, double-blind, placebo-controlled trial.
To determine if a 6-month course of therapy with IMREG-1, a leukocyte-derived immunomodulator, slows disease progression in patients with AIDS-related complex. Randomized, double-blind trial. Five academic- and three community-based clinics. Immunocompromised patients (143) with HIV. IMREG-1 or placebo every 2 weeks (13 doses). Twelve of forty-eight patients on placebo and 5 of 95 patients on IMREG-1 experienced adverse events (AIDS-defining opportunistic infection or neoplasm, wasting syndrome, HIV-associated encephalopathy, or peripheral sensory neuropathy). Based on an intention-to-treat analysis, Kaplan-Meier event probabilities were 26% for the placebo group and 6% for the IMREG-1 group (P less than 0.001); based on the Cox proportional hazards model, the relative risk for patients on placebo compared with patients on IMREG-1 was 5.1 (95% CI, 1.8 to 14.8). The frequency of symptoms significantly increased from baseline in patients receiving placebo. The mean decrease in CD4+ cells from baseline was 80 x 10(6) cells/L in the placebo group and 29 x 10(6) cells/L in patients on IMREG-1, with 20% (8) and 38% (32) of patients, respectively, showing a trend toward an increase (P = 0.04). In patients receiving IMREG-1, the size and rate of delayed hypersensitivity responses were larger than in the placebo group. Patients with AIDS-related complex experienced fewer adverse events and constitutional symptoms after IMREG-1 treatment. The slower loss of CD4+ cells and increased size and rate of delayed hypersensitivity responses most likely reflect the effect of IMREG-1 on the immune system. No toxicity related to IMREG-1 administration was observed.


[Monomicrobian necrotizing fasciitis of the leg due to multidrug-resistant Acinetobacter baumannii in a healthy adult: about a case].
Necrotizing fasciitis is a rapidly progressive soft tissue infection characterized by extensive necrosis in the deep and superficial fascia. This is a polymicrobial infection in about 70% of cases. Monomicrobian infection is usually caused by β-hemolytic group A streptococcus. Monomicrobian necrotizing fasciitis due to multidrug-resistant Acinetobacter baumannii is rare and usually occurs in immunocompromised patients with a medical history. In these subjects, the infection is severe and fatal due to the decompensation of the underlying defects and septic shock. The occurrence of this clinical disease in healthy subjects is rare. We report the case of a 54-year-old healthy man with monomicrobian necrotizing fasciitis of the left leg due to multidrug-resistant Acinetobacter baumannii; patient's outcome was favorable after extensive surgical debridement.


Rational construction of reliable fluorescent probes for rapid detection and imaging evaluation of hazardous thiophenol in real-food and biosystems.
Thiophenol (PhSH), a highly reactive aromatic thiol, plays an essential role as a common industrial raw material in food, pesticides, pharmaceuticals, and cosmetics. In this work, we designed and constructed two fluorescent probes CM-PhSH and CM-Ratio-PhSH by a rational strategy. Specifically, coumarin fluorophores with excellent optical properties were modified, and olefinic unsaturated bonds served as reaction sites for the detection of PhSH. Based on this, the introduction of the nitro group at specific positions of the CM-PhSH changed the fluorescence emission of the CM-Ratio-PhSH, eventually obtaining a novel ratiometric fluorescent probe CM-Ratio-PhSH for PhSH detection. Surprisingly, these two probes exhibited advantages such as high specificity and low limit of detection (LOD) for CM-PhSH 32.3 nM and CM-Ratio-PhSH 40.2 nM, respectively. Furthermore, subsequent experiments demonstrated CM-PhSH and CM-Ratio-PhSH could be successfully used for highly selective and rapid detection of PhSH in aqueous solutions, live cells, and complex food samples.


Laparoscopic surgery for recurrent Crohn's disease.
The aim of this study was to assess the feasibility of laparoscopic surgery for recurrent Crohn's disease, and the role of repeated laparoscopy in reoperation. Between January 1994 and May 2002, 61 laparoscopic operations were attempted in 52 patients with ileal or ileocolonic Crohn's disease. Of these, 16 procedures were performed for recurrence at the anastomotic site (recurrent group). The remaining 45 operations were performed as primary procedures (control group). The median follow-up was 48 (range 3-90) months. The median time to reoperation was 46 months. The incidence of enteric fistula and the conversion rate did not differ significantly between the two groups. Although the operating time was significantly longer in the recurrent group, there were no differences in the rate of postoperative complications (three in the recurrent group and six in the control group) and hospital stay (both median 8 days). Laparoscopic surgery for recurrent Crohn's disease is feasible in selected patients without an increase in conversion rate or postoperative complications.


Elderly case of pseudo-unilateral occult macular dystrophy with Arg45Trp mutation in RP1L1 gene.
To report a case of pseudo-unilateral occult macular dystrophy (OMD) with an Arg45Trp mutation in the RP1L1 gene and had unilateral functional changes for about 9 years. A 64-year-old woman with a decimal visual acuity of 1.0 in both eyes complained about difficulties with visual tasks because of presbyopia. At the age of 65 years, her visual acuity in the left eye decreased to 0.2, while that in the right eye was 0.7. The fundus of both eyes was normal except for drusen. After 10 years and at the age of 75 years, her visual acuity in the right eye decreased to 0.3. Focal macular electroretinograms (ERGs) at this time were severely attenuated in both eyes, while the full-field ERGs were within normal limits. Ophthalmoscopy showed that the fundus of both eyes was still normal. Genetic analysis revealed a heterozygous mutation, Arg45Trp, in the RP1L1 gene. These findings indicate that the phenotype in some cases of OMD with an Arg45Trp mutation in the RP1L1 gene can be unilateral for a considerable period.


Pharmacological characterization of the novel dihydropyridine potassium channel opener, (9R)-9-(3-iodo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (A-325100), and the regulation of cardiovascular function in conscious and anesthetized beagle dogs.
The pharmacological profile of the novel dihydropyridine K channel opener (KCO), (9R)-9-(3-iodo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (A-325100), is described in numerous in vitro assays. Furthermore, the cardiovascular effects of A-325100 are characterized in both the anesthetized and conscious dog. In vitro, A-325100 selectively activated KATP currents and potently relaxed vascular smooth muscle (IC50 between 7.69x10 M and 7.78x10 M), an effect that was abolished by glyburide. Moreover, A-325100 did not interact with L-type Ca2+ channels at concentrations up to 30 microM. In anesthetized dogs A-325100 produced a dose-dependent reduction in systemic vascular resistance and mean arterial pressure concomitant with dose-dependent increases in dP/dtmax and heart rate. In conscious telemetry-instrumented dogs oral administration of A-325100 produced a similar response profile, including dose-dependent reductions in MAP and increases in heart rate and dP/dtmax. When concentration-dependent changes in MAP, heart rate, and dP/dtmax were compared relative to circulating plasma concentrations, A-325100 produced similar effects in both the anesthetized and conscious dog. In conclusion, the present study provides the first pharmacological description of the novel and selective tricyclic dihydropyridine KCO, A-325100. When studied in vivo, A-325100 produced similar concentration-dependent cardiovascular effects in both models consistent with its mode of action and independent of route of administration. Thus, these data demonstrate that the hemodynamic effects of vasoactive compounds, such as KCOs, can be effectively profiled in both the conscious and anesthetized dog.


Inactivation of sarin and soman by cyclodextrins in vitro.
Cyclodextrins catalyzed the inactivation of sarin and soman but did not inactivate tabun and VX. Furthermore, sarin and soman showed greater affinity for beta-cyclodextrin than for alpha- or gamma-cyclodextrins. Thus beta-cyclodextrin appears to be an attractive starting material for the preparation of a catalyst able to inactivate sarin and soman more effectively. Such a catalyst might contribute to improving the therapy of poisoning caused by these two nerve agents.


Wireless transmission of voltage transients from a chronically implanted neural stimulation device.
Objective.Consistent transmission of data from wireless neural devices is critical for monitoring the condition and performance of stimulation electrodes. To date, no wireless neural interface has demonstrated the ability to monitor the integrity of chronically implanted electrodes through wireless data transmission.Approach.In this work, we present a method for wirelessly recording the voltage transient (VT) response to constant-current, cathodic-first asymmetric pulsing from a microelectrode array. We implanted six wireless devices in rat sciatic nerve and wirelessly recorded VT measurements throughout a 38 week implantation period.Main results.Electrode maximum cathodic potential excursion (Emc), access voltage, and driving voltage (extracted from each VT) remained stable throughout the 38 week study period. Average Emc(from an applied +0.6 V interpulse bias) in response to 4.7µA, 200.2µs pulses was 267 ± 107 mV at week 1 post-implantation and 282 ± 52 mV at week 38 post-implantation. Access voltage for the same 4.7µA pulsing amplitude was 239 ± 65 mV at week 1 post-implantation and 268 ± 139 mV at week 38 post-implantation.Significance.The VT response recorded via reverse telemetry from the wireless microelectrode array did not significantly change over a 38 week implantation period and was similar to previously reported VTs from wired microelectrodes with the same geometry. Additionally, the VT response recorded wirelessly in phosphate buffered saline before and after device implantation appeared as expected, showing significantly less electrode polarization and smaller access voltage than the VT responsein vivo.


Increasing agar content improves the sol-gel and mechanical features of starch/agar binary system.
Starch/agar systems are highly potential for versatile applications such as packaging and biomedical materials. Here, how combined factors affect the features of a starch/agar binary system were explored. An increase of starch amylose/amylopectin ratio from 0/100 to 50/50 increased the sol-gel transition temperature and gel hardness of the aqueous starch/agar mixture. An increased agar content (mainly from 30% to 70%) allowed increases in both the tensile strength (reaching 50-60 MPa) and elongation at break of the starch/agar binary films. This phenomenon should be related to the strengthened crystalline structure and the weakened hydrogen bonding between starch chains (reflected by infrared spectroscopy). Furthermore, a higher relative humidity (from 30% to 70%) allowed enhanced chain interactions and probably nanoscale molecular order but weakened the crystalline structure, leading to reduced tensile strength and increased elongation at break. This work could facilitate the design of starch/agar binary systems with improved sol-gel and mechanical performance.


Prolonged endurance challenge at moderate altitude: effect on serum eosinophil cationic protein, eosinophil dynamics, and lung function.
Eosinophils contain granule proteins such as eosinophil cationic protein (ECP) that have proinflammatory effects on airways. ECP may be released on activation of eosinophils into the plasma and is widely used as a marker of bronchial hyperreactivity and allergic inflammation. Environmental factors as well as intense physical exertion may influence eosinophil-related bronchial hyperreactivity. To investigate the effect of endurance exercise at moderate altitude on levels of circulating eosinophils, serum ECP, serum osmolality (sOS), and dynamic pulmonary function parameters in healthy mountaineers. Alpine field study performed in the Alps of Upper Styria in Austria. Type of exercise: Ascent of a mountain at maximal speed. Thirty healthy male volunteers from a troop of military mountaineers. Mean ECP concentration increased by 66% at the summit checkpoint (H2) and remained at 63% above baseline (base checkpoint [H0]) after descent (H4), while the blood eosinophil count decreased concomitantly from 250/microL at H0 (preexercise) to 118/microL (53%) at H2 and to 22/microL (81%) at H4. The total serum ECP concentration adjusted to sOS correlated negatively with blood eosinophil count (r = - 0.37; p < 0.0001) and PaO(2) (r = - 0.34; p < 0.001), but positively with the peak expiratory flow (PEF) [r = 0.45; p < 0.0001]. Although sOS correlated with serum ECP at H2 (r = 0.47; p = 0.02) and at 12 h after the start of the experiment (H12) [r = 0.57; p = 0.003], the relationship between total ECP and sOS (r = 0.19; p = 0.034) was less pronounced. FEV(1) in percentage of FVC (%FEV(1)/FVC) [the Tiffenau test], forced expiratory flow rate at 25% of vital capacity, and PEF were significantly higher at H2 than at H0 and H4. %FEV(1)/FVC decreased to 88% (p < 0.01) and 83% (p < 0.001) predicted at H12 and 24 h after start of the experiment, respectively. Results provide strong evidence for nonspecific activation of blood eosinophils during prolonged intense aerobic exercise at moderate altitude, modifying both eosinophil dynamics and regulation of ECP release in healthy subjects.


Rapid quantification of active pharmaceutical ingredient for sugar-free Yangwei granules in commercial production using FT-NIR spectroscopy based on machine learning techniques.
Rapid quantification methods for sugar-free Yangwei granules were developed based on near-infrared (NIR) spectroscopy combined with machine learning approaches as a quality control strategy for Chinese medicine granules (CMGs). Different machine learning approaches-i.e., interval partial least squares optimized by the genetic algorithm (GA-iPLS), the backpropagation artificial neural network (BP-ANN), and the particle swarm optimization-support vector machine (PSO-SVM)-were used to develop prediction models for three active pharmaceutical ingredients (APIs), namely, albiflorin, paeoniflorin, and benzoylpaeoniflorin. The partial least squares (PLS) algorithm was used for linear model calibration and comparison of the prediction performance of these developed models. The performance of the final models was assessed by the correlation coefficient (R), root mean square error of calibration set (RMSEC), and root mean square error of prediction set (RMSEP). All models performed well in model fitting and provided satisfactory prediction accuracy. The results indicate that the machine learning approaches are more stable, predictable, and suitable for CMGs when a high-accuracy analysis is required. In summary, NIR spectroscopy coupled with machine learning techniques is a suitable tool for the straightforward quantification of CMGs.


Systolic honks in young children.
Three children with loud systolic honks were studied noninvasively with phonocardiography and echocardiography. It was shown that the precordial honk, like the late systolic mitral murmur and the clicking apical systolic sound, is part of a continuum of auscultatory sounds that result from a defect of mitral valve support and are classified under the general heading of mitral valve prolapse syndrome. Prolapse of one or both of the mitral valve leaflets is believed to cause the characteristic auscultatory findings of click, murmur or honk. The timing of these sounds in systole varies with different physiologic or pharmacologic maneuvers. Variations in the onset of prolapse are associated with changes in left ventricular end-diastolic dimensions.


Effect of clinical pharmacist intervention on the treatment of acute pancreatitis.
Background The participation of clinical pharmacists in the treatment of acute pancreatitis has rarely been reported. Objective The aim of this study was to retrospectively evaluate the impact of intervention of clinical pharmacists on the treatment of acute pancreatitis. Setting An academic teaching hospital in Taizhou, Jiangsu, China. Method Two hundred and twenty-eight patients with acute pancreatitis were retrospectively enrolled from July 2017 to July 2018 and divided into an intervention group (n = 119) and a control group (n = 109) according to whether a clinical pharmacist was involved. No significant differences in the baseline clinical characteristics were found between the groups. Clinical pharmacists participated in drug formulation and adjustment, pharmaceutical care, and follow-up. Main outcome measure Clinical outcomes, average hospital stays, costs, incidence of adverse drug reactions, 1-month subsequent visit rate, and patient satisfaction between the two groups were measured. Results The clinical symptoms of patients in both groups were relieved after treatment. There were no significant differences between the groups in computed tomography grades after treatment, incidence of adverse drug reactions, or average hospital stays. However, the intervention group had lower total costs of hospitalization, drugs and antibiotics but higher rates of 1-month subsequent visits and satisfaction compared with the control group. Conclusion The intervention of clinical pharmacists in the treatment of acute pancreatitis can effectively reduce costs of hospitalization, drug and antibiotics and improve follow-up compliance and patient satisfaction.


High-intensity focused ultrasound selectively disrupts the blood-brain barrier in vivo.
High-intensity focused ultrasound (HIFU) has been shown to generate lesions that destroy brain tissue while disrupting the blood-brain barrier (BBB) in the periphery of the lesion. BBB opening, however, has not been shown without damage, and the mechanisms by which HIFU induces BBB disruption remain unknown. We show that HIFU is capable of reversible, nondestructive, BBB disruption in a targeted region-of-interest (ROI) (29 of 55 applications; 26 of 55 applications showed no effect); this opening reverses after 72 h. Light microscopy demonstrates that HIFU either entirely preserves brain architecture while opening the BBB (18 of 29 applications), or generates tissue damage in a small volume within the region of BBB opening (11 of 29 applications). Electron microscopy supports these observations and suggests that HIFU disrupts the BBB by opening capillary endothelial cell tight junctions, an isolated ultrastructural effect that is different from the mechanisms through which other (untargeted) modalities, such as hyperosmotic solutions, hyperthermia and percussive injury disrupt the BBB.


Human herpesvirus 6A active infection in patients with autoimmune Hashimoto's thyroiditis.
Hypothyroidism due to Hashimoto's thyroiditis (HT) is the commonest autoimmune endocrine illness in which antibodies against thyroid organ result in inflammation. The disease has a complex etiology that involves genetic and environmental influences. Viral infections may be involved in triggering of the disease as their molecular mimicry enhance autoimmune responses. Human herpesvirus-6 (HHV-6) is recognized for its contribution to some autoimmune diseases. In the current study, the prevalence of HHV-6 active infection in patients with HT and with non-autoimmune thyroid disorders were compared with patients with euthyroidism. In addition, a correlation between presence of HHV-6 infections and HT was investigated. A total of 151 patients with clinically and laboratory confirmed HT, 59 patients with non-autoimmune thyroid disorders, and 32 patients with normal thyroid function were included in the study. For further confirmation of HT disease, all the precipitants were tested for anti-thyroid peroxidase (TPO), and anti-thyroglobulin (TG) antibodies. For detection of both HHV-6 types A and B, nested PCR and restriction enzyme digestion were used. HHV-6 DNA positive samples were further investigated by DNA sequencing analysis. HHV-6A DNA was found in serum sample of 57 out of 151 patients (38%) with HT, which was significantly more often than in patients with non-autoimmune thyroid disorders (p=0.001). However, HHV-6 DNA was not detected in serum samples of euthyroid subjects. The results support a possible role for active HHV-6A infection, demonstrated by the presence of HHV-6 DNA in sera, in the development of HT.


Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions.
HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.


Role of the pioneer transcription factor GATA2 in health and disease.
The transcription factor GATA2 is involved in human diseases ranging from hematopoietic disorders, to cancer, to infectious diseases. GATA2 is one of six GATA-family transcription factors that act as pioneering transcription factors which facilitate the opening of heterochromatin and the subsequent binding of other transcription factors to induce gene expression from previously inaccessible regions of the genome. Although GATA2 is essential for hematopoiesis and lymphangiogenesis, it is also expressed in other tissues such as the lung, prostate gland, gastrointestinal tract, central nervous system, placenta, fetal liver, and fetal heart. Gene or transcriptional abnormalities of GATA2 causes or predisposes patients to several diseases including the hematological cancers acute myeloid leukemia and acute lymphoblastic leukemia, the primary immunodeficiency MonoMAC syndrome, and to cancers of the lung, prostate, uterus, kidney, breast, gastric tract, and ovaries. Recent data has also linked GATA2 expression and mutations to responses to infectious diseases including SARS-CoV-2 and Pneumocystis carinii pneumonia, and to inflammatory disorders such as atherosclerosis. In this article we review the role of GATA2 in the etiology and progression of these various diseases.


Immunoelectron microscopy identifies several types of GABA-containing efferent synapses in the guinea-pig organ of Corti.
Using an immunoperoxidase technique, we have localized by light and electron microscopy GABA-immunostained fibers within a component of the efferent innervation of the organ of Corti. At the light microscopic level, GABA-immunostained fibers were observed within the inner spiral bundle (below the inner hair cells) and the tunnel spiral bundle. The immunostaining was clearly more intense in the upper turns than in the basal turns. Mostly in the upper turns, GABA-immunostained fibers were seen crossing the tunnel of Corti to reach the outer hair cells where they formed large immunostained patches at the base of the cells. Unevenly distributed throughout these upper turns, immunostained fibers were seen climbing along the outer hair cells and traveling near the non-sensorineural Hensen's cells. The electron microscopic observations of GABA-immunostained fibers in the upper turns allowed us to identify within the inner spiral bundle vesiculated varicosities synapsing with radial dendrites connected to the inner hair cells. In the outer hair cell area, the GABA-immunostained fibers made several kinds of synaptic contacts. They included a minor population of the large axosomatic synapses with the basal pole of the outer hair cells and many axodendritic synapses with the spiral dendrites connected to these cells. Occasionally, the GABA-immunostained climbing fibers also synapsed with the outer hair cells at a supranuclear level. These result confirm previous light microscopic data dealing with the projection of the GABA-immunostained fibers along the cochlear partition. Moreover, they extend them in characterizing several kinds of GABA-immunostained synapses. These latter findings agree with previous neurochemical electrophysiological data which suggests an efferent neurotransmitter role for GABA. Nevertheless, such an existence of an efferent innervation predominantly projecting to the upper turns of the cochlea adds another criterion distinguishing the "apical" from the "basal" cochlea.


Laser induced thermotherapy (LITT) of experimental liver metastasis-detection of residual tumors using Gd-DTPA enhanced MRI.
The aim of this study was to evaluate the accuracy of Gd-DTPA MRI in the detection of recurrent tumor after laserinduced thermotherapy (LITT) of experimental liver metastases. LITT was performed at different energy levels in VX-2 tumor-bearing rabbits (n = 80). MRI and histology were placed at 0, 24, 96 hours, and 14 days. Signal intensities were calculated of the transition between thermally damaged and undamaged tissue (transition zone = TZ) and of the surrounding tissue (reference zone = RZ). Tumor recurrence was seen in 47 animals. At 24 hours sensitivity, specificity and accuracy was 92, 100, and 95% in TZ and 23, 100, and 50% in RZ. At 14 days sensitivity, specificity and accuracy was 100, 11, and 60% in TZ and 100, 89, and 95% in RZ. Recurrence is best excluded in TZ at 24 hour and in RZ at 14 day with an accuracy up to 95%.


Comparative efficacy of forphenicinol, cyclosporine, and amphotericin B in experimental murine coccidioidomycosis.
Cohorts of ten mice, uninfected and infected (intratracheal injection of coccidioidal arthroconidia), were treated for 23 days by intravenous injections of either 5% glucose solution, an immunostimulant (forphenicinol), an immunodepressant (cyclosporine), or amphotericin B. All mice were autopsied (survivors at 26 days postinoculation) and suspensions of lungs, livers, and spleens were cultured. All uninfected animals survived and gained weight, whereas, only 20% of the infected controls survived, and all lost weight. Treatment with forphenicinol had no effect on survival or weight. Cyclosporine secured 90% survival at the lowest dose and 60% at the higher doses, with no net loss of weight; however, all cultures of organs yielded heavy growth of Coccidioides immitis. With amphotericin B, all mice survived and gained weight; four mice from each of the two treatment groups yielded modest growth of C. immitis from the lungs, and one mouse of each group yielded sparse growth from liver and spleen. The paradox of no effect from an immunostimulant and therapeutic effect from an immunodepressant correlated with susceptibility testing of C. immitis in vitro.


Variations in sub-national road traffic fatality trends in a low-income country.
In most low- and middle-income countries (LMICs), road traffic fatality (RTF) trends are presented in aggregated form at the national level. This practice omits important information regarding RTF risk at sub-national levels. This ecological study assesses the extent of RTF variations at different sub-national levels in Pakistan, a low-income country. Based on official statistics, significant variations in three RTF indicators i.e. per population, per registered vehicles, and per crash were compared by regression analyses at two sub-national levels i.e. provincially (2000-2009) and district-wise (2004). The national RTF counts are based on data from four provinces. From 2000 to 2009, RTF per population and per registered vehicles decreased in all provinces except Balochistan. RTF per crash in Punjab decreased from 0.61 to 0.56 (beta coefficient (β) year = -0.0082, P = <0.001), whereas in Balochistan it increased from 0.40 to 0.58 (β year = 0.0708, P = <0.001) over the same period. District-level comparisons were possible only in Punjab where RTF per crash varied from 0.25 to 2.15 and correlated (β = 0.50, P = 0.003) with RTF per population. Sub-national RTF surveillance is necessary in LMICs like Pakistan in order to prioritize available resources on high-risk jurisdictions such as the Balochistan province and districts of Punjab where high RTF per population and per crash exist.


Intra-oral squamous cell carcinoma in patients under 40 years of age. A report of 13 cases and review of the literature.
The results of the treatment of 13 patients under the age of 40 presenting with primary intra-oral squamous cell carcinoma have been presented. 31% (four patients) survived 3 years from first presentation and all patients who died had recurrent disease within 12 months of surgery. These figures suggest that younger patients with intra-oral cancer have a prognosis similar to an older, more typical cohort.


Quantum computing for near-term applications in generative chemistry and drug discovery.
In recent years, drug discovery and life sciences have been revolutionized with machine learning and artificial intelligence (AI) methods. Quantum computing is touted to be the next most significant leap in technology; one of the main early practical applications for quantum computing solutions is predicted to be in quantum chemistry simulations. Here, we review the near-term applications of quantum computing and their advantages for generative chemistry and highlight the challenges that can be addressed with noisy intermediate-scale quantum (NISQ) devices. We also discuss the possible integration of generative systems running on quantum computers into established generative AI platforms.


Treatment of concurrent metastatic renal cell carcinoma and chronic myelogenous leukemia--easier said than done? A case report.
Treating two active malignancies concurrently can be exceedingly difficult. Complications can occur from the different treatment regimens, especially if they share common targets, and the progressing diseases can make managing treatment side-effects even more challenging. We report a case of a patient with coexisting CML and mRCC who progressed on multiple lines of mRCC therapy while experiencing significant dose limiting side-effects.


Self-regulatory processes in early childhood as predictors of Hispanic children's BMI z-scores during the elementary school years: Differences by acculturation and gender.
Over the last decade, longitudinal research has shown that children's general, top-down self-regulation during early childhood is negatively associated with children's weight status in elementary school. The samples in these previous studies have been primarily White, and no study to date has examined this issue in a sample of Hispanic children from low-income families-a population at high risk for childhood obesity. The present study followed 130 Hispanic children over a time period of three to just under five years, examining the degree to which multiple measures of general, top-down self-regulation, along with a measure of appetite regulation (eating in the absence of hunger), predicted children's BMI z-scores in the early elementary school years. Results showed that children's ability to delay gratification in the preschool years was negatively associated with later BMI z-scores and that children's eating in the absence of hunger was positively associated. In separate models by gender, these relationships were significant only for girls. Moreover, analyses run separately for children of mothers low or high on acculturation showed that the relationship between delay of gratification and later BMI z-scores was significant only for children whose mothers were low on acculturation. Possible socialization and environmental factors contributing to these findings are considered.


[Tumor banks and complex data management: Current and future challenges].
Tumor banks are asked to clinical and translationnal research project development in oncology. They strongly participate to the assessment, then to the validation of diagnostic, prognostic and predictive biomarkers. The progressive change of these structures leads to induce a professionalization of their functioning and to identify them as key actors in oncology by the stakeholders of the public and private worlds. The progresses made in biotechnologies and therapeutics are rapidly modifying the impact and the proper functioning of the biobanks. These latter are now facing different challenges, in particular for their sustainability. Among the major issues, the integration of the clinical and biological data becoming increasingly complex leads to urgently consider an optimization of the role of different biobanks in France. Their goal is to be an attractive counterpart face to the international competition. The purpose of this review is to briefly describe the current evolution of the biobanks, then their present and future challenges, and finally the role made by the pathologists in these new issues in oncology field.


Desensitization of nicotine-stimulated [3H]dopamine release from mouse striatal synaptosomes.
Potential desensitization of brain nicotinic receptors was studied using a [3H]dopamine release assay. Nicotine-stimulated [3H]dopamine release from mouse striatal synaptosomes was concentration-dependent with an EC50 of 0.33 +/- 0.13 microM and a Hill coefficient of 1.44 +/- 0.18. Desensitization by activating concentrations of nicotine had a similar EC50 and a half-time of 35 s. Concentrations of nicotine that evoked little release also induced a concentration-dependent desensitization (EC50 = 6.9 +/- 3.6 nM, t1/2 = 1.6-2.0 min, nH = 1.02 +/- 0.01). Both types of desensitization produced a maximum 75% decrease in [3H]dopamine release. Recovery from desensitization after exposure to low or activating concentrations of nicotine was time-dependent with half-times of 6.1 min and 12.4 min, respectively. Constants determined for binding of [3H]nicotine to striatal membrane at 22 degrees C included a KD of 3.7 +/- 0.5 nM, Bmax of 67.5 +/- 2.2 fmol/mg, and Hill coefficient of 1.07 +/- 0.06. Association of nicotine with membrane binding sites was biphasic with half-times of 9 s and 1.8 min. The fast rate process contributed 37% of the total reaction. Dissociation was a uniphasic process with a half-time of 1.6 min. Comparison of constants determined by the release and binding assays indicated that the [3H]-nicotine binding site could be the presynaptic receptor involved in [3H]dopamine release in mouse striatal synaptosomes.


Protective effect of magnesium lithospermate B against dextran sodiumsulfate induced ulcerative colitis in mice.
Anti-platelet drugs have been used to treat inflammatory bowel disease. In this study, we observed the therapeutic effects of magnesium lithospermate B, a main component of salvianolate, on colitis induced by dextran sodiumsulfate (DSS). Colitis was induced by 5% DSS oral administration in BALB/C male mice. Magnesium lithospermate B (60-240mg/kg) was given by subcutaneous injection for 2 weeks. Then, mice were sacrificed; serum and colon tissues were collected for biomarker assay, histological examination, immunohistochemical study and real-time quantitative polymerase chain reaction. DSS induced gross bleeding, inflammation, crypt damage and mucosal damage in colon. Treatment with magnesium lithospermate B could reduce colon inflammation induced by DSS. Magnesium lithospermate B could reverse the high CD40/CD40L expression and hypercoagulable state induced by DSS in colon. This study showed that magnesium lithospermate B could be used to treat colitis. The protective effects of magnesium lithospermate B may be due to its effects on CD40/CD40L expression and blood clotting status.


Analysis of complement deposition and processing on Chlamydia trachomatis.
Chlamydia trachomatis (C. trachomatis) is the leading cause of sexually transmitted bacterial infections worldwide, with over 120 million annual cases. C. trachomatis infections are associated with severe reproductive complications in women such as extrauterine pregnancy and tubal infertility. The infections are often long lasting, associated with immunopathology, and fail to elicit protective immunity which makes recurrent infections common. The immunological mechanisms involved in C. trachomatis infections are only partially understood. Murine infection models suggest that the complement system plays a significant role in both protective immunity and immunopathology during primary Chlamydia infections. However, only limited structural and mechanistic evidence exists on complement-mediated immunity against C. trachomatis. To expand our current knowledge on this topic, we analyzed global complement deposition on C. trachomatis using comprehensive in-depth mass spectrometry-based proteomics. We show that factor B, properdin, and C4b bind to C. trachomatis demonstrating that C. trachomatis-induced complement activation proceeds through at least two activation pathways. Complement activation leads to cleavage and deposition of C3 and C5 activation products, causing initiation of the terminal complement pathway and deposition of C5b, C6, C7, C8, C9 on C. trachomatis. Interestingly, using immunoelectron microscopy, we show that C5b-9 deposition occurred sporadically and only in rare cases formed complete lytic terminal complexes, possibly caused by the presence of the negative regulators vitronectin and clusterin. Finally, cleavage analysis of C3 demonstrated that deposited C3b is degraded to the opsonins iC3b and C3dg and that this complement opsonization facilitates C. trachomatis binding to human B-cells.


Total Synthesis of (±)-Englerin A Using An Intermolecular [3+2] Cycloaddition Reaction of Platinum-Containing Carbonyl Ylide.
Total synthesis of (±)-Englerin A has been achieved starting from γ,δ-ynone 5 in 14 steps. The key feature of this synthesis is the highly efficient and stereoselective preparation of 8-oxabicyclo[3.2.1]octane derivative 6, a core skeleton of Englerin A, based on an inverse electron-demand [3+2] cycloaddition reaction of the platinum-containing carbonyl ylide, which was developed in our laboratory.


Fluorescence study on the conformation of a cyclic enkephalin analog in aqueous solution.
Conformational parameters of the potent cyclic enkephalin analogs [D-Cys2, D-Cys5]enkephalinamide and [D-Cys2, Trp4, D-Cys5]enkephalinamide were determined by steady-state fluorescence measurements. The very low tyrosine fluorescence quantum yield observed with [D-Cys2, D-Cys5]enkephalinamide reflects a close intramolecular interaction between the phenol ring of Tyr1 and the disulfide bridge. Evaluation of resonance energy transfer between Tyr1 (donor) and Trp4 (acceptor) of [D-Cys2, Trp4, D-Cys5]enkephalinamide on the basis of Förster's equation resulted in an average intramolecular distance of 9.7 +/- 0.2 A between the two aromatic rings. This mean distance is nearly identical with the average Tyr1 - Trp4 distance (9.5 +/- 0.3 A) previously determined with the linear analog [D-Ala2, Trp4, Met5]enkephalin.


Loss in milk yield and related composition changes resulting from clinical mastitis in dairy cows.
Relationships between clinical mastitis and milk yield and composition in dairy cows were reviewed. Requirements for inclusion were: data had to be collected after 1975; dependent variables for milk yield and milk composition had to be defined at the cow level; mastitis cases had to be defined by clinical signs, and at least 250 lactations had to be considered. Twenty studies dealing with milk-yield loss and, for four of them, also with related composition changes were selected. Study populations, design of data collection, and analysis methods differed widely between studies. As expected from these differences--but also due to structural-variation factors such as type of pathogen, animal and production level--estimates for milk-yield losses differed in average magnitude and pattern. Literature data regarding changes in milk-fat % and total-protein % changes were contradictory. Critiques of materials and methods allowed us to propose some final recommendations for values to be used as basic inputs in economic calculations of losses caused by mastitis.


Effects of exercise training on coronary heart disease risk factors in renal transplant recipients.
Multiple risk-factor interventions that include lifestyle changes have been proved to be effective in reducing risk profile in persons at high risk for developing coronary heart disease (CHD). There have not been similar studies involving transplant recipients. The purpose of this study is to examine effects of exercise training on cardiovascular risk profile during the first year after renal transplantation. We used traditional CHD risk factors and the Framingham CHD prediction methods. Ninety-six transplant recipients were randomly assigned to 2 groups at 1 month posttransplantation: the exercise training (EX group; n = 51) and usual care groups (UC group; n = 45). Testing was performed at baseline and 12 months posttransplantation and included maximal exercise testing and evaluation of CHD risk factors and risk-factor categories, determined by means of the Framingham equations. Overall 10-year CHD risk score did not change in either group. All patients showed increases in total cholesterol (TC) level, high-density lipoprotein fraction of cholesterol (HDL-C), and body mass index over time. No differences were observed between groups, except for a trend toward greater improvement in HDL cholesterol levels in the EX group (P = 0.07). Significantly more patients in the EX group moved out of the high-risk category in TC-HDL ratio. All patients remained in the high-risk category for physical fitness. There was a significant negative correlation of CHD risk and maximal exercise capacity (r = -0.406; P < 0.001). Exercise training alone does not reduce CHD risk during the first year after transplantation. Research to determine the effects of multiple risk interventions during a longer period in transplant recipients is warranted.


Laboratory evaluation of alum, ferric and ferrous-water treatment residuals for removing phosphorous from surface water.
Numerous drinking water plants and agricultural wastewaters generate water treatment residuals (WTR) during coagulation processes. These WTRs may be effective at reducing nutrients entering waterways, thereby decreasing the potential formation of algal blooms. Of the WTRs used in this study, Al-based WTR (Al-WTR) was the most effective achieving a 20 °C cumulative adsorbed concentrations (qe) after 28 days of desorption of 63-76 mg PO4/kg Al-WTR depending on the initial spiked concentration. When the isotherm temperature was 5 °C, Al-WTR effectiveness decreased. Ferric chloride WTR (Fe-WTR) was only effective when 0.6 mg/L of PO4 was spiked to surface water with 0.01 mg/PO4 stored at 20 °C yielding a 28 day cumulative qe 5.67 mg PO4/kg Fe-WTR. At 5 °C, the cumulative qe after extended desorption was 1-4.63 mg/kg Fe-WTR. Ferrous sulfate based WTR (Fe2-WTR) was not capable of adsorbing any additional PO4 regardless of the spiked concentration or temperature.


The surgeon and the intensivist: reaching consensus in intensive care triage.
Decisions regarding admissions/discharges in the surgical intensive care unit (SICU) can potentially strain the relationship between the critical care team and the primary surgery service. We hypothesized that a multidisciplinary system of arbitration, led by an intensivist, is a safe and workable solution to SICU patient triage, which leads to consensus between critical care team and primary services. Demographic, illness severity, readmission, and outcome data were collected prospectively on consecutive patients in a large academic center SICU. Arbitration was directed by an intensivist and a charge nurse, with regular meetings. Representation from various hospital departments (admissions, operating room, nursing, and housekeeping) was included. Decisions on patient discharge from the SICU were compared between the primary service (represented by the Chief resident) and the SICU arbitrator. A total of 289 patients were admitted to SICU during the 2-month study period, with 952 arbitration decisions. Good agreement exists between the primary service and the arbitrator regarding SICU patient suitability for discharge (Kappa = 0.85). Seventeen patients (5.9%) were readmitted, with 14 (82%) surviving to hospital discharge. None of the readmitted patients was originally discharged over the primary service objection. Day of discharge APACHE II scores of readmitted patients did not differ from those not readmitted (8.2 vs 7.7). Readmissions had longer hospital stays, equivalent SICU stays, and higher mortality (18%) than for patients overall (2.8%). A dedicated intensivist, supported by a multidisciplinary team, can make arbitration decisions in the SICU that seem to be safe and generally concordant with the primary surgical team of the patient. Additional larger-scale investigation of arbitration in the SICU is warranted.


Targeting p73 in cancer.
p73 is a member of the p53 family of tumor suppressors. Transactivating isoforms of p73 (TAp73) have p53-like, anti-proliferative and pro-apoptotic activities that are crucial for an efficient chemotherapy response. In line with this, genetic studies in mice have confirmed that TAp73 acts as a tumor suppressor. However, in contrast to p53, which is commonly inactivated in human cancer by point mutations, the TP73 gene is almost never mutated. Instead, the tumor suppressor activity of TAp73 is inhibited through a variety of mechanisms including epigenetic silencing and complex formation with inhibitory proteins. All these mechanisms have in common that they are in principle reversible and therefore amenable to therapeutic intervention. Here, we will review how tumor cells control the tumor suppressor activity of TAp73 and discuss possible strategies targeting p73 for reactivation.


High-pressure liquid chromatographic analysis of aniline and its metabolites.
A high-pressure liquid chromatographic method has been developed for the determination of nanomole quantities of aniline; its metabolites o- and p-aminophenol, phenylhydroxylamine, nitrosobenzene and nitrobenzene; and azobenzene and azoxybenzene which form non-enzymatically by condensation of reactive metabolites. These compounds were separated by reverse-phase chromatography (mu-Bondapak C18 column) and detected spectrophotometrically. The first four components were eluted using methanol-water (15:85) containing 0.26 M ammonium acetate and 0.015 M nickel acetate as mobile phase. The remaining compounds were eluted with methanol-water (50:50). The stabilities of the metabolites were studied electrochemically and results were used in the development of the chromatographic system.


Is kernicterus due to inhibition of brain hexose-monophosphate shunt activity by bilirubin?
Degradation of biogenic amines in the central nervous system is accomplished by the monoamine oxidase system. The by-products of this reaction, hydrogen peroxide and amino aldehydes, are toxic to neurones. Detoxification of these by-products is normally mediated by generation of NADPH via the hexosemonophosphate (HMP) shunt. It is proposed that inhibition of the HMP shunt by unconjugated bilirubin leads to the toxic accumulation of hydrogen peroxide and aldehydes.


Xanthomas and the inherited hyperlipoproteinemias in children and adolescents.
Early recognition of the hyperlipoproteinemias is a crucial element in preventing premature coronary artery disease. Xanthomas provide a cutaneous marker of the silent, underlying pathology. Identifying them, and understanding their relation to the inherited hyperlipoproteinemias may facilitate early diagnosis of hyperlipoproteinemias in pediatric patients. The dermatologist plays an important role in identifying these lesions and in subsequently facilitating prompt referral and treatment.


A Potential Role of Phospholipase 2 Group IIA (PLA2-IIA) in P. gingivalis-Induced Oral Dysbiosis.
Porphyromonas gingivalis is an oral pathogen with the ability to induce oral dysbiosis and periodontal disease. Nevertheless, the mechanisms by which P. gingivalis could abrogate the host-microbe symbiotic relationship leading to oral dysbiosis remain unclear. We have recently demonstrated that P. gingivalis specifically increased the antimicrobial properties of oral epithelial cells, through a strong induction of the expression of PLA2-IIA in a mechanism that involves activation of the Notch-1 receptor. Moreover, gingival expression of PLA2-IIA was significantly increased during initiation and progression of periodontal disease in non-human primates and interestingly, those PLA2-IIA expression changes were concurrent with oral dysbiosis. In this chapter, we present an innovative hypothesis of a potential mechanism involved in P. gingivalis-induced oral dysbiosis and inflammation based on our previous observations and a robust body of literature that supports the antimicrobial and proinflammatory properties of PLA2-IIA as well as its role in other chronic inflammatory diseases.


Distribution and spatial autocorrelation of viral hepatitis B and C in Paraná, Brazil: an ecological study, 2011-2019.
to analyze the distribution and spatial autocorrelation of hepatitis B and C detection rates in the state of Paraná, Brazil. this was an ecological study of hepatitis B and C notifications held on the Notifiable Health Conditions Information System, between 2011 and 2019. Percentage change in detection rates between the first and last three-year periods was estimated. Spatial autocorrelation was analyzed using Moran's index. there were 16,699 notifications of hepatitis B, with a greater reduction in detection in the North (-30.0%) and Northwest (-25.9%) macro-regions. There were clusters of high occurrence in the Foz do Iguaçu, Francisco Beltrão and Cascavel regions between 2011 and 2019. There were 10,920 notifications of hepatitis C, with a greater reduction in detection in the Northwest macro-region (-18.9%) and an increase in the West (51.1%). The Paranaguá region recorded a high detection cluster between 2011 and 2016. hepatitis B and C showed heterogeneous distribution between health regions.


Differential expression of two novel odorant receptors in the locust (Locusta migratoria).
Olfaction in animals is important for host localization, mating and reproduction in heterogeneous chemical environments. Studying the molecular basis of olfactory receptor neurons (ORNs) systems can elucidate the evolution of olfaction and associated behaviours. Odorant receptors (ORs) in insects have been identified, particularly in the holometabolous model Drosophila, and some of them have been functionally studied. However, ORs in the locust-a hemimetabolous model insect and the most important insect crop pest-have not yet been identified, hindering our understanding of locust olfaction. Here, we report for the first time four putative ORs in Locusta migratoria: LmigOR1, LmigOR2, LmigOR3 and LmigOR4. These four putative OR genes encoded proteins with amino acids of 478, 436, 413 and 403 respectively. Sequence identity among them ranged from 19.7% to 35.4%. All ORs were tissue-specifically expressed in olfactory organs, without sex-biased characteristics. However, LmigOR1, LmigOR3 and LmigOR4 were only expressed in the antenna, while LmigOR2 could also be detected in mouthparts. In situ hybridization demonstrated that the LmigOR1antisense probe labelled olfactory receptor neurons (ORNs) in almost all segments of the antenna, but only a few segments housed ORNs expressing LmigOR2. The number of neurons labelled by LmigOR1 antisense probes in each antennal segment was much greater (>10 neurons/segment) than that labelled by LmigOR2 probes (generally 1-3 neurons/segment). Furthermore, some of the labelled neurons could be attributed to the basiconic sensilla, but LmigOR1 and LmigOR2 were expressed in different subtypes. Our results strongly suggested that these newly discovered genes encode locust ORs and the differential expression patterns of LmigOR1 and LmigOR2 implied distinct functions. These results may offer insights into locust olfaction and contribute to the understanding of the evolution of insect chemoreception.


TB positive cases go up in ongoing COVID-19 pandemic despite lower testing of TB: An observational study from a hospital from Northern India.
The whole world is wrestling against SARS-CoV-2 infection (COVID-19). COVID-19-TB co-infection is also reported but there are limited number of studies which analyze the impact of COVID-19 pandemic in TB diagnosis and management. In this retrospective study, we observed that the TB diagnosis was reduced in pandemic time. Before COVID-19 pandemic (March-December 2019), there were 644 TB tests out of which 127 were TB positive. In ongoing COVID-19 pandemic (January-October 2020), 484 TB tests were performed and 146 patients were TB positive. Male accounted for 64%/57% of TB cases in 2019/2020 whereas female patients were 35%/42% in 2019/2020. Increase in female TB positive cases was a noticeable feature. The newly diagnosed with TB cases in 2019/2020 were 112/130 respectively. Though, we have seen only 7 COVID-TB co-infection cases, we could not establish the causal relationship in COVID-TB co-infection. The increase in the number of TB positive cases during COVID-19 pandemic clearly showed how adversely COVID-19 has affected TB diagnosis and management. Anticipating the increase in TB cases in future, we emphasize the need to ensure continuous TB testing and treatment despite the pandemic burden. Further study on the COVID-TB co-infection in high TB-burden countries like India, is required to enable analyses of interactions, risk factors in COVID-19-TB co-infection.


TAS-102 Monotherapy and Combination Therapy with Bevacizumab for Metastatic Colorectal Cancer.
To evaluate the effectiveness and safety of TAS-102 monotherapy and combination therapy with bevacizumab in the treatment of metastatic colorectal cancer. The PubMed, Web of Science, MEDLINE, and Cochrane Library databases were searched for the literature on TAS-102 treatment of metastatic colorectal cancer. Extracted data include median overall survival (mOS), median progression-free survival (mPFS), and the incidence of adverse events for meta-analysis. Our study found that the mOS of patients treated with TAS-102 monotherapy was 6.95 (95% CI: 6.26-7.72) months and the mPFS was 2.53 (95% CI: 2.31-2.78) months. The mOS in patients treated by TAS-102 combined with bevacizumab was 10.41 (95% CI: 8.40-12.89) months, and the mPFS is 4.35 (95% CI: 3.05-6.20) months. In the control experiment, the patients' mOS and mPFS were improved. TAS-102+B vs. TAS-102 (OR = 0.41, 95% CI: 0.18-0.93; OR = 0.72, 95% CI: 0.63-0.83) and TAS-102 vs. placebo (OR = 0.44, 95% CI: 0.29-0.67; OR = 0.51, 95% CI: 0.42-0.62) were studied to actively prevent the occurrence of neutropenia, leukopenia, febrile neutropenia, anemia, and vomiting. TAS-102 monotherapy and combination therapy with bevacizumab can significantly improve the survival of patients and prevent specific adverse events from happening.


'Thinking outside the box': complementary and alternative therapies use in paediatric oncology patients.
The aim of this study was to determine the prevalence of complementary and alternative medicine (CAM) use among children with cancer who had received or were receiving treatment at a large hospital in the UK, including the identification of the most commonly used therapies and parental motives for doing so. Using a cross-sectional survey design, questionnaires were sent to parents of paediatric patients diagnosed with cancer. Of the 49 respondents, 32.7% reported using some type of CAM. The most commonly used therapies included multivitamins, aromatherapy massage, diets and music as therapy. Most children had used more than one therapy. Many of the factors that motivated parents to use CAM were related to helping or supporting their child's medical treatment. The main benefits identified from using CAM included increased confidence, pain relief and relaxation. The longer the time since diagnosis the more children tended to use CAM. The reasons for parents not using CAM included the child doing well and therefore not seeing the need for CAM use; not being aware of CAM; CAM not being offered and lack of information available. Parents identified a need for more information to be available both at ward level and for information about CAM to be discussed by medical staff, particularly at the start of treatment. The results indicate that CAM is frequently used by children and young people with cancer and that their use plays a substantial role in helping children through their conventional cancer treatment.


Convective heat processing of turkey roll: effects on sensory quality and energy usage.
Twenty-four frozen, raw, boneless, ready-to-cook turkey rolls were cooked in an institutional electric convection oven to an internal temperature of 77 degrees C. Six treatment combinations of three cooking temperatures (105 degrees C, 135 degrees C, and 165 degrees C) and two holding conditions (not chilled and chilled for 24 hours) were studied. Turkey rolls from each treatment combination were subjected to three hot-holding times (0, 60, and 120 minutes). Electrical energy usage was monitored during heat processing of the turkey rolls, reheating the turkey slices, and hot holding the turkey slices. Aroma, juicy mouthfeel, texture, flavor, and flavor off-notes of the cooked turkey were evaluated by seven judges using 150-mm unstructured line scales. Chew counts also were recorded. Turkey cooked at 105 degrees C took significantly more time to cook (331 vs. 227 and 203 minutes) but consumed significantly less energy (3.4 vs. 3.8 and 4.5 kWh) than turkey rolls cooked at 135 degrees C and 165 degrees C, respectively. Significantly higher juicy mouthfeel scores were obtained when the turkey roll was cooked in the convection oven at an oven temperature of 105 degrees C, the turkey was not chilled, and the slices were held hot for 60 minutes or less.


Bioptic Telescope Use in Naturalistic Driving by People with Visual Impairment.
The purpose of this study was to investigate the telescope use behaviors in natural daily driving of people with reduced visual acuity licensed to drive with a bioptic (a small spectacle-mounted telescope). A large dataset (477 hours) of naturalistic driving was collected from 19 bioptic drivers (visual acuity 20/60 to 20/160 without the telescope). To reduce the data volume, a multiloss 50-layer deep residual neural network (ResNet-50) was used to detect potential bioptic telescope use events. Then, a total of 120 hours of selected video clips were reviewed and annotated in detail. The frequency of looking through their telescopes ranged from 4 to 308 times per hour (median: 27, interquartile range [IQR], 19-75), with each bioptic use lasting median 1.4 seconds (IQR, 1.2-1.8). Thus, participants spent only 1.6% (IQR, 0.7%-3.5%) driving time with their telescopes aiding their vision. Bioptic telescopes were used most often for checking the road ahead (84.8%), followed by looking at traffic lights (5.3%), and reading road signs (4.6%). In daily driving, the bioptic drivers mostly (>98% of driving time) drove under low visual acuity conditions. The bioptic telescope was mainly used for observing road and traffic conditions in the distance for situational awareness. Only a small portion of usage was for road sign reading. This study provides new insights into how the vision rehabilitation device-bioptic telescopes are used in daily driving. The findings may be helpful for designing bioptic driving training programs.


Corrigendum to "A rapid review of the use of face mask in preventing the spread of COVID-19" [International Journal of Nursing Studies Advances 3 (2021) 100013].
[This corrects the article DOI: 10.1016/j.ijnsa.2020.100013.].


Phenyl radicals react with dinucleoside phosphates by addition to purine bases and H-atom abstraction from a sugar moiety.
Laser-induced acoustic desorption combined with mass spectrometry has been used to demonstrate that phenyl radicals can attack dinucleoside phosphates at both the sugar and base moieties, that purine bases are more susceptible to the attack than pyrimidine bases, and that the more electrophilic the radical, the more efficient the damage to dinucleoside phosphates.


Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau.
The microtubule-associated protein tau accumulates in neurodegenerative diseases known as tauopathies, the most common being Alzheimer's disease. One way to treat these disorders may be to reduce abnormal tau levels through chaperone manipulation, thus subverting synaptic plasticity defects caused by tau's toxic accretion. Tauopathy models were used to study the impact of YM-01 on tau. YM-01 is an allosteric promoter of triage functions of the most abundant variant of the heat shock protein 70 (Hsp70) family in the brain, heat shock cognate 70 protein (Hsc70). The mechanisms by which YM-01 modified Hsc70 activity and tau stability were evaluated with biochemical methods, cell cultures, and primary neuronal cultures from tau transgenic mice. YM-01 was also administered to acute brain slices of tau mice; changes in tau stability and electrophysiological correlates of learning and memory were measured. Tau levels were rapidly and potently reduced in vitro and ex vivo upon treatment with nanomolar concentrations of YM-01. Consistent with Hsc70 having a key role in this process, overexpression of heat shock protein 40 (DNAJB2), an Hsp70 co-chaperone, suppressed YM-01 activity. In contrast to its effects in pathogenic tauopathy models, YM-01 had little activity in ex vivo brain slices from normal, wild-type mice unless microtubules were disrupted, suggesting that Hsc70 acts preferentially on abnormal pools of free tau. Finally, treatment with YM-01 increased long-term potentiation in tau transgenic brain slices. Therapeutics that exploit the ability of chaperones to selectively target abnormal tau can rapidly and potently rescue the synaptic dysfunction that occurs in Alzheimer's disease and other tauopathies.


Prioritizing changes in management practices associated with reduced winter honey bee colony losses for US beekeepers.
Beekeepers attempt to manage their honey bee colonies in ways that optimize colony health. Disentangling the impact of management from other variables affecting colony health is complicated by the diversity of practices used and difficulties handling typically complex and incomplete observational datasets. We propose a method to 1) compress multi-factored management data into a single index, to holistically investigate the real world impact of management on colony mortality, and 2) simplify said index to identify the core practices for which a change in behavior is associated with the greatest improvement in survivorship. Experts scored the practices of US beekeepers (n = 18,971) documented using four years of retrospective surveys (2012-2015). Management Index scores significantly correlated with loss rates, with beekeepers most in line with recommendations suffering lower losses. The highest ranked practices varied by operation type, as recommendations accounted for the current prevalence of practices. These results validate experts' opinion using empirical data, and can help prioritize extension messages. Improving management will not prevent all losses; however, we show that few behavioral changes (in particular related to comb management, sources of new colonies and Varroa management) can lead to a non-negligible reduction in risk.


Occurrence of calcium oxalate in karri (Eucalyptus diversicolor F. Muell.) forest ecosystems of south western Australia.
The amount of calcium in Eucalyptus diversicolor (karri) ecosystems is high in comparison with other eucalypt forest ecosystems in Australia. A large proportion of this calcium is present as crystalline Ca oxalate. Whewellite (CaC2O4·H2O) accumulates in leaf tissue of the over- and understorey species. Up to 70% of the calcium in the leaves of karri is stored as whewellite, the highest concentrations occurring in the oldest leaves. Synthesis of Ca oxalate by karri may be related in part to the high levels of exchangeable soil calcium. Oxalate of plant origin is rapidly metabolized on the forest floor during decomposition of leaf litter. About 70% of the whewellite in fresh karri leaf litter is degraded during the first wet season following leaf fall. However, additional oxalate is formed in the soil and litter layer from microbial production of oxalic acid. These crystals are of the dihydrate calcium salt, weddelite (CaC2CO4· 2H2O). Microbial production of oxalate, particularly by ectomycorrhizal fungi, may be an important mechanism for mobilizing of phosphate from the strongly phosphateadsorbing soils on which these forests grow.


Libet's intention reports are invalid: A replication of Dominik et al. (2017).
In the "Libet experiment" the onset of movement-related brain activity preceded the reported time of the conscious intention to move, suggesting that conscious intention may not play a role in initiating voluntary movements (Libet, Gleason, Wright, & Pearl, 1983). Dominik et al. (2017) provided evidence that the intention reports employed in the Libet experiment, which Libet et al. (1983) found to precede movement reports, are invalid. In the study by Dominik et al., intention reports preceded movement reports only when participants had prior experience making movement reports. Individuals without such experience reported intention around the same time as movement. These findings suggest that Libet's intention reports do not reflect experiences of intention, but, rather, inferences based on prior experience with movement reports. Our study replicated the core findings of Dominik et al. We argue that Libet's intention reports are invalid and explore the phenomenology of intention in the Libet experiment.


Intense orthodontic force induces the three dental pulp nitric oxide synthase isoforms and leads to orofacial discomfort in rats.
The objective of this study was to evaluate the role of nitric oxide synthase (NOS) isoforms influence during tooth movement with different forces. 100 male Wistar rats (n = 10/group) were divided into a Sham group (animals not submitted to device installation nor Induced Toot Movement [ITM]), Negative Control Group (NCG) (animals submitted to device installation but not to ITM) and three experimental groups (F1, F2 and F3) (submitted to ITM with forces of 25, 50 and 100 gF respectively). A daily count of biting and scratching on the vibrissae and the Grimace scale were applied. After 4 (D4) and 11 (D11) days, the molar diastema was measured, and the animals were euthanized for histological (vascular parameters) and immunohistochemistry (iNOS, eNOS and nNOS) in the dental pulp. On D4, there was significant movement in the F3 group (P = .001) and on D11 in F1, F2 and F3 (P < .001). The number of bites (P < .001) and scratching (P = .006) was higher in F2-F3, and F3 had higher Grimace scores (P < .001) and weight loss (P < .001). At D4, there was an increase in pulp ectasia in F2-F3 (P = .021) and a reduction in the number of vessels in F3 (P = .005). In D4 and D11, there was a significant increase in immunostaining for iNOS and eNOS in F1 (P = .025 and P < .001 respectively) and F2 (P = .007 and P < .001 respectively). At D4, F2 and F3 showed higher immunostaining for nNOS (P = .027). Thus, IDM induced inflammatory changes in the dental pulp reflecting in force-dependent pain/suffering signs.


Characteristics and clinical significance of the lymphocytic alveolitis in interstitial lung disorders.
Although the mechanisms responsible for lung damage and respiratory function deterioration for each type of alveolitis are not entirely known, with the opportunity to study the cells present in the lower respiratory tract, their functions and the mediators released in different conditions, we will be able to better understand the link between the inflammatory process, the acute tissue damage, the progression of the disease and the pulmonary scarring. This knowledge will be helpful in a better management of patients with interstitial lung diseases modulated by immunologic mechanisms.


Threshold, enzymatic, and pathologic changes associated with prolonged transcutaneous pacing in a chronic heart block model.
Previous studies have shown that 30 minutes of transcutaneous cardiac pacing (TCP) can induce mild, clinically insignificant myocardial damage. Longer use of TCP may cause more severe cardiac damage which might result in an increase in the capture threshold for subsequent transvenous cardiac pacing (TVP). To assess this possibility, we examined changes induced by TCP in a canine chronic heart block model. Heart block was induced in conditioned dogs (n = 8) by His bundle ablation. Seven to 10 days after induction of heart block, six animals were paced. Cardiac enzymes were drawn before pacing and at 4, 24, 48, and 72 hours after pacing. Although there was a significant rise in CK at 4 and 24 hours (P less than 0.05), there was no detectable rise in the MB fraction in any of the paced animals. There was no elevation of LDH after pacing, although three animals did develop an LDH1/LDH2 isoenzyme flip indicative of myocardial damage. Animals were sacrificed 72 hours after pacing and their hearts were examined for gross and microscopic changes. The hearts of the paced animals revealed subendocardial, subepicardial, and perivascular areas of basophilic degeneration involving less than 1% of the myocardium in four of six animals. No evidence of such damage was seen in two heart-blocked control animals not undergoing pacing. TVP and TCP capture thresholds assessed before and after a 60-minute TCP pacing period showed no significant change. Hence, use of TCP for a 60-minute period prior to TVP appears to be a safe emergency pacing technique.


Changes in circulating stem cells and endothelial progenitor cells over a 12-month period after implantation of a continuous-flow left ventricular assist device.
Changes in circulating CD34+CD45low stem cells (SC) and CD34+CD45low+KDR+ endothelial progenitor cells (EPC) may reflect pathological endothelial activation. Non-pulsatile/continuous-flow left ventricular assist devices (CF-LVAD) can enhance this process. The aim of this study was to analyse the impact of 12-month CF-LVAD treatment on SC and EPC. We analysed changes in SC and EPC from the pre-implantation period up until 12 months after implantation over 3-month intervals in 14 patients. Data from 12 patients with heart failure (HF) and from 13 healthy volunteers were used as controls. Baseline EPC were significantly higher in CF-LVAD and HF patients than in healthy controls, substantially decreasing 3 months after CF-LVAD implantation and then returning to high baseline values at 12 months. Changes in circulating SC and EPC may reflect pathological endothelial activation after CF-LVAD implantation.


Acquired von Willebrand factor deficiency caused by LVAD is ADAMTS-13 and platelet dependent.
The high shear rates induced by left ventricular assist devices cause acquired von Willebrand disease (aVWD). We hypothesised that an ex vivo model could be established to study whether mechanical shear stress alone causes aVWD or whether this process depends also on the VWF cleavage protein ADAMTS-13 and on platelets. Healthy volunteers and two patients with congenital ADAMTS-13 deficiency donated blood. In vitro closed extracorporeal circuits were established using medically approved left ventricular assist devices (LVAD). VWF multimers were quantified by gel electrophoresis; VWF antigen, ristocetin cofactor activity (VWF:RCo), ADAMTS-13 levels and platelet function were assessed. The high shear stress in the extracorporeal circulation rapidly decreased VWF:RCo and thereby the VWF:RCo/VWF:Ag ratio by 47% (p<0.01) to pathologically low values. Concomitantly, high molecular weight multimers (HMWM) decreased: up to 14-15 mers were visible on the gels at baseline, which were reduced by a maximum of 6-7 mers, corresponding to an average 68% lower densitometry signal of HMWM (p<0.001). This was accompanied by marked reduction of aggregation by various agonists (p<0.005). In contrast, the two patients with congenital thrombocytopenic purpura with virtually complete deficiency of ADAMTS-13 activity had only a minimal or no decrease in multimers (p<0.005 vs. healthy controls). Similarly, no or minimal depletion of large multimers occurred, when normal plasma circulated without platelets. An in vitro model for LVAD associated aVWD demonstrated that ADAMTS-13 and platelets contribute to the depletion of HMWM of VWF.


Identification and enumeration of asbestos fibers in the mining environment: mission and modification to the Federal Asbestos Standard.
Since the promulgation of the first Federal Asbestos Standard by the Occupational Safety and Health Administration in 1972, other federal agencies have modified the standard to better carry on their own unique missions. The instruments used to identify and measure asbestos, the sampling protocol, and the criteria used to define asbestos, have been modified to some degree. The Mine Safety and Health Administration regulates and controls asbestos dust in the mining and mineral commodity industries. However, crushed stone and processed ores contain mineral fragments that are frequently difficult to distinguish from asbestos. Mineral nomenclature, instruments for particle analysis, and sampling strategy must be accommodated to some degree to make asbestos control workable and meaningful. Precedent in other agencies has made consideration of these changes possible. Newly identified amphibole asbestos minerals have further complicated the agency's regulatory charge. Changes in its Asbestos Standard are now being considered. Crushed taconite ore in the Eastern Mesabi highlights many of these issues.