Extracellular pectin-RALF phase separation mediates FERONIA global signaling function.

The FERONIA (FER)-LLG1 co-receptor and its peptide ligand RALF regulate myriad processes for plant growth and survival. Focusing on signal-induced cell surface responses, we discovered that intrinsically disordered RALF triggers clustering and endocytosis of its cognate receptors and FER- and LLG1-dependent endocytosis of non-cognate regulators of diverse processes, thus capable of broadly impacting downstream responses. RALF, however, remains extracellular. We demonstrate that RALF binds the cell wall polysaccharide pectin. They phase separate and recruit FER and LLG1 into pectin-RALF-FER-LLG1 condensates to initiate RALF-triggered cell surface responses. We show further that two frequently encountered environmental challenges, elevated salt and temperature, trigger RALF-pectin phase separation, promiscuous receptor clustering and massive endocytosis, and that this process is crucial for recovery from stress-induced growth attenuation. Our results support that RALF-pectin phase separation mediates an exoskeletal mechanism to broadly activate FER-LLG1-dependent cell surface responses to mediate the global role of FER in plant growth and survival.

Neurosurgery in feline epilepsy, including clinicopathology of feline epilepsy syndromes.

Feline epilepsy is treated with antiseizure medications, which achieves fair to good seizure control. However, a small subset of feline patients with drug-resistant epilepsy requires alternative therapies. Furthermore, approximately 50 % of cats with epileptic seizures are diagnosed with structural epilepsy with or without hippocampal abnormality and may respond to surgical intervention. The presence of hippocampal pathology and intracranial tumors is a key point to consider for surgical treatment. This review describes feline epilepsy syndrome and epilepsy-related pathology, and discusses the indications for and availability of neurosurgery, including lesionectomy, temporal lobectomy with hippocampectomy, and corpus callosotomy, for cats with different epilepsy types.

Effects of orally administered Euglena gracilis and its reserve polysaccharide, paramylon, on gastric dysplasia in A4gnt knockout mice.

Euglena gracilis is widely utilized as food or supplement to promote human and animal health, as it contains rich nutrients. In this study, we administered spray-dried powder of E. gracilis and paramylon, ß-glucan stored in E. gracilis cells, to A4gnt knockout (KO) mice. A4gnt KO mice are a mutant mouse model that spontaneously develops gastric cancer through hyperplasia-dysplasia-adenocarcinoma sequence in the antrum of the stomach, and we observed the effects of E. gracilis and paramylon on the early involvements of A4gnt KO mice. Male and female 10-week-old A4gnt KO mice and their age-matched wildtype C57BL/6J mice were orally administered with 50 mg of E. gracilis or paramylon suspended in saline or saline as a control. After 3-week administration, animals were euthanatized and the stomach was examined histopathologically and immunohistochemically. Gene expression patterns of the stomach, which have been reported to be altered with A4gnt KO, and IgA concentration in small intestine were also analyzed with real-time PCR and ELISA, respectively. Administration of Euglena significantly reduced the number of stimulated CD3-positive T-lymphocytes in pyloric mucosa of A4gnt KO mice and tend to reduce polymorphonuclear leukocytes infiltration. Euglena administration further downregulated the expression of Il11 and Cxcl1 of A4gnt KO mice. Euglena administration also affected IgA concentration in small intestinal contents of A4gnt KO mice. Paramylon administration reduced the number of CD3-positive lymphocytes in pyloric mucosa of A4gnt KO mice, and downregulated the expressions of Il11 and Ccl2 of A4gnt KO mice. Although we found no significant effects on gross and microscopic signs of gastric dysplasia and cell proliferation, the present study suggests that the administration of Euglena and paramylon may ameliorate the early involvements of A4gnt mice through the effects on inflammatory reactions in the gastric mucosa. The cancer-preventing effects should be studied with long-term experiments until actual gastric cancer formation.

Orally administered brown seaweed-derived ß-glucan effectively restrained development of gastric dysplasia in A4gnt KO mice that spontaneously develop gastric adenocarcinoma.

ß-Glucan refers to a heterogeneous group of chemically defined storage polysaccharides containing ß-(1,3)-d-linked glucose polymers with branches connected by either ß-(1,4) or ß-(1,6) glycosidic linkage. To date, an extensive amount of scientific evidence supports their multifunctional biological activities, but their potential involvement in the progression of premalignant lesions remains to be clarified. A4gnt KO mice that lack α1,4-N-acetylglucosamine-capped O-glycans in gastric gland mucin are a unique animal model for gastric cancer because the mutant mice spontaneously develop gastric cancer through hyperplasia-dysplasia-adenocarcinoma sequence. In particular, A4gnt KO mice show gastric dysplasia during 10-20 weeks of age. Here we investigated the putative gastro-protective activity of brown seaweed-derived ß-glucan (Laminaran) against development of gastric dysplasia, precancerous lesion for gastric cancer in A4gnt KO mice. The mutant mice at 12 weeks of age were randomly assigned into three treatment groups namely, wildtype control + distilled water (normal control), A4gnt KO mice + distilled water (untreated control), and A4gnt KO mice + 100 mg/kg Laminaran. After 3 weeks, the stomach was removed and examined for morphology and gene expression patterns. In contrast to the untreated control group, administration of Laminaran substantially attenuated gastric dysplasia development and counterbalanced the increased induction in cell proliferation and angiogenesis. Furthermore, Laminaran treatment effectively overcame the A4gnt KO-induced alteration in the gene expression profile of selected cytokines as revealed by real-time PCR analysis. Collectively, our present findings indicate that ß-glucan can potentially restrain the development of gastric dysplasia to mediate their tissue-preserving activity.

Estimating Population Health Benefits Associated with Specialty and Traditional Drugs in the Year Following Product Approval.

OBJECTIVE: Compared to traditional drugs, specialty drugs tend to be indicated for lower prevalence diseases. Our objective was to compare the potential population health benefits associated with specialty and traditional drugs in the year following product approval. METHODS: First, we created a dataset of estimates of incremental quality-adjusted life-year (QALY) gains and incremental life-year (LY) gains for US FDA-approved drugs (1999-2011) compared to standard of care at the time of approval identified from a literature search. Second, we categorized each drug as specialty or traditional. Third, for each drug we identified estimates of US disease prevalence for each pertinent indication. Fourth, in order to conservatively estimate the potential population health gains associated with each new drug in the year following its approval we multiplied the health gain estimate by 10% of the identified prevalence. Fifth, we used Mann-Whitney U tests to compare the population health gains for specialty and traditional drugs. RESULTS: We identified QALY gain estimates for 101 drugs, including 56 specialty drugs, and LY gain estimates for 50 drugs, including 34 specialty drugs. The median estimated population QALY gain in the year following approval for specialty drugs was 4200 (IQR = 27,000) and for traditional drugs was 694 (IQR = 24,400) (p = 0.245). The median estimated population LY gain in the year following approval for specialty drugs was 7250 (IQR = 39,200) and for traditional drugs was 2500 (IQR = 58,200) (p = 0.752). CONCLUSIONS: Despite often being indicated for diseases of lower prevalence, we found a trend towards specialty drugs offering larger potential population health gains than traditional drugs, particularly when measured in terms of QALYs.

The Decline in Vitamin Research Funding: A Missed Opportunity?

Background: The National Nutrition Research Roadmap has called for support of greater collaborative, interdisciplinary research for multiple areas of nutrition research. However, a substantial reduction in federal funding makes responding to these calls challenging. Objectives: The objectives of this study were to examine temporal trends in research funding and to discuss the potential consequences of these trends. Methods: We searched the NIH RePORTER database to identify NIH research grants and USASpending to identify National Science Foundation and USDA research grants awarded from 1992 to 2015. We focused on those that pertained to vitamin research. For the years 2000 to 2015, we examined funding trends for different vitamins, including vitamins A, B (one-carbon B-vitamins were considered separately from other B-vitamins), C, D, E, and K. Results: From 1992 to 2015, total federal research spending increased from ∼$14 to $45 billion (2016 US dollars). Although vitamin research spending increased from ∼$89 to $95 million, the proportion of grants awarded for vitamin research declined by more than two-thirds, from 0.65% in 1992 to 0.2% in 2015. Federal agencies awarded 6035 vitamin research grants over the time period, with vitamin A associated with the most research projects per year on average (n = 115) and vitamin K the fewest (n = 8). Vitamin D research projects were associated with the greatest average yearly project value ($34.8 million). Conclusions: Vitamin research has faced a disproportionate decline in research funding from 1992 to 2015. Insufficient federal research funding streams risk stalling progress in vitamin research and leaving important advancements unrealized.

Aversion learning can reduce meal size without taste avoidance in rats.

OBJECTIVE: Nausea and aversive food responses are commonly reported following bariatric surgery, along with post-surgical reduction in meal size. This study investigates whether a meal size limit can be conditioned by associating large meals with aversive outcomes. METHODS: In rats, the intake of meals exceeding a pre-defined size threshold was paired with lithium chloride-induced gastric illness, and the effects on self-determined food intakes and body weight were measured. RESULTS: Rats given LiCl contingent on the intake of a large meal learned to reliably reduce intake below this meal size threshold, while post-meal saline or LiCl before meals did not change meal size. It was further demonstrated that this is not a conditioned taste aversion and that this effect transferred to foods not explicitly trained. Finally, when rats received LiCl following all large meals, the number of small meals increased, but total food intake and body weight decreased. CONCLUSIONS: While further work is needed, this is the first demonstration that meal size may be conditioned, using an aversion procedure, to remain under a target threshold and that this effect is distinct from taste avoidance. Corresponding reduction in food intake and body weight suggests that this phenomenon may have implications for developing weight loss strategies and understanding the efficacy of bariatric surgery.

Despite high costs, specialty drugs may offer value for money comparable to that of traditional drugs.

Specialty drugs are often many times more expensive than traditional drugs, which raises questions of affordability and value. We compared the value of specialty and traditional drugs approved by the Food and Drug Administration (FDA) in the period 1999-2011. To do this, we identified published estimates of additional health gains (measured in quality-adjusted life-years, or QALYs) and increased costs of drug and health care resource use that were associated with fifty-eight specialty drugs and forty-four traditional drugs, compared to preexisting care. We found that specialty drugs offered greater QALY gains (0.183 versus 0.002 QALYs) but were associated with greater additional costs ($12,238 versus $784), compared to traditional drugs. The two types of drugs had comparable cost-effectiveness. However, the distributions across the two types differed, with 26 percent of specialty drugs--but only 9 percent of traditional drugs--associated with incremental cost-effectiveness ratios of greater than $150,000 per QALY. Our study suggests that although specialty drugs often have higher costs than traditional drugs, they also tend to confer greater benefits and hence may still offer reasonable value for money.

Efficiency of bacteriophage therapy against Cronobacter sakazakii in Galleria mellonella (greater wax moth) larvae.

Cronobacter sakazakii, an opportunistic pathogen found in milk-based powdered infant formulae, has been linked to meningitis in infants, with high fatality rates. A set of phages from various environments were purified and tested in vitro against strains of C. sakazakii. Based on host range and lytic activity, the T4-like phage vB_CsaM_GAP161, which belongs to the family Myoviridae, was selected for evaluation of its efficacy against C. sakazakii. Galleria mellonella larvae were used as a whole-animal model for pre-clinical testing of phage efficiency. Twenty-one Cronobacter strains were evaluated for lethality in G. mellonella larvae. Different strains of C. sakazakii caused 0 to 98% mortality. C. sakazakii 3253, with an LD50 dose of ~2.0×10(5) CFU/larva (24 h, 37 °C) was selected for this study. Larvae infected with a dose of 5×LD50 were treated with phage GAP161 (MOI=8) at various time intervals. The mortality rates were as high as 100% in the groups injected with bacteria only, compared to 16.6% in the group infected with bacteria and treated with phage. Phage GAP161 showed the best protective activity against C. sakazakii when the larvae were treated prior to or immediately after infection. The results obtained with heat-inactivated phage proved that the survival of the larvae is not due to host immune stimulation. These results suggest that phage GAP161 is potentially a useful control agent against C. sakazakii. In addition, G. mellonella may be a useful whole-animal model for pre-screening phages for efficacy and safety prior to clinical evaluation in mammalian models.

Cost-effectiveness in the contemporary management of critical limb ischemia with tissue loss.

BACKGROUND: The care of patients with critical limb ischemia (CLI) and tissue loss is notoriously challenging and expensive. We evaluated the cost-effectiveness of various management strategies to identify those that would optimize value to patients. METHODS: A probabilistic Markov model was used to create a detailed simulation of patient-oriented outcomes, including clinical events, wound healing, functional outcomes, and quality-adjusted life-years (QALYs) after various management strategies in a CLI patient cohort during a 10-year period. Direct and indirect cost estimates for these strategies were obtained using transition cost-accounting methodology. Incremental cost-effectiveness ratios (ICERs), in 2009 U.S. dollars per QALYs, were calculated compared with the most conservative management strategy of local wound care with amputation as needed. RESULTS: With an ICER of $47,735/QALY, an initial surgical bypass with subsequent endovascular revision(s) as needed was the most cost-effective alternative to local wound care alone. Endovascular-first management strategies achieved comparable clinical outcomes but at higher cost (ICERs ≥$101,702/QALY); however, endovascular management did become cost-effective when the initial foot wound closure rate was >37% or when procedural costs were decreased by >42%. Primary amputation was dominated (less effectiveness and more costly than wound care alone). CONCLUSIONS: Contemporary clinical effectiveness and cost estimates show an initial surgical bypass is the most cost-effective alternative to local wound care alone for CLI with tissue loss and can be supported even in a cost-averse health care environment.

The binding of curcumin to various types of canine amyloid proteins.

Curcumin is a constituent phenol compound of turmeric, and has been used as a dietary spice and Indian medicine. Curcumin has been reported to inhibit the formation of amyloid ß fibrils and aggregation. In this study, the binding activity of curcumin to various types of canine amyloid was examined. Tissue samples used were lesions of AA, AL, amyloid of canine amyloid-producing odontogenic tumor (Aapot), and senile cardiovascular amyloid (ScA). Curcumin stained all types of amyloid. The binding of curcumin to AA, ScA, and AL was lost by the KMnO(4) treatment, but Aapot maintained the binding. These findings indicate that curcumin binds several types of amyloid, while the binding sites of amyloid molecules might be different from that of Congo red.

The rise of Chinese military medicine: opportunity for mercy ship, not gunboat, diplomacy.

Recent exchanges between the United States and China at the presidential and cabinet level have emphasized the need for an enhanced military-to-military relationship to further mutual understanding and promote cooperation. This article explores the historic context of military medical relations between the two nations as well as the rationale and opportunities for increased interaction through medical diplomacy. Specific areas for potential collaboration are discussed with recommendations for future action.

Quantitative analysis of trace chromium in blood samples. Combination of the advanced oxidation process with catalytic adsorptive stripping voltammetry.

A new method for pretreating blood samples for trace Cr analysis is described. The advanced oxidation process (AOP with H2O2 and 5.5-W UV irradiation for 60 min) is used to remove biological/organic species for subsequent analysis. Prior to the AOP pretreatment, acid (HNO3) is used at pH 3.0 to inhibit the enzyme catalase in the blood samples. Catalytic adsorptive stripping voltammetry at a bismuth film electrode gives a Cr concentration of 6.0 +/- 0.3 ppb in the blood samples. This concentration was confirmed by dry-ashing the blood samples and subsequent analysis by atomic absorption spectroscopy. This current method may be used to monitor chromium, a trace metal in humans, and the efficacy and safety of chromium supplements as adjuvant therapy for diabetes.