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A study was conducted to investigate the biochemistry of digestion of field pea (Pisum sativum L.) albumins and globulins in the stomach and along the small intestine of weaned piglets with a particular emphasis on the respective roles of these compartments in pea protein digestion. Twenty-four piglets were weaned at 28 d of age. They were allocated to 2 diets (control and pea) and 3 slaughter times (3, 6, or 9 h after the last meal) in a 2 x 3 factorial arrangement of treatments in a randomized complete block design. Pea flour provided 30% of total dietary protein in the pea diet. The diets were fed for 2 wk after weaning. After slaughter, gastrointestinal tract (GIT) compartments were weighed, digesta were collected, and pH was measured. Digesta from the stomach and cranial, middle, and caudal small intestine (SI) were extracted for soluble proteins and analyzed for specific pea proteins using SDS-PAGE, immunoblotting, and mass spectrometry. Tissue weight of the whole GIT (P = 0.015), cecum (P < 0.001), and colon (P < 0.001) was greater in the pea diet. Digesta pH in the stomach and caudal SI was lower (P = 0.02) in the pea diet than the control diet. In the stomach, vicilin, lectin, and pea albumin 2 were not digested, whereas legumin was only partly digested. Legumin and vicilin were totally digested in the SI in less than 3 h. A resistant peptide of 15 kDa located at the N-terminus of pea albumin 2 was transiently detected at 3 h. A protein band at 20 kDa was consistently identified as lectin. It was present in high intensity in intestinal digesta of pea-fed piglets at all times after the meal compared with those fed the control diet (P < 0.001). Various proteins of, presumably, endogenous origin displayed differential digestion patterns between the control and the pea-fed piglets (P <0.05). In conclusion, differences in digestion between specific pea proteins were observed along the GIT of piglets. They could be partly explained by differences in protein digestion in the stomach. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic human disease, but to date, only one therapy (tolvaptan) is approved to treat kidney cysts in ADPKD patients. Cyclin-dependent kinase 5 (CDK5), an atypical member of the cyclin-dependent kinase family, has been implicated as a target for treating ADPKD. However, no compounds have been disclosed to date that selectively inhibit CDK5 while sparing the broader CDK family members. Herein, we report the discovery of CDK5 inhibitors, including GFB-12811 , that are highly selective over the other tested kinases. In cellular assays, our compounds demonstrate CDK5 target engagement while avoiding anti-proliferative effects associated with inhibiting other CDKs. In addition, we show that the compounds in this series exhibit promising in vivo PK profiles, enabling their use as tool compounds for interrogating the role of CDK5 in ADPKD and other diseases.

By successive enzymatic and chemical modifications, novel fluorinated polyhydroxyalkanoates were synthesized and characterized. Unsaturated polyhydroxyalkanoate, PHAU, was first produced by fermentation using marine bacteria Pseudomonas raguenesii , and a graft copolymer PHAU- g -C 8 F 17 was further prepared by controlled thiol-ene reaction in the presence of perfluorodecanethiol (PFDT). The PFDT grafting is realized by two different processes. In the first method, PHAU was previously solubilized in toluene. The grafting in solution is more efficient than the direct heterogeneous grafting onto a PHAU film. The degrees of grafting were determined by 1 H NMR. The characterization of the microstructure by SEM-EDX and modulated and conventional DSC showed the formation of microdomains due to the organization of the hydrophobic segments of graft PFDT. Biomaterials prepared by 3D printing and coated by PHAU- g -C 8 F 17 have the potential to be used as novel contrast agents as shown by Hahn echo experiments.

Nanoparticles have recently emerged as valuable tools in biomedical imaging techniques. Here PEGylated and fluorinated nanocapsules based on poly(3-hydroxyalkanoate) containing a liquid core of perfluorooctyl bromide PFOB were formulated by an emulsion-evaporation process as potential 19 F MRI imaging agents. Unsaturated poly(hydroxyalkanoate), PHAU, was produced by marine bacteria using coprah oil and undecenoic acid as substrates. PHA-g-(F; PEG) was prepared by two successive controlled thiol-ene reactions from PHAU with firstly three fluorinated thiols having from 3 up to 17 fluorine atoms and secondly with PEG-SH. The resulting PHA-g-(F; PEG)-based PFOB nanocapsules, with a diameter close to 250-300 nm, are shown to be visible in 19 F MRI with an acquisition time of 15 min. The results showed that PFOB-nanocapsules based on PHA-g-(F; PEG) have the potential to be used as novel contrast agents for 19 F MRI.

Purpose: Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action of the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase inhibitors (TKIs), like lapatinib, may have added therapeutic value in combination with mAbs through enhanced ADCC activity. Using clinical data, we examined the impact of lapatinib on HER2/EGFR expression levels and natural killer (NK) cell gene signatures. We investigated the ability of three TKIs (lapatinib, afatinib, and neratinib) to alter HER2/immune-related protein levels in preclinical models of HER2-positive (HER2 + ) and HER2-low breast cancer, and the subsequent effects on trastuzumab/pertuzumab-mediated ADCC., Experimental Design: Preclinical studies (proliferation assays, Western blotting, high content analysis, and flow cytometry) employed HER2 + (SKBR3 and HCC1954) and HER2-low (MCF-7, T47D, CAMA-1, and CAL-51) breast cancer cell lines. NCT00524303 provided reverse phase protein array-determined protein levels of HER2/pHER2/EGFR/pEGFR. RNA-based NK cell gene signatures (CIBERSORT/MCP-counter) post-neoadjuvant anti-HER2 therapy were assessed (NCT00769470/NCT01485926). ADCC assays utilized flow cytometry-based protocols., Results: Lapatinib significantly increased membrane HER2 levels, while afatinib and neratinib significantly decreased levels in all preclinical models. Single-agent lapatinib increased HER2 or EGFR levels in 10 of 11 (91%) tumor samples. NK cell signatures increased posttherapy ( P = 0.03) and associated with trastuzumab response ( P = 0.01). TKI treatment altered mAb-induced NK cell-mediated ADCC in vitro , but it did not consistently correlate with HER2 expression in HER2 + or HER2-low models. The ADCC response to trastuzumab and pertuzumab combined did not exceed either mAb alone., Conclusions: TKIs differentially alter tumor cell phenotype which can impact NK cell-mediated response to coadministered antibody therapies. mAb-induced ADCC response is relevant when rationalizing combinations for clinical investigation., (©2020 American Association for Cancer Research.)

Traditional transmissive polarimetric methods can be used for wavelengths above 123 nm where birefringent materials transmit light and create significant birefringence. Below 123 nm, no suitable solution is known to measure the four Stokes parameters on a large wavelength range. Therefore, we study here an innovative reflective (rather than transmissive) polarimeter working in the far ultraviolet (FUV) range from 90 to 130 nm. We take advantage of the phase shift created by reflections as well as the different reflectivities for p (orthogonal ⊥ ) and s (parallel ∥ to the plane of incidence) polarizations to design an FUV polarimeter. Simulation of the analyzer and modulator using Mueller matrices coupled to polarimetric efficiencies calculations allowed optimization of reflective polarimeters for the first time, to the best of our knowledge. This opens up a new perspective for FUV polarimetry below 123 nm.

The nonselective Ca 2+ -permeable transient receptor potential (TRP) channels play important roles in diverse cellular processes, including actin remodeling and cell migration. TRP channel subfamily C, member 5 (TRPC5) helps regulate a tight balance of cytoskeletal dynamics in podocytes and is suggested to be involved in the pathogenesis of proteinuric kidney diseases, such as focal segmental glomerulosclerosis (FSGS). As such, protection of podocytes by inhibition of TRPC5 mediated Ca 2+ signaling may provide a novel therapeutic approach for the treatment of proteinuric kidney diseases. Herein, we describe the identification of a novel TRPC5 inhibitor,  GFB-8438 , by systematic optimization of a high-throughput screening hit, pyridazinone 1 . GFB-8438 protects mouse podocytes from injury induced by protamine sulfate (PS) in vitro . It is also efficacious in a hypertensive deoxycorticosterone acetate (DOCA)-salt rat model of FSGS, significantly reducing both total protein and albumin concentrations in urine., Competing Interests: The authors declare the following competing financial interest(s): M.Y., M.W.L., M.D., G.M., T.T.T., M.C-L.G., X-R.P-Z., A.W.-B., M.B., J.F.R., P.M., and J.-C.H. are current or past employees of Goldfinch Bio Inc., (Copyright © 2019 American Chemical Society.)

Background: With Nordic walking, or walking with poles, one can travel a greater distance and at a higher rate than with walking without poles, but whether the activity is beneficial for patients with cardiovascular disease is unknown., Objective: This randomized controlled trial was undertaken to determine whether Nordic walking was more effective than walking without poles on walk distance to support rehabilitation training for patients with acute coronary syndrome (ACS) and peripheral arterial occlusive disease (PAOD)., Methods: Patients were recruited in a private specialized rehabilitation centre for cardiovascular diseases. The entire protocol, including patient recruitment, took place over 2 months, from September to October 2013. We divided patients into 2 groups: Nordic Walking Group (NWG, n=21) and Walking Group without poles (WG, n=21). All patients followed the same program over 4 weeks, except for the walk performed with or without poles. The main outcome was walk distance on the 6-min walk test. Secondary outcomes were maximum heart rate during exercise and walk distance and power output on a treadmill stress test., Results: We included 42 patients (35 men; mean age 57.2±11 years and BMI 26.5±4.5kg/m 2 ). At the end of the training period, both groups showed improved walk distance on the 6-min walk test and treatment stress test as well as power on the treadmill stress test (P<0.05). The NWG showed significantly greater walk distance than the WG (P<0.05). Both ACS and PAOD groups showed improvement, but improvement was significant for only PAOD patients., Conclusions: After a 4-week training period, Nordic walking training appeared more efficient than training without poles for increasing walk distance on the 6-min walk test for patients with ACS and PAOD., (Copyright © 2017. Published by Elsevier Masson SAS.)

Context: The multidimensional nature of the fibromyalgia syndrome means that different instruments need to be used to assess the patients' perception of this constellation of physical and psychological symptoms and their impact on their daily lives. Six questionnaires (Multidimensional Fatigue Inventory MFI, Fibromyalgia Impact Questionnaire FIQ, Multiple Ability Self-report Questionnaire MASQ, State-Trait Anxiety Inventory STAI, Beck Depression Inventory-II BDI-II and Patient Global Impression of Change PGIC) were linguistically validated into 12 languages., Methods: The standardized cross-cultural adaptation process includes the following steps: forward translation, backward translation, and review of the version by a clinician and comprehension tests on subjects in the target country., Results: Regardless of the instruments and dimensions studied, the same translation and cultural adaptation issues arose: (1) an issue that is strictly related to translation, for example, the word "things" was translated as "something"; (2) literal translation is possible but culturally irrelevant, for example the expression "to walk several blocks", which is a completely abstract concept in Europe, was translated as "to walk for more than one kilometre"; (3) the translation needed to be reformulated or the tense needed to be changed for idiomatic reasons. For example, the present perfect does not exist in German and so the present simple was used in the first version. The imperfect was eventually used with adverbs such as "lately"., Conclusions: Linguistic adaptation was completed according to a recognized and rigorous method allowing for the wide-scale use of these patient-reported outcomes instruments in international studies., (Copyright 2010 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Background: Guidelines for allergic rhinitis are more effective than free-treatment choice in the control of seasonal allergic rhinitis., Objective: To validate the ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines in the treatment of intermittent and persistent allergic rhinitis induced by pollens., Design: A multicenter, open-label, parallel, pragmatic randomized study compared two therapeutic strategies during a 2-week treatment course. In the first strategy ('guidelines group'), 417 patients were treated according to ARIA with ebastine as oral antihistamine. In the second strategy ('free-choice treatment group'), investigators had a free choice for the treatment of 422 patients., Main Outcome Measures: Quality of life measured using the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), work productivity and daily symptom medication scores., Results: 94.2% patients returned the baseline visit questionnaires and 88.6% returned the posttreatment period questionnaires. RQLQ scores were similar in the two groups at baseline. After treatment, there were improvements in the overall score and in all domains in both treatment groups. According to pragmatic methodology, the improvements show that the guidelines group (-1.70 +/- 1.20) is more effective than the free-choice treatment group (-1.52 +/- 1.22) with a gamma risk of 2%. Individual RQLQ scores, work productivity, and daily symptom scores were significantly improved in the guidelines group by comparison to the free-choice treatment group., Conclusion: A treatment based on ARIA guidelines offers patients a significant improvement in comparison to the use of a nonstandardized treatment regimen., (Copyright 2009 S. Karger AG, Basel.)

Background: Allergic rhinitis is a disease impairing quality of life, sleep, and work. A new classification for allergic rhinitis, Allergic Rhinitis and its Impact on Asthma (ARIA), has recently been proposed., Objective: To study the effect of allergic rhinitis using ARIA definitions to determine severity and duration., Methods: A total of 3052 patients consulting general practitioners for allergic rhinitis were studied. Patients were classified according to the 4 classes of ARIA. In all patients, quality of life (Rhinoconjunctivitis Quality-of-Life Questionnaire), sleep (Jenkins questionnaire), and work performance (Allergy-Specific Work Productivity and Activity Impairment questionnaire) were assessed., Results: Mild intermittent rhinitis was diagnosed in 11% of the patients, mild persistent rhinitis in 8%, moderate/severe intermittent rhinitis in 35%, and moderate/severe persistent rhinitis in 46%. The severity of rhinitis has more of an effect on quality of life, sleep, daily activities, and work performance than the duration of rhinitis. In moderate/severe rhinitis, more than 80% of patients report impaired activities, as opposed to only 40% with mild rhinitis., Conclusion: It seems that the term moderate/severe should be replaced by severe. A study in the general population is necessary, however, to assess the prevalence of the 4 ARIA classes of allergic rhinitis, especially in patients who are not consulting physicians for their symptoms.

A prospective multicentre study involving 219 patients with seasonal or aperiodic rhinitis was performed to assess the acceptability of a local treatment combining antihistamine (azelastine) and corticoid (beclomethasone) drugs. The drugs were administered either together (morning and evening, with a 5-minute interval) or separately (azelastine in the morning and evening, and beclomethasone later during the morning and in the afternoon) for 15 days. Treatment acceptability was measured by a nine-fold questionnaire (7-point scale, mean score per question). Patient participation, protocol and therapy compliance, and treatment efficacy and tolerance were also studied. The acceptability of the association was satisfactory (mean score for general facility of treatment: 4.7/6) and did not differ between administration schedules. Patients found treatment easy, and were not bothered by the bulk of the bottles or the risk of mixing them up. This acceptability was confirmed by the low percentage (4%) of patients refusing to be included in the study (refusing any treatment by nasal spray). The general acceptability was confirmed by the results for therapy compliance, general efficacy and tolerance: 94.9% of the patients took more than 75% of the administrations prescribed, 77.6% of the patients and 85.2% of the practitioners judged treatment efficacy as good or excellent, and 84.6% of the patients and 91.4% of the practitioners judged tolerance as good or excellent. Moreover, most of the adverse events consisted of minor signs of local intolerance, and were identical to those observed when the two treatments were administered alone.

From January 1981 to December 1995, 8,421 patients having a mammographic opacity corresponding to breast cancer were examined. The opacities were divided into two groups: zones of increased density (ZID), (1,449 patients), and a reference group comprising all other types of opacities (6,972 patients). Mammograms were reviewed retrospectively, as well as clinical, histological and biological parameters in both groups. Diagnosis of ZID was often difficult, sometime's guided by the presence of microcalcifications, which were more frequent. Sonography and direct mammographic magnification proved to be particularly helpful for a correct diagnosis. Most prognostic factors were poorer in ZID as compared to the reference group. The 5 year survival rate was 78% (84% for the reference group). Breast cancer that appears on mammograms as a ZID is often more difficult to diagnose and factors of poor prognosis are more often observed than in breast cancer with other types of opacities. To improve their detection sonography and direct mammographic magnification can be very helpful.

Objective: Our goal was to evaluate dynamic contrast-enhanced subtraction MRI in the diagnosis of isolated clustered calcifications of the breast., Materials and Methods: One hundred seventy-two patients underwent surgical biopsy for isolated clustered breast calcifications. Their mammograms showed round (n = 88) or linear/irregular (n = 84) microcalcifications. All patients had a preoperative Gd-DOTA-enhanced subtraction dynamic study. Any early contrast enhancement in the breast parenchyma concomitant with early enhancement of normal vessels was considered positive., Results: Fifty-eight in situ carcinomas, 22 invasive carcinomas, and 92 benign lesions were found at histological analysis. Dynamic MR sequences showed early contrast enhancement in 76 of 80 malignant lesions (sensitivity 95%) and in 45 of 92 benign lesions (specificity 51%). Two invasive and two intraductal carcinomas did not show early contrast enhancement. Three independent observers agreed in rating early contrast enhancement in 143 of 172 lesions., Conclusion: Poor specificity limits the diagnostic accuracy of dynamic contrast-enhanced subtraction MRI in distinguishing benign from malignant microcalcifications on mammography.

In December 1993, AFEDA conducted an epidemiological survey in order to establish the prevalence of ragweed-induced pollinosis and to evaluate how well the public was informed about this danger. A survey by telephone was made, taking a random sample of the population drawn by lot from telephone directories in the Rhône district. This involved about 300,000 homes. Those in which at least one person was under 50 were questioned. The questionnaire included a section aimed at everyone, and another section aimed at homes where at least one person suffered from pollinosis in August and/or September, in Lyon. 1,800 homes were selected at random, 905 persons responded: 22.4% were off target, 77.6% matched up to the chosen target. Of these, 32.9% were aware of Ragweed and 31.9% knew of the dangers. The 702 homes targeted made a total of 2,060 persons, 59.6% of which live in town and 40.4% in suburban areas; 51.6% are women and 48.4% men. 53 people, i.e. 2.57%, presented at least one of the following symptoms in 1993: rhinitis 86.8%, conjunctivitis 69.8%, itching of the pharynx and/or ears 47.2%, tracheitis and/or asthma 41.5%. 77.4% received medication. In 1993, the prevalence of ragweed-induced symptoms is a certainty for 1.8% of the population, if we evaluate only those patients presenting these symptoms every year. This prevalence therefore does not take account of new cases nor of newcomers to the district. Moreover, we have probably under-estimated this prevalence, owing to the torrential rain that fell in Lyon in late August 1993. This made a break in the pollen curve, a phenomenon that has never yet been observed in 13 years of recording pollen calendars.

The authors reviewed the accuracy of stereotaxic fine-needle aspiration cytology. Two hundred-twenty-eight lesions were studied: 103 benign lesions, 125 cancers. Inadequate sample was obtained in 26% of cases. None of the cytology reports were false-positive, whereas 77% of the suspect cytologic reports were malignant on histology. In strongly suspicious lesions at mammography, the decision to perform surgical biopsy should not be postponed as false negative cytologic findings (7 cases) are possible. In patients with a low suspicious lesion, cytology found six cancers. The benign-to-malignant ratio of excisional biopsies of non palpables lesions should be reduced by stereotaxic fine-needle aspiration cytology.

Objective: Our purpose was to demonstrate the clinical efficacy and effect of hormone replacement therapy in menopause on quality of life., Study Design: A randomized, open, 6-month comparison of hormone replacement therapy (estradiol transdermal system [Estraderm TTS] plus chlormadinone) and symptomatic treatment (verapipride) was performed. Analysis was by intention to treat., Results: In 499 postmenopausal women with moderate and severe symptoms enrolled by 101 physicians, hormone replacement therapy was superior to symptomatic treatment on all assessments of quality of life and clinical efficacy. The effects were independent of the incidence of hot flushes., Conclusion: The effect of hormone replacement therapy on the quality of life of postmenopausal women was significantly superior to symptomatic treatment.

A prospective study was designed to assess the quality of skin analgesia provided by the EMLA anaesthetic cream, an eutectic mixture of local anaesthetics (prilocaine and lidocaine). The children, aged 3 months to 15 years, and scheduled for genital and urinary surgery, were allocated to two groups, those aged less than or equal to 5 years (35 +/- 14 months, n = 17), and those aged greater than 5 years (97 +/- 26 months, n = 22). The cream (1.6 +/- 0.6 g) was applied by a nurse in the ward as a thick layer on the area of skin to be anaesthetised (on the dorsum of the hand and at the elbow), and covered by a closed adhesive dressing. This required 2.6 +/- 1.7 min, and was considered to be very easy (72%) or easy (28%). The venepuncture (22 or 20 gauge catheter) was carried out by one of the seven anaesthetists of the paediatric surgical units, 92 +/- 51 min after the cream had been applied. The children aged less than or equal to 5 years complained of pain of intensity 7.5 +/- 2.2 (CHEOPS scale, range 4 to 13) and, for those aged greater than 5 years, 24 +/- 21 on a visual analogic scale (range 0 to 100). Local adverse effects occurred in ten patients (skin paleness, erythema, or both). It was concluded that EMLA cream provides convenient analgesia for venepuncture in toddlers and children.

The advantage of EMLA cream for regional blocks (spinal or caudal blocks) was assessed in 46 children. The study included three groups: group 1, with 1 to 6 month-old children (n = 11); group 2, with children aged between 6 months and 5 years (n = 21), scheduled for emergency surgery and with full stomach; group 3, with 5 to 10 year-old children (n = 14), who were to have a regional block as an alternative to general anaesthesia. The cream was applied as a thick layer on the area of skin to be anaesthetised and covered by a closed adhesive dressing, approximately 2.2 h before performing the regional block. A dose of 1 to 2 g was used in children of more than 1 year, and 0.5 to 1 g for those of less than 1 year. All the blocks were carried out by the same anaesthetist. The technique was considered as being little (45/46) or not constraining (1/46). Patient cooperation in carrying out the regional block was judged to be good or very good in 34/46 children. Additional sedation was required in 7 children of groups 2 and 3. The block was as easy to carry out as usual in 37/46 children. In all three groups, most children complained of little or no pain. Local adverse effects occurred in 19/46 patients, consisting of erythema (14), skin paleness (4), or both (1). The investigator qualified the use of EMLA cream as satisfactory or very satisfactory in 36/46. It is concluded that EMLA cream provides convenient analgesia for regional blocks in toddlers and children.