To evaluate the Dutch newborn screening (NBS) for medium‐chain acyl‐CoA dehydrogenase (MCAD) deficiency since 2007, a nationwide retrospective, observational study was performed of clinical, ...laboratory and epidemiological parameters of patients with MCAD deficiency born between 2007 and 2015. Severe MCAD deficiency was defined by ACADM genotypes associated with clinical ascertainment, or variant ACADM genotypes with a residual MCAD enzyme activity <10%. Mild MCAD deficiency was defined by variant ACADM genotypes with a residual MCAD enzyme activity ≥10%. The prevalence of MCAD deficiency was 1/8300 (95% CI: 1/7300‐1/9600). Sensitivity of the Dutch NBS was 99% and specificity ~100%, with a positive predictive value of 86%. Thirteen newborns with MCAD deficiency suffered from neonatal symptoms, three of them died. Of the 189 identified neonates, 24% had mild MCAD deficiency. The acylcarnitine ratio octanoylcarnitine (C8)/decanoylcarnitine (C10) was superior to C8 in discriminating between mild and severe cases and more stable in the first days of life. NBS for MCAD deficiency has a high sensitivity, specificity, and positive predictive value. In the absence of a golden standard to confirm the diagnosis, the combination of acylcarnitine (ratios), molecular and enzymatic studies allows risk stratification. To improve evaluation of NBS protocols and clinical guidelines, additional use of acylcarnitine ratios and multivariate pattern‐recognition software may be reappraised in the Dutch situation. Prospective recording of NBS and follow‐up data is warranted covering the entire health care chain of preventive and curative medicine.
Spasticity is a medical problem with a high incidence that significantly impact on the quality of life of patients and their families.
To analyze and to answer different questions about the use of ...botulinum toxin type A (BTA) in our clinical practice.
A group of experts in neurology develop a list of topics related with the use of BTA. Two big groups were considered: spasticity in adults and in children with cerebral palsy. A literature search at PubMed for English, French, and Spanish language articles published up to June 2016 was performed. The manuscript was structured as a questionnaire that includes those questions that, according to the panel opinion, could generate more controversy or doubt. The initial draft was reviewed by the expert panel members to allow for modifications, and after subsequent revisions for achieving the highest degree of consensus, the final text was then validated. Different questions about diverse aspects of spasticity in adults, such as methods for evaluating spasticity, infiltration techniques, doses, number of infiltration points, etc. Regarding spasticity in children with cerebral palsy, the document included questions about minimum age of infiltration, methods of analgesia, etc.
This review is a tool for continuous training for neurologist and rehabilitation specialist and residents of both specialties, about different specific areas of the management of BTA.
Biomimetic calcium-deficient hydroxyapatite (CDHA) as a bioactive material exhibits exceptional intrinsic osteoinductive and osteogenic properties because of its nanostructure and composition, which ...promote a favorable microenvironment. Its high reactivity has been hypothesized to play a relevant role in the in vivo performance, mediated by the interaction with the biological fluids, which is amplified by its high specific surface area. Paradoxically, this high reactivity is also behind the in vitro cytotoxicity of this material, especially pronounced in static conditions. The present work explores the structural and physicochemical changes that CDHA undergoes in contact with physiological fluids and to investigate its interaction with proteins. Calcium-deficient hydroxyapatite discs with different micro/nanostructures, coarse (C) and fine (F), were exposed to cell-free complete culture medium over extended periods of time: 1, 7, 14, 21, 28, and 50 days. Precipitate formation was not observed in any of the materials in contact with the physiological fluid, which would indicate that the ionic exchanges were linked to incorporation into the crystal structure of CDHA or in the hydrated layer. In fact, CDHA experienced a maturation process, with a progressive increase in crystallinity and the Ca/P ratio, accompanied by an uptake of Mg and a B-type carbonation process, with a gradual propagation into the core of the samples. However, the reactivity of biomimetic hydroxyapatite was highly dependent on the specific surface area and was amplified in nanosized needle-like crystal structures (F), whereas in coarse specimens the ionic exchanges were restricted to the surface, with low penetration in the material bulk. In addition to showing a higher protein adsorption on F substrates, the proteomics study revealed the existence of protein selectivity toward F or C microstructures, as well as the capability of CDHA, and more remarkably of F-CDHA, to concentrate specific proteins from the culture medium. Finally, a substantial improvement in the material's ability to support cell proliferation was observed after the CDHA maturation process.
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Viticulture holdings of Mendoza Argentina, were classified by the allocation and the stratum size according to their total acreage based on the data of the last three National Agricultural Censuses ...(1988, 2002 and 2008). There are different behaviors in each stratum according to each growing zone. It has been observed that in all “oasis” smaller is the holding, higher is the rate of shrinkage. On the other hand the bigger sizes grow and the acreage concentration of these units has increased significantly. Behaviors were clustered according to their path: taking into account its relationship with both zonal and provincial level stratum averages. Areas like the Oasis Sur have suffered a major a regressive process that has involved almost all the strata. The Uco Valley has shown a significant dynamism in units of more than 25 ha, while the small holdings have moved back, but with lower rates than the average of these strata. The Oasis Norte has also been subject to a bipolar process where a significant loss of small vineyards with the rise of new big holdings. Oasis Este is the only one that remains with lower regression rates.
Abstract Introduction We report on our evaluation of the strain-promoted cyclooctyne-azide cycloaddition reaction for use in tumor pretargeting, comprising a side-by-side comparison of probes 1 – 3 ...bearing three distinct cyclooctyne moieties based respectively on the 1st and 2nd generation difluorinated cyclooctyne and the 1st generation dibenzocyclooctyne. Methods The probes were synthesized and labeled with177 Lu with high yields. The probe stability and reactivity towards azides were evaluated in PBS and mouse serum, and their blood clearance, biodistribution and in vivo reactivity were evaluated in tumor-free mice. Results In serum the three probes exhibited sufficient stability for a pretargeting application with half-lives of 12–19 h. In PBS, probes 2 and 3 were more reactive towards azido-conjugated Rituximab (Rtx-N3 ) than 1 , but in contrast to 1 , their reactivity decreased in mouse serum and mouse serum albumin solutions, as a result of covalent and non-covalent interactions with albumin. Biodistribution data confirmed the interactions with serum proteins in circulation:177 Lu- 1 showed a fast elimination from blood (t1/2,β = 0.31 h), while177 Lu- 2 and177 Lu- 3 were retained in blood for longer periods of time (t1/2,β = 1.08 and 3.58 h, respectively). Dual isotope biodistribution experiments assessing the reaction between125 I-Rtx-N3 and177 Lu- 1 – 3 in circulation in mice showed a very limited retention of 2 and 3 in blood rich organs, indicating a minimal reactivity, while no such retention was observed for 1. Conclusion The low reactivity of the studied cyclooctynes, and their serum interactions preclude their use at the low in vivo concentrations typical for pretargeting applications.
We applied voxel-based morphometry, an indirect volumetric technique, to MRI volumes of patients carrying the spinocerebellar ataxia type 2 mutation to determine patterns of brain atrophy. Nine ...patients were compared to 27 controls matched for age, sex and handedness. An optimised voxel-based morphometry protocol was used for pre-processing to minimize systematic bias. We observed significant volume loss in the cerebellar hemispheres, vermis, pons, mesencephalon and thalamus. Also affected were several supratentorial areas such as the right orbito-frontal cortex, right temporo-mesial cortex and the primary sensorimotor cortex bilaterally. The volumetric changes of cerebellar hemispheres were inversely correlated to cerebellar symptoms rated by a cerebellar ataxia scale. Two mechanisms could contribute to the observed cortical atrophy. It could be either the result of primary supratentorial degeneration as part of the disease process and/or secondary atrophy due to cerebellar deafferentation.
Introduction
P‐glycoprotein (P‐gp) is an efflux transporter responsible for the transport of various drugs across the blood‐brain barrier (BBB). Loss of P‐gp function with age may be one factor in ...the development and progression of neurodegenerative diseases. The aim of this study was to assess the effect of aging on BBB P‐gp function. Furthermore, the relationship between BBB P‐gp activity and peripheral P‐gp activity in CD3‐positive leukocytes was investigated. Finally, plasma pharmacokinetics of carbon 11–labeled (R)‐verapamil was evaluated.
Methods
(R)‐11Cverapamil and positron emission tomography were used to assess gray matter P‐gp function. Because (R)‐11Cverapamil is a substrate for P‐gp, the volume of distribution of (R)‐11Cverapamil in the brain inversely reflects P‐gp function in the BBB.
Results
Mean volume of distribution values for 5 young healthy volunteers (age range, 21–27 years) and 5 elderly healthy volunteers (age range, 59–68 years) were 0.62 ± 0.10 and 0.73 ± 0.07, respectively (P=.03). The activity index of P‐gp activity in CD3‐positive leukocytes was 2.88 ± 0.77 in young volunteers and 1.76 ± 0.58 in elderly volunteers (P=.02).
Conclusion
This study showed decreased P‐gp activity during aging. Consequently, the brain may be exposed to higher drug and toxin levels in elderly subjects.
Clinical Pharmacology & Therapeutics (2006) 79, 540–548; doi: 10.1016/j.clpt.2006.02.004
The main debate in the treatment of Phenylketonuria (PKU) is whether adult patients need the strict phenylalanine (Phe)-restricted diet. Physicians and patients lack evidence-based guidelines to help ...them make well-informed choices. We have carried out the first randomised double-blind placebo-controlled trial into the effects of short-term elevation of Phe levels on neuropsychological functions and mood of adults with PKU. Nine continuously treated adults with PKU underwent two 4-week supplementation periods: one with Phe, mimicking normal dietary intake, and one with placebo in randomly allocated order via a randomisation coding list in a double-blind cross-over design. A set of neuropsychological tests (Amsterdam Neuropsychological Tasks) was administered at the end of each study period. In addition, patients and for each patient a friend or relative, completed weekly Profile of Mood States (POMS) questionnaires, evaluating the patients' mood. Phe levels were measured twice weekly. Mean plasma Phe levels were significantly higher during Phe supplementation compared with placebo (p = 0.008). Neuropsychological tests demonstrated an impairment in sustained attention during Phe supplementation (p = 0.029). Both patients and their friend or relative reported lower scores on the POMS questionnaires during Phe supplementation (p = 0.017 and p = 0.040, respectively). High plasma Phe levels have a direct negative effect on both sustained attention and on mood in adult patients with PKU. A Phe-restricted “diet for life” might be an advisable option for many.
Class III pistil-specific extensin-like proteins (PELPIII) are specifically localized in the intercellular matrix of tobacco (Nicotiana tabacum) styles. After pollination the majority of PELPIII are ...translocated into the callosic layer and the callose plugs of the pollen tubes, which could suggest a function of PELPIII in pollen tube growth. PELPIII may represent one of the chemical and/or physical factors from the female sporophytic tissue that contributes to the difference between in vivo and in vitro pollen tube growth. PELPIII glycoproteins were purified and biochemically characterized. Because of their high proline (Pro) and hydroxy-Pro (Hyp) content, PELPIII proteins belong to the class of Pro/Hyp-rich glycoproteins. The carbohydrate moiety of PELPIII is attached through O-glycosidic linkages and comprises more than one-half the total glycoprotein. Deglycosylation of PELPIII revealed two backbones, both reacting with PELPIII-specific antibodies. N-terminal amino acid sequencing of these backbones showed that PELPIII is encoded by the MG14 and MG15 genes. Two heterogeneous N-terminal sequences of MG14 and MG15, both starting downstream of the predicted signal peptide cleavage site, seem to be present, which indicates a novel N-terminal processing. Monosaccharide analysis showed that the carbohydrate moiety of PELPIII almost completely consists of arabinose and galactose in an equal molar ratio. Carbohydrate linkage analysis showed terminal and 2-linked arabinofuranosyl residues, as well as terminal and 6-, 3-, and 3,6-linked galactopyranosyl residues to be present, indicating the presence of both extensin-like and Type II arabinogalactan oligosaccharide units. The ability of β-glucosyl Yariv reagent to bind with PELPIII confirmed the arabinogalactan protein-like characteristics of these proteins.
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