Sodium citrate supplementation: An updated revision and practical recommendations on exercise performance, hydration status, and potential risks

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The Importance of Stereochemically Active Lone Pairs For Influencing Pb II and As III Protein Binding

The toxicity of heavy metals, which is associated with the high affinity of the metals for thiolate rich proteins, constitutes a problem worldwide. However, despite this tremendous toxicity concern, the binding mode of As III and Pb II to proteins is poorly understood. To clarify the requirements for toxic metal binding to metalloregulatory sensor proteins such as As III in ArsR/ArsD and Pb II in PbrR or replacing Zn II in δ‐aminolevulinc acid dehydratase (ALAD), we have employed computational and experimental methods examining the binding of these heavy metals to designed peptide models. The computational results show that the mode of coordination of As III and Pb II is greatly influenced by the steric bulk within the second coordination environment of the metal. The proposed basis of this selectivity is the large size of the ion and, most important, the influence of the stereochemically active lone pair in hemidirected complexes of the metal ion as being crucial. The experimental data show that switching a bulky leucine layer above the metal binding site by a smaller alanine residue enhances the Pb II  binding affinity by a factor of five, thus supporting experimentally the hypothesis of lone pair steric hindrance. These complementary approaches demonstrate the potential importance of a stereochemically active lone pair as a metal recognition mode in proteins and, specifically, how the second coordination sphere environment affects the affinity and selectivity of protein targets by certain toxic ions. Experimental and computational methods have been employed to study the influence of the lone pair of As III and Pb II for the binding of these ions in proteins using designed peptide models. The results show that the mode of coordination of As III and Pb II is greatly influenced by the steric bulk within the second coordination environment of the metals (see figure).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90414/1/chem_201102786_sm_miscellaneous_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/90414/2/2040_ftp.pd

Anderson-Fabry disease: a multiorgan disease.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A . FD causes glycolipids, such as globotriaosylceramide (Gb3), to accumulate in the vascular endothelium of several organs (fig.2), including the skin, kidneys, nervous system, and heart, thereby triggering inflammation and fibrosis . These processes generally result in organ dysfunction, which is usually the first clinical evidence of FD. Patients with classic FD have various symptoms, eg, acroparesthesias, hypohidrosis, angiokeratomas, corneal opacities, cerebrovascular lesions, cardiac disorders, andrenal dysfunction.However, evolving knowledge about the natural course of disease suggests that it is more appropriate to describe FD as a disease with a wide spectrum of heterogeneously progressive clinical phenotypes. Indeed, most female heterozygotes develop symptoms due to yet undetermined mechanisms and a high percentage of females develops vital organ involvement including the kidneys, heart and/or brain about a decade later than males . Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect early lesions in the kidney. The principal clinical manifestationsin Fabry disease consist of artery associated complications (such as cerebral disease and nephropathy), but the pathophysiology of this specific vasculopathy is unclear. Several studies indicate that the specific vascular lesions that are present in Fabry disease occur as a result of vascular dysfunction with major components being endothelial dysfunction, alterations in cerebral perfusion and a pro-thrombotic phenotype. Fabry cardiac involvement has several clinical manifestations (table 10): concentric left ventricular hypertrophy without left ventricular dilation and severe loss of left ventricular systolic function, mitral and aortic valvulopathy, disorders of the atrioventricular conduction or repolarization, and compromised diastolic function. The neurological manifestations of Fabry disease include both peripheral nervous system and CNS involvement, with globotriaosylceramide accumulation found in Schwann cells and dorsal root ganglia together with deposits in CNS neurones. The main involvement of the CNS is attributable to cerebrovasculopathy, with an increased incidence of stroke. The abnormal neuronal accumulation of glycosphingolipid appears to have little clinical effect on the natural history of Fabry disease, with the possible exception of some reported mild cognitive abnormalities. The pathogenesis of Fabry vasculopathy remains poorly understood, but probably relates, in part, to abnormal functional control of the vessels, secondary to endothelial dysfunction as a consequence of α-galactosidase A deficiency. The diagnosis of Fabry disease is made in hemizygous males after the detection of the presence of angiokeratomas (fig 19 A, B), irregularities in sweating, edema, scant body hair, painful sensations, and of cardiovascular, gastrointestinal, renal, ophthalmologic, phlebologic, and respiratory involvement. A deficiency of alpha-gal A in serum, leukocytes, tears, tissue specimens, or cultured skin fibroblasts further supports the diagnosis in male patients. Since heterozygous women show angiokeratomas in only about 30% of cases and may have alpha-gal A levels within normal range, genetic analysis is recommended. The resultant storage of undegraded glycolipids leads to the progressive development of potentially life-threatening manifestations affecting multiple organ systems in the body. The Mainz Severity Score Index (MSSI) (table 12), a scoring system for patients with Fabry disease has been proven to be representative in patients with 'classic' Fabry disease and may be useful for monitoring clinical improvement in patients receiving enzyme replacement therapy. The MSSI of patients with AFD was significantly higher than that of patients with other severe debilitating diseases

Effect of muscular exercise on patients with muscular dystrophy: A systematic review and meta-analysis of the literature

Background: Muscular dystrophy causes weakness and muscle loss. The effect of muscular exercise in these patients remains controversial. Objective: To assess the effects of muscular exercise vs. no exercise in patients with muscular dystrophy. Methods: We performed a comprehensive systematic literature search in the Medline, Embase, Web of Science, Scopus, and Pedro electronic databases, as well as in the reference literature. We included randomized clinical trials (RCTs) that reported the effect of muscular exercise on muscle strength, endurance during walking, motor abilities, and fatigue. Data were extracted independently by two reviewers. Mean difference (MD) and 95% confidence intervals (CI) were used to quantify the effect associated with each outcome. We performed pairwise meta-analyses and trial sequential analyses (TSA) and used GRADE to rate the overall certainty of evidence. Results: We identified 13 RCTs involving 617 patients. The median duration of exercise interventions was 16 weeks [interquartile range [IQR] 12-24]. In the patients with facio-scapulo-humeral dystrophy and myotonic dystrophy, no significant difference in extensor muscle strength was noted between the exercise and the control groups [four studies, 115 patients, MD 4.34, 95% CI -4.20 to 12.88, I2 = 69%; p = 0.32; minimal important difference [MID] 5.39 m]. Exercise was associated with improved endurance during walking [five studies, 380 patients, MD 17.36 m, 95% CI 10.91-23.81, I2 = 0; p < 0.00001; MID 34 m]. TSA excluded random error as a cause of the findings for endurance during walking. Differences in fatigue and motor abilities were small. Not enough information was found for other types of dystrophy. Conclusions: Muscular exercise did not improve muscle strength and was associated with modest improvements in endurance during walking in patients with facio-scapulo-humeral and myotonic dystrophy. Future trials should explore which type of muscle exercise could lead to better improvements in muscle strength. PROSPERO: CRD42019127456

Inflammation in ischemic stroke subtypes.

Determining the cause of stroke does influence choices for management. categorization of subtypes of ischemic stroke has had considerable study, but definitions are hard to formulate and their application for diagnosis in an individual patient is often problematic. Cerebral ischemia initiates a complex cascade of events at genomic, molecular, and cellular levels, and inflammation is important in this cascade. In 1993 for For the Trial of Org 10172 in Acute Stroke Treatment (TOAST), Adams et al] conducted a placebo-controlled, randomized, blinded study of the low-molecular-weight heparinoid given to patients within 24 hours after stroke and developed a system for diagnosis of subtype of ischemic stroke that uses components of existing diagnostic schemes. The type of acute ischemic stroke was classified according to the TOAST classification: 1) Large Artery AtheroSclerosis (LAAS); 2) CardioEmbolic Infarct (CEI); 3) LACunar infarct (LAC); 4) stroke of Other Determined Etiology (ODE); 5) stroke of UnDetermined Etiology (UDE) (see Fig. (1)). On the basis of pathophysiologic differences of each stroke subtype it's possible to hypothesize a different pattern of immuno-inflammatory activation in relation of ischemic stroke subtype. A nonspecific systemic inflammatory response occurs after both ischemic and hemorrhagic stroke, either as part of the process of brain damage or in response to complications such as deep venous thrombosis. Several studies have reported that higher levels of inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) are associated with worse outcome after ischemic stroke. Our group reported that patients with cardioembolic subtype showed significantly higher median plasma levels of TNF-α, IL-6, IL-1β whereas the lacunar subtype showed significantly lower median plasma levels of TNF-α, IL-6 and IL-1β. Our findings underlined the significant association was noted between the severity of neurological deficit at admission, the diagnostic subtype and some inflammatory variable

The relationship between emotional regulation and eating behaviour: a multidimensional analysis of obesity psychopathology

The aim of this study is to show that the differences among eating behaviours are related to the emotional dysregulation connected to the mental dimensions being part of the obese psychopathology. Eating behaviours can be considered a diagnostic feature at the initial screening for determining the obesity treatment: nutritional or bariatric surgery

The psychophysical impact that COVID-19 has on children must not be underestimated

Italy has been one of the European countries that has been most affected by the COVID\u201019 pandemic. By 16 April 2020, 159,107 Italian residents had tested positive for COVID\u201019 and these included 1,123 children, up to nine years of age (0.7%) and 1,804 adolescents, aged between 10 and 19 years old (1.1%) (1). These data were in line with the case studies reported for the Chinese population, where the respective percentage (proportion) was 0.9% and 1.2% respectively (2). A five\u2010year\u2010old Italian child, who had been affected by many previous and unspecified pathologies, died after testing positive for COVID\u201019 infection (1). The lower vulnerability of the paediatric population to COVID\u201019 seems eviden

Gastric cancer is the leading cause of death in Italian adult patients with common variable immunodeficiency

An increased prevalence of malignant lymphoma and of gastric cancer has been observed in large cohorts of patients with common variable immunodeficiency (CVID), the most frequently symptomatic primary immunodeficiency. Surveillance strategies for cancers in CVID should be defined based on epidemiological data. Risks and mortality for cancers among 455 Italian patients with CVID were compared to cancer incidence data from the Italian Cancer Registry database. CVID patients showed an increased cancer incidence for all sites combined (Obs = 133, SIR = 2.4; 95%CI = 1.7\u20133.5), due to an excess of non-Hodgkin lymphoma (Obs = 33, SIR = 14.3; 95%CI = 8.4\u201322.6) and of gastric cancer (Obs = 25; SIR = 6.4; 95%CI = 3.2\u201312.5). CVID patients with gastric cancer and lymphoma had a worse survival in comparison to cancer-free CVID (HR: 4.8, 95%CI: 4.2\u201344.4 and HR: 4.2, 95%CI: 2.8\u201344.4). Similar to what observed in other series, CVID-associated lymphomas were more likely to be of B cell origin and often occurred at extra-nodal sites. We collected the largest case-series of gastric cancers in CVID subjects. In contrast to other reports, gastric cancer was the leading cause of death in CVID. Standardized mortality ratio indicated a 10.1-fold excess mortality among CVID patients with gastric cancer. CVID developed gastric cancer 15 years earlier than the normative population, but they had a similar overall survival. Only CVID diagnosed at early stage gastric cancer survived >24 months. Stomach histology from upper endoscopy performed before cancer onset showed areas of atrophic gastritis, intestinal metaplasia or dysplasia. CVID patients might progress rapidly to an advanced cancer stage as shown by patients developing a III-IV stage gastric cancer within 1 year from an endoscopy without signs of dysplasia. Based on high rate of mortality due to gastric cancer in Italian CVID patients, we hereby suggest a strategy aimed at early diagnosis, based on regular upper endoscopy and on Helicobacter pylori infection treatment, recommending an implementation of national guidelines

Mechanistic Analysis of Nucleophilic Substrates Oxidation by Functional Models of Vanadium-Dependent Haloperoxidases: A Density Functional Theory Study

Density functional theory has been used to investigate the structural, electronic, and reactivity properties of an established functional model for vanadium-dependent haloperoxidases, K[VO(O 2 )Hheida] (Hheida 2– = 2,2′-[(2-hydroxyethyl)imino]diacetate). Possible solution species were determined on the basis of potential exogenous donors present under the conditions necessary for reactivity. The energetically favored solution-state species is a 1:1 complex of Hheida and vanadium with a coordinated hydroxyethyl donor trans to the vanadium–oxido bond which is in agreement with the reported solid-state structure for K[VO(O 2 )Hheida]. Transition states of the oxidation reaction were located for four substrates: chloride, bromide, iodide, and dimethyl sulfide. The role of protonation and its effects on reactivity were examined for each substrate. Protonation of the peroxido moiety leads to a significant drop in the activation barrier for oxidation. In contrast no transition states could be located for an oxido-transfer process involving the oxido ligand. Barriers of activation calculated for halide oxidation were similar, providing support to the hypothesis that the p K a of the halide in acetonitrile is responsible for the decrease in reactivity between I – , Br – , and Cl – . The results presented herein provide a mechanistic correlation between a functional model and the enzyme, making K[VO(O 2 )Hheida] a “complete” functional model for vanadium-dependent haloperoxidase.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55972/1/515_ftp.pd

Neurological complications of Anderson-Fabry disease

Characteristic clinical manifestations of AFD such as acroparesthesias, angiokeratoma, corneal opacity, hypo/ and anhidrosis, gastrointestinal symptoms, renal and cardiac dysfunctions can occur in male and female patients, although heterozygous females with AFD usually seems to be less severely affected. The most prominent CNS manifestations consist of cerebrovascular events such as transient ischaemic attacks (TIAs) and (recurrent) strokes . For the most part, CNS complications in AFD have been attributed to cerebral vasculopathy, including anatomical abnormalities. The natural history of Fabry patients includes transitory cerebral ischaemia and strokes, even in very young persons of both genders. The mechanism is partly due to vascular endothelial accumulation of Gb-3. White matter lesions (WML) on MRI occur. Both males and females can be safely treated with enzyme replacement; and thus screening for Fabry disease of young stroke populations should be considered. There are, however, no hard data of treatment effect on mortality and morbidity. Stroke in Anderson-Fabry disease study of 721 patients with cryptogenic stroke, aged 18-55 years, showed a high prevalence of Fabry disease in this group: 5% (21/432) of men and 3% (7/289) of women. Combining results for both sexes showed that 4% of young patients with stroke of previously unknown cause had Fabry disease, corresponding to about 1-2% of the general population of young stroke patients. Cerebral micro- and macro-vasculopathy have been described in Fabry disease. Neuronal globotriaosylceramide accumulation in selective cortical and brain stem areas including the hippocampus has been reported by autopsy studies in FD, but clinical surrogates as well as the clinical relevance of these findings have not been investigated so far. Another Neurologic hallmarks of Fabry disease (FD) include small fiber neuropathy as well as cerebral micro- and macroangiopathy with premature stroke. Cranial MRI shows progressive white matter lesions (WML) at an early age, increased signal intensity in the pulvinar, and tortuosity and dilatation of the larger vessels. Conventional MRI shows a progressive load of white matter lesions (WMLs) due to cerebral vasculopathy in the course of FD. Another study has been conducted to quantify brain structural changes in clinically affected male and female patients with FD. The peripheral neuropathy in Fabry disease manifests as neuropathic pain, reduced cold and warm sensation and possibly gastrointestinal disturbances. Patients with Fabry disease begin having pain towards the end of the first decade of life or during puberty. Children as young as 6 years of age have complained of pain often associated with febrile illnesses with reduced heat and exercise tolerance. The patients describe the pain as burning that is often associated with deep ache or paresthesiae. Some patients also have joint pain. A high proportion of patients with Fabry disease is at increased risk of developing neuropsychiatric symptoms, such as depression and neuropsychological deficits. Due to both somatic and psychological impairment, health-related quality of life (QoL) is considerably reduced in patients with Fabry disease. Targeted screening for Fabry disease among young individuals with stroke seems to disclose unrecognized cases and may therefore very well be recommended as routine in the future. Furthermore, ischemic stroke is related to inflammation and arterial stiffness [and no study had addressed this relationship in patients with AF disease and cerebrovascular disease, so this topic could represent a possible future research line