Effect of the lipopolysaccharide antagonist Planktothrix sp. FP1 cyanobacterial extract on human polymorphonuclear leukocytes

CyP is a lipopolysaccharide (LPS)-like molecule extracted from the freshwater cyanobacterium Oscillatoria planktothrix FP1, which has been reported to be a potent competitive inhibitor of bacterial LPS. In the present study the ability of CyP to affect human polymorphonuclear leukocyte (PMN) function was investigated. PMNs were isolated from venous blood by standard density-gradient centrifugation. Cell migration was measured by use of the Boyden chamber assay. Interleukin (IL)-8 and tumor necrosis factor (TNF)-α production was measured using a sandwich-type enzyme-linked immunosorbent assay. PMN intracellular reactive oxygen species (ROS) levels were assessed by the use of a fluorescent probe coupled to spectrophotometry. CyP 10-100 μg/ml was chemotactic for PMNs without affecting the chemotactic response to either E. coli LPS or N-formyl-Met-Leu-Phe (fMLP). CyP per se did not affect PMN production of either IL-8 or TNF-α, but concentration-dependently reduced LPS-induced production of both cytokines. On the contrary, CyP had no effect either on fMLP-induced production of IL-8 or on PMN oxidative burst (at rest and after stimulation with fMLP), a response which is known to be independent from LPS-operated pathways. In human PMNs CyP behaves as a selective and effective LPS antagonist. These findings support the therapeutic potential of CyP in endotoxin-dependent disease.     

Associated anomalies among infants with oral clefts at birth and during a 1-year follow-up

Reports of birth defects rates may focus on defects observed in the newborn period or include defects diagnosed at older ages. However, little information is available on the rates of additional anomalies detected after birth or on the ages at which such anomalies are diagnosed. The aims of this work were to describe the initial diagnoses of oral clefts, isolated or associated with other defects, in newborn infants ascertained in hospitals of the ECLAMC network, and diagnostic changes that occurred due to detection of additional defects during a 1-year follow-up period. Seven hundred ten liveborn infants with cleft lip only (CLO), cleft lip with cleft palate (CLP), or cleft palate (CP) were ascertained between 2003 and 2005. Prevalence estimates of isolated and associated (ASO) clefts, diagnoses in infants with associated clefts, and the percentage of isolated clefts that were reclassified as associated were established. Birth prevalence estimates (per 1,000) were as follows: Total: 1.7; CLP: 0.94 (ASO = 23.5%); CP: 0.46 (ASO = 42.3%); CLO: 0.28 (ASO = 7.6%). Initial diagnoses in infants with associated clefts included 38 infants with chromosomal abnormalities, 33 with non-chromosomal syndromes, 16 with malformation sequences, and 98 with multiple anomalies of unknown etiology. Seven percent of newborns initially classified as isolated were later reclassified as associated. Ten infants without associated defects or clinically suspected syndromes were diagnosed as syndromic only through laboratory findings or family history, illustrating the difference between the terms associated versus isolated, which refers to presence or absence of associated anomalies, and syndromic versus non-syndromic, which refers to etiology.     

p85 regulatory subunit of PI3K mediates cAMP-PKA and estrogens biological effects on growth and survival

Cyclic adenosine 3'5' monophosphate (cAMP) and protein kinase A (PKA) cooperate with phosphatidylinositol 3' kinase (PI3K) signals in the control of growth and survival. To determine the molecular mechanism(s) involved, we identified and mutagenized a specific serine (residue 83) in p85alpha(PI3K), which is phosphorylated in vivo and in vitro by PKA. Expression of p85alpha(PI3K) mutants (alanine or aspartic substitutions) significantly altered the biological responses of the cells to cAMP. cAMP protection from anoikis was reduced in cells expressing the alanine version p85alpha(PI3K). These cells did not arrest in G1 in the presence of cAMP, whereas cells expressing the aspartic mutant p85D accumulated in G1 even in the absence of cAMP. S phase was still efficiently inhibited by cAMP in cells expressing both mutants. The binding of PI3K to Ras p21 was greatly reduced in cells expressing p85A in the presence or absence of cAMP. Conversely, expression of the aspartic mutant stimulated robustly the binding of PI3K to p21 Ras in the presence of cAMP. Mutation in the Ser 83 inhibited cAMP, but not PDGF stimulation of PI3K. Conversely, the p85D aspartic mutant amplified cAMP stimulation of PI3K activity. Phosphorylation of Ser 83 by cAMP-PKA in p85alpha(PI3K) was also necessary for estrogen signaling as expression of p85A or p85D mutants inhibited or amplified, respectively, the binding of estrogen receptor to p85alpha and AKT phosphorylation induced by estrogens. The data presented indicate that: (1) phosphorylation of Ser 83 in p85alpha(PI3K) is critical for cAMP-PKA induced G1 arrest and survival in mouse 3T3 fibroblasts; (2) this site is necessary for amplification of estrogen signals by cAMP-PKA and related receptors. Finally, these data suggest a general mechanism of PI3K regulation by cAMP, operating in various cell types and under different conditions.     

Dopaminergic receptor D5 mRNA expression is increased in circulating lymphocytes of Tourette syndrome patients

Tourette syndrome (TS) is a neuropsychiatric disorder in which dopaminergic dysfunction and immune system abnormalities seem to coexist. Using real-time PCR, we determined mRNA expression of dopamine receptors (DRs) D1-5 in peripheral blood lymphocytes (PBLs) from 15 TS patients and 15 sex- and age-matched healthy controls (HCs). DRD5 mRNA levels in cells from TS were higher than in cells from HCs. In TS patients with obsessive-compulsive disorder, DRD5 mRNA levels in PBLs showed a highly positive correlation with the severity of compulsive symptoms. DRD5 mRNA upregulation in PBLs from TS patients may represent a peripheral marker of dopaminergic dysfunction and supports the involvement of the immune system in TS.     

Reversible worsening of Parkinson disease motor symptoms after oral intake of Uncaria tomentosa (cat's claw)

Uncaria tomentosa (UT), also known as cat's claw, isa Peruvian Rubiaceae species widely used in traditional medicine for the treatment of a wide range of health problems. There is no report about the use, safety, and efficacy of UT in neurological disorders. We describe reversible worsening of motor signs in a patient with Parkinson disease after oral intake of UT, and some possible explanations are discussed.     

Therapy with interferon-beta modulates endogenous catecholamines in lymphocytes of patients with multiple sclerosis

Objective

To investigate the endogenous dopaminergic/adrenergic system of lymphocytes in multiple sclerosis (MS) patients during treatment with interferon (IFN)-β.

Methods

Patients with relapsing-remitting MS undergoing IFN-β treatment were prospectively studied during the first year of treatment. Circulating lymphocytes were obtained at baseline and after 1, 3, 6 and 12 months of treatment and assayed for catecholamine (CA) production and mRNA expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in the synthesis of CA), β₂-adrenoceptors (AR) and D2, D3 and D5 dopaminergic receptors (DR).

Results

In cells from patients treated with IFN-β for 12 months the production of CA hugely increased and was less sensitive to IFN-γ-induced inhibition. Expression of mRNA for TH, β₂-AR and DRD5 was already enhanced after 1 month and further increased up to 6–12 months of treatment. On the contrary, DRD2 mRNA progressively decreased and DRD3 mRNA did not significantly change over the whole study period.

Conclusions

In MS patients IFN-β treatment enhances the ability of lymphocytes to produce CA, and induces extensive modifications of both β₂-AR and DR-operated pathways. The clinical relevance of these effects deserves consideration.     

Age-related changes in periodic leg movements during sleep in patients with restless legs syndrome

ObjectiveThe aim of this study was to evaluate and statistically describe the age-related changes in leg movements (LMs) during sleep in a large group of subjects with restless legs syndrome (RLS).Subjects and methodsOne hundred eight untreated patients affected by idiopathic RLS were included in this study (mean age 52.0 years, min 7.5, max 83.2 years). The time structure of their polysomnographically recorded LMs was analyzed using an approach particularly appropriate for assessing their quantity, periodicity, and distribution during the night.ResultsPeriodic LMs during sleep (PLMS) increased in number gradually in the age groups. Their typical interval was approximately 24–28 s before the age of 55 years but at approximately 14–16 s after the age of 65 years. PLMS index reached a plateau at 15–25 years of age and remained stable up to 65 years; after this age, it showed an important increase. Periodicity index (PI) increased progressively up to the age of 35 years and then remained stable up to the age of 85 years. No correlation was found between PLMS index and PI. The number of PLMS per hour of sleep declined through the night in subjects aged 15–75 years; after this age, PLMS tended to be equally distributed across the entire night.ConclusionsThe use of three main parameters derived from the analysis of leg motor activity during sleep in RLS patients (PLMS index, PI and PLMS time distribution) is capable of providing us with important information about the age-related changes of PLMS in this condition, which can be used in the evaluation of the sleep motor patterns in these subjects.     

Iron Infusion and Induced Hypophosphatemia: The Role of Fibroblast Growth Factor‐23

The mechanism of action of fibroblast growth factor‐23 (FGF23) is becoming increasingly clearer as a result of studies that have defined its structure and pleiotropic effects. Furthermore, data are emerging on the effects exerted on this hormone by iron administration. Ten main iron formulations are recognized (with clear differences in composition and possible reactions of intolerance and anaphylaxis), which are indicated for iron deficiency anemia, including nephropathic subjects, as suggested by medical guidelines. With some types of iron formulation (especially iron carboxymaltose) a particular side effect has been observed: hypophosphatemia, mediated by FGF23. This review aims to draw attention to this correlation and the contradiction represented by the presence of both positive and negative modulation by FGF23, with the effects induced by its increase even after long‐term treatment with iron formulation. However, more evidence is needed to understand the reasons for this differential stimulation.     

Effectiveness of Physiotherapy on Freezing of Gait in Parkinson's Disease: A Systematic Review and Meta-Analyses

Freezing of gait is considered one of the most disabling gait disorders in patients with PD. An effective treatment for freezing of gait is missing, thus current management requires a multidisciplinary approach. Among treatment options, physiotherapy is acknowledged to be crucial; however, a systematic review that demonstrates its efficacy is missing. This review aims at examining the short- and long-term effects of physiotherapy in improving freezing of gait in PD patients. Five electronic databases were searched for English-language full-text articles, and only randomized controlled trials were considered. The freezing of gait questionnaire was selected as the primary outcome measure because it is the only validated measure used to evaluate the severity and impact of freezing of gait on patients’ daily life. From 1,130 trials, 19 relevant studies, including 913 patients, were selected. The included studies varied for sample size, methodology, and type of intervention. None of the studies had a low risk of bias, but the majority of randomized control trials presented a low risk for at least 6 of 13 biases. Our findings provide evidence for short-term effectiveness of physiotherapy in improving freezing of gait (physiotherapy vs. no treatment: effect size = –0.28 [–0.45, –0.11], P = 0.001; physiotherapy vs. control: effect size = 0.43 [–0.65, –0.21], P < 0.0001), particularly when tailored interventions are applied. These results seem to be maintained at the follow-up examinations (effect size = –0.52 [–0.78, –0.26]; P = 0.001). Promising findings on the potential benefits of physiotherapy in improving freezing of gait were found, although further randomized control trial studies are still needed. Questions remain on the type and duration of intervention that best fits for treating freezing of gait symptom in PD. © 2019 International Parkinson and Movement Disorder Society