Magnetic resonance imaging assessment of substantia nigral iron deposition in Parkinson's disease: a meta-analysis.

OBJECTIVE: The pathogenesis of Parkinson's disease (PD) is associated with abnormal iron accumulation. Magnetic resonance imaging (MRI) studies have shown that patients with Parkinson's disease have an increased amount of iron in their substantia nigra (SN). We have undertaken a meta-analysis of studies using MRI in PD, to explore the potential role of MRI in diagnosing PD using abnormal iron deposition in SN as a candidate biomarker. MATERIALS AND METHODS: Searches of PubMed, Embase, and Medline databases revealed 16 studies that compared PD patients and healthy controls (HC). A sensitivity analysis and subgroup analysis were performed to evaluate the reliability of our results. Estimates were pooled by the fixed-effects model. As an expression of I2, we computed the proportion of variation due to heterogeneity. RESULTS: We included 16 studies with sample sizes of 435 PD and 355 HC in our meta-analysis. Results showed that SN iron deposition was significantly elevated (p<0.00001) in patients with PD compared to HC ones (SMD=0.72, 95% confidence interval 0.57 to 0.87, p<0.00001). CONCLUSIONS: Our findings, based on a homogeneous group-level analysis, suggest that MRI-based SN iron deposition could be used to distinguish PD from HC. For a more rigorous investigation of SN iron deposition in PD, larger cohort studies are needed.

Differentially expressed proteins identified by TMT proteomics analysis in children with verrucous epidermal naevi.

BACKGROUND: Verrucous epidermal naevi (VEN) are benign skin tumours, considered keratinocytic epidermal naevi, that appear at birth or early childhood. VEN may display a range of appearances, depending on patient age. Although the number of studies regarding VEN is increasing, the exact mechanism of VEN is still unknown. OBJECTIVES: The aim of this study was to analyse the changes in the expression of protein factors in lesions of VEN children by TMT labelling-based quantitative proteomics. METHODS: A total of 8 children with VEN (5 for experiment and 3 for validation) and 8 healthy children (5 for experiment and 3 for validation) presented to the Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Boao Super Hospital, between January 2019 and November 2019. The lesions and lesion-adjacent tissues from children with VEN and naevus-adjacent normal skin tissues from children with pigmented naevi were defined as the VEN group, VENC group and C group, respectively. We performed a proteomics analysis to screen for differentially expressed proteins in the lesions of these individuals. We further performed Western blotting to validate the relative expression levels of nine targeted proteins in the validation group. RESULTS: According to the proteomics results, a total of 4970 proteins were identified, and 4770 proteins were quantified. Among these proteins, 586 proteins were up- or downregulated at least 1.3-fold with a P-value < 0.05 (upregulated: 399, downregulated: 187) in lesions between the VEN group and the C group. These proteins played important roles in multiple biological functions, such as cornification, epidermal cell differentiation and neutrophil activation, and formed a complicated protein-protein interaction network. Of the 586 up- or downregulated proteins, nine were selected for further validation. According to Western blotting analysis results, the relative expression levels of Involucrin, NDUFA4, Loricrin, Keratin type II cytoskeletal 6A (Cytokeratin 6A), BRAF, Filaggrin, S100A7 and Desmocollin-3 were significantly upregulated in VEN children and may be associated with skin barrier dysfunction, epidermal cell overgrowth and differentiation, inflammation and immune and oxidative phosphorylation, which are involved in the pathogenesis of VEN. CONCLUSIONS: According to TMT-based proteomics and Western blotting results, we identified eight noteworthy proteins, Involucrin, NDUFA4, Loricrin, Keratin type II cytoskeletal 6A, BRAF, Filaggrin, S100A7 and Desmocollin-3, that were upregulated in the lesions of VEN children and may be associated with the pathogenesis of VEN. Our findings provide new starting points for identifying precise pathogenic mechanisms or therapeutic targets for VEN.

[Analysis of risk factors of ventricular arrhythmia in patients with Brugada syndrome].

Objective: To investigate the risk factors of ventricular arrhythmias in patients with Brugada syndrome. Methods: Clinical data of 60 Brugada syndrome patients admitted in the department of cardiology of the First Affiliated Hospital of Nanjing Medical University from March 2003 to December 2016 were collected and retrospectively analyzed. The age at diagnosis was (43.2±13.1) years (0.6-83.0 years), 98.3% were males (n=59), and the patients were followed up to (92±41) months (12-169 months). The 12-lead surface electrocardiogram (ECG) recorded at the time of diagnosis and showing the highest type 1 ST elevation, either spontaneously or after provocative drug test, was used for the analysis. Patients were divided into ventricular arrhythmia (VA, n=12) group and non-ventricular arrhythmia (non-VA, n=48) group depending on the presence or absence of clinical VA event. The demographic data and ECG data of the 2 groups were compared, and the independent risk factors of VA events were analyzed by stepwise logistic regression. Results: Incidence of family history of sudden death (7/12 vs. 22.9% (11/48)) and percentage of type 1 ST elevation in the peripheral ECG leads (6/12 vs. 16.67% (8/48)) were significantly higher in VA group than in non-VA group (both P<0.05). Max Tpeak-Tend (Max-Tpe) interval ((144±53)ms vs. (110±16)ms) and dispersion of Tpe ((74±50)ms vs. (43±17)ms) were significantly higher in VA group than in non-VA group (both P<0.05). The area under receiver operating characteristic (ROC) curves for the Max-Tpe interval was 0.693 and Max-Tpe interval ≥140 ms was determined as an optimized cutoff point with increased risk of VA event, which had a sensitivity of 50.0%, a specificity of 98.0%, a positive predictive value of 85.7%, and a negative predictive value of 88.7% for predicting VA event. The ROC curves for the dispersion of Tpe was 0.775 and dispersion of Tpe ≥45 ms was determined as an optimized cutoff point for predicting VA event, which had a sensitivity of 91.7%, a specificity of 64.6%, a positive predictive value of 39.3%, and a negative predictive value of 96.9% for predicting VA event. In multivariate analysis, Max-Tpe interval ≥140 ms (OR=27.53, 95%CI 1.07-706.77, P=0.045) and family history of sudden death (OR=24.63, 95%CI 2.05-295.38, P=0.011) were found to be the independent risk factors of arrhythmic events. Conclusions: Max-Tpe interval ≥140 ms and family history of sudden death are risk factors of VA event in included patients with Brugada syndrome.

The genetics of birth timing: insights into a fundamental component of human development.

The timing of birth necessitates the coupling of fetal maturation with the onset of parturition, and occurs at characteristic, but divergent gestations between mammals. Preterm birth in humans is an important but poorly understood outcome of pregnancy that uncouples fetal maturation and birth timing. The etiology of preterm birth is complex, involving environmental and genetic factors whose underlying molecular and cellular pathogenic mechanisms remain poorly understood. Animal models, although limited by differences with human physiology, have been crucial in exploring the role of various genetic pathways in mammalian birth timing. Studies in humans of both familial aggregation and racial disparities in preterm birth have contributed to the understanding that preterm birth is heritable. A significant portion of this heritability is due to polygenic causes with few true Mendelian disorders contributing to preterm birth. Thus far, studies of the human genetics of preterm birth using a candidate gene approach have met with limited success. Emerging research efforts using unbiased methods may yield promising results if concerns about study design can be adequately addressed. The findings from this frontier of research may have direct implications for the allocation of public health and clinical resources as well as spur the development of more effective therapeutics.

Flow cytometry analysis of peripheral blood lymphocytes in patients with choroidal melanoma.

PURPOSE: To evaluate peripheral blood lymphocyte subpopulations in patients with choroidal melanoma. METHODS: In this prospective study, peripheral blood lymphocytes of 226 patients afflicted with choroidal melanoma were analyzed by flow cytometry and compared with those of 49 age-matched and gender-matched control subjects. Subpopulations of peripheral blood lymphocytes were further identified by monoclonal antibodies specific to cell-surface markers. Statistical analysis was performed by a Student t test. RESULTS: There was no overall difference between the patients with choroidal melanoma and the control subjects with regard to peripheral blood lymphocyte subpopulations. However, when the patients were divided into subgroups based on their clinical characteristics, differences in natural killer (NK) cell population and activated T cells were noted in two subgroups. Patients with ciliary body involvement showed a statistically significant reduction in NK cells (194 +/- 101 vs 260 +/- 178 per mm3; P = .01). The number of activated T cells in this subgroup of patients was increased but not statistically significantly (7.32 +/- 4.79 vs 6.09 +/- 4.34 per mm3; P = .08). In patients with extrascleral extension, a statistically significant increase in activated T cells was noted (9.84 +/- 7.41 vs 6.25 +/- 4.3 per mm3; P = .02). The NK cells in this subgroup of patients were also reduced, but the reduction did not achieve statistical significance (178 +/- 123 vs 248 +/- 167 per mm3; P = .24). CONCLUSIONS: We noted statistically significant differences in peripheral blood lymphocytes in two subgroups of patients with clinically less favorable choroidal melanoma.

Epidural coadministration of ketamine, morphine and bupivacaine attenuates post-herpetic neuralgia--a case report.

The N-methyl-D-aspartate (NMDA) receptor system plays an important role in nociceptive signal modulation in the central nerve system. There is considerable evidence that NMDA receptor antagonists can abolish hypersensitivity of nociceptors in animal models. In this case report, we described a patient who suffered post-herpetic neuralgia with severe pain, allodynia, and hyperesthesia over right side T2 to T8 dermatomes. Treatment with conventional doses of non-steroid anti-inflammatory drug (NSAID), antidepressant, anticonvulsant and benzodiazepine failed to provide satisfactory pain relief. With the patient's consent, we administered subanalgesic doses of ketamine (10 mg), morphine (1 mg), and 6 ml bupivacaine (0.1%) through the thoracic epidural route. After the treatment, hyperalgesia and allodynia improved dramatically, and the receptive field also reduced. After four weeks' treatment, satisfactory pain relief was achieved with conventional analgesics treatment. The combination of relatively low doses of morphine, ketamine and bupivacaine epidurally provides effective pain relief in this case. The result strongly suggests a synergy from this combination that warrants a formal study of the dose-response relationship involved in this treatment and the mechanism by which this effect is achieved. This regimen provides a promising treatment for the neuropathic pain with limited side effects.

Magnetically labeled secretin retains receptor affinity to pancreas acinar cells.

Previously, we have developed a colloidal dextran-stabilized monocrystalline iron oxide nanocompound (MION-46) as a magnetic label for magnetic resonance imaging (MRI). In an effort to use this magnetic label to visualize pancreatic receptor function by MRI in vivo, we investigated the potential of secretin as a vector molecule. Secretin receptors, abundant on exocrine pancreas cells, recognize secretin through its amidated carboxyl terminal. In order to conjugate secretin to MION, we utilized the specific interaction between biotin and streptavidin, since direct conjugation of human secretin to MION has previously resulted in low yields and low affinity of the conjugate (unpublished results). Initially, we biotinylated the N-terminal primary amino group of secretin (60% yield). In a separate step, streptavidin (SA) was immobilized onto the surface dextran molecules of MION (79% yield) by reductive amination. Each secretin molecule was conjugated to one biotin molecule and each MION particle to an average of two SA molecules. The biotinylated secretin was then conjugated to MION through the biotin-streptavidin interaction (90% yield). The secretin-biotin-streptavidin-MION construct thus contained approximately two secretin molecules per MION. An in vitro competitive binding assay of pancreatic acinar cells demonstrated that the magnetically labeled secretin retained affinity to the secretin receptors. In vivo distribution studies in rats showed a significantly higher pancreatic accumulation of the secretin-biotin-streptavidin-MION construct as compared to the control group that had received unmodified MION. Our data indicate that bioactive peptides can be attached to dextran-coated iron oxide particles through the biotin-streptavidin interaction while retaining receptor affinity. Such target-specific agents have potential use in MR imaging to probe for a variety of receptor systems.

Residential releases of number 2 fuel oil: a contributor to indoor air pollution.

OBJECTIVES: Analysis of data from the New York City Fire Department showed that residential fuel oil releases frequently occur in quantities ranging from 5 to 1000 gal, primarily from storage tank leaks and overfill. A risk assessment was conducted to determine whether Number 2 fuel oil basement spills pose a significant risk to human health. METHODS: Exposure was derived from a simulated field study spill of Number 2 fuel oil in a townhouse basement to develop emission rates for the indicator constituent xylene. Distribution of xylene throughout the townhouse was determined using a multizone contaminant dispersal model. RESULTS: Spills of 85 and 21 gal resulted in xylene exposure estimates as high as 20 and 5 mg/kg/day, respectively. CONCLUSIONS: A spill of about 21 gal or more of Number 2 fuel oil would present a human health risk for central nervous and reproductive systems for 8 days or longer. Tank inspection and supervised delivery would provide effective prevention at minimal expense.