Clinical research advances of CFHR5 nephropathy: a recent review.

CFHR5 nephropathy is a type of clinical C3 glomerulopathy, which is a monogenic genetic disease caused by the internal replication of CFHR5 gene, a protein related to the complement regulatory factor H family. The disease seems to be prevalent only in people of Greek Cypriot descent. Because of the special variation of the internal replication of exon 2 and exon 3 of CFHR5 protein in the occurrence of disease, it has had a serious impact on local residents. At present, the mechanism of glomerular damage caused by CFHR5 protein mutations is still unclear. The purpose of this article is to review the clinical research advances of this disease in the past 10 years, including the study of mutant genes, the analysis of mutant proteins and the role of alternative pathways in glomerular injury. It covers the progress in diagnosis and clinical treatment of the disease and looks forward to the future development prospects of its treatment. It is hoped that the recent results will be summarized for the follow-up in-depth study of CFHR5 nephropathy.

Immune-mediated hematological disease in dogs is associated with alterations of the fecal microbiota: a pilot study.

BACKGROUND: The dog is the most popular companion animal and is a valuable large animal model for several human diseases. Canine immune-mediated hematological diseases, including immune-mediated hemolytic anemia (IMHA) and immune thrombocytopenia (ITP), share many features in common with autoimmune hematological diseases of humans. The gut microbiome has been linked to systemic illness, but few studies have evaluated its association with immune-mediated hematological disease. To address this knowledge gap, 16S rRNA gene sequencing was used to profile the fecal microbiota of dogs with spontaneous IMHA and ITP at presentation and following successful treatment. In total, 21 affected and 13 healthy control dogs were included in the study. RESULTS: IMHA/ITP is associated with remodeling of fecal microbiota, marked by decreased relative abundance of the spirochete Treponema spp., increased relative abundance of the pathobionts Clostridium septicum and Escherichia coli, and increased overall microbial diversity. Logistic regression analysis demonstrated that Treponema spp. were associated with decreased risk of IMHA/ITP (odds ratio [OR] 0.24-0.34), while Ruminococcaceae UCG-009 and Christensenellaceae R-7 group were associated with increased risk of disease (OR = 6.84 [95% CI 2-32.74] and 8.36 [95% CI 1.85-71.88] respectively). CONCLUSIONS: This study demonstrates an association of immune-mediated hematological diseases in dogs with fecal dysbiosis, and points to specific bacterial genera as biomarkers of disease. Microbes identified as positive or negative risk factors for IMHA/ITP represent an area for future research as potential targets for new diagnostic assays and/or therapeutic applications.

Orbital stability analysis and photometric characterization of the second Earth Trojan asteroid 2020 XL5.

Trojan asteroids are small bodies orbiting around the L4 or L5 Lagrangian points of a Sun-planet system. Due to their peculiar orbits, they provide key constraints to the Solar System evolution models. Despite numerous dedicated observational efforts in the last decade, asteroid 2010 TK7 has been the only known Earth Trojan thus far. Here we confirm that the recently discovered 2020 XL5 is the second transient Earth Trojan known. To study its orbit, we used archival data from 2012 to 2019 and observed the object in 2021 from three ground-based observatories. Our study of its orbital stability shows that 2020 XL5 will remain in L4 for at least 4 000 years. With a photometric analysis we estimate its absolute magnitude to be [Formula: see text], and color indices suggestive of a C-complex taxonomy. Assuming an albedo of 0.06 ± 0.03, we obtain a diameter of 1.18 ± 0.08 km, larger than the first known Earth Trojan asteroid.

Increased serum interleukin-6, not minimal hepatic encephalopathy, predicts poor sleep quality in nonalcoholic cirrhotic patients.

BACKGROUND: Sleep-wake disturbances are common in patients with cirrhosis and have a considerable effect on health-related quality of life; however, the underlying mechanism behind the phenomenon is unclear. Cytokines are involved in the mediation of signalling pathways regulating fibrogenesis, leading to cirrhosis. In addition, increased cytokines could contribute to sleep disturbances. AIM: To determine the relationship between pro-inflammatory cytokines and sleep disturbance in cirrhotic patients. METHODS: Ninety-eight nonalcoholic cirrhotic patients without overt hepatic encephalopathy were enrolled in this cross-sectional study. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. The Psychometric Hepatic Encephalopathy Score (PHES) was used to examine cognitive performance and define minimal hepatic encephalopathy (MHE). The Hospital Anxiety and Depression Scale (HADS) was used to evaluate the mood status of the patients. Pro-inflammatory cytokines that include interleukin 6 (IL-6) and tumour necrosis factor-α, as well as HBV-DNA or HCV-RNA levels were determined in patients. RESULTS: A total of 56 (57%) cirrhotic patients were identified as 'poor' sleepers (PSQI > 5). After multivariate analysis, IL-6 (P = 0.001) and HADS scores (P = 0.002) were found to be independent predictive factors of poor sleep quality. No significant relationships were observed between the sleep indices and the presence of MHE. HCV-RNA, but not HBV-DNA, viraemia was associated with sleep disturbance in cirrhotic patients. CONCLUSIONS: Sleep disturbance is found commonly in cirrhotic patients and a high serum IL-6 level is predictive of poor sleep quality. Minimal hepatic encephalopathy by itself may not contribute to sleep dysfunction in cirrhotic patients.

Dietary Influence on Calcitropic Hormones and Adiposity in Caucasian and African American Postmenopausal Women Assessed by Structural Equation Modeling (SEM).

OBJECTIVES: To examine differences in hydroxycholecalciferol (25(OH)D) and parathyroid hormone (PTH) concentrations between Caucasian and African American (AA) postmenopausal women, as well as the effects of dietary calcium, protein and vitamin D intakes on 25(OH)D, PTH, and body adiposity using structural equation modeling (SEM). DESIGN: Population-based prospective cohort study. SETTING: Academic research using the baseline data from two longitudinal studies. Participants Included n=113 Caucasian and n=40 African American, postmenopausal women who completed the baseline data collection and met inclusion criteria (dietary calcium intake <900 mg/day and being generally healthy) between 2006 and 2010. MAIN OUTCOME: Dietary intake of calcium and vitamin D, assessed by dietary records, were examined in relation to calcitropic hormones concentrations and adiposity markers. Independent t-tests, confirmatory factor analysis, SEM and multi-group analyses were conducted to examine the aforementioned relationships as well as group differences among hormones, dietary intake, anthropometrics, age and other factors. RESULTS: Dietary calcium and protein intakes were significantly lower in AA women. Years since menopause were significantly higher in AA compared to Caucasian women. PTH and 25(OH)D levels were significantly lower in AA compared to Caucasian women. Dietary calcium and protein intakes did not influence body adiposity in either group of women. Dietary vitamin D had minimal indirect (via 25(OH)D levels) influence on adiposity. CONCLUSION: The study confirmed the positive relationship of 25(OH)D with adiposity markers and both AA and Caucasian women. The study provides a unique example of the use of SEM in nutrition research within a clinical context. This model should be further tested in other populations.

Nontyphoidal salmonella urinary tract infection in a case of hyperparathyroidism and nephrocalcinosis.

Nontyphoidal Salmonella infections often present with self-limited gastroenteritis. Extraintestinal focal infections are uncommon but have high mortality and morbidity. Urinary tract infection caused by nontyphoidal Salmonella is usually associated with structural abnormalities of the urinary tract. Nephrocalcinosis and nephrolithiasis are the major risk factors. Although primary hyperparathyroidism has been reported to increase the risk of nephrocalcinosis and nephrolithiasis, little is known about the association between hyperparathyroidism and Salmonella urinary tract infection. We report the case of a 37-year old man who had a history of primary hyperparathyroidism and bilateral nephrocalcinosis and who developed urinary tract infection. Salmonella Group D was isolated from his urine specimen. Salmonella should be considered as a possible causality organism in patients with primary hyperparathyroidism and nephrocalcinosis who develop urinary tract infection. These patients need to be aware of the potential risks associated with salmonellosis.

Cytomegalovirus disease after liver transplantation: a nationwide population-based study.

BACKGROUND: Cytomegalovirus (CMV) disease is a significant complication after liver transplantation. The estimated incidence varies among studies, which have been conducted in single regional centers and with small cohorts. In this study, we investigated the occurrence of CMV disease among liver transplant recipients in a national cohort in Taiwan. METHODS: This retrospective study used data from the Taiwan National Health Insurance Research Database. All liver transplant recipients in the catastrophic illness database from 2000 to 2009 were enrolled. Cases of CMV disease were identified from the admission database with the use of the ICD-9-CM code 078. RESULTS: The national cohort consisted of 1,721 liver transplant recipients (1,200 men and 521 women) with a mean age of 43.9 ± 8.9 years at the time of transplantation. The mean follow-up duration was 3.6 ± 2.7 years. The mortality rate was 14.9% at 1 year and 20.5% at 5 years. During the study period, 84 patients (4.9%) were diagnosed with CMV disease. The overall prevalence of CMV disease was 14.5 per 100 person-years. The cumulative incidences of post-transplantation CMV infection at 3 months, 6 months, 1 year, 2 years, 5 years, and 10 years were 1.2%, 2.7%, 3.8%, 4.2%, 4.8%, and 4.9%, respectively. The most common CMV-related diseases were colitis, hepatitis, and pneumonia. CONCLUSIONS: The risk of CMV disease was significantly elevated in the first 6 months after liver transplantation in the Taiwanese cohort.

A practical approach to minimize the interaction of dietary vitamin K with warfarin.

WHAT IS KNOWN AND OBJECTIVE: The many interactions between warfarin and other drugs and foods generate great challenges for clinicians and patients in maintaining stable anitcoagulation. Interactions due to variable vitamin K content of different dietary items influence the therapy of nearly all patients on warfarin. Unfortunately, there is no widely acceptable, patient-friendly strategy for managing such interactions. In this contribution, we propose a practical approach to managing this troublesome interaction, consisting of 'maintaining constant weekly dietary vitamin K intake scores'. METHODS: Twenty-three vitamin K-rich vegetables commonly seen in Taiwanese meals were identified and classified into seven score grades according to their relative vitamin K content per serving. The scores were based on published vitamin K content of different foods. RESULTS AND DISCUSSION: The vitamin K score was equivalent to 5 points for spinach and garland chrysanthemum per bowel, followed by (baby) bok choy, amaranth, arden lettuce (4 points); leaf mustard, edible rape, sweet potato leaf, bai cai and Chinese leek (3 points); and okra and Chinese celery (0·5 points). This classification can be used to guide patients in recording their weekly vitamin K scores with a view to maintaining it when on warfarin. WHAT IS NEW AND CONCLUSION: We suggest a novel approach to patient counselling on warfarin to maintain consistent dietary vitamin K intake and achieve a more stable anticoagulation response. A prospective randomized controlled trial to validate this pragmatic approach would be useful.

Nontyphoidal Salmonella urinary tract infection in a case of hyperparathyroidism and nephrocalcinosis / Infección de las vías urinaria por Salmonella no tifoidea en un caso de hiperparatiroidismo y nefrocalcinosis

Nontyphoidal Salmonella infections often present with self-limited gastroenteritis. Extraintestinal focal infections are uncommon but have high mortality and morbidity. Urinary tract infection caused by nontyphoidal Salmonella is usually associated with structural abnormalities of the urinary tract. Nephrocalcinosis and nephrolithiasis are the major risk factors. Although primary hyperparathyroidism has been reported to increase the risk of nephrocalcinosis and nephrolithiasis, little is known about the association between hyperparathyroidism and Salmonella urinary tract infection. We report the case of a 37-year old man who had a history of primary hyperparathyroidism and bilateral nephrocalcinosis and who developed urinary tract infection. Salmonella Group D was isolated from his urine specimen. Salmonella should be considered as a possible causality organism in patients with primary hyperparathyroidism and nephrocalcinosis who develop urinary tract infection. These patients need to be aware of the potential risks associated with salmonellosis.

Las infecciones por Salmonella no tifoidea se presentan a menudo con gastroenteritis auto-limitada. Las infecciones extra-intestinales focales son poco frecuentes, pero tienen una alta mortalidad y morbilidad. La infección de las vías urinarias causada por la Salmonella no tifoidea se asocia generalmente a anomalías estructurales de las vías urinarias. La nefrocalcinosis y la nefrolitiasis son los principales factores de riesgo. Aunque se ha reportado que el hiperparatiroidismo primario aumenta el riesgo de la nefrocalcinosis y la nefrolitiasis, poco se sabe sobre la asociación entre el hiperparatiroidismo y la infección de las vías urinarias por Salmonella. Damos a conocer aquí el caso de un hombre de 37 años con una historia de hiperparatiroidismo primario y nefrocalcinosis bilateral, que desarrolló una infección de las vías urinarias. La Salmonella del grupo D fue aislada de su muestra de orina. La Salmonella se debe considerar como un posible organismo de causalidad en pacientes con hiperparatiroidismo primario y nefrocalcinosis que desarrollan infección del tracto urinario. Estos pacientes necesitan tomar conciencia de los riesgos potenciales asociados con la salmonellosis.

The vitamin D receptor in dopamine neurons; its presence in human substantia nigra and its ontogenesis in rat midbrain.

There is growing evidence that vitamin D is a neuroactive steroid capable of regulating multiple pathways important for both brain development and mature brain function. In particular, there is evidence from rodent models that prenatal vitamin D deficiency alters the development of dopaminergic pathways and this disruption is associated with altered behavior and neurochemistry in the adult brain. Although the presence of the vitamin D receptor (VDR) has been noted in the human substantia nigra, there is a lack of direct evidence showing that VDR is present in dopaminergic cells. Here we confirm that the VDR is present in the nucleus of tyrosine hydroxylase (TH)-positive neurons in both the human and rat substantia nigra, and it emerges early in development in the rat, between embryonic day 12 (E12) and E15. Consistent evidence based on immunohistochemistry, real-time PCR and western blot confirmed a pattern of increasing VDR expression in the rat midbrain until weaning. The nuclear expression of VDR in TH-positive neurons during critical periods of brain development suggests that alterations in early life vitamin D status may influence the orderly development of dopaminergic neurons.

Role of Rho kinase isoforms in murine allergic airway responses.

Inhibition of Rho-associated coiled-coil forming kinases (ROCKs) reduces allergic airway responses in mice. The purpose of this study was to determine the roles of the two ROCK isoforms, ROCK1 and ROCK2, in these responses. Wildtype (WT) mice and heterozygous ROCK1 and ROCK2 knockout mice (ROCK1(+/-) and ROCK2(+/-), respectively) were sensitised and challenged with ovalbumin. ROCK expression and activation were assessed by western blotting. Airway responsiveness was measured by forced oscillation. Bronchoalveolar lavage was performed and the lungs were fixed for histological assessment. Compared with WT mice, ROCK1 and ROCK2 expression were 50% lower in lungs of ROCK1(+/-) and ROCK2(+/-) mice, respectively, without changes in the other isoform. In WT lungs, ROCK activation increased after ovalbumin challenge and was sustained for several hours. This activation was reduced in ROCK1(+/-) and ROCK2(+/-) lungs. Airway responsiveness was comparable in WT, ROCK1(+/-), and ROCK2(+/-) mice challenged with PBS. Ovalbumin challenge caused airway hyperresponsiveness in WT, but not ROCK1(+/-) or ROCK2(+/-) mice. Lavage eosinophils and goblet cell hyperplasia were significantly reduced in ovalbumin-challenged ROCK1(+/-) and ROCK2(+/-) versus WT mice. Ovalbumin-induced changes in lavage interleukin-13, interleukin-5 and lymphocytes were also reduced in ROCK1(+/-) mice. In conclusion, both ROCK1 and ROCK2 are important in regulating allergic airway responses.

Treatment with dextromethorphan improves endothelial function, inflammation and oxidative stress in male heavy smokers.

BACKGROUND: Dextromethorphan (DM) is reported to reduce the inflammation-mediated degeneration of dopaminergic neurons. OBJECTIVE: The goal of this study was to test if DM can improve the endothelial dysfunction and inflammatory markers in heavy smokers. PATIENTS AND METHODS: Forty habitual smoking healthy male volunteers (mean age, 31.5 +/- 1.4 years) were randomly given either DM (120 mg day(-1)) or a placebo for 6 months. We determined endothelial function using the brachial artery diameter changes in flow-mediated dilatation (FMD) and measured their inflammatory and oxidative markers. A sex-and-age matched non-smoking group (n = 20) was compared as normal parameters. RESULTS: Habitual smokers showed impaired baseline endothelial function in FMD (smoking vs. non-smoking: 6.3 +/- 1.8 vs. 10.2 +/- 2.3% respectively, P < 0.01). Without change in smoking behavior, lipid and metabolic parameters, a significant increase in FMD was found in the DM-treated group (32%), accompanied by a decrease in high-sensitivity C-reactive protein (hs-CRP), phospholipase A(2), matrix metalloproteinase-3, interleukin 6 (IL-6) and tumor necrosis factor-alpha receptor II (TNF-alpha RII) (all P < 0.05), but unchanged in von Willebrand factor (VWF)and plasminogen activator inhibitor-1 (PAI-1). An increase in plasma glutathione peroxidase and a decrease in spot urinary excretion of 8-epi-prostaglandin F(2a) were found in DM-treated smokers. CONCLUSIONS: Our study suggests that a 6-month treatment with DM can improve endothelial function and attenuate vascular oxidative stress and inflammation markers in habitual smokers.

Correlation of transmenopausal bone mass in healthy white women: a long-term longitudinal study.

INTRODUCTION: It is well established that menopause is associated with accelerated bone loss. However, no study has tested whether bone mass after the menopause transition is correlated with the premenopausal bone mass; that is, whether a high premenopausal bone mass will be predicatively high after menopause in an individual. MATERIALS AND METHODS: We examined the association of transmenopausal bone mass in 54 healthy premenopausal white women age 46 years or older at the initiation. These subjects experienced normal menopause and stayed in the study at least 1 year after their last menses without hormone replacement therapy. Bone mass of the lumbar spine (L2-L4) and total body were measured semiannually for 9.5 years. RESULTS AND DISCUSSION: In the 6-year period for which the data were analyzed, we found statistically significant correlations (p<0.05) over the 5.5-year and 5-year periods around menopause for pairwise transmenopausal lumbar spine Z-score and total body bone mineral content, respectively. The correlation declined with increase of the time interval across menopause. We conclude that for a limited time interval, bone mass after menopause is correlated with that before menopause.

Platelet-activating factor-acetylhydrolase A379V (exon 11) gene polymorphism is an independent and functional risk factor for premature myocardial infarction.

BACKGROUND: Oxidation of low density lipoproteins is an initial step of atherogenesis that generates pro-inflammatory phospholipids, including platelet-activating factor (PAF). PAF is degraded by PAF-acetylhydrolase (PAF-AH), which has been postulated to be a risk factor for myocardial infarction (MI). The role of PAF-AH for the onset of premature MI is unclear. METHODS: Polymorphisms located in putatively functional regions were investigated in a cohort of patients having premature MI onset prior to 46 years of age (n = 200) and a sex-age-matched control group (n = 200). The activity of PAF-AH and coronary angiograms were evaluated for the severity of coronary atherosclerosis. RESULTS: The V allele of A379V (exon 11) polymorphism on PAF-AH gene was more frequent in patients with premature MI (P = 0.001). This V allele polymorphism was also associated with a lower activity of plasma PAF-AH and a more complex coronary atherosclerosis (p Trends <0.05). Multiple logistic regression analysis showed that this polymorphism was an independent risk factor (Odds Ratio [OR] 1.66, 95% CI 1.14.1 to 5.80, P = 0.008) as well as smoking (OR 3.72, 95% CI 1.77 to 9.28, P = 0.001), diabetes mellitus (OR 2.25, 95% CI 1.40 to 5.32, P = 0.007) and hypertension (OR 1.88, 95% CI 1.25 to 5.36, P = 0.003) for the onset of premature MI. CONCLUSION: We conclude that a functional and significant association between the A379V polymorphism on exon 11 of PAF-AH gene and premature MI exists in this Taiwanese population. This polymorphism is significantly associated with the PAF-AH activity and the severity of coronary atherosclerosis.

Stromelysin-1 promoter 5A/6A polymorphism is an independent genetic prognostic risk factor and interacts with smoking cessation after index premature myocardial infarction.

OBJECTIVE: To evaluate the prognostic roles of multiple polymorphisms and smoking cessation for premature myocardial infarction (MI). METHODS: We studied 170 patients with MI onset before the age of 45 years (range 27-45 years, 84% men) and analyzed the traditional risk factors and several candidate genes' associations with their subsequent coronary events. RESULTS: Follow-up data were available for a total of 162 individuals (95.3%) with the other 38 individuals (4.7%) being lost-to-follow-up premature MI patients. During a mean period of 4.43 years' follow-up, diabetes mellitus (DM), hypertension, hypercholesterolemia and Killip's status > or =II were more frequent among patients with subsequent cardiac events (all P-values <0.05). The frequency of 5A allele of stromelysin-1 gene was significantly higher among event group (P = 0.01). Smoking cessation after MI, use of beta-blocker or angiotensin-converting enzyme inhibitor (ACEI) could improve outcome (all P-values <0.05). After multivariate analysis, we found that DM was an independent risk factor for survival [Hazard ratio (HR) 2.45, P = 0.01]. Successful smoking cessation and therapy with ACEI could have a protective effect (HR 0.33 and 0.09, P = 0.01 and <0.01, respectively). The stromelysin-1 5A gene polymorphism was also an independent survival predictor (HR 2.51, P = 0.03). In addition, smoking cessation could significantly modify the risk, especially among patients with 5A allele polymorphism (HR 6.75 vs. 1.50). CONCLUSION: We thus conclude that the stromelysin-1 gene polymorphism alone or in combination with smoking cessation can influence the prognosis after index premature MI.

A survey of haplotype variants at several disease candidate genes: the importance of rare variants for complex diseases.

BACKGROUND: The haplotype based association method offers a powerful approach to complex disease gene mapping. In this method, a few common haplotypes that account for the vast majority of chromosomes in the populations are usually examined for association with disease phenotypes. This brings us to a critical question of whether rare haplotypes play an important role in influencing disease susceptibility and thus should not be ignored in the design and execution of association studies. METHODS: To address this question we surveyed, in a large sample of 1873 white subjects, six candidate genes for osteoporosis (a common late onset bone disorder), which had 29 SNPs, an average marker density of 13 kb, and covered a total of 377 kb of the DNA sequence. RESULTS: Our empirical data demonstrated that two rare haplotypes of the parathyroid hormone (PTH)/PTH related peptide receptor type 1 and vitamin D receptor genes (PTHR1 and VDR) with frequencies of 1.1% and 2.9%, respectively, had significant effects on osteoporosis phenotypes (p = 4.2 x 10(-6) and p = 1.6 x 10(-4), respectively). Large phenotypic differences (4.0 approximately 5.0%) were observed between carriers of these rare haplotypes and non-carriers. Carriers of the two rare haplotypes showed quantitatively continuous variation in the population and were derived from a wide spectrum rather than from one extreme tail of the population phenotype distribution. CONCLUSIONS: These findings indicate that rare haplotypes/variants are important for disease susceptibility and cannot be ignored in genetics studies of complex diseases. The study has profound implications for association studies and applications of the HapMap project.

Vitamin D receptor gene polymorphisms are linked to and associated with adult height.

BACKGROUND: The vitamin D receptor (VDR) gene is important to human stature, as it mediates metabolic pathways, calcium homeostasis, and phosphate homeostasis, which influence growth. METHODS: We examined the relationship between VDR and adult height in 1873 white subjects from 406 nuclear families. Four SNPs, namely -4817A/G at intron 1, FokI C/T at exon 2 start codon, BsmI A/G at intron 8, and TaqI T/C at exon 9 in VDR were tested for linkage and association with adult height variation by the program QTDT (quantitative transmission disequilibrium test). The bT haplotype of the BsmI and TaqI loci was further tested for its association with height in unrelated samples randomly chosen from the 406 nuclear families by traditional population association methods. RESULTS: All four tested SNPs were linked to adult height. Within family associations with height were detected at BsmI and TaqI loci (p = 0.048 and 0.039, respectively). Analyses based on BsmI/TaqI haplotypes also revealed evidence for linkage (p = 0.05) and association (p = 0.001) with height. The bT haplotype was significantly associated with higher adult height (p = 0.033, within family association test). Such an association might be female specific and influenced by menstrual status. CONCLUSIONS: Our results strongly suggest that VDR may be linked to and associated with adult height variation in white populations.