Early Phase Of Disease Research Articles

Vitamin D deficiency leads to sensory and sympathetic denervation of the rat synovium

Vitamin D deficiency is associated with increased susceptibility to inflammatory arthritis. Sensory and sympathetic synovial nerves are critical to the development of inflammatory arthritis and spontaneously degenerate in the early phases of disease. These nerves contain vitamin D receptors and vitamin D influences nerve growth and neurotrophin expression. We therefore examined the density of synovial nerves and neurotrophin-containing cells in vitamin D-deficient rats. Seven-week-old Sprague–Dawley rats were fed either control or vitamin D-deficient diets for 4weeks. Knee synovium sections extending from the patella to the meniscus were immunostained for total nerves, myelinated and unmyelinated nerves, sympathetic nerves, peptidergic and non-peptidergic sensory nerves, and neurotrophins and immune cell markers. In control rats, intimal innervation by unmyelinated sensory fibers was denser than subintimal innervation. In contrast, sympathetic innervation was confined to the subintima. Many sensory axons contained markers for both peptidergic and non-peptidergic nerves. Nerve growth factor (NGF) was primarily expressed by intimal CD163-negative type B synoviocytes, while neurturin, a ligand selective for non-peptidergic sensory neurons, was expressed by synovial mast cells. In vitamin D-deficient rats, there were significant reductions in sensory nerves in the intima and sympathetic nerves in the subintima. While there was no significant change in NGF-immunoreactivity, the number of neurturin-expressing mast cells was significantly reduced in the intima, suggesting that intimal reductions in sensory nerves may be related to reductions in neurturin. Vitamin D deficiency therefore may increase susceptibility to inflammatory arthritis by depleting sensory and sympathetic synovial nerves as a result of reduced synovial neurotrophin content.

Preclinical inflammatory rheumatic diseases: an overview and relevant nomenclature.

Chronic inflammatory and autoimmune conditions result from an interplay between genetic and environmental factors culminating in the phenotypes of established disease. The transition from health to established disease is relatively well understood in rheumatoid arthritis (RA), which provides an exemplar for other diseases. This article addresses terminologies to describe the phases of disease leading to RA, disease initiation and the point from which disease duration should be timed, the future research agenda suggested by this approach to the definition of phases of disease, and the importance of capturing the patient perspective in research into the earliest phases of disease.

G.P.56: A de novo mutation of the MYH7 gene in a large Chinese family with autosomal dominant myopathy

Laing distal myopathy (LDM) is an autosomal dominant myopathy which is caused by mutation in the slow/beta cardiac myosin heavy chain (<i>MYH7</i>) gene. It has been recently reported that LDM presents with a wide range of clinical manifestations. We herein report a large Chinese family with autosomal dominant myopathy. The affected individuals in the family presented foot drop at early childhood, and progressive distal and proximal limb weakness. Their characteristic symptoms were scapular winging and scoliosis in early disease phase, and impairment of ambulation in advanced phase. At first, we had suspected limb girdle muscular dystrophy (LGMD), but had not reached a correct diagnosis. Next, we performed linkage analysis and detected four linkage regions on chromosomes 1q23.2-24.1, 14q11.2-12, 15q26.2-26.3 and 17q24.3. Through whole exome sequencing, we found a de novo p.K1617del causative mutation in the <i>MYH7</i> gene. Therefore, we have diagnosed the disease as LDM, which is the first case in China. Our patients had more severe clinical manifestations by mimicking LGMD in comparison with the patients with the same mutation reported elsewhere.

The brain structural and cognitive basis of odor identification deficits in mild cognitive impairment and Alzheimer's disease.

BackgroundThe objectives of this study were to explore the relationship between olfactory impairment, cognitive measures, and brain structure volumes in healthy elderly individuals, compared to patients with amnestic mild cognitive impairment (aMCI) or early Alzheimer’s disease (AD). The primary aim was to elucidate possible differences in cognitive scores and brain structure volumes between aMCI/AD patients with relatively intact odor identification (OI) ability and those with reduced ability.MethodsTwelve patients with aMCI, six with early AD, and 30 control subjects were included. OI abilities were assessed with the Brief Smell Identification Test (B-SIT) and Sniffin Sticks Identification Test (SSIT). Neuropsychological tests of executive functions and memory were performed. Brain structural volumes were obtained from T1 weighted 3D MRI at 3 Tesla. Statistical comparisons between the patients with aMCI and AD indicated no significant differences in performance on most tests. Since the groups were small and AD patients were in an early phase of disease, all patients were subsequently considered together as a single group for studying OI. Patients were subdivided into relatively intact (scores >50%) and reduced OI (≤ 50% score) on the olfactory tests.ResultsThe aMCI/AD group with reduced OI ability, as measured by both B-SIT and SSIT, had significantly smaller hippocampal volume as compared to the patient group with OI scores > 50%. There was a significant association between OI scores and hippocampal volume in the patient (not the control) group. Similar changes with tests of executive function and memory were not found. Low OI scores on B-SIT were associated with conversion from aMCI to AD in patients. The reduced OI patient group was significantly faster on Rey complex figure copying than the fairly intact OI group.ConclusionThe results from this pilot study suggest that the reduction in the size of hippocampus in connection with early AD is associated more with loss of OI ability rather than loss of memory, thus demonstrating that impaired OI is an early marker of medial temporal lobe degeneration.

Perinatal antibiotic-induced shifts in gut microbiota have differential effects on inflammatory lung diseases

Resident gut microbiota are now recognized as potent modifiers of host immune responses in various scenarios. Recently, we demonstrated that perinatal exposure to vancomycin, but not streptomycin, profoundly alters gut microbiota and enhances susceptibility to a TH2 model of allergic asthma. Here we sought to further clarify the etiology of these changes by determining whether perinatal antibiotic treatment has a similar effect on the TH1/TH17-mediated lung disease, hypersensitivity pneumonitis. Hypersensitivity pneumonitis was induced in C57BL/6 wild-type or recombination-activating gene 1-deficient mice treated perinatally with vancomycin or streptomycin by repeated intranasal administration of Saccharopolyspora rectivirgula antigen. Disease severity was assessed by measuring lung inflammation, pathology, cytokine responses, and serum antibodies. Microbial community analyses were performed on stool samples via 16S ribosomal RNA pyrosequencing and correlations between disease severity and specific bacterial taxa were identified. Surprisingly, in contrast to our findings in an allergic asthma model, we found that the severity of hypersensitivity pneumonitis was unaffected by vancomycin, but increased dramatically after streptomycin treatment. This likely reflects an effect on the adaptive, rather than innate, immune response because the effects of streptomycin were not observed during the early phases of disease and were abrogated in recombination-activating gene 1-deficient mice. Interestingly, Bacteroidetes dominated the intestinal microbiota of streptomycin-treated animals, while vancomycin promoted the expansion of the Firmicutes. Perinatal antibiotics exert highly selective effects on resident gut flora, which, in turn, lead to very specific alterations in susceptibility to TH2- or TH1/TH17-driven lung inflammatory disease.

Guanabenz, which enhances the unfolded protein response, ameliorates mutant SOD1-induced amyotrophic lateral sclerosis

Approximately 20% of familial amyotrophic lateral sclerosis (FALS) cases are caused by mutant superoxide dismutase type 1 (mtSOD1). Although the mechanisms of mtSOD1-induced toxicity remain poorly understood, evidence suggests that accumulation of misfolded SOD1 is fundamental to its toxicity and the death of motor neurons. Misfolded mtSOD1 can accumulate inside the endoplasmic reticulum (ER), leading to ER stress, with activation of the unfolded protein response (UPR). We have previously carried out genetic studies focused on PERK (which is an eIF2α kinase that is rapidly activated in response to ER stress and leads to a repression in translation) and GADD34 (which participates in the dephosphorylation of eIF2α). We reported that mtSOD1 transgenic mice that are haploinsufficient for PERK have a significantly accelerated ALS disease, while mtSOD1 mice that are mutated for GADD34 have a remarkably ameliorated disease. Guanabenz, a centrally acting oral drug approved for the treatment of hypertension, enhances the PERK pathway by selectively inhibiting GADD34-mediated dephosphorylation of eIF2α. We have now treated G93A mtSOD1 transgenic mice with guanabenz and found a significant amelioration of disease with a delay in the onset and prolongation of the early phase of disease and survival. Guanabenz-treated G93A mice have less accumulation of mtSOD1 and an enhanced phosphorylation of eIF2α at endstage. This study further emphasizes the importance of the PERK pathway in the pathogenesis of FALS and as a therapeutic target in ALS, and identifies guanabenz as a candidate drug for the treatment of ALS patients.

An electrophysiological classification associated with Guillain-Barré syndrome outcomes.

Guillain-Barré syndrome (GBS) is an acute, post-infectious, inflammatory, autoimmune peripheral neuropathy with a highly diverse clinical course and outcome. We classified GBS on the basis of patients' first nerve conduction and validated this system to be associated with outcome on the basis of electrophysiological characteristics during the acute phase of GBS. We retrospectively evaluated 40 GBS patients who underwent their first electrophysiological study within 14 days of onset and classified GBS into four patterns: (1) acute inflammatory demyelinating polyneuropathy (AIDP) pattern with sensory nerve conduction abnormalities (motor-sensory AIDP: MS-AIDP), (2) AIDP pattern without sensory nerve conduction abnormalities (motor AIDP: M-AIDP), (3) acute motor axonal neuropathy (AMAN) pattern, and (4) minor abnormalities pattern. We compared the clinical, electrophysiological, and laboratory findings between groups and determined subgroups associated with poor outcome. The MS-AIDP and AMAN patterns more frequently exhibited prolonged recovery compared with the M-AIDP and minor abnormalities patterns and were associated with prolonged recovery (specificity, 100%; sensitivity, 73%; P < 0.001). The period of inability to walk independently was significantly longer in the MS-AIDP and AMAN patterns than in the M-AIDP and minor abnormalities patterns (median 85 vs. 10 days; P < 0.001). In conclusion, our classification of GBS using a single nerve conduction study in the early phase of disease is associated with outcomes. This classification can be used to counsel individual patients and guide decision-making with respect to treatment.

Osteopontin-CD44v6 interaction mediates calcium deposition via phospho-Akt in valve interstitial cells from patients with noncalcified aortic valve sclerosis.

The activation of valve interstitial cells (VICs) toward an osteogenic phenotype characterizes aortic valve sclerosis, the early asymptomatic phase of calcific aortic valve disease. Osteopontin is a phosphorylated acidic glycoprotein that accumulates within the aortic leaflets and labels VIC activation even in noncalcified asymptomatic patients. Despite this, osteopontin protects VICs against in vitro calcification. Here, we hypothesize that the specific interaction of osteopontin with CD44v6, and the related intracellular pathway, prevents calcium deposition in human-derived VICs from patients with aortic valve sclerosis. On informed consent, 23 patients and 4 controls were enrolled through the cardiac surgery and heart transplant programs. Human aortic valves and VICs were tested for osteogenic transdifferentiation, ex vivo and in vitro. Osteopontin-CD44 interaction was analyzed using proximity ligation assay and the signaling pathways investigated. A murine model based on angiotensin II infusion was used to mimic early pathological remodeling of the aortic valves. We report osteopontin-CD44 functional interaction as a hallmark of early stages of calcific aortic valve disease. We demonstrated that osteopontin-CD44 interaction mediates calcium deposition via phospho-Akt in VICs from patients with noncalcified aortic valve sclerosis. Finally, microdissection analysis of murine valves shows increased cusp thickness in angiotensin II-treated mice versus saline infused along with colocalization of osteopontin and CD44 as seen in human lesions. Here, we unveil a specific protein-protein association and intracellular signaling mechanisms of osteopontin. Understanding the molecular mechanisms of early VIC activation and calcium deposition in asymptomatic stage of calcific aortic valve disease could open new prospective for diagnosis and therapeutic intervention.

Severe fever with thrombocytopenia syndrome in children: a case report.

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel bunyavirus (SFTSV) in China. Humans of all ages living in endemic areas have high risk of acquiring SFTS. Most clinical data so far have been from adults and no clinical study was available from children yet. The present study identified four SFTSV infected children through hospital based surveillance. A prospective observational study was performed to obtain their clinical and laboratory characteristics.Case presentationThe patients’ age ranged from 4–15 years old and two were male. On hospitalization, fever, malaise and gastrointestinal syndromes were the most commonly presenting symptoms. Hemorrhagic symptoms or neurological manifestation was not recorded in any of the four pediatric patients. Hematological abnormalities at admission into hospital included leucopenia (4 cases), thrombocytopenia (1 case) and bicytopenia (1 case). The abnormal parameters included elevated aminotransferase (1 case), alanine transaminase (2 case), and lactate dehydrogenase (3 case). Laboratory parameters indicative of renal damage was not observed during the hospitalization. All the patients recovered well without sequelae being observed.ConclusionCompared with adults, pediatric patients with SFTSV infection seem to have less vague subjective complaints and less aggressive clinical course. Thrombocytopenia is suggested to be used less rigorously in recognizing SFTSV infection in pediatric patients, especially at early phase of disease.

A PROSPECTIVE, SYSTEMATIC LITERATURE REVIEW AND META-ANALYSES TO EVALUATE GLOBAL AND REGIONAL BRAIN VOLUMES BY STRUCTURAL MRI AS BIOMARKERS OF ALZHEIMER'S DISEASE (AD) PROGRESSION

and MMSE was found in the occipital lobes for the combined AD+MCI+HC (Pearson 0.82, p1⁄40.0465) and AD (Pearson 0.99, p1⁄40.01) groups. Conclusions:Based on relatively small number of studies, no apparent relationship between change on brain amyloid burden and cognition in AD was found. In contrast, the negative correlation seen in MCI suggests that PiB PET changes may be a useful biomarker in earlier disease phases. The significant finding in the correlation between changes in amyloid deposition in the occipital lobe and MMSE warrants further study. Limitation included the paucity of studies having longitudinal data on both brain amyloid burden and clinical measures and heterogeneity amongst studies.

Acute necrotizing pancreatitis: laboratory, clinical, and imaging findings as predictors of patient outcome.

In patients with acute necrotizing pancreatitis, we analyzed whether laboratory and clinical findings determined in the early phase of disease and morphologic features on contrast-enhanced CT (CECT) at the beginning of the late phase of disease are helpful in predicting patient outcome and whether CECT findings provide additional information in establishing prognosis compared with the laboratory and clinical findings. A retrospective analysis of 99 patients with acute necrotizing pancreatitis was performed. Four laboratory variables (albumin, calcium, C-reactive protein, WBC count) and three clinical variables (Acute Physiology, Age, Chronic Health Evaluation [APACHE] II score; Simplified Acute Physiology Score [SAPS] II; persistent organ failure) were assessed. Five morphologic features on CECT including Balthazar grade and CT severity index were reviewed. The endpoints of patient outcome were peripancreatic or pancreatic infection, need for intervention, duration of organ failure, ICU and hospital stays, and death. Based on receiver operating characteristic curve analysis for infection, high-and low-risk groups for each prognostic variable were calculated and univariable and multivariable Cox regression analyses were carried out. In our study population of 99 patients (63 men, 36 women; median age, 52 years; age range, 18-84 years), 25 patients (25%) developed infection, 42 patients (42%) experienced organ failure, and 12 patients (12%) died. Regarding the laboratory and clinical variables, albumin level, APACHE II score, and particularly persistent organ failure were the strongest independent predictors of patient outcome. Regarding the imaging variables, Balthazar grade and a morphologic feature that takes the distribution of intrapancreatic necrosis into account were the strongest independent predictors. In the multivariable analysis of all studied variables, imaging variables were independent and strong predictors of patient outcome and provided additional information in establishing prognosis compared with clinical and laboratory findings. In patients with suspected or proven acute necrotizing pancreatitis, performing CECT at the beginning of the late phase of disease is recommended to identify patients at increased risk for adverse outcomes.

The co-inertia approach in identification of specific microRNA in early and advanced atherosclerosis plaque

MicroRNAs (miRs) are short, non-coding RNAs that regulate gene expression by absolute or partial binding to mRNA, which results in transcript degradation and translation blocking. Atherosclerosis, as a complex and progressive disease, represents one of the main causes of cardiovascular clinical complications and even death. We applied co-inertia analysis (CIA) as a novel computation method, to determine which miRs are potentially associated with differences in gene expression levels originating from microarray data of early and advanced atherosclerotic plaque. As the CIA has not been applied in the field of atherosclerosis yet, we hypothesized that using CIA we can get novel information about the miRs that have significant role in early phase of disease or in severe phase of disease. The characteristic split in the data along the axes of performed CIA showed the difference in the gene expression pattern between early atherosclerosis and advanced atherosclerotic plaque. The advanced atherosclerotic plaques showed more homogenous gene expression pattern than early atherosclerosis samples. In early carotid lesions five out of five algorithms predicted miR-24, four out of five predicted miR-155, miR-145, and miR-100 as early active miRs. These miRs could be “protective” in plaque evolution context because they were not active in advanced plaques according to our results. They were reported previously as atheroprotective, which in a way represents confirmation of CIA application in atherosclerosis. We detected 13 new miRs which could be active in early plaque phenotype according to CIA prediction. In the advanced plaques we predicted miR-221, miR-222, miR-127 and miR-146 which were previously revealed to have atherogenic properties. In addition to miRs that have literature support, we also found new 8 miRs that, with described function so far, could present a novelty in research of atherosclerotic plaque evolution. All of these examples show that CIA results have a great potential to be of interest in future research in atherosclerotic plaque progression. We validated the applicability of CIA in the field of atherosclerosis, but we also found new interesting miR competitors that have strong potential to serve as markers and plaque development factors. These results should be experimentally confirmed in further research with ultimate goal to discover new mediators and blood markers, which could improve the prevention and therapy of this complex disease.

Detection of changes in the locus coeruleus in patients with mild cognitive impairment and Alzheimer's disease: High‐resolution fast spin‐echo T1‐weighted imaging

AimNeuronal degeneration in the locus coeruleus occurs in the early phase of Alzheimer's disease, similar to mild cognitive impairment. The locus coeruleus produces norepinephrine, a deficiency of which causes both memory disturbance and psychological symptoms. Thus, we evaluated signal alterations in the locus coeruleus of patients with Alzheimer's disease and mild cognitive impairment using a high-resolution fast spin-echo T1-weighted imaging.MethodsA total of 22 patients with Alzheimer's disease, 47 patients with mild cognitive impairment and 26 healthy controls were prospectively examined by high-resolution fast spin-echo T1-weighted imaging at 3 Tesla. Signal intensities in the locus coeruleus were manually measured and expressed relative to those in the adjacent white matter structures as contrast ratios.ResultsLocus coeruleus contrast ratios were significantly reduced in patient groups with Alzheimer's disease, mild cognitive impairment that converted to Alzheimer's disease and mild cognitive impairment that did not convert to Alzheimer's disease (1.80–16.09% [median, 9.30%], 3.45–14.84% [median 6.87%] and 3.01–19.19% [median 7.72%], respectively) compared with the healthy control group (6.24–20.94% [median 14.35%]; P < 0.0001). The sensitivity and specificity for discriminating these diseases were 85.0% and 69.2%, respectively, which suggests that this measurement can be carried out reliably. There was no significant difference in the locus coeruleus contrast ratios among the Alzheimer's disease, mild cognitive impairment-converted and mild cognitive impairment-non-converted groups.ConclusionsHigh-resolution fast spin-echo T1-weighted imaging can show signal attenuation in the locus coeruleus of patients with Alzheimer's disease or with mild cognitive impairment whose pathology may or may not eventually convert to Alzheimer's disease. Geriatr Gerontol Int 2015; 15: 334–340.

Interferon γ -induced chemokines in psoriatic arthritis.

Interferon γ-inducible protein (IP-10) chemokine is implicated in the pathogenesis of psoriatic arthritis (PsA). It was shown that chemokine (C-X-C motif) receptor (CXCR) 3 and CXCR4 were expressed by both blood-derived plasmacytoid dendritic cells (pDCs) and pDCs isolated from rheumatoid arthritis (RA) and PsA synovial fluid (SF) and that IP-10, chemokine (C-X-C motif) ligand (CXCL)-11, and CXCL-12 present in RA and PA SF stimulated chemotaxis of blood-derived pDCs. High circulating levels of IP-10 and chemokine (C-C motif) ligand (CCL) 2 have been found in PsA patients, with a T helper cells (Th) 1 immune predominance in the early phase of the disease. Moreover a decline of IP-10 levels has been observed in long lasting PsA, with a significant increase of the CCL2/IP-10 ratio, suggesting a shift from Th1 to Th2 immune response in long duration PsA. IP-10 levels in PsA patients are significantly higher in presence of autoimmune thyroiditis. IP-10 has been suggested to be a good marker to monitor the activity or progression of PsA. Attempts have been made to modulate or inhibit the production of IP-10 in PsA in order to modify the course of the disease.

The Effects of Different Antioxidants on the Activity of Cerebrocortical MnSOD and Na,K-ATPase from post mortem Alzheimer’s Disease and Age-matched Normal Brains

Among the markers and targets of the early phase of Alzheimer's disease (AD) pathogenesis MnSOD (mitochondrial dysfunction) and Na-pump (disturbances in function/regulation) are often highlighted. This paper focused on comparison of the effects of three antioxidants on the activity of cerebrocortical MnSOD and Na,K-ATPase from post mortem Alzheimer's disease and age-matched normal brains. Antioxidant compounds with different origins: natural glutathione, synthetic UPF peptides (glutathione analogues) and phytoestrogen genistein were investigated. Firstly, MnSOD and Na,K-ATPase activities were found to be decreased in the post mortem AD brains compared with age-matched controls. Secondly, GSH had no effect on MnSOD activity, but decreased Na,K-ATPase activity both in the control and AD brains. Thirdly, UPF1 and UPF17 increased MnSOD activity, and UPF17 suppressed Na,K-ATPase activity. Further studies are needed to clarify, if the inhibitory effect of UPF17 on Na,K-ATPase could abolish the beneficial effect gained from MnSOD activation. Both the antioxidative potential of genistein and its potency to up-regulate Na,K-ATPase activity make it an attractive candidate substance to suppress the early phase of the pathogenesis of AD.

Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells

How cells degenerate from oxidative stress in aging-related disease is incompletely understood. This study’s intent was to identify key cytoprotective pathways activated by oxidative stress and determine the extent of their protection. Using an unbiased strategy with microarray analysis, we found that retinal pigmented epithelial (RPE) cells treated with cigarette smoke extract (CSE) had overrepresented genes involved in the antioxidant and unfolded protein response (UPR). Differentially expressed antioxidant genes were predominantly located in the cytoplasm, with no induction of genes that neutralize superoxide and H2O2 in the mitochondria, resulting in accumulation of superoxide and decreased ATP production. Simultaneously, CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, including CHOP, which was cytoprotective because CHOP knockdown decreased cell viability. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP and developed epithelial–mesenchymal transition, as suggested by decreased LRAT abundance, altered ZO-1 immunolabeling, and dysmorphic cell shape. Mildly degenerated RPE from early age-related macular degeneration (AMD) samples had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling. Although oxidative stress is thought to induce an antioxidant response with cooperation between the mitochondria and the ER, herein we show that mitochondria become impaired sufficiently to induce epithelial–mesenchymal transition despite a protective UPR. With similar responses in early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress despite a protective UPR during the early phases of aging-related disease.

Weight gain and increased central obesity in the early phase of Parkinson's disease

Weight loss is strongly associated with Parkinson's disease (PD) and impacts symptoms and disease progression. The aim of this study was to describe changes in body composition and to explore how body weight (BW), relates to disease progression and medication in the early phase of PD. Participants in a prospective community-based case-control study of PD were followed-up three years after initial diagnosis. Anthropometric and bioelectrical impedance spectroscopy (BIS) measurements were used together with Mini Nutritional Assessment (MNA), a 24-hrecall (24-HR) and a 3-day food registration (3-DFR) to complete the evaluation of nutritional status. Disease severity was assessed using the Mini Mental State Examination (MMSE), the Unified Parkinson's Disease Rating Scale motor score (UPDRS III), and the Hoehn and Yahr rating. The PD patients' BW gained 1.62kg (±4.60, P=0.009), an increase that significantly correlated with fat mass (FM) (r=0.74), waist size (r=0.65), waist/height ratio (r=0.64), and total skin fold (r=0.77). Linear regression showed an association between change in BW and physical activity level (PAL) (B=-8.554; P=0.025) confirmed by the multiple linear regression. Linear regression also revealed an association between change in FM and MMSE (B=0.654; P=0.027). In early PD, weight gain was revealed over three years accompanied by an increase in FM and waist circumference. An inverse relation was revealed between change in BW and PAL. The MMSE, UPDRS III, and Hoehn and Yahr rating were unchanged. Medication and swallowing difficulties were not associated with change in BW.

The endothelial protein C receptor impairs the antibacterial response in murine pneumococcal pneumonia and sepsis

Pneumococcal pneumonia is a frequent cause of gram-positive sepsis and has a high mortality. The endothelial protein C receptor (EPCR) has been implicated in both the activation of protein C (PC) and the anti-inflammatory actions of activated (A)PC. The aim of this study was to determine the role of the EPCR in murine pneumococcal pneumonia and sepsis. Wild-type (WT), EPCR knockout (KO) and Tie2-EPCR mice, which overexpress EPCR on the endothelium, were infected intranasally (pneumonia) or intravenously (sepsis) with viable Streptococcus pneumoniae and euthanised at 24 or 48 hours after initiation of the infection for analyses. Pneumonia did not alter constitutive EPCR expression on pulmonary endothelium but was associated with an influx of EPCR positive neutrophils into lung tissue. In pneumococcal pneumonia EPCR KO mice demonstrated diminished bacterial growth in the lungs and dissemination to spleen and liver, reduced neutrophil recruitment to the lungs and a mitigated inflammatory response. Moreover, EPCR KO mice displayed enhanced activation of coagulation in the early phase of disease. Correspondingly, in pneumococcal sepsis EPCR KO mice showed reduced bacterial growth in lung and liver and attenuated cytokine release. Conversely, EPCR-overexpressing mice displayed higher bacterial outgrowth in lung, blood, spleen and liver in pneumococcal sepsis. In conclusion, EPCR impairs antibacterial defense in both pneumococcal pneumonia and sepsis, which is associated with an enhanced pro-inflammatory response.

Why is there persistent disease despite biologic therapy? Importance of early intervention.

This short article hypothesizes that the major reason for persistent disease despite biologic therapy is the inappropriately late timing of therapy with biologic agents. There is clear evidence to support this hypothesis. This short review will indicate that patients treated at an earlier phase of disease can achieve a clinical remission rate of 70% and a response rate of above 95%.

In and out of the bone: can the osteocyte escape skeletal jail and yet regulate mineralization?

An increase in the levels of fibroblast growth factor 23 (FGF23) develops in the early phase of chronic kidney disease (CKD). However, the initial trigger of CKD-mineral and bone disorder (CKD-MBD) is a matter of debate. Fang and associates provide evidence, in a mouse model of early CKD, that osteocytes and osteocyte-like cells play an important role at the earliest stage of CKD-MBD. The osteocytes may become a target of intervention in CKD-MBD.