Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.

Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilized to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation and stimulus response curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior, lateral-medial and anterior-posterior direction. Mean SICI, between interstimulus interval of 1-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in posterior-anterior (P = 0.044) and lateral-medial (P = 0.005) but not the anterior-posterior (P = 0.08) directions. A significant correlation between mean SICI oriented in a posterior-anterior direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between interstimulus interval 1-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in posterior-anterior (P = 0.035) and lateral-medial (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the anterior-posterior direction was comparable between ALS and controls (P = 0.482). The index of excitation was significantly increased in ALS patients when recorded with the TMS coil oriented in posterior-anterior (P = 0.041) and lateral-medial (P = 0.003) directions. In ALS patients, a significant increase in the stimulus response curve gradient was evident compared to controls when recorded with TMS coil oriented in posterior-anterior (P < 0.001), lateral-medial (P < 0.001) and anterior-posterior (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets.

Emerging insights into the pathogenesis and therapeutic strategies for vascular endothelial injury-associated diseases: focus on mitochondrial dysfunction.

As a vital component of blood vessels, endothelial cells play a key role in maintaining overall physiological function by residing between circulating blood and semi-solid tissue. Various stress stimuli can induce endothelial injury, leading to the onset of corresponding diseases in the body. In recent years, the importance of mitochondria in vascular endothelial injury has become increasingly apparent. Mitochondria, as the primary site of cellular aerobic respiration and the organelle for "energy information transfer," can detect endothelial cell damage by integrating and receiving various external stress signals. The generation of reactive oxygen species (ROS) and mitochondrial dysfunction often determine the evolution of endothelial cell injury towards necrosis or apoptosis. Therefore, mitochondria are closely associated with endothelial cell function, helping to determine the progression of clinical diseases. This article comprehensively reviews the interconnection and pathogenesis of mitochondrial-induced vascular endothelial cell injury in cardiovascular diseases, renal diseases, pulmonary-related diseases, cerebrovascular diseases, and microvascular diseases associated with diabetes. Corresponding therapeutic approaches are also provided. Additionally, strategies for using clinical drugs to treat vascular endothelial injury-based diseases are discussed, aiming to offer new insights and treatment options for the clinical diagnosis of related vascular injuries.

Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group.

PURPOSE: Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework has been widely adopted. The Clinical Genome Resource Low Penetrance/Risk Allele Working Group was formed to address these challenges and promote harmonization within the clinical community. METHODS: The work presented here is the product of internal and community Likert-scaled surveys in combination with expert consensus within the Working Group. RESULTS: We formally recognize risk alleles and low-penetrance variants as distinct variant classes from those causing highly penetrant disease that require special considerations regarding their clinical classification and reporting. First, we provide a preferred terminology for these variants. Second, we focus on risk alleles and detail considerations for reviewing relevant studies and present a framework for the classification these variants. Finally, we discuss considerations for clinical reporting of risk alleles. CONCLUSION: These recommendations support harmonized interpretation, classification, and reporting of variants at the low end of the penetrance spectrum.

Use of rumination time in health risk assessment of prepartum dairy cows.

The objectives of this observational cohort study were to evaluate the associations of rumination time (RT) in the last week of pregnancy with transition cow metabolism, inflammation, health, and subsequent milk production, reproduction, and culling. Pregnant nulliparous (n = 199) and parous (n = 337) cows were enrolled 21 d before expected calving. Rumination time and physical activity were monitored automatically by sensors from d -21 to 15 relative to calving. Blood samples were collected on d -14, -5, 4, 8, and 12 ± 1 relative to calving. Diagnoses of clinical health problems were performed by researchers from calving to 15 DIM. In classification 1, cows were ranked based on average daily RT in the last week of pregnancy and classified into terciles as short RT (SRT), moderate RT (MRT), or long RT (LRT) for association analyses. In classification 2, RT deviation from the parity average was used in a receiver operating characteristic curve to identify the best threshold to predict postpartum clinical disease. Cows were then classified as above the threshold (AT) or below the threshold (BT). Compared with cows with LRT, cows with SRT had greater serum concentrations of nonesterified fatty acids (0.47 vs. 0.40 ± 0.01 mmol/L), BHB (0.58 vs. 0.52 ± 0.01 mmol/L), and haptoglobin (0.22 vs. 0.18 ± 0.008 g/L) throughout the transition period, and reduced concentrations of glucose, cholesterol, albumin, and magnesium in a time-dependent manner. Parous cows with SRT had higher odds of postpartum clinical disease (adjusted odds ratio [AOR] = 3.7; 95% CI: 2.1-6.4), lower odds of pregnancy by 210 DIM (AOR = 0.34; 95% CI = 0.15-0.75), and lower milk production (46.9 vs. 48.6 ± 0.5 kg/d) than parous cows with LRT. Deviation in prepartum RT had good predictive value for clinical disease in parous cows (area under the curve = 0.65; 95% CI = 0.60-0.71) but not in nulliparous (area under the curve = 0.51; 95% CI = 0.42-0.59). Separation of parous cows according to the identified threshold (≤-53 min from the parity average) resulted in differences in serum concentrations of nonesterified fatty acids (AT = 0.31 ± 0.006, BT = 0.38 ± 0.014 mmol/L), BHB (AT = 0.49 ± 0.008, BT = 0.53 ± 0.015 mmol/L), and globulin (AT = 32.3 ± 0.3, BT = 34.8 ± 0.5 g/L) throughout the transition period, as well as in serum cholesterol, urea, magnesium, albumin, and haptoglobin in a time-dependent manner. Below threshold parous cows had higher odds of clinical disease (AOR = 3.7; 95% CI = 2.1-6.4), reduced hazard of pregnancy (adjusted hazard ratio = 0.64, 95% CI: 0.47-0.89), greater hazard of culling (adjusted hazard ratio = 2.1, 95% CI: 1.2-3.6), and lower milk production (46.3 ± 0.7 vs. 48.5 ± 0.3 kg/d). External validation using data from 153 parous cows from a different herd and the established threshold in RT deviation (≤-53 min) resulted in similar predictive value, with the odds of postpartum disease 2.4 times greater in BT than AT (37.5% vs. 20.1%). In conclusion, RT in the week preceding calving was a reasonable predictor of postpartum health and future milk production, reproduction, and culling in parous cows but not in nulliparous cows.

Clinical disease activity index applicability in lupus arthropathy: Unraveling underdiagnosed joint activity.

INTRODUCTION: Lupus arthropathy (LA) ranges from arthralgia and non-deforming arthritis to severe forms such as Jaccoud-type deformities and mutilating arthritis. Considering the evolving concept of LA, measuring arthritis activity in lupus patients may require a more practical and sensitive tool other than the classical composite scores. METHODS: In this cross-sectional study, we evaluated the articular pattern of a sample of SLE patients which were divided into those that scored in articular domain on Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and those with activity arthritis using the Clinical Disease Activity Index (CDAI). After all, we analyzed the association between CDAI and arthritis by SLEDAI-2K as well as its association with the presence or not of Jaccoud-type arthropathy (JA). RESULTS: A total of 127 patients with SLE were evaluated. According to SLEDAI-2K, 17 (13.4%) patients have scored in its joint criteria and 32 patients (25.19%) were considered to have some articular activity by CDAI. A total of 16 patients (50%) who scored some activity on CDAI did not score in articular domain of SLEDAI-2K. Also, the presence of Jaccoud-type arthropathy was significantly associated with arthritis activity according to the CDAI score (p = .014) but not with SLEDAI-2K joint criteria (p = .524). CONCLUSION: The CDAI was not directly associated with the presence of arthritis by the joint criteria of SLEDAI-2K and the presence of JA was significantly associated with the CDAI but not with arthritis at SLEDAI-2K.

Diastolic dysfunction and sex-specific progression to HFpEF: current gaps in knowledge and future directions.

Diastolic dysfunction of the left ventricle (LVDD) is equally common in elderly women and men. LVDD is a condition that can remain latent for a long time but is also held responsible for elevated left ventricular filling pressures and high pulmonary pressures that may result in (exercise-induced) shortness of breath. This symptom is the hallmark of heart failure with preserved ejection fraction (HFpEF) which is predominantly found in women as compared to men within the HF spectrum. Given the mechanistic role of LVDD in the development of HFpEF, we review risk factors and mechanisms that may be responsible for this sex-specific progression of LVDD towards HFpEF from an epidemiological point-of-view and propose future research directions.

Framework and baseline examination of the German National Cohort (NAKO).

The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19-74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2-3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4-5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years.

Maintenance of dNTP pool homeostasis and genomic stability.

As an important precursor for DNA synthesis, the four deoxyribonucleoside triphosphates (dATP, dTTP, dGTP, and dCTP) are necessary raw materials for DNA replication, recombination, and repair in cells. The correct synthesis and integrity of DNA are important manifestations of the genome stability, so the stability of the dNTP library state is essential to maintain the stability of the genome and the cell. In terms of the quality of the dNTP library, the incorporation of some heterogeneous dNTPs, such as oxidized dNTPs, into DNA can easily cause base substitutions and even DNA breaks and rearrangements, which will greatly damage the stability of the genome. At the same time, the cell has also evolved the corresponding NTP pyrophosphatase to remove it, and to correct the damaged DNA and repair the DNA gap by forming a DNA damage repair network. In terms of the number of dNTP libraries, the imbalance of the dNTP concentration and ratio will also cause base and frameshift mutations, which will also cause genome instability. As a result, cells have evolved a huge enzyme-controlled network to carry them out under precise control. This article mainly reviews the potential harm of damage to dNTP library components in cells, the clearance of damaged dNTPs, the regulation on the balance between dNTP library components, and finally discusses clinical diseases related to dNTP library homeostasis. It provides insights on the research of the correlation between the stability of the cellular dNTP library and the genome, and finally provides some theoretical basis for the treatment of related diseases.

Clinical disease activity and flare in SLE: Current concepts and novel biomarkers.

Systemic lupus erythematosus (SLE) is a complex and heterogeneous systemic autoimmune disease associated with innate and adaptive immune dysregulation. SLE occurs primarily in females of childbearing age, with increased prevalence and severity in minority populations. Despite improvements in treatment modalities, SLE patients frequently experience periods of heightened disease activity and flare that can lead to permanent organ damage, increased morbidity, and early mortality. Such outcomes impair quality of life and inflict a significant socioeconomic burden. Predicting changes in SLE disease activity could allow for closer monitoring and preemptive treatment, but existing clinical, demographic and serologic markers have been only modestly predictive. Novel, proactive approaches to clinical disease management are thus critically needed. Panels of blood biomarkers can detect a breadth of immune pathway dysregulation that captures SLE heterogeneity and disease activity. Alterations in the balance of pro-inflammatory and regulatory soluble mediators have been associated with changes in clinical disease activity and are detectable several weeks prior to clinical flare occurrence. A soluble mediator score has been highly predictive of impending flare in both European American and African American SLE patients, and this score does not require a priori knowledge of specific pathway activation in the patient. We review current concepts of disease activity and flare in SLE, focusing on the potential of novel blood biomarkers to characterize and predict changes in disease activity. Measuring the disordered immune response in SLE in this way promises to improve disease management and prevent organ damage in SLE.

Epidemiologic significance of Toxoplasma gondii infections in turkeys, ducks, ratites and other wild birds: 2009-2020.

Toxoplasma gondii infections are common in humans and animals worldwide. Wild and domestic avian species are important in the epidemiology of T. gondii infections because felids prey on them and excrete millions of oocysts in the environment, disseminating the infection. Herbivorous birds are also excellent sentinels of environmental contamination with T. gondii oocysts because they feed on the ground. Toxoplasma gondii infections in birds of prey reflect infections in intermediate hosts. Humans can become infected by consuming undercooked avian tissues. Here, the authors reviewed prevalence, persistence of infection, clinical disease, epidemiology and genetic diversity of T. gondii strains isolated from turkeys, geese, ducks, ratites and avian species (excluding chickens) worldwide 2009-2020. Genetic diversity of 102 T. gondii DNA samples isolated worldwide is discussed. The role of migratory birds in dissemination of T. gondii infection is discussed.

[Analysis of animal models of stable chronic obstructive pulmonary disease based on clinical features of traditional Chinese medicine and western medicine].

This study analyzed the advantages and disadvantages of existing animal models in China and abroad and their goodness of fit based on the clinical characteristics and diagnostic criteria of stable chronic obstructive pulmonary disease(COPD) in traditional Chinese medicine(TCM) and western medicine, followed by the collation and summarization of model evaluation methodologies. The results showed that the existing animal models of stable COPD were mainly modeled via smoke exposure or the combination of multiple methods like smoke exposure plus lipopolysaccharide or protease or bacterial infection. These animal models generally failed to simulate the clinical characteristics of TCM, and their goodness of fit in western medicine was higher than that in TCM. There is a lack of research on the animal models of stable COPD and the disease-syndrome combination models. Although the modeling is guided by the pathogenesis or mechanism of diseased humans, the established models were still not identical with the actual clinical situations. In-depth research is needed to develop quantitative standards for stable COPD models.

Epidemiologic significance of Toxoplasma gondii infections in chickens (Gallus domesticus): the past decade.

Toxoplasma gondii infections are common in humans and animals worldwide. Domestic free-range chickens (Gallus domesticus) are excellent sentinels of environmental contamination with T. gondii oocysts because they feed on the ground. Chickens can be easily infected with T. gondii; however, clinical toxoplasmosis is rare in these hosts. Chickens are comparatively inexpensive and thus are good sentinel animals for T. gondii infections on the farms. Here, the authors reviewed prevalence, the persistence of infection, clinical disease, epidemiology and genetic diversity of T. gondii strains isolated from chickens worldwide for the past decade. Data on phenotypic and molecular characteristics of 794 viable T. gondii strains from chickens are discussed, including new data on T. gondii isolates from chickens in Brazil. This paper will be of interest to biologists, epidemiologists, veterinarians and parasitologists.

Circular RNA PRKCI and microRNA-545 relate to sepsis risk, disease severity and 28-day mortality.

This study aimed to explore the clinical values of circular RNA protein kinase C iota (circ-PRKCI) and its target microRNA-545 (miR-545) in sepsis patients. Plasma samples of 121 sepsis patients and 60 healthy controls (HCs) were collected, then circ-PRKCI and miR-545 expressions were detected using RT-qPCR. Sepsis patients' demographics, biochemical indexes, medical histories, infection information were recorded. Besides, comprehensive disease scores (APACHE II score and SOFA score) were assessed within 24 h after admission. According to the survival status, 28-day mortality was calculated. Decreased circ-PRKCI expression and increased miR-545 expression were observed in sepsis patients compared to HCs, both of which had close correlations with sepsis risk. Besides, circ-PRKCI was negatively correlated with miR-545 in sepsis patients and HCs, respectively. Circ-PRKCI was negatively correlated with serum creatinine, white blood cell, C-reactive protein, APACHE II score, SOFA score, but positively correlated with albumin, which also related to blood stream infection (as primary infection site) and anaerobes infection in sepsis patients. Whereas the miR-545 showed a roughly opposite tendency. Decreased circ-PRKCI and increased miR-545 expressions were discovered in deaths compared to survivors, and both of them had values for predicting 28-day mortality risk in sepsis patients, which were slightly lower than the predictive values of APACHE II score and SOFA score for predicting 28-day mortality risk. Multivariate logistic analyses displayed circ-PRKCI as an independent factor predicting decreased 28-day mortality risk. In conclusion, circ-PRCKI insufficiency and miR-545 sufficiency were related to sepsis risk, clinical disease severity and 28-day mortality risk.

Incidence and outcome after first molecular versus overt recurrence in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia included in the ALL Ph08 trial from the Spanish PETHEMA Group.

BACKGROUND: Disease recurrence occurs in 20% to 40% of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who are treated with chemotherapy and tyrosine kinase inhibitors (TKIs). In the current study, the authors report the incidence, treatment, and outcome after first disease recurrence in young and older adults treated in the ALL Ph08 trial (ClinicalTrials.gov identifier NCT01491763). METHODS: Patients aged 18 to 55 years with de novo Ph+ ALL were treated with imatinib concurrently with standard-dose induction and consolidation therapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) when possible. In patients with first disease recurrence, the authors analyzed the type of recurrence, timing, location, presence of kinase domain mutations, type of treatment, and outcomes. RESULTS: Of the 125 patients, 28 patients (22%) developed disease recurrence before (4 patients) or after (24 patients) HSCT, with the recurrences being molecular in 11 patients (39%) and overt in 17 patients (61%). T315I was the most common mutation noted at the time of disease recurrence. Change in TKI was the most frequent treatment for patients with molecular disease recurrence whereas rescue chemotherapy and TKI change followed by second allo-HSCT when possible were performed for the most part in patients with overt disease recurrence. A total of 20 patients (71%) achieved response. The median disease-free survival (DFS) and overall survival (OS) were 8.5 months and 15.3 months, respectively. A trend for better DFS and OS was observed in patients with molecular recurrence compared with those with overt recurrence (median of 16.9 months vs 6.3 months [P = .05] and 28.7 months vs 11.5 months [P = .05] for DFS and OS, respectively). CONCLUSIONS: Disease recurrence was frequent in young and older adults with Ph+ ALL who were treated with imatinib and chemotherapy with HSCT. Although the majority of patients responded to rescue therapy, their outcomes were poor, especially with regard to overt disease recurrence.

Long-term effects of postpartum clinical disease on milk production, reproduction, and culling of dairy cows.

Two retrospective studies examining data of 7,500 lactating cows from a single herd were performed with the objective of evaluating the long-term effects of clinical disease during the early postpartum period on milk production, reproduction, and culling of dairy cows through 305 days in milk (DIM). In the first study, data regarding health, milk production, reproduction, and culling of 5,085 cows were summarized. Cows were classified according to incidence of clinical problem (metritis, mastitis, lameness, digestive problem, or respiratory problem) during the first 21 DIM (ClinD21). During 305 d of lactation, cows that had ClinD21 produced, on average, 410 kg less milk, 17 kg less fat, and 12 kg less protein compared with cows that did not have ClinD21 (NoClinD21). Although the interval to first breeding was not different between groups of interest, pregnancy rate through 305 DIM was lower in cows that had ClinD21 [adjusted hazard ratio (AHR) = 0.81]. When individual breedings were analyzed, cows that had ClinD21 presented lower rates of pregnancy per breeding for breedings performed before 150 DIM, reduced numbers of calving per breeding for breedings performed before 200 DIM, and greater number of pregnancy losses for all breedings performed through 305 DIM. The rate of culling from calving through 305 DIM was higher in cows that had a single ClinD21 (AHR = 1.79) and in cows that had multiple ClinD21 (AHR = 3.06), which resulted in a greater proportion of cows leaving the herd by 305 DIM (NoClinD21 = 22.6%; single ClinD21 = 35.7%; multiple ClinD21 = 53.8%). In the second study, data regarding postpartum health and 305-d yields of milk, fat, and protein were collected from 2,415 primiparous cows that had genomic testing information. Genomic estimated breeding values (EBV) were used to predict 305-d yields of milk, fat, and protein. Genomic EBV and predicted yields of milk, fat, and protein did not differ between cows that had ClinD21 and those that did not have ClinD21. In contrast, the observed 305-d yields of milk, fat, and protein were reduced by 345, 10, and 10 kg, respectively, in cows that had ClinD21 compared with cows that did not have ClinD21. We conclude that clinical disease diagnosed and treated during the first 21 DIM has long-term effects on lactation performance, reproduction, and culling of dairy cows, which contribute to detrimental consequences of health problems on sustainability of dairy herds. Replication of our studies in multiple herds will be important to confirm our findings in a larger population.

Late embryonic losses in supplemented grazing lactating dairy cows: Risk factors and reproductive performance.

The main objective of this study was to evaluate the risk factors for late embryonic loss (LEL) in supplemented grazing dairy cows. Additional objectives were to assess the incidence of LEL and its association with the reproductive performance of cows. A data set containing productive, reproductive, and health records of 13,551 lactations was used. A retrospective case-control study involving 631 cows with LEL (cases) and 2,524 controls (4 controls per case within each study year) was run. A case of LEL was defined when the embryo had no heartbeat or there was evidence of detached membranes or floating structures including embryo remnants by ultrasonography (US) at 28 to 42 d post-artificial insemination (AI), whereas a non-case was defined as a cow diagnosed with positive pregnancy by US 28 to 42 d post-AI and reconfirmed as pregnant 90 ± 7 d post-AI. Four controls per case were randomly selected from the non-cases with a temporal matching criterion (±3 d around the date of the fecundating AI of the case). Multivariable logistic models were offered with the following predictors: year of LEL (2011 through 2015), season of LEL (summer vs. fall vs. winter vs. spring), parity (1 vs. 2 vs. ≥3), uterine disease (UD), non-uterine disease (NUD), body condition score at parturition, body condition score at 28 to 42 d post-AI (BCS-LEL), days in milk (DIM), and daily milk yield (MY). Statistical significance was set at P < 0.05 and a tendency was set at P ≤ 0.10. We found that 4.7, 22, and 23% of cows had LEL, UD, and NUD, respectively. Cases tended to have higher daily MY than controls (32.5 vs. 31.8 kg); also, cases had much longer calving to pregnancy interval (226 vs. 118 d), lower hazard of pregnancy [hazard ratio = 0.39, 95% confidence interval (CI) = 0.35-0.43], and higher odds for non-pregnancy [odds ratio (OR) = 2.89, 95% CI = 2.37-3.54] than controls. We found that the odds for LEL increased with parity number (OR = 2.48, 95% CI = 1.99-3.08 for parity ≥3) and with BCS-LEL <2.50 (OR = 1.81, 95% CI = 1.33-2.47). Conversely, the odds for LEL decreased with BCS-LEL >3.00 (OR = 0.70, 95% CI = 0.53-0.91). The odds for LEL increased with UD (OR = 1.23, 95% CI = 1.01-1.49), NUD (OR = 1.24, 95% CI = 1.01-1.54), DIM (OR = 1.03, 95% CI = 1.00-1.05), and daily MY (OR = 1.14, 95% CI = 1.04-1.25) in univariable models only. Finally, the odds for LEL were not associated with year, season, DIM, and body condition score at parturition. In conclusion, LEL is associated with extended calving to pregnancy interval, and among its risk factors are parity number and BCS-LEL.

Association of polymorphism rs1053005 in STAT3 with chronic hepatitis B virus infection in Han Chinese population.

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is involved in hepatitis B virus (HBV) infection and HBV-related hepatocellular carcinoma (HCC). The association between polymorphism rs1053005 and haplotypes formed by rs1053004 and rs1053005 in the 3'UTR of STAT3 and chronic HBV infection has yet to be investigated. METHODS: This study included 567 patients with chronic HBV infection (239 chronic hepatitis, 141 liver cirrhosis and 187 HCC), 98 HBV infection resolvers, and 169 healthy controls. STAT3 rs1053004 and rs1053005 polymorphisms were genotyped by TaqMan SNP Genotyping Assays. RESULTS: The rs1053004 genotype CC [P value by Bonferroni correction (P c ) = 0.002] and allele C (P c = 0.019) were more frequent in patients with chronic HBV infection than in healthy controls. The rs1053005 genotype GG was also more frequent in patients with chronic HBV infection than in healthy controls (P c = 0.046). The rs1053004-rs1053005 haplotype T-G was less frequent in patients with chronic HBV infection than in healthy controls (Pc < 0.001). Haplotype C-A was more frequent in patients with liver cirrhosis than in patients with HCC (P c = 0.042). The rs1053004 genotype TC, rs1053005 genotype AG and rs1053004-rs1053005 haplotype T-A were associated with higher HBV DNA levels. CONCLUSIONS: STAT3 rs1053004 and rs1053005 polymorphisms and haplotypes formed by rs1053004 and rs1053005 are associated with chronic HBV infection and the haplotypes appear to be also associated with the development of liver disease. Studies in large sample sizes of patients and control populations are required to verify and extend these findings.

Characterization of annual disease progression of multiple sclerosis patients: A population-based study.

BACKGROUND: Previous research characterizing factors influencing multiple sclerosis (MS) disease progression has typically been based on time to disease milestones (Kaplan-Meier, Cox hazard regression, etc.). A limitation of these methods is the handling of the often large groups of patients not reaching the milestone. OBJECTIVE: To characterize clinical factors influencing MS disease progression as annual transitions from each Expanded Disability Status Scale (EDSS). METHOD: The annual progression of 11,964 patients from the Swedish MS Registry was analysed with 10 multinomial logistic regressions, that is, one for transition from each full EDSS with explanatory variables age, sex, age at onset, time in current EDSS, highest prior EDSS, MS course and treatment. RESULTS: All factors (except sex) investigated had statistically significant impacts on transitions from at least one EDSS. However, significance and size of the effect are dependent on the EDSS state of the patient. Greater age, longer time in a state, highest prior EDSS, having progressive MS and treatment had significant impacts, whereas age at onset had minor impact. CONCLUSION: Our study confirms that established factors associated with MS disease worsening in time to disease milestones also have impacts on annual progression. This approach adds granularity to what EDSS these factors have an influence.

Less than 7 hours of sleep per night is associated with transitioning to systemic lupus erythematosus.

Background The role of sleep in the etiology of systemic lupus erythematosus (SLE) has not been well studied. We examined whether sleep duration was associated with subsequent transitioning to SLE in individuals at risk for SLE. Methods Four hundred and thirty-six relatives of SLE patients who did not have SLE themselves at baseline were evaluated again an average of 6.3 (± 3.9) years later. Fifty-six individuals transitioned to SLE (≥ 4 cumulative American College of Rheumatology (ACR) criteria). Sleep duration, medication use and medical history were assessed by questionnaire; ACR criteria were confirmed by medical record review. Vitamin D was measured by ELISA. Generalized estimating equations, accounting for correlation within families, assessed associations between baseline sleep and the outcome of transitioning to SLE. Results Reporting sleeping less than 7 hours per night at baseline was more common in those who subsequently transitioned than those who did not transition to SLE (55% versus 32%, p = 0.0005; OR: 2.8, 95% CI 1.6-4.9). Those who transitioned to SLE were more likely to sleep less than 7 hours per night than those who did not transition to SLE adjusting for age, sex and race (OR: 2.8, 95% CI 1.6-5.1). This association remained after individual adjustment for conditions and early symptoms that could affect sleep, including prednisone use, vitamin D deficiency and number of ACR criteria (OR: 2.0, 95% CI 1.1-4.2). Conclusion Lack of sleep may be associated with transitioning to SLE, independent of early clinical manifestations of SLE that may influence sleep duration. Further evaluation of sleeping patterns and biomarkers in at-risk individuals is warranted.

Serum IP-10 is useful for identifying renal and overall disease activity in pediatric systemic lupus erythematosus.

BACKGROUND: Traditional serological biomarkers often fail to assess systemic lupus erythematosus (SLE) disease activity and discriminate lupus nephritis (LN). The aim of this study was to identify novel markers for evaluating renal and overall disease activity in Chinese patients with pediatric systemic lupus erythematosus (pSLE). METHODS: The study included 46 patients with pSLE (35 girls, 11 boys; average age 13.3 ± 2.6 years) and 31 matched healthy controls (22 girls, 9 boys; average age 12.3 ± 2.4 years). The SLE Disease Activity Index (SLEDAI) and renal SLEDAI were used to assess disease activity. Nine different soluble mediators in plasma, including tumor necrosis factor alpha (TNF-α), platelet-derived growth factor-BB (PDGF-BB), interferon (IFN) gamma inducible protein 10 (IP-10), interleukin (IL)-1ß, IFN-γ, IL-17A, IL-2, Fas and Fas ligand, were measured by Luminex assay and compared between patients with active and inactive pSLE as well as between patients with pSLE with active and inactive renal disease. Receiver operating characteristic curve analysis was used to measure the discrimination accuracy. RESULTS: Of the 46 patients with pSLE, 30 (65.2%) had LN. These patients had significantly elevated levels of serum TNF-α, PDGF-BB, IP-10 and Fas. The serum levels of IP-10 were also significantly higher in patients with active pSLE. We found that IP-10 was also more sensitive and specific than conventional laboratory parameters, including anti-double-stranded DNA and complement components C3 and C4, for distinguishing active lupus from quiescent lupus. The serum level of IP-10 was also significantly increased in children with pSLE with active renal disease relative to those with inactive renal disease. There was also a positive correlation between serum IP-10 levels and renal SLEDAI scores as well as with 24 h urine protein. CONCLUSIONS: Serum IP-10 is useful for identifying renal and overall disease activity in children with pSLE.