[Efficacy and safety of pegylated interferon alpha-2b for patients with myeloproliferative neoplasm].

Objective: To evaluate the efficacy and safety of pegylated interferon alpha-2b (PEG-IFN-α2b) in the treatment of myeloproliferative neoplasm (MPN). Methods: Thirty-four MPN patients receiving PEG-IFN-α2b treatment in the Second Hospital of Tianjin Medical University from August 2019 to October 2022 were prospectively included. Among the patients, 9 were male and 25 were female, and the median age [M (Q1, Q3)] was 57 (19, 78) years. Patients' clinical characteristics were collected and the follow-up was performed. As of January 30, 2023, the follow-up period [M(Q1, Q3)] was 24 (16, 33) months. The efficacy, safety and changes in immune cell and cytokine levels after 12 and 24 months of treatment were analyzed. Results: During the follow-up period, 4 patients dropped out, and the efficacy was evaluable in 30 patients. Following 12 and 24 months of treatment, the complete hematologic response (CHR) rates were 57.1% (16/28) and 75.0% (18/24), respectively. The complete molecular response (CMR)+partial molecular response (PMR) rates were 27.3% (6/22) and 55.0% (11/20), respectively. The bone marrow histopathological overall response rates (ORR) were 34.6% (9/26) and 47.6% (10/21), respectively. At 12 and 24 months of treatment, the proportions of CD8+HLA-DR+T cells, effector T cell subpopulations, CD56bright natural killer (NK) cells, and plasmacytoid dendritic cells (pDC) were higher than the pre-treatment levels, while the proportion of CD56dim NK cells was lower than the pre-treatment level (all P<0.05). The levels of motif chemokine ligand 10 (CXCL10), tumor necrosis factor (TNF)-α and TNF-ß in bone marrow all increased from those prior to treatment, while the levels of vascular endothelial growth factor (VEGF) and interleukin (IL-4) decreased from those prior to treatment (all P<0.05). Among hematological adverse reactions, white blood cells decrease [47% (16/34)] was observed with high incidence. Among non-hematological adverse reactions, asthenia [44.1% (15/34)] and transaminases increase [32.3% (11/34)] were observed with high incidences. Conclusions: PEG-IFN-α2b has high hematologic, molecular, and bone marrow histopathological response rates in the treatment of MPN. It can reduce malignant clone loads and regulate the immune microenvironment and is safe and well tolerated overall.

[Gilbert's syndrome: hyperbilirubinemia enemy or friend].

Gilbert's syndrome is a kind of benign inherited disease of bilirubin binding disorder, mainly due to the homozygous polymorphism A(TA)7TAA in the promoter of the gene for uridine diphosphate -glucuronosyltransferase 1A1 (UGT1A1), which is a TA insertion into the promoter, designated as UGT1A1*28, with UGT activity reduction to 30% of the normal value. Therefore, circulating fat-soluble unconjugated bilirubin cannot be converted into water-soluble conjugated bilirubin, leading to unconjugated hyperbilirubinemia. Bilirubin has a strong affinity for erythrocyte phospholipids, which interferes with membrane composition and dynamics, resulting in increased erythrocytes fragility, easy rupture, and gradual shortening of survival time. However, there are no obvious sign of hemolysis or abnormal iron metabolism, erythrocytes and bone marrow morphology. A small amount of chronic hemolysis stimulates extramedullary (normal bone marrow morphology) hematopoiesis, ensuing compensatory increase in circulating erythrocytes and hemoglobin. Hyperbilirubinemia may also weaken gastrointestinal motility, increase passive diffusion and absorption across the intestinal mucosal epithelium by 1.5 to 2 times, thereby aggravating or worsening hyperbilirubinemia mainly with unconjugated bilirubin circulation, which indicates that there is a causal relationship between the circulating bilirubin concentration and rapid erythrocytes turnover and hemolysis rate in patients with Gilbert's syndrome. Interestingly, bilirubin also has significant antioxidant and anti-mutagenic activities, and the potential health benefits of mild hyperbilirubinemia in Gilbert's syndrome include reduced prevalence of cardiovascular disease, type 2 diabetes mellitus (and related risk factors), certain cancers, and cardiovascular-related and all-cause mortality. Exogenous bilirubin and biliverdin supplements in intestinal epithelial cells can be absorbed and may increase circulating concentration of these antioxidant compounds. With this information, we hope to raise awareness of the potentially harmful and beneficial effects of benign hyperbilirubinemia, and explore and develop beneficial medical interventions.

Morbidity and Safety of Iliac Crest Reference Array Pins in Navigated Total Hip Arthroplasty: A Prospective Cohort Study.

BACKGROUND: Navigated total hip arthroplasty (THA) can employ intra-osseous pins through a separate incision to secure reference arrays to the iliac crest. This study is the first to investigate the consequences of pin use in THA in vivo. METHODS: A prospective, consecutive series of 43 patients presenting for navigated THA were included. Two temporary 125 × 4 mm Schanz screws were inserted into the iliac crest for the attachment of a reference array. Telephone follow-up occurred at 6 and 12 weeks post-operatively. Patients were asked about pain, interference with daily activities, how often the wound was noticed, and duration of discomfort. Patient body mass index was recorded. RESULTS: The follow-up rate was 100%. Pin site pain at any time post-operatively was reported by 24 patients (56%). This improved to 30%, 9%, and 2% at 3, 6, and 12 weeks, respectively. On average, pain lasted for 16 days total. The most common complaints after pain were clothing discomfort (23%), pain when wearing a belt (12%), or pain when mobilizing (9%). For the majority (98%) of patients, all symptoms had resolved by 12 weeks. There was no nerve injury, pin site fracture, infection, or screw breakage. Patients with body mass index greater than 30 kg/m2 were up to 3 times more likely to experience pin site pain (P = .05), and had a longer duration of pain (P = .04). CONCLUSION: Surgeons and patients should be aware that using navigational pins for array fixation carries low complication rates but often will cause pain and irritation that resolves in the short term.

[Clinical value of endoscopicultrsaonography and multi-slice spiral CT in Siewert â ¡and â ¢ type adenocarcinoma of esophagogastric junction].

Objective: To investigate the clinical value of endoscopic ultrasonography (EUS) and Multi-slice Spiral CT (MSCT) in the preoperativestaging of tumor(T) and lymph node (N) metastasis in patients with SiewertⅡand Ⅲ typeadenocarcinoma of esophagogastric junction(AEG). Methods: Clinical data of 145 Siewert Ⅱ and Ⅲ type AEG patientswithout preoperative chemoradiotherapy were retrospectively reviewed. Theyall received preoperative EUS and MSCT examination and underwent surgical resection, and the results of EUS and MSCT were compared with their postoperative pathologic staging. Results: The sensitivity, specificity, and accuracy of EUS for T stage in Siewert Ⅱ and Ⅲ type AEG were higher than those of MSCT. The total accuracy of EUS and MSCT were 90.3% and 63.5%, respectively, and the difference was statistically significant (χ(2)=29.52, P<0.01). The sensitivity of EUS for T1, T2 and T3 were 89.5%, 91.1% and 85.2%, respectively, which were significantly higher than 42.1%, 66.7% and 29.6% of MSCT (χ(2)=9.47, P<0.01 for T1; χ(2)=8.07, P<0.01 for T2; χ(2)=17.40, P<0.01 for T3). In addition, the total accuracy of EUS and MSCT for lymph node metastasis status of Siewert Ⅱ and Ⅲ type AEG were 75.9% and 64.8%, respectively, showing a statistically significant difference(χ(2)=4.23, P=0.04). The sensitivity of EUS for N1 and N2 were 82.1% and 79.2%, respectively, which were significantly higher than 53.6% and 60.4% of MSCT (χ(2)=5.24, P=0.02; χ(2)=4.48, P=0.03). There was no statistical significance for sensitivity of EUS and MSCT in N0 and N3 (P>0.05). Conclusion: EUS diagnosis of T and N staging in Siewert Ⅱ/Ⅲ type AEG showed significantly greater performance than MSCT.

[The effects and mechanisms of berberine on proliferation of papillary thyroid cancer K1 cells induced by high glucose].

Objective: To study the effect and mechanisms of berberine (BBR) on the proliferation of papillary thyroid cancer K1 cells induced by high glucose. Methods: K1 cells were cultured under 5.5 mmol/L or 25 mmol/L glucose condition with or without different concentration of BBR (0, 10, 40 and 80 µmol/L) for 24 hours. The proliferations of K1 cells in each condition were detected by MTT. Western blot was used to measure the expression of nuclear factor erythroid 2-related factor 2(Nrf2), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt) and phosphorylated-Akt (p-Akt). The distribution pattern of Nrf2 in K1 cells was determined using immunofluorescent staining. Results: Compared with 5.5 mmol/L condition, the proliferation rate [(126.64±5.41) % vs (87.31±3.67)%], expression levels of PI3K (0.425±0.019 vs 0.272±0.039), p-Akt/Akt (0.446±0.021 vs 0.168±0.035) and Nrf2 (0.597±0.014 vs 0.308±0.026), and Nrf2 distribution (93.0% vs 23.1%) in nuclear of K 1 cells under 25 mmol/L condition were significantly elevated, respectively (all P<0.01). Addition of BBR in 25 mmol/L condition dose dependently (10, 40, 80 µmol/L) lowered the proliferation rate of K1 cells [(111.76±4.10)%, (70.03±2.18)%, (32.41±3.76)% vs (126.64±5.41)%, all P<0.05], and suppressed the expression of PI3K, p-Akt/Akt, Nrf2, and Nrf2 nuclear distribution (P<0.05). Conclusions: BBR dose dependently inhibited the proliferation of high glucose-induced K1 cells. This effect was associated with the suppression on of PI3K/Akt signaling activation, Nrf2 expression and its nuclear translocation.

An acute intraocular pressure challenge to assess retinal ganglion cell injury and recovery in the mouse.

We describe a model of acute intraocular pressure (IOP) elevation in the mouse eye that induces reversible loss of inner retinal function associated with oxidative stress, glial cell activation and minimal loss of retinal ganglion cell (RGC) number. Young healthy mouse eyes recover inner retinal function within 7-days but more persistent functional loss is seen in older mice. Manipulation of diet and exercise further modify RGC recovery demonstrating the utility of this injury model for investigating lifestyle and therapeutic interventions. We believe that systematic investigation into the characteristics and determinants of RGC recovery following an IOP challenge will shed light on processes that govern RGC vulnerability in the early stages of glaucoma.

Menopause is associated with lumbar disc degeneration: a review of 4230 intervertebral discs.

OBJECTIVE: The main objective of this study was to investigate, in a population of normal postmenopausal women, the association between menopause and severity of lumbar disc degeneration from the first lumbar to the first sacral vertebra on magnetic resonance imaging. METHODS: Between January 2010 and May 2013, 846 normal women and 4230 intervertebral discs were retrospectively analyzed. Age, height, weight and years since menopause (YSM) were recorded. Disc degeneration was evaluated using the modified Pfirrmann grading system. RESULTS: Compared to premenopausal and perimenopausal women, postmenopausal women had more severe disc degeneration after removal of age, height and weight effects (p < 0.0001). Postmenopausal women were divided into six subgroups for every 5 YSM. When YSM was below 15 years, there was a significant difference between every two groups, i.e. groups 1-5 YSM, 6-10 YSM and 11-15 YSM (p < 0.01). A positive trend was observed between YSM and severity of disc degeneration, respectively, i.e. L1/L2 (r = 0.235), L2/L3 (r = 0.161), L3/L4 (r = 0.173), L4/L5 (r = 0.146), L5/S1 (r = 0.137) and all lumbar discs (r = 0.259) (p < 0.05 or 0.01). However, when YSM was above 15, there was no difference, i.e. groups 16-20 YSM, 21-25 YSM and 26-30 YSM (p > 0.05), and the significance correlation also disappeared (p > 0.05). CONCLUSION: Menopause is associated with disc degeneration in the lumbar spine. The association almost entirely occurred in the first 15 years since menopause, suggesting estrogen decrease may be a risk factor for lumbar disc degeneration.

Serum uric acid is associated with arterial stiffness in men with newly diagnosed type 2 diabetes mellitus.

BACKGROUND: Increased serum uric acid levels and vascular atherosclerosis are very common in diabetes. However, few studies focused on the relationship between serum uric acid and aortic or peripheral arterial stiffness in newly diagnosed diabetic patients. This study investigated the association between serum uric acid levels and carotid-femoral pulse wave velocity (cfPWV) or carotid-radial (cr) PWV in male patients with newly diagnosed type 2 diabetes mellitus (T2DM). METHODS: 106 male patients with newly diagnosed T2DM were recruited. cfPWV and crPWV as well as anthropometric parameters, blood pressure, serum uric acid, blood glucose, fasting insulin, C-reactive protein and blood lipids were measured. RESULTS: The subjects were divided into low uric acid (UA) subgroup and high UA subgroup according to uric acid median. cfPWV and crPWV were significantly higher in high UA subgroup. Serum uric acid significantly correlated with cfPWV (r = 0.533, P < 0.001), crPWV (r = 0.334, P = 0.001), waist circumference (r = 0.350, P < 0.001), waist-to-hip ratio (r = 0.254, P = 0.009), fasting insulin (r = 0.432, P < 0.001), HOMA-IR (r = 0.173, P = 0.042), fasting blood glucose (r = -0.271, P = 0.005), haemoglobin A1c (r = -0.202, P = 0.038), and HDL-cholesterol (r = -0.267, P = 0.006) after correction for age. Stepwise multiple regressions showed that the independent determinants of cfPWV were serum uric acid, age, C-reactive protein, HDL-cholesterol, and smoking status. And the independent determinants of crPWV were serum uric acid, age, diastolic blood pressure, and HDL-cholesterol. CONCLUSIONS: Serum uric acid is significantly associated with increased aortic and peripheral arterial stiffness in men with T2DM at the early stage.

Development of a cyclic voltammetry method for the detection of Clostridium novyi in black disease.

Black disease is an acute disease of sheep and cattle. The pathogen is the obligate anaerobe, Clostridium novyi. Due to difficulties of anaerobic culturing in the country or disaster sites, a simple, rapid, and sensitive method is required. In this study, an electrochemical method, the cyclic voltammetry method, basing on loop-mediated isothermal amplification (LAMP), electrochemical ion bonding (positive dye, methylene blue), was introduced. DNA extracted from C. novyi specimens was amplified through the LAMP reaction. Then the products combined were with methylene blue, which lead to a reduction in the oxidation peak current (ipA) and the reduction peak current (ipC) of the cyclic voltammetry. The changes of ipA/ipC were real-time measured by special designed electrode, so the DNA was quantitatively detected. The results displayed that this electrochemical detection of C. novyi could be completed in 1-2 h with the lowest bacterial concentration of 10(2) colony forming units/mL, and high accuracy (96.5%), sensitivity (96%), and specificity (97%) compared to polymerase chain reation. The cyclic voltammetry method was a simple and fast method, with high sensitivity and high specificity, and has great potential to be a usable molecular tool for fast diagnosis of Black disease.

[Clinical characteristics of myeloid tumors combined with the proliferation of large granular lymphocytes].

Myeloid neoplasms (MNs) belong to a group of hematological malignancies characterized by the abnormal biological functions of hematopoietic stem progenitor cells. The abnormal immune and hematopoietic microenvironment of patients with MN interact with malignant clonal hematopoietic stem cells, promoting the occurrence and development of their diseases. MN large granular lymphocyte proliferation (MN-LGLP) is a special and rare clinical phenomenon in this type of disease. Currently, research on this disease in domestic and international cohorts is limited. This study analyzes the clinical and laboratory characteristics of this type of patient and explores the impact of LGLP on the clinical characteristics and survival of patients with MN. Patients with MN-LGLP are prone to neutropenia and splenomegaly. The presence of LGLP is not a risk factor affecting the survival of patients with MN-LGLP. STAG, ASXL1, and TET2 are the most common accompanying gene mutations in MN-LGLP, and patients with MN-LGLP and STAG2 mutations have poor prognoses.

DNA detection of Clostridium difficile infection based on real-time resistance measurement.

We used a newly developed electrochemical method, real-time resistance measurement, based on loop-mediated isothermal amplification (LAMP), with real-time resistance monitoring and derivative analysis. DNA extracted from specimens was amplified through LAMP reaction. The 2 products of LAMP, DNA and pyrophosphate, both are negative ions; they combine with positive dye (crystal violet) and positive ions (Mg(2+)), which leads to an increase in the resistivity of the reaction liquid. The changes of resistivity were measured in real-time with a specially designed resistance electrode, to detect Clostridium difficile DNA. We found that electrochemical detection of C. difficile could be completed in 0.5-1 h, with a detection limit of 10(2) CFU/mL, with high accuracy (95.0%), sensitivity (91.1%), and specificity (97.3%) compared to PCR methods. C. difficile is commonly associated with antibiotic-induced diarrhea. Due to the difficulty in performing anaerobic culture and cytotoxicity neutralization assays, a simple, rapid, sensitive, and accurate method is preferred. We conclude that real-time resistance measurement is a rapid, sensitive, and stable method for the diagnosis of C. difficile infection that could be applied to gene chips and pocket instruments.

Ischemic postconditioning attenuates liver warm ischemia-reperfusion injury through Akt-eNOS-NO-HIF pathway.

BACKGROUND: Ischemic postconditioning (IPO) has been demonstrated to attenuate ischemia/reperfusion (I/R) injury in the heart and brain, its roles to liver remain to be defined. The study was undertaken to determine if IPO would attenuate liver warm I/R injury and its protective mechanism. METHODS: Mice were divided into sham, I/R, IPO+I/R (occlusing the porta hepatis for 60 min, then treated for three cycles of 10 sec brief reperfusion consecutively, followed by a persistent reperfusion); L-NAME+ sham (L-NAME, 16 mg/kg, i.v., 5 min before repefusion); L-NAME+I/R; and L-NAME+ IPO. Blood flow of caudate and left lobe of the liver was blocked. Functional and morphologic changes of livers were evaluated. Contents of nitric oxide, eNOS and iNOS in serum were assayed. Concentration of eNOS, iNOS, malondialdehyde (MDA) and activity of superoxide dismutase (SOD) in hepatic tissue were also measured. Expressions of Akt, p-Akt and HIF-1α protein were determined by western blot. Expressions of TNF-α and ICAM-1 were measured by immunohistochemistry and RT-PCR. RESULTS: IPO attenuated the dramatically functional and morphological injuries. The levels of ALT was significantly reduced in IPO+I/R group (p < 0.05). Contents of nitric oxide and eNOS in serum were increased in the IPO+I/R group (p < 0.05). IPO also up-regulated the concentration of eNOS, activity of SOD in hepatic tissue (p < 0.05), while reduced the concentration of MDA (p < 0.05). Moreover, protein expressions of HIF-1α and p-Akt were markedly enhanced in IPO+I/R group. Protein and mRNA expression of TNF-α and ICAM-1 were markedly suppressed by IPO (p < 0.05). These protective effects of IPO could be abolished by L-NAME. CONCLUSIONS: We found that IPO increased the content of NO and attenuated the overproduction of ROS and I/R-induced inflammation. Increased NO contents may contribute to increasing HIF-1α level, and HIF-1α and NO would simultaneously protect liver from I/R injury. These findings suggested IPO may have the therapeutic potential through Akt-eNOS-NO-HIF pathway for the better management of liver I/R injury.

Glaucomatous optic neuropathy evaluation project: a standardized internet system for assessing skills in optic disc examination.

BACKGROUND: Development of a standardized internet-based system to self-assess skills in optic disc examination for glaucoma risk assessment. DESIGN: Prospective internet-based observational study. PARTICIPANTS: Total of 197 participants (glaucoma subspecialists, general ophthalmologists and trainees) from 22 countries. METHODS: Forty-two optic disc images demonstrating a range of features were selected from 2500 monoscopic disc photographs of normal and glaucomatous eyes. Images were presented to clinicians via website (http://www.gone-project.com). Participants were asked to assess nine topographic features and make a subjective assessment of glaucoma likelihood. MAIN OUTCOME MEASURES: Inter-observer agreement using kappa (κ) or weighted kappa (κ(w) ). RESULTS: There was substantial level of inter-observer agreement between glaucoma subspecialists for assessment of glaucoma likelihood (κ(w) = 0.63). Inter-observer agreement was high for haemorrhage (κ= 0.83) and substantial for disc size, disc shape, cup:disc ratio, peripapillary atrophy and cup shape (κ(w) = 0.59-0.68). Subspecialists had stronger inter-observer agreement for glaucoma likelihood and for most disc characteristics than did trainees: the greatest difference being the assessment for retinal nerve fibre layer loss. Analysis of individual disc answers from ophthalmology trainees showed that discs leading to lower agreement of glaucoma likelihood tend to produce lower agreement for the assessment of cup:disc ratio, cup shape, cup depth and retinal nerve fibre layer. Discs with features of moderate to deep cup or cup:disc ratio between 0.6 and 0.8 also lead to lower agreement in glaucoma likelihood. CONCLUSIONS: This internet-based system is a readily accessible and standardized tool, for clinicians globally, that permits self-assessment and benchmarking of skills in optic disc examination.

High expression of ACE2 in the human lung leads to the release of IL6 by suppressing cellular immunity: IL6 plays a key role in COVID-19.

OBJECTIVE: The pathogenesis of coronavirus disease 2019 (COVID-19) remains clear, and no effective treatment exists. SARS-CoV-2 is the virus that causes COVID-19 and uses ACE2 as a cell receptor to invade human cells. Therefore, ACE2 is a key factor to analyze the SARS-CoV-2 infection mechanism. MATERIALS AND METHODS: We included 9,783 sequencing results of different organs, analyzed the effects of different ACE2 expression patterns in organs and immune regulation. RESULTS: We found that ACE2 expression was significantly increased in the lungs and digestive tract. The cellular immunity of individuals with elevated ACE2 expression is activated, whereas humoral immunity is dampened, leading to the release of many inflammatory factors dominated by IL6. Furthermore, by studying the sequencing results of SARS-CoV-2-infected and uninfected cells, IL6 was found to be an indicator of a significant increase in the number of infected cells. However, although patients with high expression of ACE2 will release many inflammatory factors dominated by IL6, cellular immunity in the colorectum is significantly activated. This effect may explain why individuals with SARS-CoV-2 infection have severe lung symptoms and digestion issues, which are important causes of milder symptoms. CONCLUSIONS: This finding indicates that ACE2 and IL6 inhibitors have important value in COVID-19.

Investigations on the complex flows induced by dual-swept/dual-ramp wedges in supersonic flows.

The caret inlet with a dual-swept/dual-ramp configuration has excellent stealth performance and aerodynamic capability. Most previous investigations on this configuration have focused on experiments and numerical simulations but there are relatively few theoretical investigations. In this study, the flow field characteristics of dual-swept/dual-ramp configuration are investigated analytically and numerically. An analytical approach that combines the shock dynamics with a "spatial dimension reduction" was used to analyze the characteristics of the wave structures and state parameters of the flow field. The effects of the sweep angles and inflow Mach number on the flow field characteristics are investigated. The results indicate that the problem of shock/shock interaction in two intersecting wedges of large back-swept angle is a problem of weak shock interaction. Therefore, the theory of weak shock interaction is used to investigate the flow field characteristics, including the uniformity of the flow field and the total pressure recovery performance.

Association between plasma osteoprotegerin concentrations and urinary albumin excretion in Type 2 diabetes.

AIMS: Osteoprotegerin (OPG) is a recently identified inhibitor of bone resorption. Recent studies indicate that OPG is also associated with endothelial dysfunction in Type 2 diabetes. The aim was to investigate the relationship between plasma OPG levels and urinary albumin excretion (UAE) in Type 2 diabetic patients. METHODS: This study included 154 newly diagnosed Type 2 diabetic patients and 46 healthy subjects. Plasma OPG and 24-h UAE were measured. High-resolution ultrasound was used to measure flow-mediated (endothelium-dependent arterial) dilation (FMD). RESULTS: Compared with the normoalbuminuric subgroup, OPG levels in the microalbuminuric subgroup were significantly higher, and OPG levels in macroalbuminuria subgroup were significantly higher than those in the normoalbuminuria and albuminuria subgroups. Multiple regression analysis showed that only FMD (r = -0.26), C-reactive protein (r = 0.23), fasting blood glucose (r = 0.25), 2-h blood glucose (r = 0.21), HbA(1c) (r = 0.28), UAE (r = 0.27) and retinopathy (r = 0.27) were significant factors associated with OPG. Pearson's correlation analyses showed a positive correlation between OPG and logUAE (r = 0.440) and negative correlations between OPG and FMD (r = -0.284), and between FMD and logUAE (r = -0.602). CONCLUSIONS: Plasma OPG levels are significantly associated with UAE in Type 2 diabetic patients.