TM6SF2 reduces lipid accumulation in vascular smooth muscle cells by inhibiting LOX-1 and CD36 expression.

TM6SF2, predominantly expressed in the liver and intestine, is closely associated with lipid metabolism. We have demonstrated the presence of TM6SF2 in VSMCs within human atherosclerotic plaques. Subsequent functional studies were conducted to investigate its role in lipid uptake and accumulation in human vascular smooth muscle cells (HAVSMCs) using siRNA knockdown and overexpression techniques. Our results showed that TM6SF2 reduced lipid accumulation in oxLDL-stimulated VSMCs, likely through the regulation of lectin-like oxLDL receptor 1 (LOX-1) and scavenger receptor cluster of differentiation 36 (CD36) expression. We concluded that TM6SF2 plays a role in HAVSMC lipid metabolism with opposing effects on cellular lipid droplet content by downregulation of LOX-1 and CD36 expression.

[Identification of cardioprotective substances in Panax ginseng/P. notoginseng based on mitochondrial morphological characteristics and UPLC-Triple-TOF-MS].

Panax ginseng is reputed to be capable of replenishing healthy Qi and bolstering physical strength, and P. notoginseng can resolve blood stasis and alleviate pain. P. ginseng and P. notoginseng are frequently employed to treat ischemic heart diseases caused by blockages in the heart vessels. Mitochondrial dysfunction often coexists with abnormal mitochondrial morphology, and mitochondrial plasticity and dynamics play key roles in cardiovascular diseases. In this study, primary neonatal rat cardiomyocytes were exposed to 4 hours of hypoxia(H) followed by 2 hours of reoxygenation(R). MitoTracker Deep Red and Hoechst 33342 were used to label mitochondria and nuclei, respectively. Fluorescence images were then acquired using ImageXpress Micro Confocal. Automated image processing and parameter extraction/calculation were carried out using ImagePro Plus. Subsequently, representative parameters were selected as indicators to assess alterations in mitochondrial morphology and function. The active compounds of P. ginseng and P. notoginseng were screened out and identified based on the UPLC-Triple-TOF-MS results and mitochondrial morphometric parameters. The findings demonstrated that RS-2, RS-4, SQ-1, and SQ-4 significantly increased the values of three key morphometric parameters, including mitochondrial length, branching, and area, which might contribute to rescuing morphological features of myocardial cells damaged by H/R injury. Among the active components of the two medicinal herbs, 20(R)-ginsenoside Rg_3, ginsenoside Re, and gypenoside ⅩⅦ exhibited the strongest protective effects on mitochondria in cardiomyocytes. Specifically, 20(R)-ginsenoside Rg_3 might upregulate expression of optic atrophy 1(OPA1) and mitofusin 2(MFN2), and ginsenoside Re and gypenoside ⅩⅦ might selectively upregulate OPA1 expression. Collectively, they promoted mitochondrial membrane fusion and mitigated mitochondrial damage, thereby exerting protective effects on cardiomyocytes. This study provides experimental support for the discovery of novel therapeutic agents for myocardial ischemia-reperfusion injury from P. ginseng and P. notoginseng and offers a novel approach for large-scale screening of bioactive compounds with cardioprotective effects from traditional Chinese medicines.

CDER167, a dual inhibitor of URAT1 and GLUT9, is a novel and potent uricosuric candidate for the treatment of hyperuricemia.

Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [14C]-uric acid in URAT1-expressing HEK293 cells with an IC50 value of 2.08 ± 0.31 µM, which was similar to that of RDEA3170 (its IC50 value was 1.47 ± 0.23 µM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC50 value of 91.55 ± 15.28 µM, whereas RDEA3170 at 100 µM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg-1 · d-1) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg-1 · d-1) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 µM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.

Optical control of the rotation of cholesteric liquid crystal gratings.

Two photoalignment-based methods to achieve orientational control of optical diffractions by cholesteric liquid crystal (CLC) fingerprint gratings are proposed and demonstrated. A trace of methyl red in the CLC host can effectively induce surface alignment upon linearly polarized green exposure and enable optically rewritable alignment. An effective rotation of the photo-aligned CLC grating is attained by changing the surface alignment axis. Using axially symmetric photoalignment, electrically tunable radial and concentric gratings are also realized. 1D grating diffraction is produced by operating off-axis and can be rotated by mechanically moving the axially symmetric grating. Such optical gratings have great potential for practical use in vibration detection, multi-directional optical modulations, and beam steering.

Anatomic Locking Plate for Displaced Intraarticular Calcaneal Fracture: Design and Application.

Calcaneal fracture can lead to long-term disability and have a considerable economic effect. Most calcaneal fractures are intraarticular fractures involving the posterior facet of the subtalar joint. Treating displaced intraarticular calcaneal fractures is complicated because of the lack of an optimal treatment option. Internal fixation typically involves screw-and-plate implants, which can be unfavorable owing to the lack of an anatomic design and the intraoperative bending required for the plate to contour to the irregular surface of the calcaneus. We assessed the outcomes of 30 patients treated using innovative, anatomically designed calcaneal locking plates and the perceived advantages for surgeons. Postoperative computed tomography images of the affected feet were obtained, and the functional performance was recorded. The mean average Böhler angle had increased significantly from 16.8° ± 14.9° to 28.5° ± 9.4° (p < .001). The mean average maximal fracture gap and maximal step-off in the posterior facet of the subtalar joint in the coronal computed tomography images also decreased significantly from 2.8 ± 3.7 mm to 0.8 ± 1.3 mm (p < .01) and from 3.3 ± 2.8 mm to 0.8 ± 1.2 mm (p < .001), respectively. The mean average American Orthopaedic Foot and Ankle Ankle-Hindfoot scale score was 93.9 ± 7.1 at the final follow-up visit. In addition, the surgical time was reduced because bending the plate was not required and the quality of reduction could be assessed easily by examining the gap between the cortex and the plate. The results were promising, revealing that the anatomic locking plate can be used effectively in the treatment of displaced intraarticular calcaneal fractures using simple reduction techniques with a potentially shortened operating time.

Image changes of paraspinal muscles and clinical correlations in patients with unilateral lumbar spinal stenosis.

STUDY DESIGN: This is a retrospective study. PURPOSE: To compare the morphometric parameters of the psoas major and lumbar multifidus muscles in lumbar spinal stenosis (LSS) patients exhibiting different functional performance. LSS refers to symptoms related to size reduction of the lumbar spinal canal; however, the degree of stenosis is poorly related to symptom severity and functional impairments. Morphometric changes in the paraspinal muscles have been correlated with chronic lower back pain in previous studies. However, correlations between the functional performance of LSS patients and the morphometric changes in paraspinal muscles have seldom been reported. METHODS: Sixty-six LSS patients without mechanical back pain or segmental instability were enrolled in the study. A review of their medical records and MRI images was performed. Morphometric parameters, including the fatty infiltration (FI) of the lumbar multifidus muscle as well as the relative cross-sectional area (RCSA) of the psoas major and lumbar multifidus muscles, were measured. Subjects were divided into high and low functional performance groups according to their Japanese Orthopedic Association (JOA) scores. RESULTS: The male LSS patients exhibited a larger psoas RCSA than the female patients, whereas the older patients exhibited a smaller psoas RCSA and higher multifidus FI than the younger patients. LSS patients in the high functional performance group exhibited a significantly larger psoas RCSA and lower multifidus FI. CONCLUSION: The psoas RCSA and multifidus FI can be used as predictive factors for functional performance in LSS patients.

Minimally Invasive Chevron Akin (MICA) Osteotomy Corrects Radiographic Parameters but Not Central Metatarsal Loading in Moderate to Severe Hallux Valgus without Metatarsalgia.

BACKGROUND: Central metatarsal pressure is increased in patients with hallux valgus, but the pedographic outcomes after hallux valgus (HV) correction are inconclusive. No known literature has reported the pedographic outcomes after HV correction with Minimally Invasive Chevron and Akin Osteotomy (MICA). METHODS: A prospective cohort of 31 feet from 25 patients with moderate-to-severe symptomatic HV but without metatarsalgia underwent MICA and was evaluated using radiographic parameters and pedographic measurements (Footscan®, RSscan International, Olen, Belgium). Data were collected preoperatively and 3 months after surgery. RESULTS: The radiographic parameters of the hallux valgus angle, intermetatarsal angle, distal metatarsal articular angle, first metatarsal head lateral shape, and lateral sesamoid grade significantly improved after MICA. The corrected first metatarsal length was significantly shortened by 2.3 mm, with consistent second metatarsal protrusion distance, lateral Meary's angle, and calcaneal pitch angle. Max force, max pressure, cumulative force, and cumulative pressure on the central metatarsals did not show significant changes between pre- and post-operative measurements, while these parameters significantly decreased in the hallux and first metatarsal area. CONCLUSION: MICA effectively corrects radiographic parameters but does not reduce central metatarsal loading in patients with moderate-to-severe HV without metatarsalgia.

Risk of herpes simplex virus infection in solid organ transplant recipients: A population-based cross-sectional study.

BACKGROUND: Herpes simplex virus (HSV) is an opportunistic infection antigen in solid organ transplant (SOT) recipients. However, this phenomenon has received limited attention from epidemiologists. Our study aims to determine the HSV infection risk in SOT recipients. METHODS: This was a nationwide population-based cross-sectional study based on the National Health Insurance Research Database from 2002 to 2015. We used propensity score matching to avoid selection bias and analyzed the association between HSV infection and SOT recipients with multiple logistic regression analysis. RESULTS: At a 3-year follow-up, SOT recipients had a higher risk of developing HSV, with an adjusted odds ratio (aOR) of 3.28 (95% confidence interval (CI), 2.51-4.29). Moreover, at 6-month, 1-year, and 2-year follow-ups, SOT recipients also had an increased risk of HSV than general patients with aORs of 3.85 (95% CI, 2.29-6.49), 4.27 (95% CI, 2.86-6.36), and 3.73 (95% CI, 2.74-5.08), respectively. In the subgroup analysis, lung transplant recipients (aOR = 8.01; 95% CI, 2.39-26.88) exhibited a significantly higher chance of HSV among SOT recipients, followed by kidney transplant recipients (aOR = 3.33; 95% CI, 2.11-5.25) and liver transplant recipients (aOR = 3.15; 95% CI, 2.28-4.34). CONCLUSION: HSV can develop at any time after organ transplantation. SOT recipients had a higher risk of HSV infection than the general population at 6 months, 1 year, 2 years, and 3 years after transplantation, with the highest chance at 1 year after. In addition, the patients who underwent lung transplantion were at higher risk for HSV infection than liver or kidney transplant recipients.

A novel inverse membrane bioreactor for efficient bioconversion from methane gas to liquid methanol using a microbial gas-phase reaction.

BACKGROUND: Methane (CH4), as one of the major energy sources, easily escapes from the supply chain into the atmosphere, because it exists in a gaseous state under ambient conditions. Compared to carbon dioxide (CO2), CH4 is 25 times more potent at trapping radiation; thus, the emission of CH4 to the atmosphere causes severe global warming and climate change. To mitigate CH4 emissions and utilize them effectively, the direct biological conversion of CH4 into liquid fuels, such as methanol (CH3OH), using methanotrophs is a promising strategy. However, supplying biocatalysts in an aqueous medium with CH4 involves high energy consumption due to vigorous agitation and/or bubbling, which is a serious concern in methanotrophic processes, because the aqueous phase causes a very large barrier to the delivery of slightly soluble gases. RESULTS: An inverse membrane bioreactor (IMBR), which combines the advantages of gas-phase bioreactors and membrane bioreactors, was designed and constructed for the bioconversion of CH4 into CH3OH in this study. In contrast to the conventional membrane bioreactor with bacterial cells that are immersed in an aqueous phase, the filtered cells were placed to face a gas phase in the IMBR to supply CH4 directly from the gas phase to bacterial cells. Methylococcus capsulatus (Bath), a representative methanotroph, was used to demonstrate the bioconversion of CH4 to CH3OH in the IMBR. Cyclopropanol was supplied from the aqueous phase as a selective inhibitor of methanol dehydrogenase, preventing further CH3OH oxidation. Sodium formate was added as an electron donor to generate NADH, which is necessary for CH3OH production. After optimizing the inlet concentration of CH4, the mass of cells, the cyclopropanol concentration, and the gas flow rate, continuous CH3OH production can be achieved over 72 h with productivity at 0.88 mmol L-1 h-1 in the IMBR, achieving a longer operation period and higher productivity than those using other types of membrane bioreactors reported in the literature. CONCLUSIONS: The IMBR can facilitate the development of gas-to-liquid (GTL) technologies via microbial processes, allowing highly efficient mass transfer of substrates from the gas phase to microbial cells in the gas phase and having the supplement of soluble chemicals convenient.

Clinical features of macular telangiectasia type 2 and comparison of staging system in Taiwanese patients.

PURPOSE: The purpose of this study is to report the clinical characteristics of macular telangiectasia type 2 (MacTel 2) in Taiwan. MATERIALS AND METHODS: Retrospective analysis of patients diagnosed with MacTel 2 over a 7-year period in Changhua Christian Hospital. Best-corrected visual acuity (BCVA), fundus photography, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography (OCTA) images were reviewed. Differences in BCVA and central macular thickness (CMT) were compared between the initial/baseline and final visits. The staging was performed according to the Gass and Blodi classification and OCTA. RESULTS: There were 38 eyes in 19 patients were collected (Male: Female = 5:14). The mean age at diagnosis was 65.90 ± 8.26 years and the follow-up duration was 39.26 ± 28.31 months. All patients had both eyes affected, and eight of the 19 patients had a history of diabetes mellitus (DM). The mean initial logarithm of the minimum angle of resolution (logMAR) BCVA was 0.40 ± 0.31 and the mean final logMAR BCVA was 0.61 ± 0.53. Difference of BCVA equal or more than two lines between both eyes was noted in 63.1% (12 of 19) of patients at the initial visit and in 78.9% (15 of 19) of patients at the final follow-up. The mean CMT was 224.42 ± 38.50 µm at baseline and 222.05 ± 40.27 µm at the final visit. OCT illustrated macular hole in three eyes of three patients. At the final follow-up, retinal-choroidal anastomosis was noted in 17 eyes. Subretinal neovascularization (SRNV) was not present in any eye. CONCLUSION: Bilateral involvement, asymmetrical BCVA in both eyes, low incidence of SRNV, and high prevalence of DM were characteristics of patients of MacTel 2 in Taiwan.

RNA analysis of diet-induced sarcopenic obesity in rats.

Obesity has been suggested as a risk factor for sarcopenia. Sarcopenic obesity (SO), as a new category of obesity, is a high-risk geriatric syndrome in elderly individuals. However, knowledge about the molecular pathomechanisms of SO is still sparse. In the present study, starting at 13 months, male Sprague-Dawley (SD) rats were fed a high-fat diet (HFD) and normal diet (ND) for 28 weeks to establish a rodent animal model of SO with an identical protocol, which was further assessed and verified as a successful SO model. Through RNA-seq analysis of gastrocnemius muscle in SO rats, we found that differentially expressed genes (DEGs) and alternative splicing events (ASEs) focused mainly on inflammatory, immune-response, skeletal muscle cell differentiation, fat cell differentiation and antigen processing and presentation. Furthermore, as the core regulation factor of skeletal muscle, the mef2c (myocyte enhancer Factor 2C) gene also has a significant alternative 3' splice site (A3SS) and down-regulated expression in HFD-induced SO. The alternative genes targeted by mef2c identified by GO analysis were enriched in transcript regulation of RNA polymerase II promoter. In conclusion, these explorative findings in aging high-fat-fed rats might serve as a firm starting point for understanding the pathway and mechanism of sarcopenic obesity.

Incidence and predictive value of social frailty among community-dwelling older adults in Southwest China: A prospective cohort study.

Background: Few studies have focused on the incidence and correlation of social frailty (SF) with adverse health events in Southwest China. This study aims to explore the predictive value of SF for adverse health events. Methods: A 6-year prospective cohort study was employed, a total of 460 community-dwelling older adults aged 65 years and above were analyzed to provide a baseline in 2014. Participants completed two longitudinal follow-ups at 3 (2017, 426 participants involved) and 6 (2020, 359 participants involved) years later. A modified social frailty screening index was used in this study, and adverse health events such as physical frailty (PF) deterioration, disability, hospitalization, falls, and mortality were evaluated. Results: Among these participants in 2014, the median age was 71 years, 41.1% were male, and 71.1% were married or cohabiting, up to 112 (24.3%) of them were classified as SF. It was observed that aging (OR = 1.04, 95% CI = 1.00-1.07, P = 0.047) and having family members die in the past year (OR = 2.60, 95% CI = 0.93-7.25, P = 0.068) were risk factors of SF, whereas having a mate (OR = 0.40, 95% CI = 0.25-0.66, P = 0.000) and having family members to help with care (OR = 0.53, 95% CI = 0.26-1.11, P = 0.092) were protective factors of SF. The cross-sectional study demonstrated that SF was only significantly associated with disability (OR = 12.89, 95% CI = 2.67-62.13, P = 0.001) at wave 1. Baseline SF significantly explained the incidence of mortality at the 3-year (medium-term, OR = 4.89, 95% CI = 2.23-10.71, P = 0.000) and 6-year follow-ups (long-term, OR = 2.22, 95% CI = 1.15-4.28, P = 0.017). Conclusion: SF prevalence was higher in the Chinese older population. Older adults with SF had a significantly increased incidence of mortality at the longitudinal follow-up. Consecutive comprehensive health management of SF (e.g., avoiding living alone and increasing social engagement) is urgently needed for the purposes of early prevention and multidimensional intervention in adverse health events, including disability and mortality.

Nitidine chloride regulates cell function of bladder cancer in vitro through downregulating Lymphocyte antigen 75.

Nitidine chloride (NC) is effective on cancer in many tumors, but its effect on bladder cancer (BC) is unknown. We conducted cell function experiments to verify the antineoplastic effect of NC on BC cell lines (5637, T24, and UM-UC-3) in vitro. Then, mRNAs of NC-treated and NC-untreated BC cells were extracted for mRNA sequencing. Differentially expressed genes (DEGs), expression analysis, and drug molecular docking were conducted to discover the target gene of NC. Finally, functional enrichment was analyzed to explore the underlying mechanisms. NC dramatically inhibited proliferation, migration, and invasion, and it induced apoptosis and arrested the S and G2/M phases of BC cell lines. Lymphocyte antigen 75 (LY75) appeared to be the target of NC. LY75 was highly expressed and had the ability to distinguish BC tissue from non-cancerous tissue. Then, drug molecular docking confirmed the targeting relationship between NC and LY75. Gene enrichment analysis showed that the downregulated genes, after being treated with NC, were mainly enriched in pathways relevant to cell pathophysiological processes. NC inhibits BC cell proliferation, migration, and invasion, induces apoptosis, and arrests cell cycles by downregulating the expression of LY75. This study provides molecular and theoretical bases for NC treatment of BC.

Electrical control of shape of laser beam using axially symmetric liquid crystal cells.

This work demonstrates the electrical tuning of laser beam shape using an axially symmetric dye-dope liquid crystal (ASDDLC) device that is fabricated using a photo-alignment method. Various beam shapes can be obtained by linearly polarized Gaussian laser beams through an ASDDLC device under various applied voltages. The far-field intensity patterns generated by laser beams of selected shapes under various applied voltages are simulated, and the results are consistent with experiment. A rotatable petal-shaped beam is obtained by controlling the polarization of the output donut-shaped beam. The tenability of beam shape of light with a wavelength of 1064 nm, which is commonly used in biomedical applications, is also demonstrated.

[Differential liver histopathological features of chronic HBV infection patients with normal and mildly elevated serum ALT].

To study the liver histopathological features that are distinctive between chronic hepatitis B virus (HBV) infection patients who have normal serum alanine aminotransferase (ALT)/asparatate aminotransferase (AST) and those with mildly elevated serum ALT/AST. One-hundred-and-thrity-four chronic HBV infection patients with normal serum ALT/AST and 165 chronic HBV infection patients with mildly elevated serum ALT/AST were included in the study. Liver biopsies were performed and used to assess the histological changes by hematoxylin-eosin and reticular fiber staining; mild to severe scoring for inflammation was made as grade G0-G4 and for fibrosis stage as S0-S4. HBV DNA levels were detected by fluorescent quantitative PCR. HBV serological markers were examined by chemiluminescence. The mildly elevated serum ALT/AST group had more male patients than the normal serum ALT/AST group. In the normal serum ALT/AST group, 50.0% (67/134) of the patients had moderate histological changes and only 3.0% (4/134) had severe changes (G3-4 and/or S3-4). In the mildly elevated ALT/AST group, 65.7% (174/265) of patients had moderate histological changes and 16.2% (43/265) had severe changes (G3-4 and/or S3-4). Hepatic inflammation and fibrosis were significantly more severe in the mildly elevated serum ALT/AST group than in the normal ALT/AST group (x2 = 26.386, P less than 0.01; x2 = 15.299, P less than 0.01). In the normal ALT/AST group, the severity of inflammation and fibrosis were positively correlated with age (rs = 0.620, P less than 0.01; rs = 0.347, P less than 0.01). In the mildly elevated ALT/AST group, the severity of inflammation and fibrosis were negatively correlated with age (rs = -0.807, P less than 0.01; rs = -0.557, P less than 0.01). In both groups, the severity of inflammation and fibrosis were negatively correlated with HBV DNA levels (rs = -0.215, P less than 0.01, rs = -0.527, P less than 0.01, rs = -0.951, P less than 0.01; rs = -0.715, P less than 0.01) and were not positively correlated with HBeAg. The majority of the chronic HBV infection patients with normal serum ALT/AST and those with mildly elevated serum ALT/AST had moderate liver pathological changes. All patients with low HBV DNA levels were closely followed-up, regardless of HBeAg-positive status.

Polarization-independent liquid crystal lens based on axially symmetric photoalignment.

A polarization-independent liquid crystal lens that is based on axially symmetric photoalignment is demonstrated. This liquid crystal lens is fabricated by combining radially and azimuthally aligned liquid crystal films with gradient alignments. The configurations of liquid crystals on the substrates are confirmed both optically and using a scanning electron microscope. The focal length of the polarization-independent liquid crystal lens can be controlled by applying various voltages. The device is simple to fabricate, and very convenient to use. It therefore has great practical potential.

Metabolic alteration of Methylococcus capsulatus str. Bath during a microbial gas-phase reaction.

This study demonstrates the metabolic alteration of Methylococcus capsulatus (Bath), a representative bacterium among methanotrophs, in microbial gas-phase reactions. For comparative metabolome analysis, a bioreactor was designed to be capable of supplying gaseous substrates and liquid nutrients continuously. Methane degradation by M. capsulatus (Bath) was more efficient in a gas-phase reaction operated in the bioreactor than in an aqueous phase reaction operated in a batch reactor. Metabolome analysis revealed remarkable alterations in the metabolism of cells in the gas-phase reaction; in particular, pyruvate, 2-ketoglutarate, some amino acids, xanthine, and hypoxanthine were accumulated, whereas 2,6-diaminopimelate was decreased. Based on the results of metabolome analysis, cells in the gas-phase reaction seemed to alter their metabolism to reduce the excess ATP and NADH generated upon increased availability of methane and oxygen. Our findings will facilitate the development of efficient processes for methane-based bioproduction with low energy consumption.

Modified procedure for prolapse and hemorrhoids: Lower recurrence, higher satisfaction.

BACKGROUND: Hemorrhoidal prolapse is a common benign disease with a high incidence. The treatment procedure for prolapse and hemorrhoids (PPH) remains an operative method used for internal hemorrhoid prolapse. Although it is related to less pos-operative pain, faster recovery and shorter hospital stays, the postoperative recurrence rate is higher than that of the Milligan-Morgan hemorrhoidectomy (MMH). We have considered that recurrence could be due to shortage of the pulling-up effect. This issue may be overcome by using lower purse-string sutures [modified-PPH (M-PPH)]. AIM: To compare the therapeutic effects and the patients' satisfaction after M-PPH, PPH and MMH. METHODS: This retrospective cohort study included 1163 patients (M-PPH, 461; original PPH, 321; MMH, 381) with severe hemorrhoids (stage III/IV) who were admitted to The 2nd Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University from 2012 to 2014. Early postoperative complications, efficacy, postoperative anal dysfunction and patient satisfaction were compared among the three groups. Established criteria were used to assess short- and long-term postoperative complications. A visual analog scale was used to evaluate postoperative pain. Follow-up was conducted 5 years postoperatively. RESULT: Length of hospital stay and operating time were significantly longer in the MMH group (8.05 ± 2.50 d, 19.98 ± 4.21 min; P < 0.0001) than in other groups. The incidence of postoperative anastomotic bleeding was significantly lower after M-PPH than after PPH or MMH (1.9%, 5.1% and 3.7%; n = 9, 16 and 14; respectively). There was a significantly higher rate of sensation of rectal tenesmus after M-PPH than after MMH or PPH (15%, 8% and 10%; n = 69, 30 and 32; respectively). There was a significantly lower rate of recurrence after M-PPH than after PPH (8.7% and 18.8%, n = 40 and 61; P < 0.0001). The incidence of postoperative anal incontinence differed significantly only between the MMH and M-PPH groups (1.3% and 4.3%, n = 5 and 20; P = 0.04). Patient satisfaction was significantly greater after M-PPH than after other surgeries. CONCLUSION: M-PPH has many advantages for severe hemorrhoids (Goligher stage III/IV), with a low rate of anastomotic bleeding and recurrence and a very high rate of patient satisfaction.

Computational modeling with forward and reverse engineering links signaling network and genomic regulatory responses: NF-kappaB signaling-induced gene expression responses in inflammation.

BACKGROUND: Signal transduction is the major mechanism through which cells transmit external stimuli to evoke intracellular biochemical responses. Diverse cellular stimuli create a wide variety of transcription factor activities through signal transduction pathways, resulting in different gene expression patterns. Understanding the relationship between external stimuli and the corresponding cellular responses, as well as the subsequent effects on downstream genes, is a major challenge in systems biology. Thus, a systematic approach is needed to integrate experimental data and theoretical hypotheses to identify the physiological consequences of environmental stimuli. RESULTS: We proposed a systematic approach that combines forward and reverse engineering to link the signal transduction cascade with the gene responses. To demonstrate the feasibility of our strategy, we focused on linking the NF-kappaB signaling pathway with the inflammatory gene regulatory responses because NF-kappaB has long been recognized to play a crucial role in inflammation. We first utilized forward engineering (Hybrid Functional Petri Nets) to construct the NF-kappaB signaling pathway and reverse engineering (Network Components Analysis) to build a gene regulatory network (GRN). Then, we demonstrated that the corresponding IKK profiles can be identified in the GRN and are consistent with the experimental validation of the IKK kinase assay. We found that the time-lapse gene expression of several cytokines and chemokines (TNF-alpha, IL-1, IL-6, CXCL1, CXCL2 and CCL3) is concordant with the NF-kappaB activity profile, and these genes have stronger influence strength within the GRN. Such regulatory effects have highlighted the crucial roles of NF-kappaB signaling in the acute inflammatory response and enhance our understanding of the systemic inflammatory response syndrome. CONCLUSION: We successfully identified and distinguished the corresponding signaling profiles among three microarray datasets with different stimuli strengths. In our model, the crucial genes of the NF-kappaB regulatory network were also identified to reflect the biological consequences of inflammation. With the experimental validation, our strategy is thus an effective solution to decipher cross-talk effects when attempting to integrate new kinetic parameters from other signal transduction pathways. The strategy also provides new insight for systems biology modeling to link any signal transduction pathways with the responses of downstream genes of interest.