Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc- mouse model

The efficacy of IVIG in preventing GvHD has not been definitely demonstrated clinically. Using a xenogeneic model of GvHD in NOD/SCID/γc- (NSG) mice, we showed that weekly administration of IVIG significantly reduced the incidence and associated mortality of GvHD to a degree similar to CsA. Unlike CsA and OKT3, IVIG were not associated with inhibition of human T-cell proliferation in mice. Instead, IVIG significantly inhibited the secretion of human IL-17, IL-2, IFN-γ and IL-15 suggesting that IVIG prevented GvHD by immunomodulation. Furthermore, the pattern of modification of the human cytokine storm differed from that observed with CsA and OKT3. Finally, in a humanized mouse model of immune reconstitution, in which NSG mice were engrafted with human CD34(+) stem cells, IVIG transiently inhibited B-cell reconstitution, whereas peripheral T-cell reconstitution and thymopoiesis were unaffected. Together these in vivo data raise debate related to the appropriateness of IVIG in GvHD prophylaxis. In addition, this model provides an opportunity to further elucidate the precise mechanism(s) by which IVIG inhibit GvHD.     

Role of Tenascin-X in regulating TGF-β/Smad signaling pathway in pathogenesis of slow transit constipation

BACKGROUND Chronic constipation is a gastrointestinal functional disease that seriously harms physical and mental health and impacts the quality of life of patients.Its incidence rate is 2%-27%.Slow transit constipation(STC)is a common type of chronic functional constipation,accounting for 10.3%-45.5%of such cases.Scholars have performed many studies on the pathogenesis of STC.These studies have indicated that the occurrence of STC may be related to multiple factors,such as dysfunction of the enteric nervous system,interstitial cells of Cajal(ICC)damage,and changes in neurotransmitters regulating intestinal peristalsis.AIM To investigate the role of Tenascin-X(TNX)in regulating the TGF-β/Smad signaling pathway in the pathogenesis of STC.METHODS This study included an experimental group and a control group.The experimental group included 28 patients with severe colonic STC,and the control group included 18 patients with normal colon tissues.Immunohistochemistry(IHC)was used to detect c-Kit,a specific marker of the ICC.Western blot,immunofluorescence,and IHC were used to detect the localization and expression of TNX and TGF-β/Smad.RESULTS IHC showed that the number of ICC with positive c-Kit expression was significantly reduced in the colon of STC patients(22.17±3.28 vs 28.69±3.53,P<0.05)and that the distribution was abnormal.Western blot results showed that c-Kit and Smad7 levels were significantly decreased in the colon of STC patients(c-kit:0.462±0.099 vs 0.783±0.178,P<0.01;Smad7:0.626±0.058 vs 0.799±0.03,P<0.01)and that TNX and Smad2/3 levels were higher in the STC group(TNX:0.868±0.028 vs 0.482±0.032,P<0.01).There was no significant difference in TGF-βbetween the two groups(0.476±0.028 vs 0.511±0.044,P=0.272).Pearson correlation analysis showed that the TNX protein exhibited a strong correlation with Smad2/3 and Smad7(P<0.05,|R|>0.8)and TGF-β(P<0.05,|R|=0.7).CONCLUSION The extracellular matrix protein TNX may activate the TGF-β/Smad signaling pathway by upregulating the Smad 2/3 signaling protein and thereby induce slight or complete epithelial stromal cell transformation,leading to an abnormal distribution and dysfunction of ICC in the diseased colon,which promotes the occurrence and development of STC.     

Analysis of the rs35959442 polymorphism in Hb E/β-thalassemia in Guangxi Province of the Republic of China

Hb E [β26(B8)Glu→Lys]/β-thalassemia (β-thal) is a worldwide inherited disorder. We determined the phenotype of 65 unrelated Hb E/β-thal subjects and 70 healthy individuals in the Guangxi Province of the Republic of China (ROC). Single nucleotide polymorphism (SNP) rs35959442 in HBS1L analysis was performed using the polymerase chain reaction (PCR)/restriction enzyme method. The data suggested that the frequency of the rs35959442 polymorphism was relatively high in patients with Hb E/β-thal in Guangxi Province, ROC, when associated with Hb F augmentation.     

Advances in the study of circ RNA in myocardial ischemia/reperfusion injury

Myocardial ischemia-reperfusion injury(I/R) is a disease in which acute ischaemic myocardium is not restored or even worsened after reperfusion therapy,resulting in arrhythmias and restricted systolic function of the heart. circular RNAs are a class of stable non-coding RNAs with a circular structure. circRNAs are involved in the pathogenesis of I/R and have great potential to become new therapeutic targets. This paper, we will review the relationship between the different pathogenesis of I/R an...     

Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers

Aberrant Wnt/β-catenin signaling is widely implicated in numerous malignancies, including cancers of the gastrointestinal tract. Dysregulation of signaling is traditionally attributed to mutations in Axin, adenomatous polyposis coli, and β-catenin that lead to constitutive hyperactivation of the pathway. However, Wnt/β-catenin signaling is also modulated through various other mechanisms in cancer, including cross talk with other altered signaling pathways. A more complex view of Wnt/β-catenin signaling and its role in gastrointestinal cancers is now emerging as divergent phenotypic outcomes are found to be dictated by temporospatial context and relative levels of pathway activation. This review summarizes the dysregulation of Wnt/β-catenin signaling in colorectal carcinoma, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, with particular emphasis on the latter two. We conclude by addressing some of the major challenges faced in attempting to target the pathway in the clinic.     

Outbreaks of Streptococcus pneumoniae carriage in day care cohorts in Finland – implications for elimination of transmission

Background  

Day care centre (DCC) attendees play a central role in maintaining the circulation of Streptococcus pneumoniae (pneumococcus) in the population. Exposure within families and within DCCs are the main risk factors for colonisation with pneumococcal serotypes in DCC attendees.     

Low-dose α/β blockade in the treatment of essential hypertension

Despite the recent emphasis on combination drug therapy for hypertension, little attention has been given to α/β blockade using agents other than labetalol. The purpose of this study was to 1) compare the efficacy of low-dose α/β blockade using doxazosin + betaxolol, versus monotherapy with an angiotensin converting enzyme inhibitor (quinapril) and a diuretic (hydrochlorothiazide [HCTZ]), and 2) assess the efficacy of low-dose doxazosin. In a crossover study, 21 hypertensive subjects were treated for 3 weeks each with HCTZ, 12.5 to 25 mg/day, quinapril, 10 to 40 mg/day, and a combination of doxazosin, 1 to 4 mg + betaxolol, 5 to 10 mg daily. Doses were titrated to achieve a systolic pressure <130 mm Hg, as assessed by self-recorded home measurements. Home blood pressure decreased 11.5/7.5 mm Hg after HCTZ, 12.9/8.8 mm Hg after quinapril, and 21.2/16.5 mm Hg after doxazosin + betaxolol (P < .001/< .001 v HCTZ and P < .002/< .001 v quinapril). The target systolic pressure was achieved by 33%, 43%, and 71% of subjects, respectively (P = .04 v HCTZ, and .03 v quinapril). Among the 8 subjects in whom doxazosin dosage was increased to the maximum of 4 mg, the mean blood pressure achieved at 4 mg did not differ from that achieved at 2 mg (136/87 v 136/88 mm Hg). We conclude that oral α/β blockade is superior to monotherapy with an angiotensin converting enzyme inhibitor or a diuretic and that maximal or near maximal efficacy can be achieved at a 2-mg dose of doxazosin. Low-dose oral α/β blockade merits greater consideration in the drug therapy of essential hypertension.     

Expression of HIF-2α/EPAS1 in hepatocellular carcinoma

AIM:To investigate the expression of hypoxia-induciblefactor (HIF)-2α/endothelial PAS domain protein1 (EPAS1)in hepatocellular carcinoma (HCC).METHODS:Expression of HIF-2α/EPAS1 was investigatedimmunohistochemically on paraffin-embedded sections from97 patients with HCC.To further confirm that HIF-2α/EPAS1in HCC tissues also correlated with angiogenesis,a parallelimmunohistchemistry study of vascular endothelial growthfactor (VEGF) was performed on these 97 cases.RESULTS:HIF-2α/EPAS1 could be detected in 50 of 97cases (51.6%),including 19 weakly positive (19.8%),and 31strongly positive (31.1%),the other 47 cases were negative(48.4%).The expression of HIF-2α/EPASlwas significantlycorrelated with tumor size,capsule infiltration,portal veininvasion,and necrosis.A parallel immunohistochemicalanalysis of VEGF demonstrated its positive correlation withcapsule infiltration,portal vein invasion,and HIF-2α/EPAS1overexpression,which supported the correlation of HIF-2α/EPASlup-regulation with tumor angiogenesis.No apparentcorrelation was observed between HIF-2α/EPAS1 and capsularformation,presence of cirrhosis,and histological grade.CONCLUSION:HIF-2α/EPAS1 is expressed in most of HCCwith capsular infiltration and portal vein invasion,whichindicates a possible role of HIF-2α/EPAS1 in HCC metastasis.     

Evaluation of ¹⁸F-FDG PET/CT in early-stage cervical carcinoma

IntroductionThe purpose is to evaluate ¹⁸F-fluorodeoxy glucose-positron emission tomography (PET)/computed tomography (CT) for the detection of cervical carcinoma of the International Federation of Gynecology and Obstetrics stages Ib and IIa.MethodsTwenty-two patients with cervical carcinoma were included in this study. Eleven of them were at the International Federation of Gynecology and Obstetrics stage Ib, and the remaining patients were at stage IIa. All the patients underwent ¹⁸F-fluorodeoxy glucose-PET/CT scan, and in 15 patients, additional delayed imaging of pelvis was performed. The PET/CT findings were compared with histopathologic and follow-up results.ResultsOf the 22 patients, 20 had cervical cancer with abnormal uptake that were detected directly using PET/CT without additional information from delayed imaging of pelvis; the other 2 patients showed lesions with no abnormal uptake. The use of delayed imaging of the pelvis with PET/CT corrected 1 false-negative case. Thus, the accuracy of PET/CT for early-stage cervical carcinoma was 95.45% (21/22). The uptake of early-stage cervical carcinoma showed no statistical significance between the group of stage Ib and the group of stage IIa (P > 0.05). The false-negative rate and negative predictive value of PET/CT imaging in predicting pelvic nodal involvement were 6.25% (1/16) and 93.75%, respectively.ConclusionsPET/CT showed a high accuracy for the diagnosis of early-stage cervical cancer and a high-negative predictive value for predicting the pelvic nodal status in early-stage cervical cancer.     

Transfusion of neocytes concentrate/pooled neocytes in β-thalassemic patients

Purpose of study

Study was aimed to observe benefits of transfusion of neocytes/pooled neocytes over packed RBCs by super transfusion regimen in β-thalassemic patients and its comparison with related studies.

Materials and methods

Twelve cases were selected and were equally divided into control and study group in which packed RBCs and neocytes were transfused respectively for one year. In study group, average 8 transfusions were required over 14 in control group.

Results

A marked extension of transfusion interval was observed in study group patients receiving neocytes transfusion (avg. 45.8 days; range, 32–54) over control group patients i.e. those receiving conventional packed RBCs (avg. 26.1; range 22–30). There is an average 40.8% reduction in the volume of RBCs required in the study group compared to control group and this difference is statistically significant (p = 0.00075). In study group, 20.1% reduction in iron overload and increase of iron by 9.6% in control group was reported.

Conclusion

We observed that neocytes transfusion is effective in extending the transfusion interval as well as in reducing the blood requirement and iron over load.

     

The role of PET/CT in Cogan’s syndrome

We report on the case of a 60-year-old woman with complaints of fatigue, coughing, anorexia, atypical chest pain, recurrent fever, and also ear pain and hearing loss. A test for anti-neutrophil cytoplasmic antibody (ANCA) was myeloperoxidase positive with p-ANCA specificity. Laboratory acute phase parameters were increased. A 2-deoxy-2-[¹⁸F]fluoro-d-glucose positron emission tomography/computed tomography investigation showed pathological uptake in the aorta ascendens, with no other involvement of the large vessels. After therapy with methylprednisolon intravenously and later prednisolon orally with methothrexate, her general condition and hearing loss improved both subjectively and objectively. “Atypical” Cogan’s syndrome was diagnosed on the basis of sensorineural deafness with improvement on steroids and large-vessel vasculitis of the aortic arch.     

Characterization of breeding sites of Phlebotomus orientalis – The vector of visceral leishmaniasis in northwestern Ethiopia

We studied breeding sites of Phlebotomus orientalis (Diptera: Psychodidae) the vector of visceral leishmaniasis in northern Ethiopia. Although numbers were rather small, 165 sand flies were captured emerging from vertisol cracks. The most productive breeding sites were cracked vertisols, dry river banks and close to trees. No sand flies were caught emerging from sandy clay loam soils in peri-domestic habitats but a few were captured emerging from gaps in a stone wall. Abiotic parameters in vertisols close to trees and in open field from which P. orientalis had emerged, were compared. Soil pH was slightly alkaline and salinity was low. Organic matter contents were similar in both sites. Temperatures and RH remained relatively stable near trees from the end of the rainy season through mid dry season, yet fluctuated markedly at the shallower depth in the open field. During the rainy season, cracks in the soil were sealed resulting in significant lowering of the oxygen concentrations near the tree. Gravimetric water content of soil near trees was lower than open field at shallow depth but similar deeper down. We conclude that ambient conditions suitable for sand fly larvae at shallow depths (45 cm) are restricted to areas close to trees. However, deeper in vertisols (90 cm) suitable conditions are apparently maintained throughout the dry season even in open fallow fields.     

Roles of the CXCR1/CXCL8 axis in abnormal proliferation of bile duct epithelial cells in primary biliary cholangitis

<正>Objective To investigate the role of the CXC chemokine receptor 1(CXCR1)/CXC chemokine ligand8(CXCL8) axis in the abnormal proliferation of bile duct epithelial cells in primary biliary cholangitis(PBC).Methods 30 female C57BL/6 mice were randomly divided into the PBC model group(PBC group),reparixin intervention group(Rep group),and blank control group(Con group) in an in vivo experiment.PBC animal models were established after 12weeks of intraperitoneal injection of 2-octanoic acid co...     

Lag in maturation of the brain’s intrinsic functional architecture in attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood, and there is great interest in understanding its neurobiological basis. A prominent neurodevelopmental hypothesis proposes that ADHD involves a lag in brain maturation. Previous work has found support for this hypothesis, but examinations have been limited to structural features of the brain (e.g., gray matter volume or cortical thickness). More recently, a growing body of work demonstrates that the brain is functionally organized into a number of large-scale networks, and the connections within and between these networks exhibit characteristic patterns of maturation. In this study, we investigated whether individuals with ADHD (age 7.2–21.8 y) exhibit a lag in maturation of the brain’s developing functional architecture. Using connectomic methods applied to a large, multisite dataset of resting state scans, we quantified the effect of maturation and the effect of ADHD at more than 400,000 connections throughout the cortex. We found significant and specific maturational lag in connections within default mode network (DMN) and in DMN interconnections with two task positive networks (TPNs): frontoparietal network and ventral attention network. In particular, lag was observed within the midline core of the DMN, as well as in DMN connections with right lateralized prefrontal regions (in frontoparietal network) and anterior insula (in ventral attention network). Current models of the pathophysiology of attention dysfunction in ADHD emphasize altered DMN–TPN interactions. Our finding of maturational lag specifically in connections within and between these networks suggests a developmental etiology for the deficits proposed in these models.Attention-deficit/hyperactivity disorder (ADHD) is a serious neuropsychiatric disorder characterized by inattention, hyperactivity, and impulsivity. One influential neurodevelopmental model of the disorder posits a lag in the maturational trajectories of key features of the brain (1–4). This model has mostly been investigated by examining developmental pathways of structural features of the brain (3, 5–8). In recent years, however, theorists have increasingly used resting state functional MRI (fMRI)—scanning participants in a task-free resting state—to explore the brain’s functional architecture. This work has led to the recognition that the human brain is organized into several large-scale intrinsic connectivity networks (ICNs), each associated with specific neurocognitive functions (9, 10). ICNs have been shown to undergo significant maturation from childhood to early adulthood, with individual ICNs exhibiting spatially specific reliable patterns of integration (increased connectivity with age) and segregation (decreased connectivity with age) with other ICNs (11–17). These advances raise possibilities for investigating maturational lag in ADHD in the developing ICN architecture of the brain (18).Independent lines of research suggest that attention dysfunction in ADHD is linked to altered ICN interrelationships. According to current theoretical models (19, 20), inattention in ADHD involves altered competitive balance between (i) default network, an ICN implicated in internally directed mentation (21, 22); and (ii) several task-positive ICNs (TPNs), including dorsal attention network (DAN), ventral attention network (VAN), and frontoparietal network (FPN), which are involved in cognitively demanding externally focused processing. Consistent with these models, previous resting state fMRI studies in ADHD have reliably found abnormalities in functional connections within DMN (23, 24) and in its interconnections with TPNs (25–27). Importantly, however, it is not currently known whether these abnormalities reliably observed in ADHD are linked to maturational lag. The current study sought to investigate this question. Based on current network models of ADHD, we hypothesized that maturational lag in ADHD in the brain’s intrinsic functional architecture would be focused within DMN and in its interconnections with three TPNs: DAN, VAN, and FPN.To test this hypothesis, we used recently developed whole-brain connectomic methods (28–30). Traditional seed-based strategies examine connectivity using a single or a handful of regions of interest (ROIs) or average connectivity values across entire ICNs. However, recent work demonstrates that ICN interrelationships are not unitary; rather, connectivity alterations during maturation in DMN and TPNs are highly variable across individual connections within ICNs (13, 14, 31, 32). Thus, conventional seed-based strategies are likely to produce summary measures that do not capture underlying fine-grained patterns of variation or can miss trends that are detectable only when looking across large populations of connections. Connectomic methods remedy this problem by examining connectivity patterns among hundreds of seeds. To produce comprehensive connectomic maps, we placed 907 ROIs at regular intervals throughout the cortex and calculated connectivity between each pair of ROIs (410,871 unique connections). Using a multiple regression approach, we then calculated the effect of age and the effect of ADHD at each connection of the connectome, controlling for nuisance effects (sex, IQ, handedness, motion, and scanner site). This regression modeling yielded two comprehensive maps of effect of age and effect of ADHD, respectively. Examining patterns of spatial correspondence across populations of connections in these whole-cortex connectomic maps provides a powerful way to investigate the maturational lag hypothesis.In our connectomic framework, we operationalized maturational lag as spatial co-occurrence of effects of age and effects of ADHD at the same connections. In particular, lag exists at an individual connection when the effect of ADHD at that connection opposes the effect of maturation. The presence of lag in a population of connections can be tested statistically by using a count-based framework that compares the number of observed lagged connections to a suitable chance distribution. Alternatively, a correlation-based framework can be used to investigate whether the strength of the effect of maturation is proportionately opposed by the effect of ADHD. That is, to the extent that a connection tends to more strongly integrate with age (i.e., effect of age is more positive), then its connectivity should be correspondingly reduced in ADHD relative to typically developing controls (TDCs). Conversely, to the extent that a connection tends to more strongly segregate with age (i.e., effect of age is more negative), then its connectivity should be correspondingly increased in ADHD relative to TDCs.We used both correlation- and count-based tests to investigate the spatial co-occurrence of effects of age and opposed effects of ADHD that is predicted by the maturational lag hypothesis. ICNs exhibit substantial intra- and internetwork dependency across connections. Thus, we assessed the significance of all statistical tests with nonparametric permutation tests, which are robust to deviations from independence and normality assumptions of conventional tests (33). We calculated estimates of effect of age and effect of ADHD used in these tests from participants in the ADHD-200 sample (34). This sample consisted of 481 TDCs and 275 children with ADHD and, after demographic and quality control exclusions, encompassed 421 participants (288 TDC and 135 ADHD). In addition, we also performed a partially independent second analysis. In particular, the preceding connectomic analyses were done a second time using effect of age estimates derived from a different sample, 155 TDC participants from the multisite Autism Brain Image Date Exchange (ABIDE) sample (35). The effect of ADHD estimates were derived from the ADHD-200 sample, and thus it bears emphasis that this second analysis is not completely independent from the first. Results were remarkably similar in this second analysis, and (with the exception of a single statistical test) all significant statistical tests reported below from the first analysis were also statistically significant in the second analysis (SI Results). Although not a fully independent replication, this second analysis nonetheless provides additional support for the reliability of our findings.     

The role of hypergastrinemia in the pathogenesis of intussusception in infants

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