A novel treatment strategy utilizing panobinostat for high-risk and treatment-refractory hepatoblastoma.

BACKGROUND & AIMS: Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new therapeutic strategies for these patients, our laboratory has developed a preclinical testing pipeline. Given that histone deacetylase (HDAC) inhibition has been proposed for HB, we hypothesized that we could find an effective combination treatment strategy utilizing HDAC inhibition. METHODS: RNA sequencing, microarray, NanoString, and immunohistochemistry data of patient HB samples were analyzed for HDAC class expression. Patient-derived spheroids (PDSp) were used to screen combination chemotherapy with an HDAC inhibitor, panobinostat. Patient-derived xenograft (PDX) mouse models were developed and treated with the combination therapy that showed the highest efficacy in the PDSp drug screen. RESULTS: HDAC RNA and protein expression were elevated in HB tumors compared to normal livers. Panobinostat (IC50 of 0.013-0.059 µM) showed strong in vitro effects and was associated with lower cell viability than other HDAC inhibitors. PDSp demonstrated the highest level of cell death with combination treatment of vincristine/irinotecan/panobinostat (VIP). All four models responded to VIP therapy with a decrease in tumor size compared to placebo. After 6 weeks of treatment, two models demonstrated necrotic cell death, with lower Ki67 expression, decreased serum alpha fetoprotein and reduced tumor burden compared to paired VI- and placebo-treated groups. CONCLUSIONS: Utilizing a preclinical HB pipeline, we demonstrate that panobinostat in combination with VI chemotherapy can induce an effective tumor response in models developed from patients with high-risk, relapsed, and treatment-refractory HB. IMPACT AND IMPLICATIONS: Patients with treatment-refractory hepatoblastoma have limited treatment options with survival rates of less than 50%. Our manuscript demonstrates that combination therapy with vincristine, irinotecan, and panobinostat reduces the size of high-risk, relapsed, and treatment-refractory tumors. With this work we provide preclinical evidence to support utilizing this combination therapy as an arm in future clinical trials.

Identifying biomarkers of differential chemotherapy response in TNBC patient-derived xenografts with a CTD/WGCNA approach.

Although systemic chemotherapy remains the standard of care for TNBC, even combination chemotherapy is often ineffective. The identification of biomarkers for differential chemotherapy response would allow for the selection of responsive patients, thus maximizing efficacy and minimizing toxicities. Here, we leverage TNBC PDXs to identify biomarkers of response. To demonstrate their ability to function as a preclinical cohort, PDXs were characterized using DNA sequencing, transcriptomics, and proteomics to show consistency with clinical samples. We then developed a network-based approach (CTD/WGCNA) to identify biomarkers of response to carboplatin (MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ) and docetaxel (c, MAGED4, CERS1, ST8SIA2, KIF24, PARPBP). CTD/WGCNA multigene biomarkers are predictive in PDX datasets (RNAseq and Affymetrix) for both taxane- (docetaxel or paclitaxel) and platinum-based (carboplatin or cisplatin) response, thereby demonstrating cross-expression platform and cross-drug class robustness. These biomarkers were also predictive in clinical datasets, thus demonstrating translational potential.

Dynamics of nondegenerate vector solitons in a long-wave-short-wave resonance interaction system.

In this paper, we study the dynamics of an interesting class of vector solitons in the long-wave-short-wave resonance interaction (LSRI) system. The model that we consider here describes the nonlinear interaction of long wave and two short waves and it generically appears in several physical settings. To derive this class of nondegenerate vector soliton solutions we adopt the Hirota bilinear method with the more general form of admissible seed solutions with nonidentical distinct propagation constants. We express the resultant fundamental as well as multisoliton solutions in a compact way using Gram-determinants. The general fundamental vector soliton solution possesses several interesting properties. For instance, the double-hump or a single-hump profile structure including a special flattop profile form results in when the soliton propagates in all the components with identical velocities. Interestingly, in the case of nonidentical velocities, the soliton number is increased to two in the long-wave component, while a single-humped soliton propagates in the two short-wave components. We establish through a detailed analysis that the nondegenerate multisolitons in contrast to the already known vector solitons (with identical wave numbers) can undergo three types of elastic collision scenarios: (i) shape-preserving, (ii) shape-altering, and (iii) a shape-changing collision, depending on the choice of the soliton parameters. Here, by shape-altering we mean that the structure of the nondegenerate soliton gets modified slightly during the collision process, whereas if the changes occur appreciably then we call such a collision as shape-changing collision. We distinguish each of the collision scenarios, by deriving a zero phase shift criterion with the help of phase constants. Very importantly, the shape-changing behavior of the nondegenerate vector solitons is observed in the long-wave mode also, along with corresponding changes in the short-wave modes, and this nonlinear phenomenon has not been observed in the already known vector solitons. In addition, we point out the coexistence of nondegenerate and degenerate solitons simultaneously along with the associated physical consequences. We also indicate the physical realizations of these general vector solitons in nonlinear optics, hydrodynamics, and Bose-Einstein condensates. Our results are generic and they will be useful in these physical systems and other closely related systems including plasma physics when the long-wave-short-wave resonance interaction is taken into account.

Bleb revision with bleborhexis and clear corneal lamellar patch graft for overhanging cystic bleb.

Background: Trabeculectomy is associated with several complications. One of the common complications with mitomycin assisted trabeculectomy is thin cystic bleb leading to bleb leak, hypotony and infections. Various technique of bleb repair and reconstruction have been described, such as conjunctival advancement, or scleral, pericardial or corneal patch graft. Purpose: To demonstrate bleb revision by bleborhexis and clear corneal lamellar patch graft for a patient with thin cystic leaking bleb leading to hypotony and decreased vision. Synopsis: This was a 75-year-old one-eyed lady, diagnosed with primary angle-closure glaucoma in both eyes with absent light perception in the left eye, had undergone a combined trabeculectomy and cataract surgery in the right eye 6 years ago. She presented with diminution of vision (6/18p), introacular pressure (IOP) of of 6 mmHg, thin cystic leaking overhanging bleb, and dysesthesia. Bleb repair by bleborhexis with lamellar corneal patch graft was performed. Bleborhexis is a technique in which the overhanging fibrosed thin cystic conjunctival bleb is peeled off the cornea smoothly to leave a uniform clear corneal surface. Clear cornea, uniform diffuse bleb, well-formed anterior chamber with and IOP of 15 mmHg was noted on the first post-operative day, with a vision of 6/12p. This procedure helped meticulous reconstruction of the bleb, early recovery of vision, maintanance of normotensive eye, and save the eye from potential infections. Highlights: Bleborhexis with lamellar corneal patch graft provides for an easy and a elegant surgical technique with minimal corneal tissue damage, faster healing and patient comfort. It could be the favored technique in patients with thin overhanging clebs. Video link: https://youtu.be/GeFYHWToueU.

Biogenic Synthesis of Silver Nanoparticles (AgNPs) Using Aqueous Leaf Extract of Buchanania lanzan Spreng and Evaluation of Their Antifungal Activity against Phytopathogenic Fungi.

Nanoparticles show the multidisciplinary versatile utility and are gaining the prime place in various fields, such as medicine, electronics, pharmaceuticals, electrical designing, cosmetics, food industries, and agriculture, due to their small size and large surface to volume ratio. Biogenic or green synthesis methods are environmentally friendly, economically feasible, rapid, free of organic solvents, and reliable over conventional methods. Plant extracts are of incredible potential in the biosynthesis of metal nanoparticles owing to their bountiful availability, stabilizing, and reducing ability. In the present study, the aqueous leaf extract of Buchanania lanzan Spreng was mixed with 0.5 mM silver nitrate and incubated at 70°C for 1 h and synthesized a good quantity of AgNPs. The synthesized AgNPs were characterized using UV-visible spectroscopy, X-ray diffractometry (XRD), dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). The maximum absorption of UV-visible spectra was obtained in the range of 420-430 nm. Furthermore, SEM and TEM results inferred that the size of the particles were 23-62 nm, spherical, crystalline, uniformly distributed, and negatively charged with the zeta potential of -27.6 mV. In addition, the antifungal activities of the AgNPs were evaluated against two phytopathogenic fungi Rhizoctonia solani and Fusarium oxysporum f. sp. lycopersici in vitro using poison food techniques on PDA media. The maximum rate of mycelia inhibition was found in 150 ppm concentration of AgNPs against both phytopathogenic fungi.

A persistent plaque on the back of the hand.

We report the case of a 75-year-old woman presenting with acrodermatitis chronica atrophicans affecting the right hand dorsum, developing after an insect bite sustained in Greece. Diagnosis was confirmed by serology, PCR and histopathological findings. The plaque resolved following a 3-week course of oral doxycycline. Click https://www.wileyhealthlearning.com/#/online-courses/4ebea04b-e4de-49d3-9bbb-0d3355007e92 for the corresponding questions to this CME article.

Lowering of intraocular pressure after phacoemulsification in primary open-angle and angle-closure glaucoma: Correlation with lens thickness.

PURPOSE: To assess anterior chamber configuration changes during phacoemulsification in primary angle-closure suspect (PACS/PAC) and primary open-angle glaucoma (POAG). METHODS: Prospective observational comparative study of anterior segment optical coherence tomography (AS-OCT) findings before and after phacoemulsification on three groups of patients (PACS/PAC, POAG, and controls). Data were collected over a period of 9 months. Main outcome measures included mean change in anterior chamber depth (ACD), angle opening distance (AOD), and trabecular iris space area (TISA). RESULTS: 153 patients (51 PACS/PAC, 51 POAG, and 51 controls) were included in the study. Change in all parameters (ACD, AOD at 500 um, and AOD at 750 um) between the groups demonstrated a greater change in PACS/PAC as compared to POAG and controls. AOD at 750 µm in the temporal quadrant, which has been considered to be having the highest correlation or best representation of the angle, increased in all groups after phacoemulsification (463.59 ± 10.99 vs. 656.27 ± 9.73 mm in PACS; 521.29 ± 16.36 vs. 674.37 ± 8.72 mm in POAG; 549.27 ± 12.40 vs. 702.82 ± 13.04 mm in controls, (P < 0.001). After phacoemulsification, intraocular pressure (IOP) decreased by 2.75 ± 1.17 mm Hg in PACS/PAC (P < 0.001), 2.14 ± 1.33 mm Hg in POAG and 1.90 ± 1.25 mm Hg in controls and it was statistically significant in the PACS group compared to control (P < 0.001). CONCLUSION: Phacoemulsification with intraocular lens implantation is associated with increase in the ACD and angle parameters and a corresponding decrease in IOP. Findings were more pronounced in PACS/PAC suggesting early phacoemulsification may be a treatment option in this group.

Understanding the Role of Gibberellic Acid and Paclobutrazol in Terminal Heat Stress Tolerance in Wheat.

Understanding the physiological mechanism of tolerance under stress conditions is an imperative aspect of the crop improvement programme. The role of plant hormones is well-established in abiotic stress tolerance. However, the information on the role of gibberellic acid (GA) in abiotic stress tolerance in late sown wheat is still not thoroughly explored. Thus, we aimed to investigate the role of endogenous GA3 level in stress tolerance in contrasting wheat cultivars, viz., temperature-tolerant (HD 2643 and DBW 14) and susceptible (HD 2189 and HD 2833) cultivars under timely and late sown conditions. We created the variation in endogenous GA3 level by exogenous spray of GA3 and its biosynthesis inhibitor paclobutrazol (PBZ). Tolerant genotypes had higher antioxidant enzyme activity, membrane stability, and photosynthesis rate, lower lipid peroxidase activity, and better growth and yield traits under late sown conditions attributed to H2O2 content. Application of PBZ escalated antioxidant enzymes activity and photosynthesis rate, and reduced the lipid peroxidation and ion leakage in stress, leading to improved thermotolerance. GA3 had a non-significant effect on antioxidant enzyme activity, lipid peroxidation, and membrane stability. However, GA3 application increased the test weight in HD 2643 and HD 2833 under timely and late sown conditions. GA3 upregulated GA biosynthesis and degradation pathway genes, and PBZ downregulated kaurene oxidase and GA2ox gene expression. GA3 also upregulated the expression of the cell expansins gene under both timely and late sown conditions. Exogenous GA3 did not increase thermotolerance but positively affected test weight and cell expansins gene expression. No direct relationship existed between endogenous GA3 content and stress tolerance traits, indicating that PBZ could have conferred thermotolerance through an alternative mechanism instead of inhibiting GA3biosynthesis.

Whole-exome sequencing identifies multiple pathogenic variants in a large South Indian family with primary open-angle glaucoma.

PURPOSE: To identify the pathogenic variants associated with primary open-angle glaucoma (POAG) using whole-exome sequencing (WES) data of a large South Indian family. METHODS: We recruited a large five-generation South Indian family (n = 84) with a positive family history of POAG (n = 19). All study participants had a comprehensive ocular evaluation. We performed WES for 16 samples (nine POAG and seven unaffected controls) since Sanger sequencing of the POAG candidate genes (MYOC, OPTN, and TBK1) showed no genetic variation. We used an in-house pipeline for prioritizing the pathogenic variants based on their segregation among the POAG individual. RESULTS: We identified one novel and five low-frequency pathogenic variants with consistent co-segregation in all affected individuals. The variant c.G3719A in RPGR-interacting domain of RPGRIP1 that segregated heterozygously with the six POAG cases is distinct from variants causing photoreceptor dystrophies, reported affecting the RPGR protein complex signaling in primary cilia. The cilia in trabecular meshwork (TM) cells has been reported to mediate the intraocular pressure (IOP) sensation. Furthermore, we identified a novel c.A1295G variant in Rho guanine nucleotide exchange factors Gene 40 (ARHGEF40) and a likely pathogenic variant in the RPGR gene, suggesting that they may alter the RhoA activity essential for IOP regulation. CONCLUSION: Our study supports that low-frequency pathogenic variants in multiple genes and pathways probably affect Primary Open Angle Glaucoma's pathogenesis in the large South Indian family. Furthermore, it requires larger case-controls to perform family-based association tests and to strengthen our analysis.

Factors associated with mortality in patients with COVID-19 admitted to intensive care: a systematic review and meta-analysis.

Identification of high-risk patients admitted to intensive care with COVID-19 may inform management strategies. The objective of this meta-analysis was to determine factors associated with mortality among adults with COVID-19 admitted to intensive care by searching databases for studies published between 1 January 2020 and 6 December 2020. Observational studies of COVID-19 adults admitted to critical care were included. Studies of mixed cohorts and intensive care cohorts restricted to a specific patient sub-group were excluded. Dichotomous variables were reported with pooled OR and 95%CI, and continuous variables with pooled standardised mean difference (SMD) and 95%CI. Fifty-eight studies (44,305 patients) were included in the review. Increasing age (SMD 0.65, 95%CI 0.53-0.77); smoking (OR 1.40, 95%CI 1.03-1.90); hypertension (OR 1.54, 95%CI 1.29-1.85); diabetes (OR 1.41, 95%CI 1.22-1.63); cardiovascular disease (OR 1.91, 95%CI 1.52-2.38); respiratory disease (OR 1.75, 95%CI 1.33-2.31); renal disease (OR 2.39, 95%CI 1.68-3.40); and malignancy (OR 1.81, 95%CI 1.30-2.52) were associated with mortality. A higher sequential organ failure assessment score (SMD 0.86, 95%CI 0.63-1.10) and acute physiology and chronic health evaluation-2 score (SMD 0.89, 95%CI 0.65-1.13); a lower PaO2 :FI O2 (SMD -0.44, 95%CI -0.62 to -0.26) and the need for mechanical ventilation at admission (OR 2.53, 95%CI 1.90-3.37) were associated with mortality. Higher white cell counts (SMD 0.37, 95%CI 0.22-0.51); neutrophils (SMD 0.42, 95%CI 0.19-0.64); D-dimers (SMD 0.56, 95%CI 0.43-0.69); ferritin (SMD 0.32, 95%CI 0.19-0.45); lower platelet (SMD -0.22, 95%CI -0.35 to -0.10); and lymphocyte counts (SMD -0.37, 95%CI -0.54 to -0.19) were all associated with mortality. In conclusion, increasing age, pre-existing comorbidities, severity of illness based on validated scoring systems, and the host response to the disease were associated with mortality; while male sex and increasing BMI were not. These factors have prognostic relevance for patients admitted to intensive care with COVID-19.

Fetal growth at different gestational periods and risk of impaired childhood growth, low childhood weight and obesity: a prospective birth cohort study.

OBJECTIVE: To examine the longitudinal associations of fetal growth with adverse child growth outcomes and to assess whether maternal metabolic factors modify the associations. DESIGN: Prospective cohort study. SETTING: Born in Guangzhou Cohort Study, China. POPULATION: A total of 4818 mother-child pairs. METHODS: Fetal growth was assessed according to estimated fetal weight (EFW) from 22 weeks of gestation until birth and the measurement of the birthweight. Fetal growth Z-scores were computed from random effects in the multilevel linear spline models to represent fetal size in early pregnancy (22 weeks of gestation) and growth in mid-pregnancy (22-27 weeks of gestation), early third trimester (28-36 weeks of gestation) and late third trimester (≥37 weeks of gestation). MAIN OUTCOME MEASURES: Z-scores for childhood stunting, low weight, overweight or obesity, length/height for age (LAZ/HAZ), weight for age (WAZ) and body mass index for age (BMIZ) at the age of 3 years. Adjusted associations were examined using multiple Poisson or linear regression models. RESULTS: Increased Z-scores of fetal size in early pregnancy and growth in mid-pregnancy and early third trimester were associated with a higher risk of childhood overweight or obesity (risk ratios 1.25-1.45). Fetal growth in each period was negatively associated with stunting and low weight, with the strongest associations observed for fetal size in early pregnancy and growth in mid-pregnancy. The results for continuous outcomes (LAZ/HAZ, WAZ and BMIZ) were similar. The associations of fetal growth with overweight or obesity in childhood were stronger among mothers who were underweight and who were overweight or obese than among mothers of normal weight. CONCLUSIONS: Accelerated fetal growth before 37 weeks of gestation is associated with children who are overweight or obese, whereas the critical period for stunting and low weight occurs before 28 weeks of gestation. TWEETABLE ABSTRACT: Fetal growth during different periods is differentially associated with childhood stunting, underweight and overweight or obesity.

Screening of Onion (Allium cepa L.) Genotypes for Drought Tolerance Using Physiological and Yield Based Indices Through Multivariate Analysis.

Drought is a leading abiotic constraints for onion production globally. Breeding by using unique genetic resources for drought tolerance is a vital mitigation strategy. With a total of 100 onion genotypes were screened for drought tolerance using multivariate analysis. The experiment was conducted in a controlled rainout shelter for 2 years 2017-2018 and 2018-2019 in a randomized block design with three replications and two treatments (control and drought stress). The plant was exposed to drought stress during the bulb development stage (i.e., 50-75 days after transplanting). The genotypes were screened on the basis of the drought tolerance efficiency (DTE), percent bulb yield reduction, and results of multivariate analysis viz. hierarchical cluster analysis by Ward's method, discriminate analysis and principal component analysis. The analysis of variance indicated significant differences among the tested genotypes and treatments for all the parameters studied, viz. phenotypic, physiological, biochemical, and yield attributes. Bulb yield was strongly positively correlated with membrane stability index (MSI), relative water content (RWC), total chlorophyll content, antioxidant enzyme activity, and leaf area under drought stress. The genotypes were categorized into five groups namely, highly tolerant, tolerant, intermediate, sensitive, and highly sensitive based on genetic distance. Under drought conditions, clusters II and IV contained highly tolerant and highly sensitive genotypes, respectively. Tolerant genotypes, viz. Acc. 1656, Acc. 1658, W-009, and W-085, had higher DTE (>90%), fewer yield losses (<20%), and performed superiorly for different traits under drought stress. Acc. 1627 and Acc. 1639 were found to be highly drought-sensitive genotypes, with more than 70% yield loss. In biplot, the tolerant genotypes (Acc. 1656, Acc. 1658, W-085, W-009, W-397, W-396, W-414, and W-448) were positively associated with bulb yield, DTE, RWC, MSI, leaf area, and antioxidant enzyme activity under drought stress. The study thus identified tolerant genotypes with favorable adaptive traits that may be useful in onion breeding program for drought tolerance.

Nondegenerate solitons and their collisions in Manakov systems.

Recently, we have shown that the Manakov equation can admit a more general class of nondegenerate vector solitons, which can undergo collision without any intensity redistribution in general among the modes, associated with distinct wave numbers, besides the already-known energy exchanging solitons corresponding to identical wave numbers. In the present comprehensive paper, we discuss in detail the various special features of the reported nondegenerate vector solitons. To bring out these details, we derive the exact forms of such vector one-, two-, and three-soliton solutions through Hirota bilinear method and they are rewritten in more compact forms using Gram determinants. The presence of distinct wave numbers allows the nondegenerate fundamental soliton to admit various profiles such as double-hump, flat-top, and single-hump structures. We explain the formation of double-hump structure in the fundamental soliton when the relative velocity of the two modes tends to zero. More critical analysis shows that the nondegenerate fundamental solitons can undergo shape-preserving as well as shape-altering collisions under appropriate conditions. The shape-changing collision occurs between the modes of nondegenerate solitons when the parameters are fixed suitably. Then we observe the coexistence of degenerate and nondegenerate solitons when the wave numbers are restricted appropriately in the obtained two-soliton solution. In such a situation we find the degenerate soliton induces shape-changing behavior of nondegenerate soliton during the collision process. By performing suitable asymptotic analysis we analyze the consequences that occur in each of the collision scenario. Finally, we point out that the previously known class of energy-exchanging vector bright solitons, with identical wave numbers, turns out to be a special case of nondegenerate solitons.

Skeletal abnormalities secondary to antenatal etidronate treatment for suspected generalised arterial calcification of infancy.

BACKGROUND: Generalised arterial calcification of infancy (GACI) is a rare disorder characterised by the deposition of hydroxyapatite crystals within the vessel walls. It is associated with a high mortality rate. Bisphosphonates have been used with some success in the treatment of GACI. However, there is a paucity of data on the antenatal use of bisphosphonates for GACI. In this paper, we report development of the skeletal changes suggestive of hypophosphatasia (HPP) in an infant with GACI, whose mother was treated with etidronate during pregnancy. CASE REPORT: A Caucasian infant boy had a suspected antenatal diagnosis of GACI based on the findings suggestive of calcification of the annulus of the tricuspid valve and wall of the right ventricular (RV) outflow tract and main pulmonary artery on foetal echocardiography and the genetic analysis which showed a pathogenic heterozygous mutation in ABCC6. Based on these findings, mother was started on etidronate treatment from 26 weeks of gestation. A healthy male baby was delivered at 38 weeks of gestation. Initial postnatal echocardiogram on day 1 of life was normal with good biventricular function; subtle changes suggestive of microcalcifications were detected on the CT angiography. Serum calcium, phosphate, alkaline phosphatase and renal profile were normal. Further, the serum inorganic pyrophosphate (PPi) level was significantly low. Skeletal changes suggestive of HPP were seen on the radiographs. The baby developed cardiac dysfunction on day 4 of life with evidence of ischaemic changes on electrocardiogram (ECG).Treatment with etidronate was started in view of probable evolving coronary calcifications. Despite treatment with cardiac supportive measures and bisphosphonate, he succumbed to death in the third week of life. DISCUSSION: We believe, this is the first report of skeletal changes suggestive of HPP, arising secondary to antenatal etidronate (first generation bisphosphonate) used for the treatment of suspected GACI due to a heterozygous ABCC6 mutation.

Brain signalling systems: A target for treating type I diabetes mellitus.

From early to later stages of Type I Diabetes Mellitus (TIDM), signalling molecules including brain indolamines and protein kinases are altered significantly, and that has been implicated in the Metabolic Disorders (MD) as well as impairment of retinal, renal, neuronal and cardiovascular systems. Considerable attention has been focused to the effects of diabetes on these signalling systems. However, the exact pathophysiological mechanisms of these signals are not completely understood in TIDM, but it is likely that hyperglycemia, acidosis, and insulin resistance play significant roles. Insulin maintains normal glycemic levels and it acts by binding to its receptor, so that it activates the receptor's tyrosine kinase activity, resulting in phosphorylation of several substrates. Those substrates provide binding/interaction sites for signalling molecules, including serine/threonine kinases and indolamines. For more than two decades, our research has been focused on the mechanisms of protein kinases, CaM Kinase and Serotonin transporter mediated alterations of indolamines in TIDM. In this review, we have also discussed how discrete areas of brain respond to insulin or some of the pharmacological agents that triggers or restores these signalling molecules, and it may be useful for the treatment of specific region wise changes/disorders of diabetic brain.

Nondegenerate Solitons in Manakov System.

It is known that the Manakov equation which describes wave propagation in two mode optical fibers, photorefractive materials, etc., can admit solitons which allow energy redistribution between the modes on collision that also leads to logical computing. In this Letter, we point out that the Manakov system can admit a more general type of nondegenerate fundamental solitons corresponding to different wave numbers, which undergo collisions without any energy redistribution. The previously known class of solitons which allows energy redistribution among the modes turns out to be a special case corresponding to solitary waves with identical wave numbers in both the modes and traveling with the same velocity. We trace out the reason behind such a possibility and analyze the physical consequences.

Interleukin 4 induces apoptosis of acute myeloid leukemia cells in a Stat6-dependent manner.

Cytokines provide signals that regulate immature normal and acute myeloid leukemia (AML) cells in the bone marrow microenvironment. We here identify interleukin 4 (IL4) as a selective inhibitor of AML cell growth and survival in a cytokine screen using fluorescently labeled AML cells. RNA-sequencing of the AML cells revealed an IL4-induced upregulation of Stat6 target genes and enrichment of apoptosis-related gene expression signatures. Consistent with these findings, we found that IL4 stimulation of AML cells induced Stat6 phosphorylation and that disruption of Stat6 using CRISPR/Cas9-genetic engineering rendered cells partially resistant to IL4-induced apoptosis. To evaluate whether IL4 inhibits AML cells in vivo, we expressed IL4 ectopically in AML cells transplanted into mice and also injected IL4 into leukemic mice; both strategies resulted in the suppression of the leukemia cell burden and increased survival. Notably, IL4 exposure caused reduced growth and survival of primary AML CD34+CD38- patient cells from several genetic subtypes of AML, whereas normal stem and progenitor cells were less affected. The IL4-induced apoptosis of AML cells was linked to Caspase-3 activation. Our results demonstrate that IL4 selectively induces apoptosis of AML cells in a Stat6-dependent manner-findings that may translate into new therapeutic opportunities in AML.

Clinical and genetic characterization of a large primary open angle glaucoma pedigree.

PURPOSE: To both characterize the clinical features of large primary open angle glaucoma (POAG) pedigree from a village in southern India and to investigate the genetic basis of their disease. MATERIALS AND METHODS: Eighty-four members of a large pedigree received complete eye examinations including slit lamp examination, tonometry, gonioscopy, and ophthalmoscopy. Some were further studied with perimetry. Those diagnosed with POAG were tested for disease-causing mutations in the myocilin and optineurin genes with Sanger sequencing. RESULTS: Fourteen of 84 family members were diagnosed with POAG, while eight were clinically judged to be POAG-suspects. The family structure and the pattern of glaucoma in the pedigree are complex. Features of glaucoma in this pedigree include relatively early age at diagnosis (mean 50 ± 14 years) and maximum intraocular pressures ranging from 14 to 36 mm Hg with a mean of 23 mm Hg ± 6.5 mm Hg. Patients had an average central corneal thickness (mean 529 ± 37.8 microns) and moderate cup-to-disc ratios (0.74 ± 0.14). No mutations were detected in myocilin, optineurin, or TANK binding kinase 1 (TBK1). CONCLUSIONS: We report a five-generation pedigree with a complex pattern of POAG inheritance that includes 22 POAG patients and glaucoma suspects. Although the familial clustering of POAG in this pedigree is consistent with dominant inheritance of a glaucoma-causing gene, mutations were not detected in genes previously associated with autosomal dominant glaucoma, suggesting the involvement of a novel disease-causing gene in this pedigree.

Health-seeking behaviour among patients with faecal incontinence in a Malaysian academic setting.

BACKGROUND: Faecal incontinence (FI) is not a common presenting complaint in Malaysia, and little has been published on this topic. Since it is a treatable condition, a greater understanding of factors contributing to healthseeking behaviour is needed in order to plan effective provision of services. METHODS: A survey of 1000 patients and accompanying relatives, visiting general surgical and obstetrics and gynaecology clinics for matters unrelated to FI, was conducted at University Malaya Medical Centre between January 2009 and February 2010. A follow-up regression analysis of the 83 patients who had FI, to identify factors associated with health-seeking behaviour, was performed. Variables identified through univariate analysis were subjected to multivariate analysis to determine independence. Reasons for not seeking treatment were also analysed. RESULTS: Only eight patients (9.6%) had sought medical treatment. On univariate analysis, the likelihood of seeking treatment was significantly higher among patients who had more severe symptoms (OR 30.0, p=0.002), had incontinence to liquid stool (OR 3.83, p=0.002) or when there was an alteration to lifestyle (OR: 17.34; p<0.001). Nevertheless, the only independently-associated variable was alteration in lifestyle. Common reasons given for not seeking treatment was that the condition did not affect patients' daily activities (88.0%), "social taboo" (5.3%) and "other" reasons (6.7%). CONCLUSIONS: Lifestyle alteration is the main driver of healthseeking behaviour in FI. However, the majority do not seek treatment. Greater public and physician-awareness on FI and available treatment options is needed.

Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease.

Acute intermittent porphyria results from hydroxymethylbilane synthase (HMBS) mutations that markedly decrease HMBS enzymatic activity. This dominant disease is diagnosed when heterozygotes have life-threatening acute attacks, while most heterozygotes remain asymptomatic and undiagnosed. Although >400 HMBS mutations have been reported, the prevalence of pathogenic HMBS mutations in genomic/exomic databases, and the actual disease penetrance are unknown. Thus, we interrogated genomic/exomic databases, identified non-synonymous variants (NSVs) and consensus splice-site variants (CSSVs) in various demographic/racial groups, and determined the NSV's pathogenicity by prediction algorithms and in vitro expression assays. Caucasians had the most: 58 NSVs and two CSSVs among ∼92,000 alleles, a 0.00575 combined allele frequency. In silico algorithms predicted 14 out of 58 NSVs as "likely-pathogenic." In vitro expression identified 10 out of 58 NSVs as likely-pathogenic (seven predicted in silico), which together with two CSSVs had a combined allele frequency of 0.00056. Notably, six presumably pathogenic mutations/NSVs in the Human Gene Mutation Database were benign. Compared with the recent prevalence estimate of symptomatic European heterozygotes (∼0.000005), the prevalence of likely-pathogenic HMBS mutations among Caucasians was >100 times more frequent. Thus, the estimated penetrance of acute attacks was ∼1% of heterozygotes with likely-pathogenic mutations, highlighting the importance of predisposing/protective genes and environmental modifiers that precipitate/prevent the attacks.