Galectins-Potential Therapeutic Targets for Neurodegenerative Disorders.

Advancements in medicine have increased the longevity of humans, resulting in a higher incidence of chronic diseases. Due to the rise in the elderly population, age-dependent neurodegenerative disorders are becoming increasingly prevalent. The available treatment options only provide symptomatic relief and do not cure the underlying cause of the disease. Therefore, it has become imperative to discover new markers and therapies to modulate the course of disease progression and develop better treatment options for the affected individuals. Growing evidence indicates that neuroinflammation is a common factor and one of the main inducers of neuronal damage and degeneration. Galectins (Gals) are a class of ß-galactoside-binding proteins (lectins) ubiquitously expressed in almost all vital organs. Gals modulate various cellular responses and regulate significant biological functions, including immune response, proliferation, differentiation, migration, and cell growth, through their interaction with glycoproteins and glycolipids. In recent years, extensive research has been conducted on the Gal superfamily, with Gal-1, Gal-3, and Gal-9 in prime focus. Their roles have been described in modulating neuroinflammation and neurodegenerative processes. In this review, we discuss the role of Gals in the causation and progression of neurodegenerative disorders. We describe the role of Gals in microglia and astrocyte modulation, along with their pro- and anti-inflammatory functions. In addition, we discuss the potential use of Gals as a novel therapeutic target for neuroinflammation and restoring tissue damage in neurodegenerative diseases.

WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome.

BACKGROUND: Wolfram syndrome (WFS) is a rare disorder characterised by childhood-onset diabetes mellitus and progressive optic atrophy. Most patients have variants in the WFS1 gene. We undertook functional studies of WFS1 variants and correlated these with WFS1 protein expression and phenotype. METHODS: 9 patients with a clinical diagnosis of WFS were studied with quantitative PCR for markers of endoplasmic reticulum (ER) stress and immunoblotting of fibroblast protein extracts for WFS1 protein expression. Luciferase reporter assay was used to assess ATF-6 dependent unfolded protein response (UPR) activation. RESULTS: 6 patients with compound heterozygous nonsense mutations in WFS1 had no detectable WFS1 protein expression; 3 patients with missense variants had 4%, 45% and 48% WFS1 protein expression. One of these also had an OPA1 mutation and was reclassified as autosomal dominant optic atrophy-plus syndrome. There were no correlations between ER stress marker mRNA and WFS1 protein expression. ERSE-luciferase reporter indicated activation of the ATF6 branch of UPR in two patients tested. Patients with partial WFS1 expression showed milder visual acuity impairment (asymptomatic or colour blind only), compared with those with absent expression (registered severe vision impaired) (p=0.04). These differences remained after adjusting for duration of optic atrophy. CONCLUSIONS: Patients with WFS who have partial WFS1 protein expression present with milder visual impairment. This suggests a protective effect of partial WFS1 protein expression on the severity and perhaps progression of vision impairment and that therapies to increase residual WFS1 protein expression may be beneficial.

Endoscopic ultrasound guided fine-needle aspiration vs core needle biopsy for solid pancreatic lesions: Comparison of diagnostic accuracy and procedural efficiency.

BACKGROUND: Endoscopic ultrasound (EUS) guided core needle biopsies (CNB) are increasingly being performed to diagnose solid pancreatic lesions. However, studies have been conflicting in terms of CNB improving diagnostic accuracy and procedural efficiency vs fine-needle aspiration (FNA), which this study aims to elucidate. METHODS: Data were prospectively collected on consecutive patients with solid pancreatic or peripancreatic lesions at a single tertiary care center from November 2015 to November 2016 that underwent either FNA or CNB. Patient demographics, characteristics of lesions, diagnostic accuracy, final and follow-up pathology, use of rapid on-site evaluation (ROSE), complications, and procedure variables were obtained. RESULTS: A total of 75 FNA and 48 CNB were performed; of these, 13 patients had both. Mean passes were lower with CNB compared to FNA (2.4 vs 2.9, P = .02). Use of ROSE was higher for FNA (97.3% vs 68.1%, P = .001). Mean procedure time was shorter with CNB (34.1 minutes vs 51.2 minutes, P = .02) and diagnostic accuracy was similar (89.2% vs 89.4%, P = .98). There was no difference in diagnostic accuracy when ROSE was performed for CNB vs not performed (93.5% vs 85.7%, P = .58). Additionally, diagnostic accuracy of combined FNA and CNB procedures was 92.3%, which was comparable to FNA (P = .73) or CNB (P = .52) alone. CONCLUSION: FNA and CNB had comparable safety and diagnostic accuracy. Use of CNB resulted in less number of passes and shorter procedure time as compared to FNA. Moreover, diagnostic accuracy for CNB with or without ROSE was similar.

Short Communication: Nonprogressive HIV-1 Infection Is Associated with Expansion of IL-21R Expressing Class-Switched Memory B Cells.

HIV perturbs the functionality of B cells resulting in defective humoral responses. As efficient humoral immune responses are important in controlling HIV-disease progression, we characterized the memory B cell population for its subsets and their activation (CD38 expression) and functional [interleukin (IL)-21R expression] profile in individuals with nonprogressive [long-term nonprogressors (LTNPs), N = 16] and progressive HIV disease (progressors, N = 16) along with 10 HIV uninfected healthy controls (HCs). The frequencies of total memory B cells were similar in HCs and HIV-infected individuals, whereas the frequencies of unswitched memory B (UMB) cells and CD38+ UMB cells were significantly higher in progressors than LTNPs and HCs (p < .03). LTNPs showed higher frequencies of class-switched memory B (SMB) cells and IL-21R expressing SMB cells than seen in progressors (p = .019), which were similar to that seen in HCs. The %UMB cells correlated inversely (p = .0002, r = -0.6053) and %SMB cells correlated positively (p = .0005, r = 0.5804) with CD4 count. IL-21/IL-21R interaction is required for class switching of B cells and differentiation into antibody-secreting plasma cells. The higher expression of IL-21R on class SMB cells from LTNPs might be resulting in efficient plasma cell differentiation and the functional humoral immune response that might be responsible for mounting efficient antibody response against the encountered infections. The more insights in this area might be required to further understand the role of IL-21R expressing class SMB cells in HIV infection.

Hepatic infarction and acute pancreatitis: a case report and review of the literature.

Hepatic infarction is rare due to the unique dual hepatic blood supply from the hepatic artery and the portal vein. Herein, we report a case of hepatic infarction that occurred as a complication of acute pancreatitis. The patient was a 58-year-old male with past medical history of chronic alcoholism, who presented with epigastric abdominal pain, nausea, and vomiting. Hepatic infarction was diagnosed with computed tomography of the abdomen and pelvis without contrast, which revealed suspicion of splenic vein thrombosis and peripancreatic fat stranding along with a wedge-shaped, peripheral hypo density in the right hepatic lobe with typical morphology for hepatic infarction.

A unique case of bilateral hydronephrosis caused by a fecalith.

This is a unique case that signifies the importance to look beyond the genitourinary system for causes of hydronephrosis. In addition, we outline the manner in which a fecalith should be addressed.

Cross-reactive influenza-specific antibody-dependent cellular cytotoxicity-mediating antibodies in HIV-infected Indian individuals.

BACKGROUND: The influenza-specific antibodies mediating antibody-dependent cellular cytotoxicity (ADCC) may be important in protection against influenza. However, it is not known whether immunocompromised individuals such as HIV-infected persons who have never been vaccinated with influenza vaccine have such a response. METHODS: The anti-influenza ADCC responses were investigated in plasma samples from 50 HIV positive persons [25 long-term nonprogressors (LTNPs) and 25 progressors] and from 20 HIV-uninfected healthy individuals. None of the participants had received influenza vaccine. RESULTS: The frequencies and the magnitude of ADCC responses against two influenza A virus strains (pH1N1-A/California/7/2009 and H3N2-A/Brisbane/10/2007) were comparable in HIV-infected individuals and in healthy controls (p > .05). However, the magnitude of the ADCC response was slightly higher in LTNPs than in progressors (p = .025). The level of ADCC antibodies against pH1N1 and H3N2 correlated significantly indicating the cross-reactive nature of these antibodies (p < .0001). Additionally, the level of these ADCC antibodies was significantly associated with antibodies against the highly pathogenic avian influenza H5N1 virus (H5N1-A/Chicken/India/NIV/33487/2007). CONCLUSION: This is the first report of anti-influenza ADCC antibodies in HIV-infected Indian individuals. Identification of cross-reactive ADCC epitopes in HIV-infected individuals could improve the design of influenza vaccine for immunocompromised individuals.

Effect of Combination Antiretroviral Therapy on HIV-1-specific Antibody-Dependent Cellular Cytotoxicity Responses in Subtype B- and Subtype C-Infected Cohorts.

BACKGROUND: There is growing interest in immune therapies to clear the latent HIV-1 after combination antiretroviral therapy (cART). There is limited information on the effect of cART on antibody-dependent cellular cytotoxicity (ADCC), and no studies have directly compared ADCC in HIV-1 subtype B- and subtype C-infected subjects. The effect of improving immunocompetence on ADCC to influenza also remains unexplored. METHODS: The effect of cART on HIV-1- and influenza-specific ADCC was analyzed in 2 cohorts (39 subtype B- and 47 subtype C-infected subjects) before and after 2 years of cART. ADCC analyses included an enzyme-linked immunosorbent assay-based dimeric recombinant soluble (rs) FcγRIIIa-binding assay, antibody-dependent natural killer cell activation assay, and ADCC-mediated killing assays. RESULTS: HIV-1 subtype B and C Env-specific antibody binding to dimeric rsFcγRIIIa were reduced in subtypes B- and C-infected cohorts after 2 years of cART (both P < 0.05). Reduced ADCC-mediated killing of target cells expressing subtype B Env in the subtype B-infected cohort (P = 0.003) was observed after 96 weeks of cART, but not of subtype C Env in the subtype C-infected cohort. A greater reduction in ADCC was detected in subjects with baseline CD4 counts >300 cells/µL (P < 0.05). The resolving immunodeficiency after 96 weeks of cART resulted in improved HA-specific ADCC to 6 strains of influenza (all P < 0.01). CONCLUSIONS: cART results in HIV-1 antigen loss and reductions in HIV-1 Env-specific antibodies with Fc functionality in both subtype B- and C-infected subjects, particularly in immunocompetent subjects. Simultaneously, cART improves ADCC to diverse strains of influenza, suggesting reduction in influenza disease after cART.

Indian Long-term Non-Progressors Show Broad ADCC Responses with Preferential Recognition of V3 Region of Envelope and a Region from Tat Protein.

HIV-specific antibody-dependent cell cytotoxicity (ADCC) is likely to be important in governing protection from human immunodeficiency virus (HIV) and slowing disease progression. Little is known about the ADCC responses to HIV-1 subtype C. We characterized ADCC responses in HIV-1 subtype C-infected Indian subjects with slow disease progression and identified the dominant antigenic regions recognized by these antibodies. ADCC responses were measured in plasma from 34 long-term non-progressors (LTNPs), who were asymptomatic and maintained CD4 count above 500 cells/mm3 for the last 7 years in the absence of antiretroviral therapy (ART), and 58 ART naïve progressors with CD4 count <500 cells/mm3 against overlapping HIV-1 peptides using a flow cytometry-based antibody-dependent natural killer (NK) cell activation assay. The assay measured CD107a expression on NK cells as a marker of antibody-dependent NK cell activation and IFN-γ secretion by NK cells upon activation. The ADCC epitopes were mapped using the matrix of overlapping peptides. Indian LTNPs showed higher and broader ADCC responses compared to the progressors. The Env-C and Tat-specific ADCC responses were associated with lower plasma viral load, whereas the Env-C responses were also associated with higher CD4 counts. Five of 10 LTNP responders targeted epitopes in the V3 region (amino acids 288-330) of Env-C. Additionally, three Tat regions were targeted by ADCC antibodies from LTNPs. ADCC responses were associated with slow HIV progression in Indian subtype C-infected cohort. The frequently recognized peptides from the V3 loop of Env and the novel epitopes from Tat by the LTNPs warrants further study to understand the role of ADCC responses to these regions in control and prevention of HIV-1 infection.

Development of IFN-γ secretory ELISPOT based assay for screening of ADCC responses.

Antibody dependent cell mediated cytotoxicity has been established as one of the important protective immune mechanisms against HIV making it essential to evaluate it while testing immunogenicity of emerging vaccine candidates. IFN-γ secretory ELISPOT assay, widely used for evaluation of CTL response in HIV vaccine trials, was adapted for measuring ADCC responses and the results were compared with the standard ICS based assays. IFN-γ responses elicited by plasma samples of 23 HIV infected individuals against Env and Gag peptides using granulocytes as antigen presenting cells were assessed by both the methods. Supernatants of the activated cells in ELISPOT assay were also assessed for cytokine/chemokine estimation. ELISPOT assays detected significantly more ADCC responders against HIV-Env and Gag peptide pools than ICS assay. The magnitude of IFN-γ response in both the assay correlated significantly (p=0.002). NK cells were found to be the predominant cell type secreting IFN-γ in the assay. Although IFN-γ and IL-6 levels were significantly higher in supernatants of Env peptides stimulated cells, IP-10 and MCP-1α levels were found to be more against Gag peptides. Thus, IFN-γ secretory ELISPOT assay was found to be more sensitive in detecting ADCC responders than ICS assay making it a valuable tool for screening of ADCC responses in future vaccine trials. Differences in cytokine pattern of Env versus Gag stimulated cells warrants a need for investigating their role in protection against HIV infection.

Improvement in chronic low back pain in an obese patient with topiramate use.

The objective of this study was to demonstrate efficacy, benefit, and potential use of topiramate in treating obese patients with chronic low back pain. This is a case report from an outpatient academic pain multidisciplinary clinical center. The patient was a 30-year-old morbidly obese (body mass index [BMI]: 61.4 kg/m(2)) female suffering from chronic low back pain. With a known association between obesity and chronic low back pain, and a possible role of topiramate in treating both simultaneously, the patient was started on a therapeutic trial of topiramate. Over a period of a 12-week topiramate therapy, the patient experienced clinically meaningful and significant weight loss as well as improvement in her chronic low back pain and functionality. With more substantial evidence, pain physicians may start considering using topiramate in the multimodal management of obesity-related chronic low back pain based on their thoughtful consideration of the drug's efficacy and side effects and the patient's comorbidities and preferences.

Higher Expression of Activating Receptors on Cytotoxic NK Cells is Associated with Early Control on HIV-1C Multiplication.

Natural killer (NK) cells may be important in modulating HIV replication in early course of HIV infection. The effector function of NK cells is finely tuned by a balance between signals delivered by activating and inhibitory receptors. However, the influence of expression of these receptors on the early course of HIV replication and subsequent disease progression is not explored in the context of HIV-1C infection. The expression pattern of activating (NKp46, NKp44, NKp30, NKG2D, and NKG2C) and inhibitory (CD158b, NKG2A, and ILT2) receptors was determined in 20 patients with recent HIV-1C infection within 3-7 months of acquiring HIV infection and was compared with the expression pattern in individuals with progressive (N = 12), non-progressive HIV-1C infection (LTNPs, N = 12) and healthy seronegative individuals (N = 20). The association of the expression of these receptors on the rate of disease progression was assessed using viral load set point of recently infected individuals as a marker of disease progression. The study showed that higher cytotoxic potency of NK cells was associated with low viral load set point in recent HIV infection (r = -0.701; p = 0.0006) and higher CD4 counts (r = 0.720; p = 0.001). The expression of activating receptors (NKp46, NKp30, and NKG2D) on cytotoxic NK cells but not on regulatory NK cells was also significantly associated with low viral set point (p < 0.01) and viral load in LTNPs and progressors (p < 0.01). The study also indicated that cytotoxic NK cells might show the ability to specifically lyse HIV infected CD4 cells. This data collectively showed that early and sustained higher expression of activating receptors on cytotoxic NK cells could be responsible for increased cytotoxicity, reduced viral burden, and thus delaying the disease progression. The study to identify the molecular mechanism of the expression of these receptors in HIV infection will be helpful in further understanding of NK cell mediated control in early HIV infection.

Fourth cranial nerve palsy and bilateral acute retinal necrosis following human herpesvirus 6 infection of the central nervous system.

Acute retinal necrosis (ARN) is a rare, potentially blinding condition typically affecting immunocompetent individuals. It is defined by the clinical triad of vitreous inflammation, occlusive vasculopathy, and progressive retinal necrosis, usually located in peripheral retina with circumferential extension. Varicella zoster virus (VZV), herpes simplex virus (HSV), Epstein-Barr virus (EBV) and occasionally cytomegalovirus (CMV) are the common causative agents of ARN. Reports of human herpesvirus 6 (HHV6) infection of the central nervous system (CNS) associated with ocular inflammatory disease are extremely rare. We here report the case of a 22-year-old immunocompetent male who presented with acute bilateral ARN and fourth nerve palsy, following HHV6 infection of the CNS and EBV infectious mononucleosis.

Expansion of defective NK cells in early HIV type 1C infection: a consequence of reduced CD161 expression.

Human immunodeficiency virus (HIV)-1 infection compromises the natural killer (NK) cell function and leads to defective control on virus multiplication. One of the major features of HIV-1 infection is the expansion of a functionally compromised defective NK cell subset (CD56(-)CD16(+)). We analyzed the NK cell subsets in early HIV infection to determine the effect of NK cell perturbation on the viral load set point, a marker of disease progression. We report that the defective NK cells are expanded in early HIV infection within 6-8 months of acquiring infection and are correlated with a higher plasma viral load set point, suggesting its utility as a predictive marker for disease progression. The expression of CD161, a molecular marker responsible for proliferation and differentiation of NK cells, was significantly down-regulated in the defective NK cells as compared to slow progressors (p=0.0009) and healthy controls (p=0.0003) and was correlated with a higher viral load set point in early HIV-1 infection (r=-0.6154, p=0.03), suggesting the probable role of CD161 expression in the impaired proliferation and differentiation of defective NK cells into the functional NK cells in early HIV infection. The reduction in CD161 expression on the defective NK cells in early HIV infection is thus indicative of the role of innate immune cells in early control of HIV infection.

Al-Awadi/Raas-Rothschild/Schinzel (AARRS) phocomelia syndrome: case report and developmental field analysis.

We describe a girl infant with anomalies of the left pelvis and lower limb (pelvic, femoral, and tibial hypogenesis with absent fibula), subtle facial changes, patent foraman ovale, single umbilical artery, single kidney, and imperforate anus. The external genitalia were asymmetric and ambiguous with normal uterus and ovaries visualized by ultrasound. The anomalies are compatible with previously reported cases of Al-Awadi/Raas-Rothschild/Schinzel (AARRS) phocomelia, an autosomal recessive disorder with WNT7 gene mutations documented in one family. We suggest that AARRS phocomelia, Fuhrmann syndrome, and similar conditions comprise a spectrum, and that the anomaly pattern derives from serial action of the same signal pathways within primary (e.g., the major axes), secondary (e.g., heart or limb primordia), and/or local (e.g., tibial-fibular differentiation) developmental fields.