An Anti-C1s Monoclonal, TNT003, Inhibits Complement Activation Induced by Antibodies Against HLA.

Antibody-mediated rejection (AMR) of solid organ transplants (SOT) is characterized by damage triggered by donor-specific antibodies (DSA) binding donor Class I and II HLA (HLA-I and HLA-II) expressed on endothelial cells. While F(ab')2 portions of DSA cause cellular activation and proliferation, Fc regions activate the classical complement cascade, resulting in complement deposition and leukocyte recruitment, both hallmark features of AMR. We characterized the ability of an anti-C1s monoclonal antibody, TNT003, to inhibit HLA antibody (HLA-Ab)-induced complement activation. Complement deposition induced by HLA-Ab was evaluated using novel cell- and bead-based assays. Human aortic endothelial cells (HAEC) were cultured with HLA-Ab and human complement; production of activated complement proteins was measured by flow cytometry. Additionally, C3d deposition was measured on single antigen beads (SAB) mixed with HLA-Ab and human complement. TNT003 inhibited HLA-Ab mediated complement deposition on HAEC in a concentration-dependent manner; C3a, C4a and C5a anaphylatoxin production was also diminished by TNT003. Finally, TNT003 blocked C3d deposition induced by Class I (HLAI-Ab)- and Class II (HLAII-Ab)-specific antibodies on SAB. These data suggest TNT003 may be useful for modulating the effects of DSA, as TNT003 inhibits complement deposition and split product formation generated by HLA-I/II-Ab in vitro

Gut dysfunction in patients with multiple sclerosis and the role of spinal cord involvement in the disease.

Bowel and bladder symptoms are highly prevalent in patients with multiple sclerosis (MS). Bladder dysfunction (affecting 75% of these patients) is caused by disease in the spinal cord, whilst the pathophysiology of bowel dysfunction is unknown. Pathways regulating both the organs lie in close proximity to the spinal cord, and coexistence of their dysfunction might be the result of a common pathophysiology. If so, the prevalence of bladder symptoms should be greater in patients with MS and bowel symptoms. This hypothesis is tested in the study. We also evaluated how patient-reported symptoms quantify bowel dysfunction

Urinary, bowel and sexual symptoms in a cohort of patients with Friedreich's ataxia

BACKGROUND: Pelvic symptoms are distressing symptoms experienced by patients with Friedreich’s Ataxia (FRDA). The aim of this study was to describe the prevalence of lower urinary tract symptoms (LUTS), bowel and sexual symptoms in FRDA. METHODS: Questionnaire scores measuring LUTS, bowel and sexual symptoms were analysed with descriptive statistics as a cohort and as subgroups (Early/Late-onset and Early/Late-stage FRDA) They were also correlated with validated measures of disease severity including those of ataxia severity, non-ataxic symptoms and activities of daily living. RESULTS: 80% (n = 46/56) of patients reported LUTS, 64% (n = 38/59) reported bowel symptoms and 83% (n = 30/36) reported sexual symptoms. Urinary and bowel or sexual symptoms were significantly likely to co-exist among patients. Late-onset FRDA patients were also more likely to report LUTS than early-onset ones. Patients with a longer disease duration reported higher LUTS scores and poorer quality of life scores related to urinary symptoms. CONCLUSIONS: A high proportion of FRDA have symptoms suggestive of LUTS, bowel and sexual dysfunction. This is more marked with greater disease duration and later disease onset. These symptoms need to be addressed by clinicians as they can have a detrimental effect on patients

Novel associations for hypothyroidism include known autoimmune risk loci

Hypothyroidism is the most common thyroid disorder, affecting about 5% of the general population. Here we present the first large genome-wide association study of hypothyroidism, in 2,564 cases and 24,448 controls from the customer base of 23andMe, Inc., a personal genetics company. We identify four genome-wide significant associations, two of which are well known to be involved with a large spectrum of autoimmune diseases: rs6679677 near _PTPN22_ and rs3184504 in _SH2B3_ (p-values 3.5e-13 and 3.0e-11, respectively). We also report associations with rs4915077 near _VAV3_ (p-value 8.3e-11), another gene involved in immune function, and rs965513 near _FOXE1_ (p-value 3.1e-14). Of these, the association with _PTPN22_ confirms a recent small candidate gene study, and _FOXE1_ was previously known to be associated with thyroid-stimulating hormone (TSH) levels. Although _SH2B3_ has been previously linked with a number of autoimmune diseases, this is the first report of its association with thyroid disease. The _VAV3_ association is novel. These results suggest heterogeneity in the genetic etiology of hypothyroidism, implicating genes involved in both autoimmune disorders and thyroid function. Using a genetic risk profile score based on the top association from each of the four genome-wide significant regions in our study, the relative risk between the highest and lowest deciles of genetic risk is 2.1

Psychometric precision in phenotype definition is a useful step in molecular genetic investigation of psychiatric disorders

Affective disorders are highly heritable, but few genetic risk variants have been consistently replicated in molecular genetic association studies. The common method of defining psychiatric phenotypes in molecular genetic research is either a summation of symptom scores or binary threshold score representing the risk of diagnosis. Psychometric latent variable methods can improve the precision of psychiatric phenotypes, especially when the data structure is not straightforward. Using data from the British 1946 birth cohort, we compared summary scores with psychometric modeling based on the General Health Questionnaire (GHQ-28) scale for affective symptoms in an association analysis of 27 candidate genes (249 single-nucleotide polymorphisms (SNPs)). The psychometric method utilized a bi-factor model that partitioned the phenotype variances into five orthogonal latent variable factors, in accordance with the multidimensional data structure of the GHQ-28 involving somatic, social, anxiety and depression domains. Results showed that, compared with the summation approach, the affective symptoms defined by the bi-factor psychometric model had a higher number of associated SNPs of larger effect sizes. These results suggest that psychometrically defined mental health phenotypes can reflect the dimensions of complex phenotypes better than summation scores, and therefore offer a useful approach in genetic association investigations

Exploratory pilot study exploring clinical effects of exogenous sustained-release Melatonin on nocturia in Parkinson’s Disease

Introduction: Nocturia is one of the commonest non‐motor symptoms in Parkinson’s disease (PD). Nocturia has evolved from being understood as a symptom of urological disorders or neurogenic bladder dysfunction to being considered as a form of circadian dysregulation. Exogenous melatonin is known to help circadian function and can be an effective strategy for nocturia in PD. Methods: In this open label single‐site exploratory phase 2 pilot study, adults with PD and nocturia underwent assessments using standardised questionnaires, urodynamics studies and a bladder scan. This was followed by completion of a frequency volume charts (FVC) and two weeks sleep diary. Sustained‐release melatonin 2mg was then administered once nightly for six weeks. A repeat assessment using questionnaires, the FVC and sleep diary was performed whilst on treatment with melatonin. Companion or bed partners filled in sleep questionnaires to assess their sleep during the intervention. Results: 20 patients (12 males; mean 68.2 (SD=7.8) years; mean PD duration 8.0 (±5.5) years with PD reporting nocturia were included. Administration of melatonin was associated with a significant reduction in the primary outcome bother related to nocturia measured using the International Consultation on Incontinence Questionnaire Nocturia (ICIQ‐N) (p=0.01), number of episodes of nocturia per night (p=0.013) and average urine volume voided at night (p=0.013). No serious adverse events were reported. No significant improvement was noted in bed‐partner sleep scores. Conclusion: In this preliminary open‐label study, administration of sustained‐release melatonin 2mg was found to be safe for clinical use and was associated with significant improvements in night‐time frequency and nocturnal voided volumes in PD patients

Analysis of electrodeposited CdTe thin films grown using cadmium chloride precursor for applications in solar cells

Deposition of cadmium telluride (CdTe) from cadmium chloride (CdCl2) and tellurium oxide has been achieved by electroplating technique using two-electrode configuration. Cyclic voltammetry shows that near-stoichiometric CdTe is achievable between 1330 and 1400 mV deposition voltage range. The layers grown were characterised using X-ray diffraction (XRD), UV–Visible spectrophotometry, scanning electron microscopy (SEM), energy-dispersive X-ray analysis (EDX), photoelectrochemical (PEC) cell and DC conductivity measurements. The XRD shows that the electrodeposited CdTe layer is polycrystalline in nature. The UV–Visible spectrophotometry shows that the bandgap of both as-deposited and heat-treated CdTe films are in the range of (1.44–1.46) eV. The SEM shows grain growth after CdCl2 treatment, while, the EDX shows the effect of growth voltage on the atomic composition of CdTe layers. The PEC results show that both p- and n-type CdTe can be electrodeposited and the DC conductivity reveals that the high resistivity is at the inversion growth voltage (Vi) for the as-deposited and CdCl2 treated layers

Oral human papillomavirus is common in individuals with Fanconi anemia

Fanconi anemia is a rare genetic disorder resulting in a loss of function of the Fanconi anemia-related DNA repair pathway. Individuals with Fanconi anemia are predisposed to some cancers, including oropharyngeal and gynecologic cancers, with known associations with human papillomavirus (HPV) in the general population. As individuals with Fanconi anemia respond poorly to chemotherapy and radiation, prevention of cancer is critical. METHODS: To determine whether individuals with Fanconi anemia are particularly susceptible to oral HPV infection, we analyzed survey-based risk factor data and tested DNA isolated from oral rinses from 126 individuals with Fanconi anemia and 162 unaffected first-degree family members for 37 HPV types. RESULTS: Fourteen individuals (11.1%) with Fanconi anemia tested positive, significantly more (P = 0.003) than family members (2.5%). While HPV prevalence was even higher for sexually active individuals with Fanconi anemia (17.7% vs. 2.4% in family; P = 0.003), HPV positivity also tended to be higher in the sexually inactive (8.7% in Fanconi anemia vs. 2.9% in siblings). Indeed, having Fanconi anemia increased HPV positivity 4.9-fold (95% CI, 1.6-15.4) considering age and sexual experience, but did not differ by other potential risk factors. CONCLUSION: Our studies suggest that oral HPV is more common in individuals with Fanconi anemia. It will be essential to continue to explore associations between risk factors and immune dysfunction on HPV incidence and persistence over time. IMPACT: HPV vaccination should be emphasized in those with Fanconi anemia as a first step to prevent oropharyngeal cancers, although additional studies are needed to determine whether the level of protection it offers in this population is adequate

ANTIBACTERIAL ACTIVITY OF TABERNAEMONTANA DIVARICATA (APOCYNACEAE) SECONDARY METABOLITES CAPPED SILVER AND GOLD NANOPARTICLES

Objective: To study the antibacterial activity of Tabernaemontana divaricata (Apocynaceae) secondary metabolites capped silver nanoparticles(SNPs) and gold nanoparticles (AuNPs).Methods: In the present investigation, SNPs and AuNPs were synthesized using an aqueous extract of T. divaricata leaves. Leaf aqueous extractwas mixed with 1 mM silver nitrate and chloroauric acid for the biosynthesis of nanoparticles, and the same was analyzed using ultraviolet-visible(UV-Vis) spectrophotometer and particle size analyzer. The antibacterial activity of SNPs and AuNPs was determined against various bacterial culturesincluding laboratory isolates using the agar well diffusion method.Results: The results recorded from UV-Vis spectrum supported the biosynthesis and characterization of SNPs and AuNPs. The SNPs when comparedto AuNPs, showed the highest antibacterial activity against Gram-positive and Gram-negative bacteria.Conclusion: The present study envisions on the biosynthesis of SNPs from T. divaricata plant which are emerging as antibacterial therapy in modernmedical applications.Keywords: Antibacterial activity, Gold nanoparticles, Silver nanoparticles, Tabernaemontana divaricata