Replacement of the Cobalt Center of Vitamin B12 by Nickel: Nibalamin and Nibyric Acid Prepared from Metal-Free B12 †Ligands Hydrogenobalamin and Hydrogenobyric Acid.

The (formal) replacement of Co in cobalamin (Cbl) by NiII generates nibalamin (Nibl), a new transition-metal analogue of vitamin B12 . Described here is Nibl, synthesized by incorporation of a NiII ion into the metal-free B12  ligand hydrogenobalamin (Hbl), itself prepared from hydrogenobyric acid (Hby). The related NiII  corrin nibyric acid (Niby) was similarly synthesized from Hby, the metal-free cobyric acid ligand. The solution structures of Hbl, and Niby and Nibl, were characterized by spectroscopic studies. Hbl features two inner protons bound at N2 and N4 of the corrin ligand, as discovered in Hby. X-ray analysis of Niby shows the structural adaptation of the corrin ligand to NiII ions and the coordination behavior of NiII . The diamagnetic Niby and Nibl, and corresponding isoelectronic CoI corrins, were deduced to be isostructural. Nibl is a structural mimic of four-coordinate base-off Cbls, as verified by its ability to act as a strong inhibitor of bacterial adenosyltransferase.

Clinical identification of feeding and swallowing disorders in 0-6 month old infants with Down syndrome.

Feeding and swallowing disorders have been described in children with a variety of neurodevelopmental disabilities, including Down syndrome (DS). Abnormal feeding and swallowing can be associated with serious sequelae such as failure to thrive and respiratory complications, including aspiration pneumonia. Incidence of dysphagia in young infants with DS has not previously been reported. To assess the identification and incidence of feeding and swallowing problems in young infants with DS, a retrospective chart review of 174 infants, ages 0-6 months was conducted at a single specialty clinic. Fifty-seven percent (100/174) of infants had clinical concerns for feeding and swallowing disorders that warranted referral for Videofluroscopic Swallow Study (VFSS); 96/174 (55%) had some degree of oral and/or pharyngeal phase dysphagia and 69/174 (39%) had dysphagia severe enough to warrant recommendation for alteration of breast milk/formula consistency or nonoral feeds. Infants with certain comorbidities had significant risk for significant dysphagia, including those with functional airway/respiratory abnormalities (OR = 7.2). Infants with desaturation with feeds were at dramatically increased risk (OR = 15.8). All young infants with DS should be screened clinically for feeding and swallowing concerns. If concerns are identified, consideration should be given to further evaluation with VFSS for identification of dysphagia and additional feeding modifications.

Obstructive sleep apnea in young infants with Down syndrome evaluated in a Down syndrome specialty clinic.

Children with Down syndrome (DS) experience congenital and functional medical issues that predispose them to obstructive sleep apnea (OSA). Research utilizing stringent age criteria among samples of infants with DS and OSA is limited. This study examines clinical correlates of OSA among infants with DS. A retrospective chart review was conducted of infants ≤6 months of age referred to a DS clinic at a tertiary children's hospital over five-years (n = 177). Chi-square tests and binary logistic regression models were utilized to analyze the data. Fifty-nine infants underwent polysomnography, based on clinical concerns. Of these, 95% (56/59) had studies consistent with OSA. Among infants with OSA, 71% were identified as having severe OSA (40/56). The minimum overall prevalence of OSA among the larger group of infants was 31% (56/177). Significant relationships were found between OSA and dysphagia, congenital heart disease (CHD), prematurity, gastroesophageal reflux disease (GERD), and other functional and anatomic gastrointestinal (GI) conditions. Results indicate that odds of OSA in this group are higher among infants with GI conditions in comparison to those without. Co-occurring dysphagia and CHD predicted the occurrence of OSA in 36% of cases with an overall predictive accuracy rate of 71%. Obstructive sleep apnea is relatively common in young infants with DS and often severe. Medical factors including GI conditions, dysphagia and CHD may help to identify infants who are at greater risk and may warrant evaluation. Further studies are needed to assess the impact of OSA in infants with DS.

Modification of bacterial microcompartments with target biomolecules via post-translational SpyTagging.

Bacterial microcompartments (BMCs) are proteinaceous organelle-like structures formed within bacteria, often encapsulating enzymes and cellular processes, in particular, allowing toxic intermediates to be shielded from the general cellular environment. Outside of their biological role they are of interest, through surface modification, as potential drug carriers and polyvalent antigen display scaffolds. Here we use a post-translational modification approach, using copper free click chemistry, to attach a SpyTag to a target protein molecule for attachment to a specific SpyCatcher modified BMC shell protein. We demonstrate that a post-translationally SpyTagged material can react with a SpyCatcher modified BMC and show its presence on the surface of BMCs, enabling future investigation of these structures as polyvalent antigen display scaffolds for vaccine development. This post-translational 'click' methodology overcomes the necessity to genetically encode the SpyTag, avoids any potential reduction in expression yield and expands the scope of SpyTag/SpyCatcher vaccine scaffolds to form peptide epitope vaccines and small molecule delivery agents.

Immunotherapy Responsiveness and Risk of Relapse in Down Syndrome Regression Disorder.

Down syndrome regression disorder (DSRD) is a clinical symptom cluster consisting of neuropsychiatric regression without an identifiable cause. This study evaluated the clinical effectiveness of IVIg and evaluated clinical characteristics associated with relapse after therapy discontinuation. A prospective, multi-center, non-randomized, observational study was performed. Patients met criteria for DSRD and were treated with IVIg. All patients underwent a standardized wean off therapy after 9-12 months of treatment. Baseline, on therapy, and relapse scores of the Neuropsychiatric Inventory Total Score (NPITS), Clinical Global Impression-Severity (CGI-S), and the Bush-Francis Catatonia Rating Scale (BFCRS) were used to track clinical symptoms. Eighty-two individuals were enrolled in this study. Patients had lower BFCRS (MD: -6.68; 95% CI: -8.23, -5.14), CGI-S (MD: -1.27; 95% CI: -1.73, -0.81), and NPITS scores (MD: -6.50; 95% CI: -7.53, -5.47) while they were on therapy compared to baseline. Approximately 46% of the patients (n = 38) experienced neurologic relapse with wean of IVIg. Patients with neurologic relapse were more likely to have any abnormal neurodiagnostic study (χ2 = 11.82, p = 0.001), abnormal MRI (χ2 = 7.78, p = 0.005), and abnormal LP (χ2 = 5.45, p = 0.02), and a personal history of autoimmunity (OR: 6.11, p < 0.001) compared to patients without relapse. IVIg was highly effective in the treatment of DSRD. Individuals with a history of personal autoimmunity or neurodiagnostic abnormalities were more likely to relapse following weaning of immunotherapy, indicating the potential for, a chronic autoimmune etiology in some cases of DSRD.

Immunotherapy responsiveness and risk of relapse in Down syndrome regression disorder.

Down syndrome regression disorder (DSRD) is a clinical symptom cluster consisting of neuropsychiatric regression without an identifiable cause. This study evaluated the clinical effectiveness of IVIg and evaluated clinical characteristics associated with relapse after therapy discontinuation. A prospective, multi-center, non-randomized, observational study was performed. Patients met criteria for DSRD and were treated with IVIg. All patients underwent a standardized wean-off therapy after 9-12 months of treatment. Baseline, on-therapy, and relapse scores of the Neuropsychiatric Inventory Total Score (NPITS), Clinical Global Impression-Severity (CGI-S), and the Bush-Francis Catatonia Rating Scale (BFCRS) were used to track clinical symptoms. Eighty-two individuals were enrolled in this study. Patients had lower BFCRS (MD: -6.68; 95% CI: -8.23, -5.14), CGI-S (MD: -1.27; 95% CI: -1.73, -0.81), and NPITS scores (MD: -6.50; 95% CI: -7.53, -5.47) while they were on therapy compared to baseline. Approximately 46% of the patients (n = 38) experienced neurologic relapse with wean of IVIg. Patients with neurologic relapse were more likely to have any abnormal neurodiagnostic study (χ2 = 11.82, P = 0.001), abnormal MRI (χ2 = 7.78, P = 0.005), and abnormal LP (χ2 = 5.45, P = 0.02), and a personal history of autoimmunity (OR: 6.11, P < 0.001) compared to patients without relapse. IVIg was highly effective in the treatment of DSRD. Individuals with a history of personal autoimmunity or neurodiagnostic abnormalities were more likely to relapse following weaning of immunotherapy, indicating the potential for, a chronic autoimmune etiology in some cases of DSRD.

Assessment and Diagnosis of Down Syndrome Regression Disorder: International Expert Consensus.

Objective: To develop standardization for nomenclature, diagnostic work up and diagnostic criteria for cases of neurocognitive regression in Down syndrome. Background: There are no consensus criteria for the evaluation or diagnosis of neurocognitive regression in persons with Down syndrome. As such, previously published data on this condition is relegated to smaller case series with heterogenous data sets. Lack of standardized assessment tools has slowed research in this clinical area. Methods: The authors performed a two-round traditional Delphi method survey of an international group of clinicians with experience in treating Down syndrome to develop a standardized approach to clinical care and research in this area. Thirty-eight potential panelists who had either previously published on neurocognitive regression in Down syndrome or were involved in national or international working groups on this condition were invited to participate. In total, 27 panelists (71%) represented nine medical specialties and six different countries reached agreement on preliminary standards in this disease area. Moderators developed a proposed nomenclature, diagnostic work up and diagnostic criteria based on previously published reports of regression in persons with Down syndrome. Results: During the first round of survey, agreement on nomenclature for the condition was reached with 78% of panelists agreeing to use the term Down Syndrome Regression Disorder (DSRD). Agreement on diagnostic work up and diagnostic criteria was not reach on the first round due to low agreement amongst panelists with regards to the need for neurodiagnostic testing. Following incorporation of panelist feedback, diagnostic criteria were agreed upon (96% agreement on neuroimaging, 100% agreement on bloodwork, 88% agreement on lumbar puncture, 100% agreement on urine studies, and 96% agreement on "other" studies) as were diagnostic criteria (96% agreement). Conclusions: The authors present international consensus agreement on the nomenclature, diagnostic work up, and diagnostic criteria for DSRD, providing an initial practical framework that can advance both research and clinical practices for this condition.