A predictive model for lack of partial clinical remission in new-onset pediatric type 1 diabetes.

IMPORTANCE: >50% of patients with new-onset type 1 diabetes (T1D) do not enter partial clinical remission (PCR); early identification of these patients may improve initial glycemic control and reduce long-term complications. AIM: To determine whether routinely obtainable clinical parameters predict non-remission in children and adolescents with new-onset T1D. SUBJECTS AND METHODS: Data on remission were collected for the first 36 months of disease in 204 subjects of ages 2-14 years with new-onset type 1 diabetes. There were 86 remitters (age 9.1±3.0y; male 57%), and 118 non-remitters (age 7.0±3.1y; male 40.7%). PCR was defined as insulin-dose adjusted hemoglobin A1c of ≤9. RESULTS: Non-remission occurred in 57.8% of subjects. Univariable analysis showed that the risk for non-remission was increased 9-fold in patients with 4 diabetes-associated auto-antibodies (OR = 9.90, p = 0.010); 5-fold in patients <5 years old (odds ratio = 5.38, p = 0.032), 3-fold in those with bicarbonate of <15 mg/dL at diagnosis (OR = 3.71, p = 0.008). Combined estimates of risk potential for HC03 and the number of autoantibodies by multivariable analysis, adjusted for BMI standard deviation score, showed HC03 <15 mg/dL with a clinically significant 10-fold risk (OR = 10.1, p = 0.074); and the number of autoantibodies with a 2-fold risk for non-remission (OR = 1.9, p = 0.105). Male sex and older age were associated with decreased risk for non-remission. A receiver-operating characteristic curve model depicting sensitivity by 1-specificity for non-remission as predicted by bicarbonate <15 mg/dL, age <5y, female sex, and >3 diabetes-associated autoantibodies had an area under the curve of 0.73. CONCLUSIONS: More than 50% of children and adolescents with new-onset T1D do not undergo partial clinical remission and are thus at an increased risk for long-term complications of diabetes mellitus. A predictive model comprising of bicarbonate <15 mg/dL, age <5y, female sex, and >3 diabetes-associated autoantibodies has 73% power for correctly predicting non-remission in children and adolescents with new-onset T1D. Early identification of these non-remitters may guide the institution of targeted therapy to limit dysglycemia and reduce the prevalence of long-term deleterious complications.

Outer Hair Cell Molecular Protein, Prestin, as a Serum Biomarker for Hearing Loss: Proof of Concept.

HYPOTHESIS: At present there are no serum biomarkers available to monitor cochlear health in those at risk of hearing loss. Outer hair cells (OHCs) play an important role in cochlear function and are one of the cellular elements most vulnerable to damage, such as acoustic trauma. We hypothesized that an OHC-specific protein can serve as a biomarker for OHC damage in circulation. METHODS: After assessing auditory function, rats were exposed to intense octave band noise for 2 to 3 hours. Auditory function was assessed 14 days after trauma. Blood samples were collected and prestin concentration was measured using enzyme-linked immunosorbent assay. RESULTS: Circulating prestin was detectable in all control and noise-exposed animals. At 14 days after trauma, however, noise-exposed rats demonstrated statistically significant decrease in prestin concentrations compared with control animals. CONCLUSION: This work, for the first time, provides proof of concept that an otologic serum biomarker level can change after acoustic trauma and hearing loss. Our approach represents an entirely novel strategy in hearing diagnostics and has both research and clinical potential. Further work is needed to map out the temporal course of change in serum prestin concentrations after inner ear trauma, better define the relationship of serological and functional changes, and explore application to other etiologies of hearing loss (e.g., ototoxins).

Prestin as a biochemical marker for early detection of acquired sensorineural hearing loss.

Acquired sensorineural hearing loss and tinnitus can come about through various etiologies such as exposure to excessively loud noise or drugs with ototoxic properties. As such, acquired hearing loss is a common source of morbidity which deleteriously affects the ability to communicate. At present our ability to detect acquired hearing loss and tinnitus at its earliest stages is limited and there are no adjuncts to audiometric evaluation. The earliest cellular targets of noise and ototoxins in the cochlea are the outer hair cells (OHC). I hypothesize that serum assays of OHC specific protein, prestin, will allow detection and quantification of OHC damage before audiometric testing can identify presence of hearing loss. At present, there are no data available to evaluate this hypothesis, but initial evaluation can readily be carried out using existing experimental animal models of ototoxicity and noise-induced hearing loss. Early detection of OHC damage is critical to adoption of measures aimed at ameliorating hearing loss and tinnitus, thus reducing permanent deficits and disability.

Mice with a targeted disruption of Slc4a11 model the progressive corneal changes of congenital hereditary endothelial dystrophy.

PURPOSE: To establish an animal model of congenital hereditary endothelial dystrophy (CHED) using Slc4a11 knockout (KO) mice and evaluate the abnormalities in the cornea and kidney. METHODS: The Slc4a11 KO mouse model was generated by gene deletion. Corneal abnormalities were evaluated using slit-lamp photography, anterior segment optical coherence tomography (AS-OCT), immunohistochemistry, RT-PCR, corneal endothelial cell staining, and electron microscopy. The temporal corneal changes were also monitored. Histological and functional changes of the kidney were also evaluated. RESULTS: Successful knockout of the Slc4a11 gene was confirmed by immunohistochemistry and RT-PCR. Slit-lamp photography and AS-OCT showed progressive corneal edema. Increased corneal endothelial cell size with decreased corneal endothelial cell density was observed with increased age. Scanning electron microscopy also revealed progressive cell swelling and distortion of the hexagonal cell morphology with time. Transmission electron microscopy showed characteristic ultrastructural findings of CHED, including endothelial vacuolization, thickening of the Descemet membrane, disorganization of collagen fibril, deposition of amorphous material, and progression of these changes with age. Decreased urine osmolarity and electrolyte concentrations suggesting abnormality in water resorption were also detected. CONCLUSIONS: Our Slc4a11 KO mouse model successfully represents clinical manifestations of human CHED. We were able to show chronological corneal progression for the first time in a knockout mouse model as well as renal abnormalities.

Femoral nailing during serum bicarbonate-defined hypo-perfusion predicts pulmonary organ dysfunction in multi-system trauma patients.

OBJECTIVE: To assess the value of venous serum bicarbonate as an endpoint of resuscitation and guide to timing of femoral nailing in multi-system trauma patients. DESIGN: Retrospective cohort study. SETTING: Academic Level 1 Trauma Centre. PATIENTS: Seventy-two consecutive adult multi-system trauma patients (Injury Severity Score≥15) with femoral shaft fracture (Orthopaedic Trauma Association Class 32-A to 32-C) treated with reamed medullary nail fixation. INTERVENTION: Femoral nailing in the setting of hypo-perfusion defined by venous serum bicarbonate (SB). Threshold values of SB were determined first by correlating SB and simultaneously drawn arterial base deficit (BD). Then, corresponding values of SB to previously defined thresholds of hypo-perfusion based on BD were identified using regression analysis. MAIN OUTCOME MEASUREMENT: Pulmonary organ dysfunction (POD) component of the Denver Multiple Organ Failure scoring system. RESULTS: Simultaneous admission SB and BD values were correlated (r=-0.43, p=0.001). Adjusting for age, ISS and baseline POD, patients with SB<24.7 mequiv./L within 6 h of treatment had a 12-fold increase in POD (OR 12.2, 95% CI 1.5-98.6, p=0.019). This association was diminished, but still significant with hypo-perfusion present within 12 h prior to treatment (OR 5.6, 95% CI 1.0-29.1, p=0.042) and 24 h prior to treatment (OR 5.9, 95% CI 1.1-30.7, p=0.037). CONCLUSIONS: Medullary fixation of femoral shaft fracture in the setting of serum bicarbonate-defined hypo-perfusion is associated with increased morbidity. Appropriate damage-control measures and aggressive resuscitation prior to definitive fracture care are advised and physiologic markers such as serum bicarbonate should guide clinical decision making rather than temporal distinctions.

Common genetic variation and haplotypes of the anion exchanger SLC4A2 in primary biliary cirrhosis.

OBJECTIVES: Deficiencies of the anion exchanger SLC4A2 are thought to play a pathogenic role in primary biliary cirrhosis (PBC), as the evidenced by decreased expression and activity in PBC patients and development of disease features in SLC4A2 knockout mice. We hypothesized that genetic variation in SLC4A2 might influence this pathogenic contribution. Thus, we aimed to perform a comprehensive assessment of SLC4A2 genetic variation in PBC using a linkage disequilibrium (LD)-based haplotype-tagging approach. METHODS: Twelve single nucleotide polymorphisms (SNPs) across SLC4A2 were genotyped in 409 PBC patients and 300 controls and evaluated for association with disease, as well as with prior orthotopic liver transplant and antimitochondrial antibody (AMA) status among the PBC patients, both individually and as inferred haplotypes, using logistic regression. RESULTS: All SNPs were in Hardy-Weinberg equilibrium. No associations with disease or liver transplantation were detected, but two variants, rs2303929 and rs3793336, were associated with negativity for antimitochondrial antibodies among the PBC patients. CONCLUSIONS: The common genetic variation of SLC4A2 does not directly affect the risk of PBC or its clinical outcome. Whether the deficiency of SLC4A2 expression and activity observed earlier in PBC patients is an acquired epiphenomenon of underlying disease or is because of heritable factors in unappreciated regulatory regions remains uncertain. Of note, two SLC4A2 variants appear to influence AMA status among PBC patients. The mechanisms behind this finding are unclear.

Familial pure proximal renal tubular acidosis--a clinical and genetic study.

BACKGROUND: Inherited proximal renal tubular acidosis (pRTA) is commonly associated with more generalized proximal tubular dysfunctions and occasionally with other organ system defects. Inherited combined pRTA and distal RTA with osteopetrosis and pure pRTA associated with ocular abnormalities, a rare disease which has been recently described. Only one family with pure isolated pRTA has been reported so far and the genetic cause for this disease is unknown. Objectives. We report a unique family with isolated pRTA. The aim of the project was to define the phenotype and to try to find the gene defect causing the disease. METHODS: Clinical and metabolic evaluation of all family members was performed and a family pedigree was constructed. DNA was extracted from blood samples of affected and unaffected family members. We amplified by PCR and sequenced the coding areas and splice-sites of the genes that contribute to HCO(-)(3) reclamation in the proximal tubule. The genes studied were as follows: CA II, CA IV, CA XIV, NCB1, Na(+)/H(+) exchanger (NHE)-3, NHE-8, the regulatory proteins of NHE3, NHRF1 and NHRF2 and the Cl(-)/HCO(-)(3) exchanger, SLC26A6. RESULTS: The father and all four children had RTA with blood HCO(-)(3) levels of 11-14 meq/l and urine pH of 5.3-5.4. Increased HCO(-)(3) fractional excretion after bicarbonate loading to 40-60% confirmed the diagnosis pRTA. No other tubular dysfunction was found, and no organ system dysfunction was detected, besides short stature. No mutation was found in all candidate genes studied. CONCLUSIONS: We presented a second family in the literature with familial isolated pure pRTA. The mode of inheritance is compatible with an autosomal dominant disease. Because of the small size of the family, wide genome search was not applicable and the gene candidate approach was chosen. Nine important candidate genes were extensively studied but the molecular basis of the disease was not yet found and genotyping nine important gene candidates were negative.