Faculty Bibliography

Background/Purpose: Diagnosis of lupus nephritis (LN) relies on a kidney biopsy obtained in SLE with proteinuria. Delayed access to kidney biopsies may delay diagnosis and treatment, and can be limited by rapid access to biopsy, antithrombotic and anticoagulation treatments, thrombocytopenia, and in resource poor settings. Here, we employed urine proteomics to develop a non-invasive biomarker to predict proliferative LN.
Method(s): We quantified 1200 biomarkers (Kiloplex, RayBiotech) in urine samples collected on the day of (73%) or within 3 weeks (27%) of kidney biopsy in SLE patients with proteinuria >= 500mg/d and compared their abundance between patients with or without a subsequent biopsy with proliferative LN (ISN class III or IV +/- V). Prospective urine proteomic profiles were obtained in patients with class III, IV, or V at baseline and week 12, 24, or 52.
Result(s): A total of 237 patients were included: 138 (58%) with proliferative LN, 57 (24%) pure membranous LN, 21 (9%) ISN class I or II LN, 9 (4%) ISN class VI, and 12 (5%) did not have LN. Forty urinary proteins were differentially abundant in patients with proliferative LN, topped by CD163 (Figure 1). Urinary CD163 (uCD163) was significantly elevated in proliferative LN compared to all other groups (Figure 2). Longitudinal analysis revealed that uCD163 selectively declined in patients that achieved renal response at 12 months (Figure 3).
Conclusion(s): Urinary CD163, a cleaved M2c macrophage receptor, can help to identify proliferative LN in SLE patients with proteinuria. Noninvasive monitoring of uCD163 may lead to early diagnosis and treatment of proliferative LN, thus reducing irreversible kidney damage

Purpose: To report the technical success, adverse events, and long-term stent patencies of Gianturco Z-Stent placement for management of chronic central venous occlusive disease.
Material(s) and Method(s): 137 patients, with mean age 49 +/- 16 years (range: 16-89 years), underwent placement of Gianturco Z-Stents for chronic central venous occlusion. Number of stents placed, stent implantation location, stent sizes, technical success, adverse events, need for reintervention, follow-up evaluation, stent patencies, and mortality were recorded. Technical success was defined as recanalization and stent reconstruction with restoration of in-line venous flow. Adverse events were defined by the Society of Interventional Radiology Adverse Event Classification criteria. Primary and primary-assisted stent patencies were analyzed using Kaplan-Meier analysis.
Result(s): 208 total Z-Stents were placed. The three most common placement sites were the inferior vena cava (n=124; 60%), superior vena cava (n=44; 21%), and brachiocephalic veins (n=27; 13%). Technical success was achieved in 133 (97%) patients. There were two (1.5%) severe adverse events (two cases of stent migration to the right atrium), one (0.7%) moderate adverse event, and one (0.7%) mild adverse event. Mean follow-up was 44 +/- 53 months. Estimated 1-, 3-, and 5-year primary stent patency was 84%, 84%, and 82%, respectively. Estimated 1-, 3-, and 5-year primary-assisted patency was 92%, 89%, and 89%, respectively. 30- and 60- day mortality rates were 2.9% (n=4) and 5.1% (n=7), none of which were directly attributable to Z-Stent placement.
Conclusion(s): Gianturco Z-Stent placement is safe and effective for the treatment for chronic central venous occlusive disease with durable short- and long-term patencies

BACKGROUND:Efforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life-threatening seizures. Although previous studies of AW and relapse have highlighted the detrimental role of stress, little is known about genetic risk factors. METHODS:We conducted a genome-wide association study of AW symptom count in uniformly assessed subjects with histories of serious AW, followed by additional genotyping in independent AW subjects. RESULTS:). There were no genome-wide significant findings in African Americans (n = 1,231). Bioinformatic analyses were conducted using publicly available high-throughput transcriptomic and epigenomic data sets, showing that in humans SORCS2 is most highly expressed in the nervous system. The identified SORCS2 risk haplotype is predicted to disrupt a stress hormone-modulated regulatory element that has tissue-specific activity in human hippocampus. We used human neural lineage cells to demonstrate in vitro a causal relationship between stress hormone levels and SORCS2 expression, and show that SORCS2 levels in culture are increased upon ethanol exposure and withdrawal. CONCLUSIONS:Taken together, these findings indicate that the pathophysiology of withdrawal may involve the effects of stress hormones on neurotrophic factor signaling. Further investigation of these pathways could produce new approaches to managing the aversive consequences of abrupt alcohol cessation.

Background/Purpose: Lupus nephritis remains a major cause of morbidity/mortality in SLE. Our cohort has shown that 20% of SLE patients with lupus nephritis onset in the first year will have end-stage renal disease (ESRD) by year ten. Population studies have shown no improvement in lupus nephritis outcomes in the last decades. Clinical trials of lupus nephritis cannot address long-term renal outcomes. We addressed whether serum albumin at 12 months after renal biopsy predicted long-term renal outcome.
Method(s): 87 patients with biopsy-proven lupus nephritis were included in the analyses. Of the 87 patients, 79 (91%) were female, 49 (56%) were African American, 24 (28%) were Caucasian, and 14 (16%) were 'other'. At the time of biopsy, 33 (38%) were under 30 years of age, 38 (44%) were from 30-44, and 16 were 45 years of age or older. The median age was 32.9. The median values of albumin at biopsy and 1-year post were 3.7 and 3.9 respectively. ISN/IRP class was 24% III, 23% IV, 23% V, and 30% mixed. Albumin levels were classified as low (<3.4g/dL), medium(3.5-4.3g/dL) and high (>4.3g/dL).Kaplan-Meir curves were plotted to assess the association between albumin levels and risk of developing renal event. Renal outcomes were 1 ESRD, 6 renal insufficiency, and 14 doubling creatinine.
Result(s): Serum albumin at 12 months post renal biopsy was associated with poor renal outcomes during follow-up (p = 0.0098). Among those with low serum albumin one year after biopsy, an estimated 43% will progress to renal failure, renal insufficiency, or a doubling of creatinine within 5 years (95% confidence interval 16%-71%). In contrast, among those with high serum albumin, an estimated 13% will progress (95% CI 1%-29%).
Conclusion(s): Serum albumin 12 months post biopsy predicted good renal outcome in a linear fashion. This surrogate for renal outcome is readily available from lupus nephritis randomized clinical trials(and from some large databases, as well). Serum albumin should be added to urine protein/cras validated surrogates for long-term renal outcome in lupus nephritis. (Figure Presented)

Dysfunctional tear syndrome (DTS) is a common and complex condition affecting the ocular surface. The health and normal functioning of the ocular surface is dependent on a stable and sufficient tear film. Clinician awareness of conditions affecting the ocular surface has increased in recent years because of expanded research and the publication of diagnosis and treatment guidelines pertaining to disorders resulting in DTS, including the Delphi panel treatment recommendations for DTS (2006), the International Dry Eye Workshop (DEWS) (2007), the Meibomian Gland Dysfunction (MGD) Workshop (2011), and the updated Preferred Practice Pattern guidelines from the American Academy of Ophthalmology pertaining to dry eye and blepharitis (2013). Since the publication of the existing guidelines, new diagnostic techniques and treatment options that provide an opportunity for better management of patients have become available. Clinicians are now able to access a wealth of information that can help them obtain a differential diagnosis and treatment approach for patients presenting with DTS. This review provides a practical and directed approach to the diagnosis and treatment of patients with DTS, emphasizing treatment that is tailored to the specific disease subtype as well as the severity of the condition.

A relatively common stop codon (Q20*) was identified in the serotonin 2B receptor gene (HTR2B) in a Finnish founder population in 2010 and it was associated with impulsivity. Here we examine the phenotype of HTR2B Q20* carriers in a setting comprising 14 heterozygous HTR2B Q20* carriers and 156 healthy controls without the HTR2B Q20*. The tridimensional personality questionnaire, Brown-Goodwin lifetime aggression scale, the Michigan alcoholism screening test and lifetime drinking history were used to measure personality traits, impulsive and aggressive behavior, both while sober and under the influence of alcohol, and alcohol consumption. Regression analyses showed that among the HTR2B Q20* carriers, temperamental traits resembled a passive-dependent personality profile, and the presence of the HTR2B Q20* predicted impulsive and aggressive behaviors particularly under the influence of alcohol. Results present examples of how one gene may contribute to personality structure and behaviors in a founder population and how personality may translate into behavior.

Behavioral inhibition (BI), a temperament characterized by vigilance to novelty, sensitivity to approach-withdrawal cues and social reticence in childhood, is associated with risk for anxiety in adolescence. Independent studies link reward hyper-responsivity to BI, adolescent anxiety and dopamine gene variants. This exploratory study extends these observations by examining the impact of DRD4 genotype and reward hyper-responsivity on the BI-anxiety link. Adolescents (N = 78) completed a monetary incentive delay task in the fMRI environment. Participants were characterized based on a continuous score of BI and the 7-repeat allele (7R+) of the DRD4 functional polymorphism. Parent-report and self-report measures of anxiety were also collected. Across the entire sample, striatal activation increased systematically with increases in the magnitude of anticipated monetary gains and losses. DRD4 status moderated the relation between BI and activation in the caudate nucleus. Childhood BI was associated with parent report of adolescent anxiety among 7R+ participants with elevated levels of striatal response to incentive cues. DRD4 genotype influenced the relations among neural response to incentives, early childhood BI and anxiety. The findings help refine our understanding of the role reward-related brain systems play in the emergence of anxiety in temperamentally at-risk individuals, building a foundation for future larger scale studies.

GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. GCH1 polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined GCH1 and pain in sickle cell anemia where GCH1 rs8007267 was a risk factor for pain crises in discovery (n = 228; odds ratio [OR] 2.26; P = 0.009) and replication (n = 513; OR 2.23; P = 0.004) cohorts. In vitro, cells from sickle cell anemia subjects homozygous for the risk allele produced higher BH4. In vivo physiological studies of traits likely to be modulated by GCH1 showed rs8007267 is associated with altered endothelial dependent blood flow in females with SCA (8.42% of variation; P = 0.002). The GCH1 pain association is attributable to an African haplotype with where its sickle cell anemia pain association is limited to females (OR 2.69; 95% CI 1.21-5.94; P = 0.01) and has the opposite directional association described in Europeans independent of global admixture. The presence of a GCH1 haplotype with high BH4 in populations of African ancestry could explain the association of rs8007267 with sickle cell anemia pain crises. The vascular effects of GCH1 and BH4 may also have broader implications for cardiovascular disease in populations of African ancestry.

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of psychiatric and neurological disorders and in the mechanisms of antidepressant pharmacotherapy. Psychiatric and neurological conditions have also been associated with reduced brain levels of N-acetyl-aspartate (NAA), which has been used as a putative marker of neural integrity. However, few studies have explored the relationship between BDNF polymorphisms and NAA levels directly. Here, we present data from a single-voxel proton magnetic resonance spectroscopy study of 64 individuals and explore the relationship between BDNF polymorphisms and prefrontal NAA level. Our results indicate an association between a single nucleotide polymorphism (SNP) within BDNF, known as rs1519480, and reduced NAA level (p = 0.023). NAA levels were further predicted by age and Asian ancestry. There was a significant rs1519480 x age interaction on NAA level (p = 0.031). Specifically, the effect of rs1519480 on NAA level became significant at age 34.17 yr. NAA level decreased with advancing age for genotype TT (p = 0.001) but not for genotype CT (p = 0.82) or CC (p = 0.34). Additional in silico analysis of 142 post-mortem brain samples revealed an association between the same SNP and reduced BDNF mRNA expression in the prefrontal cortex. The rs1519480 SNP influences BDNF mRNA expression and has an impact on prefrontal NAA level over time. This genetic mechanism may contribute to inter-individual variation in cognitive performance seen during normal ageing, as well as contributing to the risk for developing psychiatric and neurological conditions.