Faculty Bibliography

Background: Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) is a rare monogenic disorder caused by SLC34A3 pathogenic variants, characterized by renal phosphate wasting, hypophosphatemia, hypercalciuria (HC), elevated 1,25-dihydroxyvitamin D, nephrocalcinosis (NC), and urinary stone disease (USD). Previously we reported a high prevalence of kidney cysts in CYP24A1 deficiency. Thus, in the current study, we characterized cyst presence in HHRH, another monogenic cause of HC, NC, and USD.
Method(s): Medical records from Mayo Clinic and Rare Kidney Stone Consortium research results were queried for all patients with genetically confirmed HHRH diagnosis. Clinical characteristics and imaging data are summarized in table 1.
Result(s): Among 12 patients with SLC34A3 pathogenic variants (7 monoallelic, 5 biallelic), 42% (5/12) were males. Median age at clinical presentation was 17 yrs (range 8-46) and at genetic confirmation 42 yrs (range 9-66). None had a family history of cystic kidney disease. Kidney cysts (Figure 1) were present in 75% (9/12), among whom median age at first kidney imaging and first cyst detection was 41 yrs (range 9-64). Median number of cysts per patient was 3 (range 1-23). The number of cysts >=5 mm in size was above the 97.5th percentile of an age-and sex-matched control population in 6/9 (67%). At least 2 cysts >=5 mm in size were found in 100% of children.
Conclusion(s): We found a strong association between HHRH and kidney cysts. Similarities in the biochemical profiles of HHRH and CYP24A1 deficiency suggest elevated active vitamin D, and/or HC may be potential factors in cyst formation. Further studies are needed to evaluate the role of the SLC34A3 gene in cyst formation. (Figure Presented)

Neurofibrillary tangles (NFTs) are a major pathologic hallmark of Alzheimer's disease (AD). Several studies have shown that amyloid β oligomers (Aβo) and tau oligomers mediate their toxicity, in part, via binding to cellular prion protein (PrP^C) and that some anti-PrP antibodies can block this interaction. We have generated a novel monoclonal anti-PrP antibody (TW1) and assessed the efficacy of passive immunization with it in a mouse model of AD with extensive tau pathology: hTau/PS1 transgenic (Tg) mice. These mice were injected intraperitoneally once a week with TW1 starting at 5 months of age. Behavior was assessed at 8 months of age and brain tissue was subsequently harvested for analysis of treatment efficacy at 9 months. Mice treated with TW1 did not show any significant difference in sensorimotor testing including traverse beam, rotarod, and locomotor activity compared to controls. Significant cognitive benefits were observed with the novel object recognition test (ORT) in the immunized mice (two-tailed, t-test p = 0.0019). Immunized mice also showed cognitive benefits on the closed field symmetrical maze (day 1 two-tailed t-test p = 0.0001; day 2 two-tailed t-test p = 0.0015; day 3 two-tailed t-test p = 0.0002). Reduction of tau pathology was observed with PHF-1 immunohistochemistry in the piriform cortex by 60% (two-tailed t-test p = 0.01) and in the dentate gyrus by 50% (two-tailed t-test p = 0.02) in animals treated with TW1 compared to controls. There were no significant differences in astrogliosis or microgliosis observed between treated and control mice. As assessed by Western blots using PHF-1, the TW1 therapy reduced phosphorylated tau pathology (two-tailed t-test p = 0.03) and improved the ratio of pathological soluble tau to tubulin (PHF1/tubulin; two-tailed t-test p = 0.0006). Reduction of tau pathology also was observed using the CP13 antibody (two-tailed t-test p = 0.0007). These results indicate that passive immunization with the TW1 antibody can significantly decrease tau pathology as assessed by immunohistochemical and biochemical methods, resulting in improved cognitive function in a tau transgenic mouse model of AD.

We recently encountered concern about the safety of bariatric surgery for a patient with cystinuria. Bariatric surgery procedures include those that cause malabsorption, like the Roux-en-Y gastric bypass procedure, and restrictive operations, such as the sleeve gastrectomy. These procedures produce beneficial effects on health and life expectancy, though whether kidney stones are prevented, as well as promoted, is not established. Although the importance of body weight to metabolic stone activity in patients with cystinuria is not established, the patient's physicians were concerned about whether any bariatric surgery procedure would affect her ability to drink sufficient quantities of water in order to reduce stone activity. Here we report the experience of a genetically defined patient with cystinuria who underwent a gastric sleeve procedure. In the months after the procedure, she lost 45 kg, though with time she regained 23 kg of that loss. She was able to maintain a urine volume of 4.0 L per day and has had no stone recurrence.XXCopyright

Adeno-associated viruses (AAVs) are a commonly used tool in neuroscience to efficiently label, trace, and/or manipulate neuronal populations. Highly specific targeting can be achieved through recombinase-dependent AAVs in combination with transgenic rodent lines that express Cre-recombinase in specific cell types. Visualization of viral expression is typically achieved through fluorescent reporter proteins (e.g., GFP or mCherry) packaged within the AAV genome. Although nonamplified fluorescence is usually sufficient to observe viral expression, immunohistochemical amplification of the fluorescent reporter is routinely used to improve viral visualization. In the present study, Cre-dependent AAVs were injected into the neocortex of wild-type C57BL/6J mice. While we observed weak but consistent nonamplified off-target double inverted open reading frame (DIO) expression in C57BL/6J mice, antibody amplification of the GFP or mCherry reporter revealed notable Cre-independent viral expression. Off-target expression of DIO constructs in wild-type C57BL/6J mice occurred independent of vendor, AAV serotype, or promoter. We also evaluated whether Cre-independent expression had functional effects via designer receptors exclusively activated by designer drugs (DREADDs). The DREADD agonist C21 (compound 21) had no effect on contextual fear conditioning or c-Fos expression in DIO-hM3Dq-mCherry⁺ cells of C57BL/6J mice. Together, our results indicate that DIO constructs have off-target expression in wild-type subjects. Our findings are particularly important for the design of experiments featuring sensitive systems and/or quantitative measurements that could be negatively impacted by off-target expression.Significance StatementAdeno-associated viruses (AAVs) are widely used in neuroscience because of their safety and ease of use. Combined with specific promoters, Cre/loxP, and stereotaxic injections, highly specific targeting of cells and circuits within the brain can be achieved. In the present study, we injected Cre-dependent AAVs into wild-type C57BL/6J mice and found Cre-independent viral expression of AAVs encoding mCherry, GFP, or hM3Dq following immunohistochemical amplification of the fluorescent reporter protein. Importantly, we observed no functional effects of the Cre-independent expression in the hippocampus, as C21 (compound 21) had no detectable effect on double inverted open reading frame (DIO)-hM3Dq-mCherry-infected neurons in C57BL/6J mice. Given the widespread use of DIO recombinant AAVs by the neuroscience community, our data support careful consideration when using DIO constructs in control animals.

Background:The COVID-19 pandemic strained hospital resources in New York City, including those for providing dialysis. New York University Medical Center and affiliations, including New York City Health and Hospitals/Bellevue, developed a plan to offset the increased needs for KRT. We established acute peritoneal dialysis (PD) capability, as usual dialysis modalities were overwhelmed by COVID-19 AKI. Methods:Observational study of patients requiring KRT admitted to Bellevue Hospital during the COVID surge. Bellevue Hospital is one of the largest public hospitals in the United States, providing medical care to an underserved population. There were substantial staff, supplies, and equipment shortages. Adult patients admitted with AKI who required KRT were considered for PD. We rapidly established an acute PD program. A surgery team placed catheters at the bedside in the intensive care unit; a nephrology team delivered treatment. We provided an alternative to hemodialysis and continuous venovenous hemofiltration for treating patients in the intensive-care unit, demonstrating efficacy with outcomes comparable to standard care. Results:From April 8, 2020 to May 8, 2020, 39 catheters were placed into ten women and 29 men. By June 10, 39% of the patients started on PD recovered kidney function (average ages 56 years for men and 59.5 years for women); men and women who expired were an average 71.8 and 66.2 years old. No episodes of peritonitis were observed; there were nine incidents of minor leaking. Some patients were treated while ventilated in the prone position. Conclusions:Demand compelled us to utilize acute PD during the COVID-19 pandemic. Our experience is one of the largest recently reported in the United States of which we are aware. Acute PD provided lifesaving care to acutely ill patients when expanding current resources was impossible. Our experience may help other programs to avoid rationing dialysis treatments in health crises.

The insect central complex (CX) is thought to underlie goal-oriented navigation but its functional organization is not fully understood. We recorded from genetically-identified CX cell types in Drosophila and presented directional visual, olfactory, and airflow cues known to elicit orienting behavior. We found that a group of neurons targeting the ventral fan-shaped body (ventral P-FNs) are robustly tuned for airflow direction. Ventral P-FNs did not generate a 'map' of airflow direction. Instead, cells in each hemisphere were tuned to 45° ipsilateral, forming a pair of orthogonal bases. Imaging experiments suggest that ventral P-FNs inherit their airflow tuning from neurons that provide input from the lateral accessory lobe (LAL) to the noduli (NO). Silencing ventral P-FNs prevented flies from selecting appropriate corrective turns following changes in airflow direction. Our results identify a group of CX neurons that robustly encode airflow direction and are required for proper orientation to this stimulus.

Stroke patients with small central nervous system infarcts often demonstrate an acute dysexecutive syndrome characterized by difficulty with attention, concentration, and processing speed, independent of lesion size or location. We use magnetoencephalography (MEG) to show that disruption of network dynamics may be responsible. Nine patients with recent minor strokes and eight age-similar controls underwent cognitive screening using the Montreal cognitive assessment (MoCA) and MEG to evaluate differences in cerebral activation patterns. During MEG, subjects participated in a visual picture-word matching task. Task complexity was increased as testing progressed. Cluster-based permutation tests determined differences in activation patterns within the visual cortex, fusiform gyrus, and lateral temporal lobe. At visit 1, MoCA scores were significantly lower for patients than controls (median [interquartile range] = 26.0 [4] versus 29.5 [3], P = 0.005), and patient reaction times were increased. The amplitude of activation was significantly lower after infarct and demonstrated a pattern of temporal dispersion independent of stroke location. Differences were prominent in the fusiform gyrus and lateral temporal lobe. The pattern suggests that distributed network dysfunction may be responsible. Additionally, controls were able to modulate their cerebral activity based on task difficulty. In contrast, stroke patients exhibited the same low-amplitude response to all stimuli. Group differences remained, to a lesser degree, 6 mo later; while MoCA scores and reaction times improved for patients. This study suggests that function is a globally distributed property beyond area-specific functionality and illustrates the need for longer-term follow-up studies to determine whether abnormal activation patterns ultimately resolve or another mechanism underlies continued recovery.