Continued use of scrotal ultrasounds for the workup of undescended testes: Confirmation bias and inaccuracies.

AIM: Scrotal ultrasounds are utilised in some primary care settings for suspected cryptorchidism, despite inaccuracies. We aim to identify the correlation between ultrasound and primary care provider (PCP) findings of undescended testicles (UDTs) as a potential source of confirmation bias. METHODS: Males referred for suspected UDT by PCPs who underwent scrotal ultrasound and paediatric urologist examination from 2014 to 2019 were included. Correlation between PCP and ultrasound findings and diagnostic accuracy were evaluated. Logistic regression was utilised to determine associations between patient factors and UDT misdiagnosis. RESULTS: Out of 145 testes, ultrasound corroborated PCPs' UDT diagnoses 87.6% of the time, 49.6% of which were confirmed as UDT by paediatric urologists. Ultrasound had a false positivity rate of 81.0% and specificity of 19.0%. Ultrasound versus paediatric urologist findings regarding testicle location were significantly different (P < 0.0001). Patients aged ≥8 years old had 5.2 times greater odds of being misdiagnosed with UDT than patients <8 years old (95% confidence interval: 1.6-16.7; P < 0.002) by PCP and ultrasound. CONCLUSION: Scrotal ultrasound highly corroborated PCPs' UDT diagnoses. Older patients were more likely to be misdiagnosed with UDT by PCP and ultrasound. As ultrasounds rarely refute PCP examinations for suspected UDTs and are highly inaccurate, confirmation bias may explain the use of ultrasound in the workup of UDT.

Oxygen regulation of breathing through an olfactory receptor activated by lactate.

Animals have evolved homeostatic responses to changes in oxygen availability that act on different timescales. Although the hypoxia-inducible factor (HIF) transcriptional pathway that controls long-term responses to low oxygen (hypoxia) has been established, the pathway that mediates acute responses to hypoxia in mammals is not well understood. Here we show that the olfactory receptor gene Olfr78 is highly and selectively expressed in oxygen-sensitive glomus cells of the carotid body, a chemosensory organ at the carotid artery bifurcation that monitors blood oxygen and stimulates breathing within seconds when oxygen declines. Olfr78 mutants fail to increase ventilation in hypoxia but respond normally to hypercapnia. Glomus cells are present in normal numbers and appear structurally intact, but hypoxia-induced carotid body activity is diminished. Lactate, a metabolite that rapidly accumulates in hypoxia and induces hyperventilation, activates Olfr78 in heterologous expression experiments, induces calcium transients in glomus cells, and stimulates carotid sinus nerve activity through Olfr78. We propose that, in addition to its role in olfaction, Olfr78 acts as a hypoxia sensor in the breathing circuit by sensing lactate produced when oxygen levels decline.

Association between severity of prenatally diagnosed hydronephrosis and receipt of surgical intervention postnatally among patients seen at a fetal-maternal center.

BACKGROUND: Hydronephrosis (HN) is the most common abnormality detected on prenatal ultrasound. This study sought to stratify outcomes of patients by severity of prenatal HN with postnatal outcomes. METHODS: This was a retrospective review of patients referred to a tertiary care fetal-maternal clinic with diagnosis of prenatal HN from 2004 to 2019. HN severity was categorized as mild, moderate, or severe. Data were analyzed to determine the association between HN severity and surgical intervention. Decision for surgery was based on factors including history of multiple urinary tract infections, evidence of renal scarring, and/or reduced renal function. Surgery-free survival time was represented by the Kaplan-Meier method, and hazard ratios were calculated using the log-rank test. RESULTS: 131 kidneys among 101 infants were prenatally diagnosed with hydronephrosis; 35.9% had mild HN, 29.0% had moderate HN, and 35.1% had severe HN. 8.5% of patients with mild HN, 26.3% of patients with moderate HN, and 65.2% of patients with severe HN required surgery. Patients with severe HN were 12.2 (95% CI 6.1-24.4; p < 0.001) times more likely to undergo surgery for HN than patients with mild HN and 2.9 (95% CI 1.5-5.3; p = 0.003) times more likely to undergo surgery than patients with moderate HN. Patients with moderate HN were 4.3 times more likely to require surgery than patients with mild HN (95% CI 1.5-12.9; p = 0.01). Median age at surgery was 11.8 months among patients with mild HN (IQR 11.7-14.1 months), 6.6 months among patients with moderate HN (IQR 4.2-16.4 months), and 5.4 months among patients with severe HN (3.7-12.4 months). CONCLUSION: Among this cohort of referrals from a fetal-maternal clinic, severity of HN correlated with increased likelihood of surgical intervention. Continued assessment of patients with prenatal HN should be evaluated to best determine the role of the pediatric urologist in cases of prenatal HN.

Robotic adrenalectomy in the pediatric population: initial experience case series from a tertiary center.

BACKGROUND: Laparoscopic resection is the most well described minimally-invasive approach for adrenalectomy. While it allows for improved cosmesis, faster recovery and decreased length of hospital stay compared with the open approach, instrument articulation limitations can hamper surgical dexterity in pediatric patients. Use of robotic assistance can greatly enhance operative field visualization and instrument control, and is in the early stages of adoption in academic centers for pediatric populations. CASE PRESENTATION: We present a single-institution series of pediatric adrenalectomy cases. The da Vinci Xi surgical system was used to perform adrenalectomies on three consecutive patients (ages, 2-13 years) at our center. Final pathology revealed ganglioneuroblastoma (n = 2) and pheochromocytoma (n = 1). Median operating time was 244 min (range, 244-265 min); median blood loss was estimated at 100 ml (range, 15-175 ml). Specimens were delivered intact and all margins were negative. Median post-operative hospital stay was 2 days (range, 1-6 days). All patients remain disease-free at median follow-up of 19 months (range, 12-30 months). CONCLUSION: Our experience continues to evolve, and suggests that robotic surgery is safe, feasible and oncologically effective for resection of adrenal masses in well-selected pediatric patients.

Cost-benefit analysis of routine pathology examination in primary shoulder arthroplasty.

BACKGROUND: The annual number of shoulder arthroplasty procedures is continuing to increase. Specimens from shoulder arthroplasty cases are routinely sent for pathologic examination. This study sought to evaluate the clinical utility and associated costs of routine pathologic examination of tissue removed during primary shoulder arthroplasty cases and to determine cost-effectiveness of this practice. METHODS: This is a retrospective review of primary shoulder arthroplasty cases. Patients whose humeral head was sent for routine pathologic examination were included. Cases were determined to have concordant, discrepant, or discordant diagnoses based on preoperative/postoperative diagnosis and pathology diagnosis. Costs were estimated in 2015 U.S. dollars, and cost-effectiveness was determined by the cost per discrepant diagnosis and cost per discordant diagnosis. RESULTS: We identified 714 cases of primary shoulder arthroplasty in 646 patients who met inclusion criteria. The prevalence of concordant diagnoses was 94.1%, the prevalence of discrepant diagnoses was 5.9%, and no cases had discordant diagnoses. There were 172 cases that had biceps tendon specimens sent for pathology examination, and none led to a change in patient care. Total estimated costs were $77,309.34 in 2015 U.S. dollars. Cost per discrepant diagnosis for humeral head specimens was $1424.09, and cost per discordant diagnosis is at least $59,811.78. DISCUSSION/CONCLUSION: Primary shoulder arthroplasty has a high rate of concordant diagnosis. Discrepant diagnoses were 5.9% in our study, and there were no discordant diagnoses. This study showed limited clinical utility in routinely sending specimens from primary shoulder arthroplasty cases for pathology examination, and calculation using a traditional life-year value of $50,000 showed that the standard for cost-effectiveness is not met.

Stanniocalcin-1 inhibits renal ischemia/reperfusion injury via an AMP-activated protein kinase-dependent pathway.

AKI is associated with increased morbidity, mortality, and cost of care, and therapeutic options remain limited. Reactive oxygen species are critical for the genesis of ischemic AKI. Stanniocalcin-1 (STC1) suppresses superoxide generation through induction of uncoupling proteins (UCPs), and transgenic overexpression of STC1 inhibits reactive oxygen species and protects from ischemia/reperfusion (I/R) kidney injury. Our observations revealed high AMP-activated protein kinase (AMPK) activity in STC1 transgenic kidneys relative to wild-type (WT) kidneys; thus, we hypothesized that STC1 protects from I/R kidney injury through activation of AMPK. Baseline activity of AMPK in the kidney correlated with the expression of STCs, such that the highest activity was observed in STC1 transgenic mice followed (in decreasing order) by WT, STC1 knockout, and STC1/STC2 double-knockout mice. I/R in WT kidneys increased AMPK activity and the expression of STC1, UCP2, and sirtuin 3. Inhibition of AMPK by administration of compound C before I/R abolished the activation of AMPK, diminished the expression of UCP2 and sirtuin 3, and aggravated kidney injury but did not affect STC1 expression. Treatment of cultured HEK cells with recombinant STC1 activated AMPK and increased the expression of UCP2 and sirtuin 3, and concomitant treatment with compound C abolished these responses. STC1 knockout mice displayed high susceptibility to I/R, whereas pretreatment of STC1 transgenic mice with compound C restored the susceptibility to I/R kidney injury. These data suggest that STC1 is important for activation of AMPK in the kidney, which mediates STC1-induced expression of UCP2 and sirtuin 3 and protection from I/R.

Dipole-mediated rectification of intramolecular photoinduced charge separation and charge recombination.

Controlling charge transfer at a molecular scale is critical for efficient light harvesting, energy conversion, and nanoelectronics. Dipole-polarization electrets, the electrostatic analogue of magnets, provide a means for "steering" electron transduction via the local electric fields generated by their permanent electric dipoles. Here, we describe the first demonstration of the utility of anthranilamides, moieties with ordered dipoles, for controlling intramolecular charge transfer. Donor-acceptor dyads, each containing a single anthranilamide moiety, distinctly rectify both the forward photoinduced electron transfer and the subsequent charge recombination. Changes in the observed charge-transfer kinetics as a function of media polarity were consistent with the anticipated effects of the anthranilamide molecular dipoles on the rectification. The regioselectivity of electron transfer and the molecular dynamics of the dyads further modulated the observed kinetics, particularly for charge recombination. These findings reveal the underlying complexity of dipole-induced effects on electron transfer and demonstrate unexplored paradigms for molecular rectifiers.

Skills in assessing the professional literature (SAPL): a 7-year analysis of student EBD performance.

PURPOSE: The primary goal of this project was to describe the level of knowledge acquisition using detailed test performance outcomes of the EBD SAPL curriculum over its first 7-years of implementation at the NYU College of Dentistry. A secondary goal was to compare performance outcomes impact of the full 60 h base SAPL curriculum as taught to 4-year DDS students vs an abbreviated 30 h base SAPL curriculum as taught to 3-year Advanced Placement DDS students. METHODS: The findings for the period 2004-2010 are reported for 1647 dental students (63.6% 4-year DDS students, 36.3% 3-year Advanced Placement DDS students). The database consisted of the score earned by each student on each individual question of the SAPL course's 4 h final examination in which each student read an original research article and answered all questions on the Literature Analysis Form. RESULTS: The major findings were overall high performance by both groups of students (SAPL exam scores of 85.8 vs 83.7, respectively) as well as very similar outcomes between these two student groups on: 1) recognizing research design elements and on interpreting those design elements for clinical application, 2) detailed performance of knowledge within the specific five traditional sections of research articles, and 3) detailed performance across 18 identified research design topics. CONCLUSION: In conclusion, both course formats appear to be highly effective for their respective student groups, but should not be interpreted as evidence favoring the shorter format given the different characteristics of the two student groups.

Prevalence of disorders of sex development in patients with hypospadias and cryptorchidism.

BACKGROUND: Hypospadias and undescended testicles (UDT) are common congenital conditions, affecting approximately 1 in 125 and 1 in 33 boys, respectively. There has been limited contemporary data regarding the prevalence of Disorders of Sex Development (DSD) in patients with a history of both hypospadias and UDT. OBJECTIVE: Our objective is to determine the prevalence of DSD among patients presenting with hypospadias and UDT. DESIGN, SETTING, AND PARTICIPANTS: Electronic medical records were reviewed, and a retrospective chart review was conducted on 177 patients that were evaluated at our institution from 2000 to 2021 with a diagnosis of hypospadias and UDT. The degree of hypospadias, presence of and palpability of UDT, and prevalence and type of DSD were recorded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The degree of hypospadias, presence of and palpability of UDT, and prevalence and type of DSD were recorded. Chi-squared and Fisher's exact tests were conducted for descriptive statistical analyses as appropriate. Logistic regression analyses were conducted, with adjusted models including demographic and relevant clinical data. RESULTS: 177 patients were identified with both hypospadias and UDT, with 17/111 (15.3 %) diagnosed with DSD. The most common etiology of DSD was mixed gonadal dysgenesis (35.3 %; n = 6). Proximal hypospadias made up only 59.6 % of those without DSD vs. 100 % of those with confirmed DSD (p = 0.0044). A significantly smaller proportion of DSD patients had bilaterally palpable gonads compared to those without DSD (29.4 % vs. 79.8 %, p < 0.0001). Compared to those with palpable testes, patients with one non-palpable testicle had up to 26.67 times greater odds of DSD. CONCLUSIONS: To date, we present the largest cohort of patients that have undergone DSD work up for the combined presentation of hypospadias and UDT. Our findings highlight an increase in DSD diagnosis in proximal hypospadias patients with non-palpable UDTs, which offers further evidence and support for pursuing DSD diagnostic work-up in all proximal hypospadias patients with UDTs.

Human umbilical cord allograft associated with higher pediatric urethrocutaneous fistula repair success rates.

BACKGROUND: Urethrocutaneous fistula (UCF) formation is a known complication following hypospadias repair, affecting between 5 and 70% of cases. Moreover, approximately 30% of patients experience refistulization after UCF repair. The use of extracellular matrices, such as AmnioCord, a dehydrated human umbilical cord allograft manufactured by MiMedx®, may mitigate high rates of refistulization. OBJECTIVE: To determine whether the use of AmnioCord during UCF repair is associated with reduced incidence of subsequent UCFs among pediatric patients. DESIGN, SETTING, AND PARTICIPANTS: Electronic medical records were retrospectively reviewed among 60 patients who underwent at least one UCF repair at a pediatric hospital in a large urban setting in the U.S. between January 2012-June 2018. Patients were followed through January 2024. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adjusted generalized estimating equation regression models were used to assess the association between AmnioCord use and rates of refistulization, while controlling for confounding variables. RESULTS: The number of fistula presentations per patient ranged from one to four; 53.3% had one fistula, 30.0% had two, and 16.6% had three or more. Overall fistula repair success rate was 56.8% but significantly differed by AmnioCord use in adjusted modelling; 69.4% of cases that received AmnioCord were successfully repaired, compared to 47.2% of cases that did not receive AmnioCord. In adjusted models, patients who received AmnioCord had 2.66 times greater odds of surgical success than patients who did not receive AmnioCord (95% CI:1.13-6.24; p = 0.02). CONCLUSIONS: This study demonstrates a positive association between AmnioCord use and successful UCF closure among pediatric patients.

A noncovalent, fluoroalkyl coating monomer for phosphonate-covered nanoparticles.

Gadolinium-containing phosphonate-coated gold nanoparticles were prepared and then non-covalently coated with an amphiphilic fluorous monomer. The monomer spontaneously self-assembles into a non-covalent monolayer shell around the particle. The binding of the shell utilizes a guanidinium-phosphonate interaction analogous to the one exploited by the Wender molecular transporter system. Particle-shell binding was characterized by a 27% decrease in 19F T1 of the fluorous shell upon exposure to the paramagnetic gadolinium in the particle and a corresponding increase in hydrodynamic diameter from 3 nm to 4 nm. Interestingly, a much smaller modulation of 19F T1 is observed when the shell monomer is treated with a phosphonate-free particle. By contrast, the phosphonate-free particle is a much more relaxive 1H T1 agent for water. Together, these observations show that the fluoroalkylguanidinium shell binds selectively to the phosphonate-covered particle. The system's relaxivity and selectivity give it potential for use in 19F based nanotheranostic agents.

Thumb Metacarpophalangeal Joint Ulnar Collateral Ligament Injuries: Management and Biomechanical Evaluation.

First described in 1955 as "gamekeeper's thumb," injuries to the ulnar collateral ligament (UCL) of the thumb metacarpophalangeal joint are common and can cause pain and instability, especially during key pinch and grasp. Although primarily diagnosed on physical examination, stress radiographs, ultrasonography, and magnetic resonance imaging can be used to diagnose UCL injuries and distinguish partial from complete tears. If complete rupture occurs, the adductor aponeurosis can become interposed between the retracted UCL stump and its insertion on the proximal phalanx, known as a "Stener lesion." When instability persists after a trial of nonsurgical management or in the setting of complete rupture, there are various methods of repair or reconstruction. Biomechanically, there are no treatments of repair or reconstruction using native tissues that provide equivalent strength to the preinjured ligament. Recently, suture tape augmentation has been used for the repair or reconstruction with excellent short-term results and earlier return to function, although there is a paucity of literature on longer term outcomes. The various methods of surgical treatment yield excellent outcomes with a low incidence of complications.

Two Parallel Headless Compression Screws for Scaphoid Fractures: Radiographic Analysis and Preliminary Outcome.

BACKGROUND: Despite surgical fixation, the scaphoid nonunion rate remains at 3% to 5%. Recent biomechanical studies have demonstrated increased stability with 2-screw constructs. The objective of our study is to determine the preliminary union rate and anatomic feasibility of 2-screw surgical fixation for scaphoid fractures. METHODS: This study is a retrospective case series of 25 patients (average age 32 years) with scaphoid fractures treated with 2 parallel headless compression screws (HCS). Postoperative evaluation included Mayo Wrist Score (MWS), range of motion, time to union, and return to activity. Bivariate analysis for gender and Pearson correlation coefficient for body size (height, weight, and body mass index) was conducted against radiographically measured scaphoid width, screw lengths, and the distance between the 2 screws. RESULTS: All fractures healed with an average time to union of 9.9 weeks (median 7.6 weeks; range: 4.1-28.3). The mean MWS was 93.3 (range: 55-100), with 3 complications (12%), one of which affected the outcome of the surgery. The bivariate analysis demonstrated that the female gender was associated with significantly smaller scaphoid width (P = .004) but a similar distance between the 2 screws (P = .281). The distance between the 2 screws and the body size demonstrated a weak-to-no correlation. CONCLUSIONS: The 2-screw construct for scaphoid fracture achieved a favorable union rate and clinical outcome. Gender was the only variable significantly associated with scaphoid width and screw length. The distance between the screws was constant regardless of gender and body size, indicating that the technique for parallel screw placement can remain consistent. TYPE OF STUDY: Therapeutic. LEVEL OF EVIDENCE: Level IV.

Systematic discovery of neoepitope-HLA pairs for neoantigens shared among patients and tumor types.

The broad application of precision cancer immunotherapies is limited by the number of validated neoepitopes that are common among patients or tumor types. To expand the known repertoire of shared neoantigen-human leukocyte antigen (HLA) complexes, we developed a high-throughput platform that coupled an in vitro peptide-HLA binding assay with engineered cellular models expressing individual HLA alleles in combination with a concatenated transgene harboring 47 common cancer neoantigens. From more than 24,000 possible neoepitope-HLA combinations, biochemical and computational assessment yielded 844 unique candidates, of which 86 were verified after immunoprecipitation mass spectrometry analyses of engineered, monoallelic cell lines. To evaluate the potential for immunogenicity, we identified T cell receptors that recognized select neoepitope-HLA pairs and elicited a response after introduction into human T cells. These cellular systems and our data on therapeutically relevant neoepitopes in their HLA contexts will aid researchers studying antigen processing as well as neoepitope targeting therapies.

Early comparison of nephrectomy options in children (open, transperitoneal laparoscopic, laparo-endoscopic single site (LESS), and robotic surgery).

OBJECTIVE: To compare the perioperative parameters of paediatric patients who underwent nephrectomy via laparo-endoscopic single site (LESS) surgery (also known as single incision laparoscopic surgery or SILS) with those who underwent nephrectomy via conventional laparoscopy (LAP), robotic-assisted laparoscopy (RALN), and open surgery (OPEN). PATIENTS AND METHODS: The medical records of 69 paediatric patients at a single institution who underwent nephrectomies for non-functioning kidneys in 72 renal units (39 OPEN, 11 LAP, 11 RALN and 11 LESS) were reviewed for patient demographics and perioperative clinical parameters. RESULTS: The minimally invasive modalities in children, including LESS nephrectomy, were associated with shorter lengths of hospital stay (P < 0.001) and decreased postoperative pain medication usage (P < 0.001) than with open surgery. Similar surgical times were noted with LESS and the other minimally invasive modalities (LAP and RALN) (P= 0.056). However, the minimally invasive modalities (LESS, LAP and RALN) were associated with slightly longer surgical times when compared with open surgery (P < 0.001), which may, in part, be secondary to learning curve factors. No differences were noted among the minimally invasive modalities for postoperative pain medication usage (P= 0.354) and length of hospital stay (P= 0.86). CONCLUSIONS: The minimally invasive modalities for nephrectomy in children, including LESS nephrectomy, are associated with shorter lengths of hospital stay and decreased postoperative pain medication use when compared with open surgery. LESS nephrectomy in children is associated with similar surgical times, lengths of hospital stay and postoperative pain medication use as the other minimally invasive modalities (LAP and RALN). Slightly longer surgical times are noted with the minimally invasive modalities, including LESS nephrectomy, when compared with open surgery, which may, in part, be secondary to learning curve factors.

10-Shogaol, an antioxidant from Zingiber officinale for skin cell proliferation and migration enhancer.

In this work, one of Zingiber officinale components, 10-shogaol, was tested with 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, metal chelating ability, and reducing power to show antioxidant activity. 10-Shogaol promoted human normal epidermal keratinocytes and dermal fibroblasts cell growths. 10-Shogaol enhanced growth factor production in transforming growth factor-ß (TGF-ß), platelet derived growth factor-αß (PDGF-αß) and vascular endothelial growth factors (VEGF) of both cells. In the in vitro wound healing assay for 12 or 24 h, with 10-shogaol, the fibroblasts and keratinocytes migrated more rapidly than the vehicle control group. Thus, this study substantiates the target compound, 10-shogaol, as an antioxidant for human skin cell growth and a migration enhancer with potential to be a novel wound repair agent.

Pediatric genitourinary tumors: Distribution, demographics, and outcomes.

Importance: The diversity of pediatric genitourinary malignancies requires a timely resource detailing tumor characteristics and survival. Objective: To determine the incidence, demographics, and outcomes of all pediatric genitourinary tumors within the United States. Methods: A population-based search for patients diagnosed with genitourinary cancers under age 15 was performed using the National Cancer Institute's Surveillance, Epidemiology, and End Results 18 registry. Information on primary tumor location, histologic type, patient age, sex, year of diagnosis, race, treatment, cause of death, and survival months was extracted. Descriptive epidemiological and survival statistics were calculated for all variables. Results: A total of 4576 cases from 1973 through 2015 were identified. The most common primary tumor sites were the kidney (80.3%), testis (12.3%), bladder (2.8%), and vagina (1.5%). Nephroblastoma (87.9%) and sarcoma (3.4%) were the most common renal malignancies. Rhabdomyosarcoma was common in the vagina, bladder, and testis at rates of 66.2%, 61.2%, and 24.6%, respectively. Germ cell tumors (71.0%) were the most common primary tumor of the testis. Ten-year overall survival (OS) for renal nephroblastoma and sarcoma was 88% and 82%, respectively. Ten-year OS for RMS of the testis was 91%, the bladder was 79%, the vagina was 79%, and the prostate was 56%. Germ cell tumor 10-year OS were 96% in the testis and 100% in the vagina. Interpretation: A better understanding of the overall distribution and outcomes associated with pediatric genitourinary cancers allows physicians to best understand the patient's disease in the context of current frequency in a genitourinary setting and reported outcomes.

Persistent Anhydramnios and Lower Urinary Tract Obstruction in a Patient With a Vesicoamniotic Shunt.

Persistent anhydramnios after placement of a vesicoamniotic shunt is a rare but potentially serious concern in a patient in utero. We present the case a male fetus who at 32-week gestation had bilateral hydroureteronephrosis, a distended bladder, and anhydramnios. A vesicoamniotic shunt was placed, but the anhydramnios persisted. Postnatally, the child was found to have a migrated shunt, left grade V vesicoureteral reflux and posterior urethral valves. He underwent a posterior urethral valves ablation and removal of the migrated shunt. The patient is now 2 years old and is doing well with no urinary tract infections or renal deterioration.

Stanniocalcin2, but Not Stanniocalcin1, Responds to Hypoxia in a HIF1-Dependent Manner in the Retina.

The quest for neuroprotective factors that can prevent or slow down the progression of retinal degeneration is still ongoing. Acute hypoxic stress has been shown to provide transient protection against subsequent damage in the retina. Stanniocalcins - STC1 and STC2 - are secreted glycoproteins that are hypoxia-regulated and were shown to be cytoprotective in various in vitro studies. Hence, we investigated the expression of stanniocalcins in the normal, degenerating and hypoxic retina. We show that the expression of Stc1 and Stc2 in the retina was detectable as early as postnatal day 10 and persisted during aging. Retinal expression of Stc2, but not Stc1, was induced in mice in an in vivo model of acute hypoxia and a genetic model of chronic hypoxia. Furthermore, we show that HIF1, not HIF2, is responsible for regulating Stc2 in cells with the molecular response to hypoxia activated due to the absence of von Hippel Lindau protein. Surprisingly, Stc2 was not normally expressed in photoreceptors but in the inner retina, as shown by laser capture microdissection and immunofluorescence data. The expression of both Stc1 and Stc2 remained unchanged in the degenerative retina with an almost complete loss of photoreceptors, confirming their expression in the inner retina. However, the absence of either Stc1 or Stc2 had no effect on retinal architecture, as was evident from retinal morphology of the respective knockout mice. Taken together our data provides evidence for the differential regulation of STC1 and STC2 in the retina and the prospect of investigating STC2 as a retinal neuroprotective factor.