Genu Valgum in Pediatric Patients Presenting With Patellofemoral Instability.

BACKGROUND: Lower extremity valgus is a commonly described factor associated with patellofemoral instability (PFI) and, if identified before skeletal maturity, can be treated with guided growth. The prevalence of valgus alignment in the pediatric and adolescent PFI population is largely unknown. PURPOSE: The aim of this study was to report the prevalence of valgus alignment in adolescent patients presenting with PFI; with secondary assessment of high-grade valgus (zone II or III), coronal asymmetry, and associations of these findings with body mass index (BMI). STUDY DESIGN: A retrospective cohort study. METHODS: A total of 279 consecutive patients (349 knees) with a diagnosis of PFI presenting to a single orthopedic pediatric sport medicine surgeon were identified. A retrospective chart review was performed to collect demographic and clinical data, chronologic and bone age, sex, BMI, mechanism of injury, and the presence of osteochondral fracture. Full-length standing hip-to-ankle alignment radiographs were graded for knee alignment mechanical zone utilizing standard linear femoral head center to talar center assessment. In addition, mechanical axis deviation, mechanical lateral distal femoral angle and medial proximal tibial angle (MPTA) were also calculated. RESULTS: Mean patient age was 14.0±2.5 years. There were 162 (58.1%) females and mean BMI was 24.3±6.4. Seventy patients (25.1%) had bilateral PFI. Standing alignment radiographs were available for 81.4% of knees (n=284). Valgus alignment was present in 172 knees with PFI (60.6%). High-grade valgus, defined as zone 2 or greater, was present in 66 knees (23.3%). Overall, 48.9% had asymmetry of coronal alignment (n=139). The mean mechanical lateral distal femoral angle was 85.4±2.8 and the mean MPTA was 88.2±2.6. There was a greater MPTA in female patients (88.8±2.4 vs. 87.5±2.7, P <0.001). A higher BMI (24.87±6.95, P =0.03) was associated with valgus alignment. CONCLUSIONS: There is a high (60%) prevalence of lower extremity valgus in adolescent patients presenting with PFI, with nearly 1 in 4 presenting with high-grade valgus. The treatment team should be aware of this association as it may be an important consideration in the pediatric and adolescent PFI populations. LEVEL OF EVIDENCE: Level III.

Soft Tissue Cam Impingement in Adolescents: MRI Reveals Impingement Lesions Underappreciated on Radiographs.

BACKGROUND: Femoroacetabular impingement (FAI) has been described as repetitive and abnormal contact between a structurally abnormal proximal femur (cam) and/or acetabulum (pincer), occurring during the terminal range of motion of the hip. While cam and pincer lesions have traditionally been defined as osseous abnormalities, there may be a subset of adolescent patients whose impingement is primarily soft tissue (nonosseous). The existence of a nonosseous cam lesion in adolescents with FAI has not been well described. PURPOSE: To identify and characterize a series of adolescent patients with nonosseous (soft cam) FAI identified on magnetic resonance imaging (MRI) and compare these patients' clinical presentation and outcome with those of a cohort with primary osseous cam FAI in the same age group. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A prospective institutional registry of patients with symptomatic FAI was reviewed. Patients were included if they had an MRI scan and a lateral radiograph of the hip (45° Dunn or frog) at a baseline visit. On MRI, the anterolateral femoral head was evaluated using radial, coronal, sagittal, or axial oblique sequences. A soft cam lesion was identified by the presence of soft tissue thickening of ≥2 mm at the anterolateral femoral head-neck junction. An alpha angle was measured on MRI scans and radiographs when a lesion was identified. The cohort with soft cam lesions was reviewed and findings and outcomes were compared with those of a cohort with osseous cam lesions. Continuous variables were first examined for normality, and then nonparametric tests-such as the Kruskal-Wallis test-were considered. The change between pre- and postoperative patient-reported outcomes (PROs) was described by mean and standard deviation and evaluated with an independent-samples t test. RESULTS: A total of 31 (9.3%) of 332 hips (mean age, 16.4 years [range 13.1-19.6 years]; women, 83.9%) were identified with a soft tissue impingment lesion on MRI at the femoral head-neck junction between the 12 and 3 o'clock positions. These lesions demonstrated a thickened perichondral ring (71%), periosteal thickening (26%), or a cartilaginous epiphyseal extension (3%). The mean alpha angle on MRI was greater than on radiographs (63.5°± 7.9° vs 51.3°± 7.9°; P < .0001). A total of 22 patients (71%) with soft impingement underwent hip preservation surgery. When compared with patients in the osseous cohort who also underwent surgical management, both groups showed similar significant improvements from pre- to postoperatively (soft: modified Harris Hip Score [mHHS], 26.9 ± 18.2; Hip disability and Osteoarthritis Outcome Score [HOOS], 31.4 ± 22.9; osseous: mHHS, 22.8 ± 20.8; HOOS, 27.4 ± 20.1; P < .0001), with a mean follow-up of 3.4 years (range, 1-7 years) in the soft cam cohort and 3 years (1-10.1 years) in the osseous cam cohort. CONCLUSION: Clinicians should be aware of nonosseous or soft cam lesions that cause impingement in adolescent patients without an obvious osseous cam on radiographs. MRI is required to detect these soft cam lesions. When nonoperative treatment fails, the PROs in these patients after operative management are comparable with those in patients with osseous cam lesions. Further research is needed to determine whether the soft cam precedes an osseous cam or whether it is a separate entity.

Suture-Bridge Fixation of Osteochondral Fractures and Osteochondritis Dissecans in the Knee: Excellent Rates of Early Lesion Stability and Osseous Union.

BACKGROUND: Preservation of articular cartilage in the setting of acute or chronic injury in the adolescent and young adult knee is paramount for long-term joint health. Achieving osseous union, minimizing implant-related injury, and eliminating the need for reoperation for traumatic chondral and osteochondral lesions (OCLs) and osteochondritis dissecans (OCD) remain a challenge for the orthopaedic surgeon. PURPOSE: To evaluate radiographic healing, patient-reported outcomes, and short-term complications after suture-bridge fixation of chondral fragments, osteochondral fractures, and OCD lesions in the knee. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The study included consecutive patients (38 patients, 40 knees) treated within a single academic sports medicine institution who underwent suture-bridge fixation of an OCL or an OCD lesion of the knee from initiation of the technique in October 2019 through March 2021. The suture-bridge technique entailed bioabsorbable knotless anchors placed on the outside margins of the lesion with multiple strands of hand-tensioned absorbable (No. 0 or No. 1 Vicryl) or nonabsorbable (1.3-mm braided polyester tape) bridging suture. Healing was assessed by radiography and magnetic resonance imaging (MRI), with MRI scans obtained on all OCD lesions and any chondral-only lesions. MRI scans were available for 33 of 40 (82.5%) knees within 1 year of surgery and were evaluated for lesion healing. Complications and rates and timing of return to sport were evaluated. Patient-reported outcomes in the OCD cohort were evaluated with the Knee injury and Osteoarthritis Outcome Score (KOOS) to determine early pain and functional improvement. RESULTS: In total, 33 (82.5%) lesions demonstrated full union, and no lesions failed treatment. MRI assessment of healing (mean, 5.8 months; range, 3-12 months) demonstrated 9 (64.3%) OCD lesions with full union, 5 (35.7%) OCD lesions with stable union, and no OCD lesions with nonunion. Of the OCLs, 17 (89.5%) had full union, 2 (10.5%) had stable union, and none had nonunion. The 7 bony OCLs without an MRI scan demonstrated complete radiographic union. In 30 (75.0%) lesions, patients returned to sports at a mean of 6.5 months (range, 3.8-10.2 months). KOOS Activities of Daily Living, Pain, Quality of Life, and Symptoms scores demonstrated significant improvement from baseline at 6 months and at 1 year. There were 2 (5%) complications, consisting of reoperation for marginal chondroplasty on an otherwise stable lesion, and re-operation for intial un-treated patellar instability, with no reoperations for failure or revision of the suture-bridge construct. CONCLUSION: In this series of OCLs and OCD lesions of the knee, suture-bridge fixation demonstrated excellent rates of MRI and radiographic union and good early outcomes with minimal short-term complications. This technique may be used for lesion salvage as an alternative to metallic and nonmetallic screw/tack constructs in the treatment of these challenging lesions. Longer term follow-up and investigation are warranted.

Radiographic Predictors of Reoperation in Adolescents Undergoing Hip Preservation Surgery for Femoroacetabular Impingement.

BACKGROUND: Femoroacetabular impingement (FAI) is a condition caused by repetitive abutment of a morphologically abnormal proximal femur and/or acetabulum that may result in chondral and labral pathology. An understanding of radiographic parameters associated with successful primary surgery has not been well established. PURPOSE: To determine preoperative radiographic parameters that predict reoperation for FAI and correlate radiographic measurements with outcomes in these patients. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A prospectively collected institutional registry of adolescent patients (age, <19 years) who underwent surgery for FAI (arthroscopic/open) was reviewed. Preoperative standing anteroposterior pelvic radiographs were analyzed for femoroepiphyseal acetabular roof (FEAR) index, as well as lateral center-edge angle (LCEA) and alpha, Tönnis, and Sharp angles. Patient-reported outcomes (PROs) (modified Harris Hip Score, Hip disability and Osteoarthritis Outcome Score) were analyzed preoperatively and at 1- and 2-year followup. Radiographic indication of risk for reoperation was evaluated using receiver operating characteristic (ROC) analysis. Spearman correlation was calculated between radiographic measurements and PROs at 2 years postoperatively. RESULTS: A total of 81 patients (91 hips) underwent primary surgery (57 surgical dislocations vs 34 arthroscopies) for FAI. The mean age at time of primary operation was 16.23 years (range, 10.4-19.6 years) (73.6% female). Eleven hips (12.1%) underwent reoperation at a mean of 20.6 months from primary surgery. The LCEA, FEAR index, Tönnis angle, and Sharp angle before index surgery were significantly different (P < .05) between patients who underwent reoperation and those who did not. ROC analysis indicated that LCEA <22°, FEAR index >-8.7°, Tönnis angle >6.0°, and Sharp angle >44° were predictors for increased risk of reoperation. Using the cutoff values from the ROC analysis in this series, 43% of patients with an LCEA ≤22° had a repeat procedure, while only 8% of those with an LCEA >22° had a repeat procedure. Similar trends were seen with the other aforementioned acetabular radiographic measurements (FEAR index, Tönnis angle, Sharp angle). Patients who did not require a reoperation demonstrated significant improvement in all PRO categories from their preoperative to 2-year postoperative visits (P < .0001). CONCLUSION: In patients undergoing treatment for FAI, a reoperation was associated with radiographic signs of hip dysplasia, indicating that patients with a shallower acetabulum are at risk for a repeat operation.

An Activity Scale for All Youth Athletes? Clinical Considerations for the HSS Pedi-FABS.

Background: The Hospital for Special Surgery Pediatric Functional Activity Brief Scale (HSS Pedi-FABS) has demonstrated normally distributed scores in children aged 10 to 18 years. It has been used to evaluate knee injuries; however, there is limited information regarding its use in evaluating other injury types. Purpose: To (1) assess the validity and utility of HSS Pedi-FABS in youth athletes with injuries to different parts of the body and (2) evaluate the association between the HSS Pedi-FABS and the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Global Health 7 (PGH), as well as PROMIS-Pain Interference (PGH-PI) and PROMIS-Fatigue (PGH-F) components. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: The authors performed a retrospective review of youth athletes aged 10 to 18 years who completed the HSS Pedi-FABS as part of their previsit intake questionnaire between April 2016 and July 2020. HSS Pedi-FABS score distributions were compared and evaluated for ceiling effects in cohorts determined by demographic, injury characteristic, and sports participation variables; a ceiling effect was determined to be present if >15% of respondents received the highest possible score. HSS Pedi-FABS scores were analyzed for a correlation with PGH, PGH-PI, and PGH-F components. Results: Included were 2274 patients (mean age, 14.6 ± 2.1 years; 53.0% female) participating in 21 distinct primary sports for 9.6 ± 7.9 hours per week. The mean HSS Pedi-FABS scores by injury group were as follows: elbow (22.7 ± 6.7), shoulder (21.0 ± 8.7), ankle (20.2 ± 8.8), knee (19.5 ± 9.1), and hip (15.4 ± 10.4) (P < .001). Broad distribution was seen in each cohort, with no floor or ceiling effects. The HSS Pedi-FABS score correlated with patient-reported hours per week (r = 0.33), days per week (r = 0.33), and years of participation (r = 0.21) (P < .001 for all). All 3 PROMIS components correlated with HSS Pedi-FABS: PGH (r = 0.28), PGH-PI (r = -0.11), and PGH-F (r = -0.15) (P < .001). Conclusion: Study findings indicated that the HSS Pedi-FABS is a valid tool for measuring physical activity level in most injured youth athletes, not just those with knee injuries. The correlation of HSS Pedi-FABS with the PGH suggests a positive relationship of childhood physical activity with general health.

The Association of α Angle on Disease Severity in Adolescent Femoroacetabular Impingement.

BACKGROUND: Femoroacetabular Impingement (FAI) is a common cause of hip pain in adolescent patients. Clinical exam and radiographic markers, such as α angle and lateral center edge angle (LCEA), are commonly used to aid in the diagnosis of this condition. The purpose of this study was to correlate preoperative α angle and LCEA with preoperative symptoms, intraoperative findings, and preoperative and postoperative patient reported outcomes (PROs) in the adolescent patient. METHODS: A retrospective analysis of prospectively collected data was conducted for all patients who underwent operative intervention for FAI at an academic institution over an 11-year period. Preoperative imaging was obtained and measured for LCEA and α angle. PROs (modified Harris Hip Score, Hip Disability and Osteoarthritis Outcome Score, and UCLA score) were collected preoperatively, as well as 1, 2, and 5 years postoperatively. Operative intervention was either open surgical hip dislocation or arthroscopic, and intraoperative disease was graded using the Beck Classification system. Patients with minimum 1-year follow-up were included in statistical analysis. RESULTS: There were 86 hips (64 female hips) included with an average age of 16.3 years (range, 10.4 to 20.5 y), with an average of 37 months of follow-up. There was no correlation between severity of preoperative symptoms or difference between pre and postoperative PROs for both α angle and LCEA. Overall, significant improvement was noted in modified Harris Hip Score, Hip Disability and Osteoarthritis Outcome Score, and UCLA Score (P<0.001 for each). Independent of preoperative symptoms, increased α angle correlated with more severe intraoperative labral disease (P<0.001), and longer length of labral tear (Corr 0.295, P<0.01). Femoral head and acetabular articular cartilage damage did not correlate with α angle or LCEA, nor did overall severity of disease. CONCLUSIONS: In adolescent patients with FAI, increased α angle was found to significantly correlate with labral pathology, including increased length of tear and severity of disease, irrespective of preoperative symptoms or postoperative patient reported outcomes. LEVEL OF EVIDENCE: Level III-retrospective.

5-Azacytidine Potentiates Anti-tumor Immunity in a Model of Pancreatic Ductal Adenocarcinoma.

Tumors evolve a variety of mechanisms to escape immune detection while expressing tumor-promoting molecules that can be immunogenic. Here, we show that transposable elements (TE) and gene encoded, tumor-associated antigens (TAA), which can be both highly immunogenic and tumor-promoting, are significantly upregulated during the transition from pre-malignancy to malignancy in an inducible model of pancreatic ductal adenocarcinoma (PDAC). Coincident with the increased presence of TEs and TAAs was the downregulation of gene transcripts associated with antigen presentation, T cell recruitment and intrinsic anti-viral responses, suggesting a unique strategy employed by PDAC to possibly augment tumorigenesis while escaping detection by the immune system. In vitro treatment of mouse and human PDAC cell lines with the DNA methyltransferase inhibitor 5-azacytidine (Aza) resulted in augmented expression of transcripts for antigen presentation machinery and T cell chemokines. When immunocompetent mice implanted with PDAC were therapeutically treated with Aza, we observed significant tumor regression that was not observed in immunocompromised mice, implicating anti-tumor immunity as the principal mechanism of tumor growth control. Analysis of PDAC tumors, immediately following Aza treatment in immunocompetent mice, revealed a significantly greater infiltration of T cells and various innate immune subsets compared to control treatment, suggesting that Aza treatment enhances tumor immunogenicity. Thus, augmenting antigen presentation and T cell chemokine expression using DNA methyltransferase inhibitors could be leveraged to potentiate adaptive anti-tumor immune responses against PDAC.

Desmoplasia and oncogene driven acinar-to-ductal metaplasia are concurrent events during acinar cell-derived pancreatic cancer initiation in young adult mice.

The five-year survival rate of patients diagnosed with advanced pancreatic ductal adenocarcinoma (PDAC) has remained static at <5% despite decades of research. With the exception of erlotinib, clinical trials have failed to demonstrate the benefit of any targeted therapy for PDAC despite promising results in preclinical animal studies. The development of more refined mouse models of PDAC which recapitulate the carcinogenic progression from non-neoplastic, adult exocrine subsets of pancreatic cells to invasive carcinoma in humans are needed to facilitate the accurate translation of therapies to the clinic. To study acinar cell-derived PDAC initiation, we developed a genetically engineered mouse model of PDAC, called KPT, utilizing a tamoxifen-inducible Cre recombinase/estrogen receptor (ESR1) fusion protein knocked into the Ptf1a locus to activate the expression of oncogenic KrasG12D and Trp53R270H alleles in mature pancreatic acinar cells. Oncogene-expressing acinar cells underwent acinar-to-ductal metaplasia, and formed pancreatic intraepithelial neoplasia lesions following the induction of oncogene expression. After a defined latency period, oncogene-expressing acinar cells initiated the formation of highly differentiated and fibrotic tumors, which metastasized to the lungs and liver. Whole-transcriptome analysis of microdissected regions of acinar-to-ductal metaplasia and histological validation experiments demonstrated that regions of acinar-to-ductal metaplasia are characterized by the deposition of the extracellular matrix component hyaluronan. These results indicate that acinar cells expressing KrasG12D and Trp53R270H can initiate PDAC development in young adult mice and implicate hyaluronan deposition in the formation of the earliest characterized PDAC precursor lesions (and the progression of pancreatic cancer). Further studies are necessary to provide a comprehensive characterization of PDAC progression and treatment response in KPT mice and to investigate whether the KPT model could be used as a tool to study translational aspects of acinar cell-derived PDAC tumorigenesis.

SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia.

Nav channels are essential for metazoan membrane depolarization, and Nav channel dysfunction is directly linked with epilepsy, ataxia, pain, arrhythmia, myotonia, and irritable bowel syndrome. Human Nav channelopathies are primarily caused by variants that directly affect Nav channel permeability or gating. However, a new class of human Nav channelopathies has emerged based on channel variants that alter regulation by intracellular signaling or cytoskeletal proteins. Fibroblast growth factor homologous factors (FHFs) are a family of intracellular signaling proteins linked with Nav channel regulation in neurons and myocytes. However, to date, there is surprisingly little evidence linking Nav channel gene variants with FHFs and human disease. Here, we provide, to our knowledge, the first evidence that mutations in SCN5A (encodes primary cardiac Nav channel Nav1.5) that alter FHF binding result in human cardiovascular disease. We describe a five*generation kindred with a history of atrial and ventricular arrhythmias, cardiac arrest, and sudden cardiac death. Affected family members harbor a novel SCN5A variant resulting in p.H1849R. p.H1849R is localized in the central binding core on Nav1.5 for FHFs. Consistent with these data, Nav1.5 p.H1849R affected interaction with FHFs. Further, electrophysiological analysis identified Nav1.5 p.H1849R as a gain-of-function for INa by altering steady-state inactivation and slowing the rate of Nav1.5 inactivation. In line with these data and consistent with human cardiac phenotypes, myocytes expressing Nav1.5 p.H1849R displayed prolonged action potential duration and arrhythmogenic afterdepolarizations. Together, these findings identify a previously unexplored mechanism for human Nav channelopathy based on altered Nav1.5 association with FHF proteins.

Use of whole exome sequencing for the identification of Ito-based arrhythmia mechanism and therapy.

BACKGROUND: Identified genetic variants are insufficient to explain all cases of inherited arrhythmia. We tested whether the integration of whole exome sequencing with well-established clinical, translational, and basic science platforms could provide rapid and novel insight into human arrhythmia pathophysiology and disease treatment. METHODS AND RESULTS: We report a proband with recurrent ventricular fibrillation, resistant to standard therapeutic interventions. Using whole-exome sequencing, we identified a variant in a previously unidentified exon of the dipeptidyl aminopeptidase-like protein-6 (DPP6) gene. This variant is the first identified coding mutation in DPP6 and augments cardiac repolarizing current (Ito) causing pathological changes in Ito and action potential morphology. We designed a therapeutic regimen incorporating dalfampridine to target Ito. Dalfampridine, approved for multiple sclerosis, normalized the ECG and reduced arrhythmia burden in the proband by >90-fold. This was combined with cilostazol to accelerate the heart rate to minimize the reverse-rate dependence of augmented Ito. CONCLUSIONS: We describe a novel arrhythmia mechanism and therapeutic approach to ameliorate the disease. Specifically, we identify the first coding variant of DPP6 in human ventricular fibrillation. These findings illustrate the power of genetic approaches for the elucidation and treatment of disease when carefully integrated with clinical and basic/translational research teams.

Effect of flip angle on the accuracy and repeatability of hepatic proton density fat fraction estimation by complex data-based, T1-independent, T2*-corrected, spectrum-modeled MRI.

PURPOSE: To evaluate the effect of flip angle (FA) on accuracy and within-examination repeatability of hepatic proton-density fat fraction (PDFF) estimation with complex data-based magnetic resonance imaging (MRI). MATERIALS AND METHODS: PDFF was estimated at 3T in 30 subjects using two sets of five MRI sequences with FA from 1° to 5° in each set. One set used 7 msec repetition time and acquired 6 echoes (TR7/E6); the other used 14 msec and acquired 12 echoes (TR14/E12). For each FA in both sets the accuracy of MRI-PDFF was assessed relative to MR spectroscopy (MRS)-PDFF using four regression parameters (slope, intercept, average bias, R(2) ). Each subject had four random sequences repeated; within-examination repeatability of MRI-PDFF for each FA was assessed with intraclass correlation coefficient (ICC). Pairwise comparisons were made using bootstrap-based tests. RESULTS: Most FAs provided high MRI-PDFF estimation accuracy (intercept range -1.25 to 0.84, slope 0.89-1.06, average bias 0.24-1.65, R(2) 0.85-0.97). Most comparisons of regression parameters between FAs were not significant. Informally, in the TR7/E6 set, FAs of 2° and 3° provided the highest accuracy, while FAs of 1° and 5° provided the lowest. In the TR14/E12 set, accuracy parameters did not differ consistently between FAs. FAs in both sets provided high within-examination repeatability (ICC range 0.981-0.998). CONCLUSION: MRI-PDFF was repeatable and, for most FAs, accurate in both sequence sets. In the TR7/E6 sequence set, FAs of 2° and 3° informally provided the highest accuracy. In the TR14/E12 sequence set, all FAs provided similar accuracy.

ßIV-Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells.

Identified over a dozen years ago in the brain and pancreatic islet, ßIV-spectrin is critical for the local organization of protein complexes throughout the nervous system. ßIV-Spectrin targets ion channels and adapter proteins to axon initial segments and nodes of Ranvier in neurons, and ßIV-spectrin dysfunction underlies ataxia and early death in mice. Despite advances in ßIV-spectrin research in the nervous system, its role in pancreatic islet biology is unknown. Here, we report that ßIV-spectrin serves as a multifunctional structural and signaling platform in the pancreatic islet. We report that ßIV-spectrin directly associates with and targets the calcium/calmodulin-dependent protein kinase II (CaMKII) in pancreatic islets. In parallel, ßIV-spectrin targets ankyrin-B and the ATP-sensitive potassium channel. Consistent with these findings, ßIV-spectrin mutant mice lacking CaMKII- or ankyrin-binding motifs display selective loss of expression and targeting of key protein components, including CaMKIIδ. ßIV-Spectrin-targeted CaMKII directly phosphorylates the inwardly-rectifying potassium channel, Kir6.2 (alpha subunit of KATP channel complex), and we identify the specific residue, Kir6.2 T224, responsible for CaMKII-dependent regulation of KATP channel function. CaMKII-dependent phosphorylation alters channel regulation resulting in KATP channel inhibition, a cellular phenotype consistent with aberrant insulin regulation. Finally, we demonstrate aberrant KATP channel phosphorylation in ßIV-spectrin mutant mice. In summary, our findings establish a broader role for ßIV-spectrin in regulation of cell membrane excitability in the pancreatic islet, define the pathway for CaMKII local control in pancreatic beta cells, and identify the mechanism for CaMKII-dependent regulation of KATP channels.

Ultrasonic attenuation and speed of sound of cornstarch suspensions.

The goal of this study is to contribute to the physics underlying the material properties of suspensions that exhibit shear thickening through the ultrasonic characterization of suspensions of cornstarch in a density-matched solution. Ultrasonic measurements at frequencies in the range of 4 to 8 MHz of the speed of sound and the frequency-dependent attenuation properties are reported for concentrations of cornstarch in a density-matched aqueous (cesium chloride brine) suspension, ranging up to 40% cornstarch. The speed of sound is found to range from 1483 ± 10 m/s in pure brine to 1765 ± 9 m/s in the 40% cornstarch suspension. The bulk modulus of a granule of cornstarch is inferred to be 1.2(± 0.1) × 10(10) Pa. The attenuation coefficient at 5 MHz increases from essentially zero in brine to 12.0 ± 1.2 dB/cm at 40% cornstarch.

Layer-dependent variation in the anisotropy of apparent integrated backscatter from human coronary arteries.

Clinical imaging of the coronary arteries in the cardiac catheterization laboratory using intravascular ultrasound (IVUS) is known to display a three-layered appearance, corresponding to the intima/plaque, media and adventitia. It is not known whether ultrasonic anisotropy arising from these tissues may alter this pattern in future IVUS systems that insonify in the forward direction or obliquely. In anticipation of such devices, the current study was carried out by imaging fresh human coronary arteries in two orthogonal directions in vitro. Twenty-six sites from 12 arteries were imaged with a side-looking IVUS system, and with an acoustic microscope both radially and axially. Side-looking IVUS and radial acoustic microscopy scans demonstrated the typical "bright-dark-bright" pattern of the backscatter, with the media being significantly darker than the other two layers. Images obtained in the axial orientation exhibited a markedly different pattern, with the relative brightness of the media significantly larger than that of the intima/plaque.