Somatostatin peptide signaling dampens cortical circuits and promotes exploratory behavior.

We sought to characterize the unique role of somatostatin (SST) in the prelimbic (PL) cortex in mice. We performed slice electrophysiology in pyramidal and GABAergic neurons to characterize the pharmacological mechanism of SST signaling and fiber photometry of GCaMP6f fluorescent calcium signals from SST neurons to characterize the activity profile of SST neurons during exploration of an elevated plus maze (EPM) and open field test (OFT). We used local delivery of a broad SST receptor (SSTR) agonist and antagonist to test causal effects of SST signaling. SSTR activation hyperpolarizes layer 2/3 pyramidal neurons, an effect that is recapitulated with optogenetic stimulation of SST neurons. SST neurons in PL are activated during EPM and OFT exploration, and SSTR agonist administration directly into the PL enhances open arm exploration in the EPM. This work describes a broad ability for SST peptide signaling to modulate microcircuits within the prefrontal cortex and related exploratory behaviors.

Evaluating whole-genome expression differences in idiopathic and diabetic adhesive capsulitis.

BACKGROUND: Diabetic patients have a greater incidence of adhesive capsulitis (AC) and a more protracted disease course than patients with idiopathic AC. The purpose of this study was to compare gene expression differences between AC with diabetes mellitus and AC without diabetes mellitus. METHODS: Shoulder capsule samples were prospectively obtained from diabetic or nondiabetic patients who presented with shoulder dysfunction and underwent arthroscopy (N = 16). Shoulder samples of AC with and without diabetes (n = 8) were compared with normal shoulder samples with and without diabetes as the control group (n = 8). Shoulder capsule samples were subjected to whole-transcriptome RNA sequencing, and differential expression was analyzed with EdgeR. Only genes with a false discovery rate < 5% were included for further functional enrichment analysis. RESULTS: The sample population had a mean age of 47 years (range, 24-62 years), and the mean hemoglobin A1c level for nondiabetic and diabetic patients was 5.18% and 8.71%, respectively. RNA-sequencing analysis revealed that 66 genes were differentially expressed between diabetic patients and nondiabetic patients with AC whereas only 3 genes were differentially expressed when control patients with and without diabetes were compared. Furthermore, 286 genes were differentially expressed in idiopathic AC patients, and 61 genes were differentially expressed in diabetic AC patients. On gene clustering analysis, idiopathic AC was enriched with multiple structural and muscle-related pathways, such as muscle filament sliding, whereas diabetic AC included a greater number of hormonal and inflammatory signaling pathways, such as cellular response to corticotropin-releasing factor. CONCLUSIONS: Whole-transcriptome expression profiles demonstrate a fundamentally different underlying pathophysiology when comparing diabetic AC with idiopathic AC, suggesting that these conditions are distinct clinical entities. The new genes expressed explain the differences in the disease course and suggest new therapeutic targets that may lead to different treatment paradigms in these 2 subsets.

Fiber-coupled vapor cell for a portable Rydberg atom-based radio frequency electric field sensor.

We demonstrate a movable, Rydberg atom-based radio frequency (RF) electric (E) field probe. The technique is based on electromagnetically induced transparency and Autler-Townes splitting. Two fibers attached to a 10 mm cubic Cs133 vapor cell are used to couple counter-propagating probe and control lasers through the cell. This all-dielectric fiber-coupled sensor can be moved from the optics table to locations more suitable for RF (gigahertz to sub-terahertz) E-field measurements and calibrations.

Trends in MD/PhD Graduates Entering Psychiatry: Assessing the Physician-Scientist Pipeline.

OBJECTIVE: The goal of this study was to identify trends in MD/PhD graduates entering psychiatry, to compare these trends with other specialties, and to review strategies for enhancing the physician-scientist pipeline. METHODS: Data on 226,588 medical students graduating from Liaison Committee on Medical Education accredited programs between 1999 and 2012 (6626 MD/PhDs) were used to evaluate the number, percentage, and proportion of MD/PhDs entering psychiatry in comparison with other specialties (neurology, neurosurgery, internal medicine, family medicine, and radiation oncology). Linear regression and multiple linear regression determined whether these values increased over time and varied by sex. RESULTS: Over 14 years, an average of 18 MD/PhDs (range 13-29) enrolled in psychiatry each year. The number of MD/PhDs going into psychiatry significantly increased, although these gains were modest (less than one additional MD/PhD per year). The proportion of students entering psychiatry who were MD/PhDs varied between 2.9 and 5.9 per 100 residents, with no significant change over time. There was also no change in the percentage of MD/PhDs entering psychiatry from among all MD/PhD graduates. The rate of increase in the number of MD/PhDs going into psychiatry did not differ significantly from other specialties except for family medicine, which is decreasing. The rate of MD/PhDs going into psychiatry was higher for women, suggesting closure of the sex gap in 17 years. CONCLUSIONS: Despite the increase in the number of MD/PhDs entering psychiatry, these numbers remain low. Expanding the cohort of physician-scientists dedicated to translational research in psychiatry will require a multipronged approach.

Patient- and Disease-Specific Factors Associated With Operative Management of de Quervain Tendinopathy.

PURPOSE: It remains unclear which factors, patient- or disease-specific, are associated with electing to undergo operative management for de Quervain tendinopathy. Our null hypothesis was that no patient- or disease-specific factors would be associated with the choice of surgical treatment of de Quervain tendinopathy. METHODS: We performed a retrospective review of consecutive patients diagnosed with de Quervain tendinopathy over 3 years by 1 of 3 fellowship-trained hand surgeons at an urban academic institution. Descriptive statistics were calculated for patient baseline and disease-specific characteristics. Cohorts were compared using bivariate analysis for all collected variables. Binary logistic regression with backward stepwise term selection was performed including independent predictors identified by bivariate analysis. RESULTS: A total of 200 patients were identified for inclusion. Bivariate analysis revealed that surgically treated patients were significantly more likely to have Medicaid insurance, psychiatric illness history, and disabled work status. Regression analysis revealed an association between surgical treatment and 2 of the factors evaluated: Medicaid insurance status and psychiatric illness history. CONCLUSIONS: Psychiatric illness and Medicaid insurance status are associated with undergoing surgical release of the first dorsal compartment. These findings support the use of a biopsychosocial framework when treating patients with de Quervain tendinopathy. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

P2 porous titanium implants improve tendon healing in an acute rat supraspinatus repair model.

BACKGROUND: Current techniques in rotator cuff repair often lack structural integrity. P2 porous titanium-coated constructs (DJO Surgical, Austin, TX, USA) promote osseointegration and soft tissue ingrowth. This study examined the ability of this material to improve the structural integrity of supraspinatus tendon repair in a rat model. We hypothesized that P2 implants placed at the tendon-to-bone interface would improve mechanical and histologic measures of supraspinatus healing. METHODS: Forty rats underwent supraspinatus repairs with P2 implants in 1 shoulder and standard repair in the other. Rats were humanely killed at time 0 (n = 3), 2 weeks (n = 8), 4 weeks (n = 15), and 12 weeks (n = 14). Tendon-to-bone composite specimens were harvested and evaluated mechanically and histologically. RESULTS: Tendon cross-sectional area was decreased in the P2 implant group at 4 weeks, percentage of relaxation was increased at 2 weeks, elastic modulus was increased at 4 weeks, and maximum load and maximum stress were both increased at 2 and 4 weeks. Histologic analysis revealed no foreign body reactions within or around the P2 implant, and healthy viable bone was visible within the P2 implant. CONCLUSION: The results support our hypothesis, specifically in early healing, in this randomized controlled animal study. These data support the use of P2 porous titanium implants to improve tendon-to-bone healing.

Effect of scapular dyskinesis on supraspinatus repair healing in a rat model.

BACKGROUND: Rotator cuff tears are common conditions that often require surgical repair to improve function and to relieve pain. Unfortunately, repair failure remains a common problem after rotator cuff repair surgery. Several factors may contribute to repair failure, including age, tear size, and time from injury. However, the mechanical mechanisms resulting in repair failure are not well understood, making clinical management difficult. Specifically, altered scapular motion (termed scapular dyskinesis) may be one important and modifiable factor contributing to the risk of repair failure. Therefore, the objective of this study was to determine the effect of scapular dyskinesis on supraspinatus tendon healing after repair. METHODS: A rat model of scapular dyskinesis was used. Seventy adult male Sprague-Dawley rats (400-450 g) were randomized into 2 groups: nerve transection of the accessory and long thoracic nerves (SD) or sham nerve transection (Sham control). After this procedure, all rats underwent unilateral detachment and repair of the supraspinatus tendon. All rats were sacrificed at 2, 4, and 8 weeks after surgery. Shoulder function, passive joint mechanics, and tendon properties (mechanical, histologic, organizational, and compositional) were evaluated. RESULTS: Scapular dyskinesis alters joint function and may lead to compromised supraspinatus tendon properties. Specifically, diminished mechanical properties, altered histology, and decreased tendon organization were observed for some parameters. CONCLUSION: This study identifies scapular dyskinesis as one underlying mechanism leading to compromise of supraspinatus healing after repair. Identifying modifiable factors that lead to compromised tendon healing will help improve clinical outcomes after repair.

Overuse activity in the presence of scapular dyskinesis leads to shoulder tendon damage in a rat model.

Shoulder tendon injuries are common clinical conditions and are a significant source of pain and dysfunction. These conditions are more common in individuals who perform repetitive overhead activities and in individuals who have abnormal scapular kinematics, termed scapular dyskinesis (SD). However, the long term consequences associated with overuse activity in the presence of SD are unknown. Therefore, the objective of this study was to determine the effect of overuse in combination with SD on joint mechanics and properties of the rotator cuff and biceps tendons. A rat model of scapular dyskinesis was used. Ninety adult male Sprague-Dawley rats (400-450 g) were randomized into three groups: nerve transection (SD), sham nerve transection + overuse (OV), or nerve transection + overuse (SD + OV). Rats were sacrificed at 2, 4, and 8 weeks after surgery. Shoulder function and passive joint mechanics were evaluated over time and tendon properties (mechanical, histological, organizational, and compositional) were measured. Results demonstrated that overuse activity and SD are each independently detrimental to tendon properties (e.g., diminished mechanical properties, disorganized collagen). However, tendon damage caused by the addition of overuse may be worse, with more parameters altered, than damage caused by the addition of SD. This study helps define the mechanical mechanisms leading to tendon damage and provides a framework for distinguishing treatment strategies for active patients and those with abnormal scapular mechanics.

Scapular dyskinesis is detrimental to shoulder tendon properties and joint mechanics in a rat model.

Shoulder tendon injuries are frequently seen in the presence of abnormal scapular motion, termed scapular dyskinesis. The cause and effect relationship between scapular dyskinesis and shoulder injury has not been directly defined. We developed and used an animal model to examine the initiation and progression of pathological changes in the rotator cuff and biceps tendon. Sixty male Sprague-Dawley rats were randomized into two groups: nerve transection (to induce scapular dyskinesis, SD) or sham nerve transection (control). The animals were euthanized 4 and 8 weeks after surgery. Shoulder function and passive joint mechanics were evaluated over time. Tendon mechanical, histological, organizational, and compositional properties were evaluated at both time points. Gross observation demonstrated alterations in scapular motion, consistent with scapular "winging." Shoulder function, passive internal range of motion, and tendon mechanical properties were significantly altered. Histology results, consistent with tendon pathology (rounded cell shape and increased cell density), were observed, and protein expression of collagen III and decorin was altered. This study presents a new model of scapular dyskinesis that can rigorously evaluate cause and effect relationships in a controlled manner. Our results identify scapular dyskinesis as a causative mechanical mechanism for shoulder tendon pathology.

Repeated cortico-striatal stimulation generates persistent OCD-like behavior.

Although cortico-striato-thalamo-cortical (CSTC) circuit dysregulation is correlated with obsessive compulsive disorder (OCD), causation cannot be tested in humans. We used optogenetics in mice to simulate CSTC hyperactivation observed in OCD patients. Whereas acute orbitofrontal cortex (OFC)-ventromedial striatum (VMS) stimulation did not produce repetitive behaviors, repeated hyperactivation over multiple days generated a progressive increase in grooming, a mouse behavior related to OCD. Increased grooming persisted for 2 weeks after stimulation cessation. The grooming increase was temporally coupled with a progressive increase in light-evoked firing of postsynaptic VMS cells. Both increased grooming and evoked firing were reversed by chronic fluoxetine, a first-line OCD treatment. Brief but repeated episodes of abnormal circuit activity may thus set the stage for the development of persistent psychopathology.

Analysis of a knotless flexor tendon repair using a multifilament stainless steel cable-crimp system.

PURPOSE: To compare the biomechanical and technical properties of flexor tendon repairs using a 4-strand cruciate FiberWire (FW) repair and a 2-strand multifilament stainless steel (MFSS) single cross-lock cable-crimp system. METHODS: Eight tests were conducted for each type of repair using cadaver hand flexor digitorum profundus tendons. We measured the required surgical exposure, repair time, and force of flexion (friction) with a custom motor system with an inline load cell and measured ultimate tensile strength (UTS) and 2-mm gap force on a servo-hydraulic testing machine. RESULTS: Repair time averaged less than 7 minutes for the 2-strand MFSS cable crimp repairs and 12 minutes for the FW repairs. The FW repair was performed with 2 cm of exposure and removal of the C-1 and A-3 pulleys. The C-1 and A-3 pulleys were retained in each of the MFSS cable crimp repairs with less than 1 cm of exposure. Following the FW repair, the average increase in friction was 89% compared with an average of 53% for the MFSS repairs. Six of the 8 MFSS specimens achieved the UTS before any gap had occurred, whereas all of the FW repairs had more than 2 mm of gap before the UTS, indicating that the MFSS was a stiffer repair. The average UTS appeared similar for both groups. CONCLUSIONS: We describe a 2-strand multifilament stainless steel single cross-lock cable crimp flexor repair system. In our studies of this cable crimp system, we found that surgical exposure, average repair times, and friction were reduced compared to the traditional 4-strand cruciate FW repair. While demonstrating these benefits, the crimp repair also produced a stiff construct and high UTS and 2-mm gap force. CLINICAL RELEVANCE: A cable crimp flexor tendon repair may offer an attractive alternative to current repair methods. The benefits may be important especially for flexor tendon repair in zone 2 or for the repair of multiple tendons.

Surface markers for locating the pulleys and flexor tendon anatomy in the palm and fingers with reference to minimally invasive incisions.

PURPOSE: Palm and finger pulley anatomy has been well described in relation to osseous structures. The goal of this study was to describe skin surface markers that locate the underlying flexor tendon and pulley system. We describe the anatomic detail of these structures and provide a guide for the surgeon for making small incisions. Using this approach, extensile exposure can be avoided, and the integrity of the complex pulley system is maintained. METHODS: We dissected 12 palms and 48 fingers in 12 cadaver hands. We marked the palm and finger creases with methylene blue before dissection. We removed palm skin, finger skin, and subcutaneous tissue over the flexor tendon sheath and retained a 2-mm strip of each skin crease in its native position. We divided the palm and palmar surface of the fingers into 4 distinct zones and measured the location of the proximal and distal extent of each pulley and the tendon anatomy relative to the proximal and distal skin crease. RESULTS: We documented the location of the proximal and distal extent of the annular and cruciate pulleys as well as the decussation of the flexor digitorum superficialis (FDS) tendon and Camper chiasm. The results allow us to establish a relationship between the skin creases and underlying anatomy by dividing the palm and finger into 4 zones. In zone A, in the palm, the A2 pulley is located in the distal third and the FDS decussation is at the proximal extent of the A2 pulley. Zone B is in the proximal phalanx and A2 lies in the proximal third of this zone, whereas the Camper chiasm lies in the middle third. Zone C is in the middle phalanx and A4 and the insertion of FDS lie in the middle third of this zone. Zone D lies in the distal phalanx and the flexor digitorum profundus tendon inserts into the middle third of this zone. CONCLUSIONS: Skin creases can be used as surface markers to accurately locate the underlying pulley and tendon system and plan for limited incisions. CLINICAL RELEVANCE: These anatomic descriptions can aid surgeons in preoperative planning and may also help minimize the required exposure for flexor tendon repair and other surgery in the fingers and palm.

Comparison of a new multifilament stainless steel suture with frequently used sutures for flexor tendon repair.

PURPOSE: To investigate the mechanical properties of some common suture materials currently in use and compare them with a new multifilament stainless steel suture. METHODS: We investigated the mechanical properties of 3-0 and 4-0 Fiberwire, 3-0 Supramid, 3-0 Ethibond, and a new 3-0 and 4-0 multifilament stainless steel suture. All suture material was tested in a knotted configuration and all but the Supramid was tested in an unknotted configuration. We measured the load, elongation at failure, and stiffness during both tests. RESULTS: The 4-0 multifilament stainless steel showed the least elongation, whereas the 3-0 multifilament stainless steel withstood the highest load of any material in both the knotted and unknotted tests. There was no difference in stiffness between the 3-0 and 4-0 multifilament stainless steel when untied; however, the 3-0 multifilament stainless steel was stiffer when tied. Soaking in a saline solution had no significant effect on the ultimate load, elongation at failure, or stiffness of any of the sutures. The 3-0 Fiberwire and 3-0 Ethibond required at least 5 throws to resist untying. CONCLUSIONS: Multifilament stainless steel exhibited promising mechanical advantages over the other sutures tested. More research is needed to determine how this material will affect the clinical outcomes of primary flexor tendon repair. CLINICAL RELEVANCE: With a secure attachment to the tendon, the multifilament stainless steel's lower elongation and better knot-holding ability may result in a higher force to produce a 2-mm gap and a higher ultimate tensile strength in a tendon repair.

Disrupted activity in the hippocampal-accumbens circuit of type III neuregulin 1 mutant mice.

Neuregulin 1 (Nrg1), a schizophrenia susceptibility gene, is involved in fundamental aspects of neurodevelopment. Mice lacking any one of the several isoforms of Nrg1 have a variety of schizophrenia-related phenotypes, including deficits in working memory and sensorimotor gating, loss of spines in pyramidal neurons in the ventral subiculum, loss of dendrites in cortical pyramidal cells, loss of parvalbumin-positive interneurons in the prefrontal cortex, and altered plasticity in corticolimbic synapses. Mice heterozygous for a disruption in exon 7 of the Nrg1 gene lack Type III (cysteine-rich-domain-containing) isoforms and have sensorimotor gating deficits that may involve changes in the activity of a circuit involving projections from the ventral hippocampus (vHPC) to medium spiny neurons in the nucleus accumbens (nACC). To explore the neural basis of these deficits, we examined electrophysiological activity in the nACC and vHPC of these mice. Under urethane anesthesia, bursts of spontaneous activity propagated from the vHPC to the nACC in both wild-type and mutant mice. However, these bursts were weaker in mutant nACC, with reduced local field potential amplitude and spiking activity. Single units in mutant nACC fired less frequently within the bursts, and more frequently outside of the bursts. Moreover, within-burst nACC spiking was less modulated by vHPC activity, as determined by phase-locking to the low-frequency oscillatory components of the bursts. These data suggest that the efficacy of vHPC input to the nACC is reduced in the Type III Nrg1 heterozygotes, supporting a role for Nrg1 in the functional profile of hippocampal-accumbens synapses.