Unusual Near-Horizon Cosmic-Ray-like Events Observed by ANITA-IV.

ANITA's fourth long-duration balloon flight in 2016 detected 29 cosmic-ray (CR)-like events on a background of 0.37_{-0.17}^{+0.27} anthropogenic events. CRs are mainly seen in reflection off the Antarctic ice sheets, creating a phase-inverted waveform polarity. However, four of the below-horizon CR-like events show anomalous noninverted polarity, a p=5.3×10^{-4} chance if due to background. All anomalous events are from locations near the horizon; ANITA-IV observed no steeply upcoming anomalous events similar to the two such events seen in prior flights.

Osteochondroma on the cranial aspect of the distal radial metaphysis causing tenosynovitis of the extensor carpi radialis tendon sheath in a horse.

CASE REPORT: A 3-year-old Thoroughbred gelding was presented with a grade 3/5 lameness of the right forelimb and effusion of the extensor carpi radialis tendon sheath (ECRTS). Radiographic and ultrasonographic examinations revealed an osteochondroma on the cranial aspect of the distal radius projecting into the fibrous lining of the ECRTS. An open surgical approach was used to remove the osteochondroma and some of the proliferative synovial tissue. CONCLUSION: Six months after surgery the clinical signs had resolved and the horse raced successfully.

Autologous bone marrow aspirate for treatment of superficial digital flexor tendonitis in 105 racehorses.

To evaluate a treatment protocol whereby superficial digital flexor (SDF) tendonitis in Thoroughbred and Standardbred racehorses was treated with autologous bone marrow aspirate (ABMA) obtained from the sternebrae. This treatment was combined with desmotomy of the accessory ligament of the SDF tendon (DAL-SDFT) in selected cases. Medical records of 105 horses treated using the reported protocol were reviewed. Signalment, history and details of treatment were recorded. Racing records were reviewed and performance recorded. Of Thoroughbreds, 82 per cent had one or more starts within the follow-up period and 59 per cent had five or more starts. Of Standardbreds, 76 per cent had one or more starts and 62 per cent had five or more starts. A statistically significant difference was found when comparing race starts between sexes, with females having less starts than males (≥1start P=0.017 and ≥5 starts P=0.008, respectively). The proportions of horses having one or more starts and five or more starts did not differ significantly if a DAL-SDFT was performed or not (P=0.31 and 0.63, respectively). Horses with a core lesion in the body of the SDFT have a good prognosis for return to racing following intralesional ABMA injection. Addition of DAL-SDFT to the treatment regimen did not significantly influence outcome.

Phenotyping animal models of diabetic neuropathy: a consensus statement of the diabetic neuropathy study group of the EASD (Neurodiab).

NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy. The discussion was divided into five areas: (1) status of commonly used rodent models of diabetes, (2) nerve structure, (3) electrophysiological assessments of nerve function, (4) behavioral assessments of nerve function, and (5) the role of biomarkers in disease phenotyping. Participants discussed the current understanding of each area, gold standards (if applicable) for assessments of function, improvements of existing techniques, and utility of known and exploratory biomarkers. The research opportunities in each area were outlined, providing a possible roadmap for future studies. The meeting concluded with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence of statistically different values between diabetic and control animals in 2 of 3 assessments (nocifensive behavior, nerve conduction velocities, or nerve structure). The participants propose that this framework would allow different research groups to compare and share data, with an emphasis on data targeted toward the therapeutic efficacy of drug interventions.

Use of ultrasound-guided autologous bone marrow transfer for treatment of suspensory ligament desmitis in 30 race horses (2003-2010).

OBJECTIVE: To evaluate the racing performance of horses that underwent ultrasound-guided intralesional injection of autologous bone marrow aspirate for treatment of selected forelimb suspensory ligament (body or branch) core lesions. DESIGN: Retrospective cohort study of 13 Standardbred and 17 Thoroughbred race horses. METHODS: Autologous bone marrow aspirated from the sternebrae was injected, under ultrasound guidance, into suspensory ligament core lesions (body or branch). Racing records were reviewed for a comparison of performance before and after surgery. RESULTS: Of the 13 Standardbreds, 9 (69%) had one or more starts within the follow-up period and 9 (69%) had five or more starts. Of the 17 Thoroughbreds, 15 (88%) had one or more starts within the follow-up period and 12 (71%) had five or more starts. Eight Standardbred horses had at least one start both before and after surgery. Earnings per start did not differ significantly between the three starts immediately after surgery compared with the three starts immediately prior to surgery. Thirteen Thoroughbred horses had at least one start both before and after surgery. Earnings per start were less for the three starts immediately after surgery compared with the three starts immediately prior to surgery. CONCLUSIONS AND CLINICAL RELEVANCE: A horse with a core lesion in the branch or body of the suspensory ligament has a good prognosis for return to racing after treatment with intralesional injection of bone marrow aspirate.

Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.

OBJECTIVE: To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). METHODS: We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: "What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?" RESULTS AND RECOMMENDATIONS: Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL.

Assessing autonomic dysfunction in early diabetic neuropathy: the Survey of Autonomic Symptoms.

OBJECTIVE: Autonomic symptoms may occur frequently in diabetic and other neuropathies. There is a need to develop a simple instrument to measure autonomic symptoms in subjects with neuropathy and to test the validity of the instrument. METHODS: The Survey of Autonomic Symptoms (SAS) consists of 11 items in women and 12 in men. Each item is rated by an impact score ranging from 1 (least severe) to 5 (most severe). The SAS was tested in observational studies and compared to a previously validated autonomic scale, the Autonomic Symptom Profile (ASP), and to a series of autonomic tests. RESULTS: The SAS was tested in 30 healthy controls and 62 subjects with neuropathy and impaired glucose tolerance or newly diagnosed diabetes. An increased SAS score was associated with the previously validated ASP (rank order correlation=0.68; p<0.0001) and with quantitative measures of autonomic function: a reduced quantitative sudomotor axon reflex test sweat volume (0.31; p<0.05) and an abnormal 30:15 ratio (0.53; p<0.01). The SAS shows a high sensitivity and specificity (area under the receiver operating characteristic curve 0.828) that compares favorably with the ASP. The SAS scale domains had a good internal consistency and reliability (Cronbach α=0.76). The SAS symptom score was increased in neuropathy (95% confidence interval [CI] 2.99-4.14) compared to control (95% CI 0.58-1.69; p<0.0001) subjects. CONCLUSIONS: The SAS is a new, valid, easily administered instrument to measure autonomic symptoms in early diabetic neuropathy and would be of value in assessing neuropathic autonomic symptoms in clinical trials and epidemiologic studies.

Insulin-like growth factor-I regulates glucose-induced mitochondrial depolarization and apoptosis in human neuroblastoma.

Neuroblastoma, a pediatric peripheral nervous system tumor, frequently contains alterations in apoptotic pathways, producing chemoresistant disease. Insulin-like growth factor (IGF) system components are highly expressed in neuroblastoma, further protecting these cells from apoptosis. This study investigates IGF-I regulation of apoptosis at the mitochondrial level. Elevated extracellular glucose causes rapid mitochondrial enlargement coupled with an increase in the mitochondrial membrane potential (Delta Psi(M)) followed by mitochondrial membrane depolarization (MMD), uncoupling protein 3 (UCP3) downregulation, caspase-3 activation and decreased Bcl-2. MMD inhibition by Bongkrekic acid prevents high-glucose-induced loss of UCP3 and apoptosis. Glucose exposure induces caspase-9 cleavage within 30 min, and caspase-9 inhibition prevents glucose-mediated apoptosis. IGF-I prevents caspase activation and mitochondrial events leading to apoptosis. These results suggest that elevated glucose produces early initiator caspase activation, followed by Delta Psi(M) changes, in neuroblastoma cells; in turn, IGF-I prevents apoptosis by preventing downstream caspase activation, maintaining Delta Psi(M) and regulating Bcl proteins.

Isolated myocardial revascularization with intermittent aortic cross-clamping: experience with 800 cases.

BACKGROUND: We investigated the clinical outcome of elective and nonelective myocardial revascularization performed with intermittent aortic cross-clamping. METHODS: Prospective data on 800 consecutive patients (from May 1996 to July 2000), who underwent isolated myocardial revascularization with intermittent aortic cross-clamping, were analyzed. A subgroup analysis was performed on the elective (n = 520), urgent (n = 226), and emergency (n = 54) procedures. RESULTS: The elective group of patients had a mean age of 61.5 +/- 9.46 years, mean Parsonnet score of 5.23 +/- 5.1, and mean number of distal anastomoses of 3.22 +/- 1.04. The hospital mortality was 0.57%. The urgent group of patients had a mean age of 63.06 +/- 10.43 years, mean Parsonnet score of 6.73 +/- 6.22, and mean number of distal anastomoses of 3.21 +/- 1.04. The hospital mortality was 3.09%. The emergency group of patients had a mean age of 63.75 +/- 9.63 years, mean Parsonnet score of 11.24 +/- 11, and mean number of distal anastomoses of 2.87 +/- 0.86. Hospital mortality was 5.55%. Postoperative hospital stay was 7.11 +/- 5.47 days for the elective group, 7.59 +/- 5.07 days for the urgent group, and 7.40 +/- 4.01 days for the emergency group. CONCLUSIONS: Intermittent aortic cross-clamping is a safe technique both in elective and nonelective patients. The mortality and morbidity in the three subgroups analyzed reflects patients' distribution against Parsonnet score.

Suramin-induced neuropathy in an animal model.

Suramin is being used either alone, or in combination with other chemotherapeutic agents, in the treatment of hormone-refractory or metastatic prostate cancer. Use of this potentially valuable chemotherapy is limited by a dose-dependent polyneuropathy. It has been difficult in human studies to characterize peripheral suramin toxicity separately from cancer-related neuropathy. To characterize suramin-induced neuropathy in a rat model, adult rats were given either a single dose of 500 mg/kg (high dose) or 50 mg/kg (low dose) weekly suramin for 2 months. Electrophysiology and peroneal/sural nerve morphometry were performed. In high dose animals, neuropathy developed within 2 weeks, most severe in the digital sensory responses (DSR) (p<0.05) and tail and hind limb compound muscle action potential (p<0.001). Histologically, there was evidence of axonal degeneration and axon atrophy. With low dose suramin, the DSR (p<0.05) and tail distal sensory and motor responses (p<0.01) were most severely affected at 2 months. Axonal degeneration was seen in teased fibers from most animals. With TEM, there were abundant characteristic lysosomal inclusion bodies in DRG and Schwann cells. Electrophysiological and histological evidence of peripheral demyelination was rare, being observed in only one animal. Suramin induced a length, dose and time-dependent axonal sensorimotor polyneuropathy associated with axonal degeneration, atrophy, and accumulation of glycolipid lysosomal inclusions.

Diagnostic accuracy and certainty from sequential evaluations in peripheral neuropathy.

Three masked neuromuscular experts analyzed the contribution of the data from sequential evaluations in predicting specific varieties of peripheral neuropathy in 72 patients. The largest improvement (16%) in diagnostic accuracy resulted from presentation of neurologic history. By contrast, diagnostic confidence increased gradually with presentation of additional medical information. Therefore, the authors conclude that for diagnostic accuracy and certainty, expert neuromuscular judgment and extensive characterizing or discriminative testing are needed.

BMS-229724 is a tight-binding inhibitor of cytosolic phospholipase A2 that acts at the lipid/water interface and possesses anti-inflammatory activity in skin inflammation models.

Cytosolic phospholipase A2 (cPLA2) catalyzes the selective release of arachidonic acid from the sn-2 position of phospholipids and is believed to play a key cellular role in the generation of arachidonic acid. BMS-229724 (4-[4-[2-[2-[bis(4-chlorophenyl)methoxy]ethyl-sulfonyl]ethoxy]phenyl]-1,1,1-trifluoro-2-butanone) was found to be a selective inhibitor of cPLA2 (IC50 = 2.8 microM) in that it did not inhibit secreted phospholipase A2 in vitro, nor phospholipase C and phospholipase D in cells. The compound was active in inhibiting arachidonate and eicosanoid production in U937 cells, neutrophils, platelets, monocytes, and mast cells. With a synthetic covesicle substrate system, the dose-dependent inhibition could be defined by kinetic equations describing competitive inhibition at the lipid/water interface. The apparent equilibrium dissociation constant for the inhibitor bound to the enzyme at the interface (K(I)*(app)) was determined to be 1. 10(-5) mol% versus an apparent dissociation constant for the arachidonate-containing phospholipid of 0.35 mol%. The unit of concentration in the interface is mole fraction (or mol%), which is related to the surface concentration of substrate, rather than bulk concentration that has units of molarity. Thus, BMS-229724 represents a novel inhibitor of cPLA2, which partitions into the phospholipid bilayer and competes with phospholipid substrate for the active site. This potent inhibition of the enzyme translated into anti-inflammatory activity when applied topically (5%, w/v) to a phorbol ester-induced chronic inflammation model in mouse ears, inhibiting edema and neutrophil infiltration, as well as prostaglandin and leukotriene levels in the skin. In hairless guinea pigs, BMS-229724 was active orally (10 mg/kg) in a UVB-induced skin erythema model in hairless guinea pigs.

Insulin-like growth factor-I and over-expression of Bcl-xL prevent glucose-mediated apoptosis in Schwann cells.

Schwann cells (SCs), the myelinating cells of the peripheral nervous system, are lost or damaged in patients suffering from diabetic neuropathy. In the current study, 2 model systems are used to study the mechanism of SC damage in diabetic neuropathy: the streptozotocin (STZ)-treated diabetic rat and cultures of purified SCs in vitro. Electron microscopy of dorsal root ganglia from STZ-treated rats reveals classic ultrastructural features of apoptosis in SCs, including chromatin clumping and prominent vacuolation. Bisbenzamide staining of SCs cultured in hyperglycemic defined media shows nuclear blebbing of apoptotic cells. Insulin-like growth factor-I (IGF-I) is protective. LY294002, a phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, blocks the effect of IGF-I. High glucose induces caspase cleavage in apoptotic SCs--an effect that is blocked by bok-asp-fmk (BAF), a caspase inhibitor. Although Bcl-xL expression remains unchanged in experimental conditions, over-expression of Bcl-xL protects SCs from apoptosis. In summary, hyperglycemia induces caspase activation and morphologic changes in SCs consistent with apoptotic death, both in vivo and in vitro. Over-expression of Bcl-xL, or IGF-I, signaling via PI 3-kinase, protects SCs from glucose-mediated apoptosis in vitro. IGF-I may be useful in preventing hyperglycemia-induced damage to SCs in patients suffering from diabetic neuropathy.

Clinical and pathologic features of focal myositis.

To clarify the nosology of focal myositis (FM), we report the clinical and pathologic features of eight patients presenting with focal enlargement of one muscle. Most patients improved without immunosuppressive therapy, and none developed polymyositis. Pathologic features were those of an inflammatory myopathy, with muscle fiber hypertrophy and moderate to severe inflammation. In most cases, a clustering of tightly packed muscle fibers, enveloped by a thick bundle of fibrosis, was associated with the diagnosis of FM. Immunohistochemistry showed T cell predominance within the interstitial infiltrates in all cases. No evidence of vasculitis was present. Our findings suggest that FM is a benign condition that has certain clinical features separating it from other inflammatory myopathies. Pathologic changes, such as large clusters of nesting muscle fibers surrounded by thick fibrosis, are more characteristic of FM than polymyositis.

Insulin-like growth factor-I promotes myelination of peripheral sensory axons.

Insulin-like growth factor-I (IGF-I) in vivo or in the presence of other permissive factors can promote myelination in the central nervous system. In the current study, we examine the role of IGF-I in the myelination of peripheral nerves. In rat cocultures of dorsal root ganglia (DRG) and Schwann cells (SC) grown in serum- and insulin-free defined medium, IGF-I induces a dose dependent upregulation in myelin proteins such as P0, corresponding to maximal SC ensheathment. Furthermore, IGF-I is essential in promoting a dose-dependent, long-term myelination of DRG sensory axons. In the absence of IGF-I, axons and SC survive, but fail to myelinate. In the presence of 10 nM IGF-I, 59% of axons are myelinated at 21 days, whereas in the absence of IGF-I myelination fails to occur. Maximum SC ensheathment occurs 48 hours after addition of IGF-I. If IGF-I is withdrawn at 48 hours, axon segregation by SC persists, however, most axons and SC do not exhibit a one-to-one relationship and little myelination is observed. IGF-I is important in myelination and is critical not only for initial SC ensheathment of the axon and upregulation of myelin proteins, but also for sustained myelination. Furthermore, IGF-I associated axonal size is not the sole determinant for myelination.

GTPases and phosphatidylinositol 3-kinase are critical for insulin-like growth factor-I-mediated Schwann cell motility.

Previously, we reported insulin-like growth factor-I (IGF-I) promotes motility and focal adhesion kinase (FAK) activation in neuronal cells. In the current study, we examined the role of IGF-I in Schwann cell (SC) motility. IGF-I increases SC process extension and motility. In parallel, IGF-I activates IGF-I receptor, insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3 (PI-3)-kinase, and FAK. LY294002, a PI-3 kinase inhibitor, blocks IGF-I-induced motility and FAK phosphorylation. The Rho family of GTPases is important in the regulation of the cytoskeleton. Overexpression of constitutively active Leu-61 Cdc42 and Val-12 Rac1 enhances SC motility which is unaffected by LY294002. In parallel, stable transfection of SC with dominant negative Asn-17 Rac1 blocks IGF-I-mediated SC motility and FAK phosphorylation, implying Rac is an upstream regulator of FAK. Collectively our results suggest that IGF-I regulates SC motility by reorganization of the actin cytoskeleton via the downstream activation of a PI-3 kinase, small GTPase, and FAK pathway.

IGF-I promotes peripheral nervous system myelination.

Insulin-like growth factor-I (IGF-I) promotes the proliferation and differentiation of Schwann cells (SC). We use SC/dorsal root ganglion neuron (DRG) cocultures to examine the effects of IGF-I on the interaction between axons and SC. As SC extend processes toward the axon in the presence of IGF-I, these processes attach to and ensheath axons. Continued IGF-I exposure leads to enhanced P0 expression and long-term myelination. No myelination occurs in the absence of IGF-I. These data imply that IGF-I is critical not only for SC attachment and ensheathment of axons but also for long-term myelination.