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.

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.

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.

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.

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.

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.

The effects of phencyclidine on spontaneous aggressive behavior in the rat.

Phencyclidine induced dose-related alterations in the pattern of spontaneous aggressive behavior in pairs of rats, in which only one animal of each pair was drug-treated. At the lowest dose tested (0.25 mg/kg, sc), phencyclidine produced attacks by the drug-treated animal and a corresponding increase in submissive behavior by the untreated partner, as well as an increase in boxing behavior by both animals. In contrast, the highest dose of phencyclidine tested (1.0 mg/kg, sc) elicited attacks and allogrooming by the untreated animal. The low dose effect is interpreted as the result of phencyclidine-induced distortion in perception of social cues, while the high dose effect may be due to a general disruption in social communication by ataxia in the phencyclidine-treated animal.

Clinical importance of age at first drink in a group of young men.

A survey of 1,012 university men aged 21 to 25 years revealed that age at first drink varied inversely with alcohol consumption and frequency of drinking, incidence of alcohol-related problems, and incidence of drug use and associated problems.

The effect of nerve growth factor, ciliary neurotrophic factor, and ACTH analogs on cisplatin neurotoxicity in vitro.

Cisplatin, used to treat ovarian, bladder, and testicular cancers, causes a sensory dose-limiting neuropathy. Preliminary observations in humans and animals suggest that nerve damage may be prevented by ACTH analogs, particularly those belonging to the melanocortin class, and by nerve growth factor (NGF). We established a rat embryo dorsal root ganglion model to study cisplatin neurotoxicity. The drug reproducibly inhibited axonal growth at concentrations similar to that known to produce toxicity in neurons. The inhibition was prevented in a dose-dependent fashion by simultaneous exposure to alpha-melanocyte stimulating hormone (alpha-MSH) or ACTH but not by excess NGF or ciliary neurotrophic factor (CNTF). The ACTH peptides were not effective in preventing suramin-induced neurotoxicity in the same model. Drug interaction and dose-response studies showed that ACTH and alpha-MSH do not act by potentiation of NGF action. ACTH analogs appear to protect against cisplatin-induced neurotoxicity directly at the cellular level.

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.

Inhibitors of blood platelet cAMP phosphodiesterase. 4. Structural variation of the side-chain terminus of water-soluble 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives.

1-(Cyclohexylmethyl)-4-[4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b] quinolin-7-yl)oxy]-1-oxobutyl]piperazine (2) was previously identified as a potent, water-soluble inhibitor of human blood platelet cAMP phosphodiesterase and of induced aggregation in vitro that demonstrated effective antithrombotic activity in animal models of thrombosis. Although 2 exhibited 25% oral bioavailability in rats, pharmacokinetic studies conducted in monkeys revealed that the parent compound was less than 5% bioavailable, the result of extensive first-pass biotransformation in the liver. In an effort to identify potent platelet aggregation inhibitors with enhanced metabolic stability, the side-chain amide moiety of 2 was replaced with chemically more stable urea (6a-s), sulfonamide (13a-m), sulfone (19a-r), and tetrazole (23a-s) moieties. Many representatives from each of these structural types effectively combined potent inhibition of ADP-induced human platelet aggregation in vitro with excellent aqueous solubility, and several are superior to 2. Within each series, the N-(cyclohexylmethyl)-, N-(2-ethylbutyl)-, N-benzyl-, and N-(4-fluorobenzyl)-substituted derivatives were evaluated for in vitro metabolic stability by incubating with the S-9 fraction of monkey liver for 2 h, and the extent of biotransformation was compared with that of the prototype 2. The sulfone 19e and the tetrazoles 23e, 23g, 23j, and 23q were significantly more stable than 2 under these conditions, and 19e and 23e were selected for evaluation in vivo. Tetrazole 23e exhibited 72% bioavailability following ip administration to rats compared with 35% bioavailability for 2 and 19e under the same conditions. However, the oral bioavailability of 19e and 23e in the rat was estimated to be only 3%, suggesting that 19e and 23e are less readily absorbed from the gastrointestinal tract than 2.

Comparative pharmacokinetics of new anti-HIV agents: 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine.

A number of 2',3'-dideoxynucleosides have been shown to inhibit the in vitro infectivity and cytopathic effect of the human immunodeficiency virus (HIV). These compounds, as their 5'-triphosphates, inhibit viral reverse transcriptase by competing with the natural substrate at the same binding site on the enzyme. Dideoxynucleoside triphosphates can also be incorporated into growing DNA chains which then blocks further DNA elongation because they lack the 3'-hydroxyl group required for further polymerization. Among these nucleosides, 2', 3'-dideoxyadenosine 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) show promising in vitro activity. Because adenosine is rapidly converted to inosine by adenosine deaminase, the in vivo conversion of ddA to ddI was studied to determine suitability of measuring plasma levels of ddI and to assess the bioavailability and pharmacokinetics of ddA. This report describes and compares the pharmacokinetics of ddA and ddI in the mouse.

Treatment of stable chronic demyelinating polyneuropathy with 3,4-diaminopyridine.

OBJECTIVE: To determine whether 3,4-diaminopyridine (3,4-DAP) would improve clinical or electrophysiologic function in patients with stable chronic demyelinating polyneuropathy. DESIGN: We conducted a prospective, randomized, placebo-controlled, blinded, crossover study of 3,4-DAP in 34 patients with demyelinating polyneuropathy. MATERIAL AND METHODS: Of the 17 men and 17 women, who were 21 to 80 years of age, 27 had hereditary motor and sensory neuropathy type I and 7 had acquired demyelinating polyneuropathy. Treatment consisted of stepped doses of 3,4-DAP (increasing to 20 mg four times daily) or placebo for 4 days. Pretreatment and posttreatment determination of the Neurologic Disability Score (NDS); isometric muscle strength testing; median, ulnar, and peroneal nerve conduction studies; and measurement of serum 3,4-DAP were performed. Quantitative computer-assisted sensory examinations were done in five patients. RESULTS: The results for the final day of treatment with 3,4-DAP or placebo and the differences between pretreatment and posttreatment findings for total NDS, sensory NDS, isometric muscle strength testing, compound muscle action potential amplitude, sensory nerve action potential amplitude, motor and sensory conduction velocities, and vibration and cold detection thresholds did not vary significantly. A small improvement of 4 points in the motor NDS (P < 0.05) was found. Five patients with electrophysiologic conduction block had no significant reduction in the degree of block. CONCLUSION: Because no improvement was noted in most measurements of neurologic function, despite use of high doses of drug, 3,4-DAP is unlikely to be beneficial in the treatment of stable chronic demyelinating polyneuropathy.

An evaluation of primary alcoholics with histories of violence.

Histories of violence were assessed in 275 consecutive male primary alcoholics who were interviewed and followed up 1 year later. After excluding individuals with primary antisocial personalities or primary drug abuse, 80 of these men were found to have histories of violence. Compared to the remaining subjects, this group was significantly younger and demonstrated significantly more social problems with school, home, and police both as adolescents and adults; these subjects were significantly more likely to have used drugs other than alcohol. The 12-month follow-up revealed a continued higher percentage of drinking among those with histories of violence as well as a greater risk for alcohol-related problems and some patterns of drug misuse. A history of prior violence may be a factor of prognostic importance in the treatment of primary alcoholism.

Pharmacokinetics and antiviral activity of a novel isonucleoside, BMS-181165, against simian varicella virus infection in African green monkeys.

A novel nucleoside analog BMS-181165 with potent activity against varicella-zoster virus was tested for efficacy in a simian varicella virus infection in African green monkeys. BMS-181165 was effective in preventing the development of a rash, decreasing the development of viremia and preventing death in infected monkeys when administered orally at 4, 16 or 64 mg/kg/day. The compound is well orally absorbed in monkeys, between 44 to 50% oral bioavailability, and may prove of value in therapy of varicella-zoster infections in humans.

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.

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.

Effect of cisplatin and ACTH4-9 on neural transport in cisplatin induced neurotoxicity.

Cisplatin causes a dose limiting peripheral neuropathy, however, the biological mechanism by which this occurs is unknown. Murine N1E.115 neuroblastoma cells and neural crest derived pigment cells have similar transport mechanisms to human neural cells and were used to study the effect of cisplatin on cellular transport. Cisplatin reduced both the number and velocity of organelles moving in the anterograde and retrograde direction, compared to control cells. Cisplatin induced inhibition of transport was prevented by the simultaneous administration of ACTH4-9. This analog alone had no effect on N1E.115 organelle, or erythrophore granule, movement. In both N1E.115 and pigment cells cisplatin inhibited transport within 1 h of exposure to the drug. The degree of inhibition did not increase insignificantly if pigment cells were incubated in cisplatin for 48 h compared to acute exposure. Microtubules in both pigment cells and N1E.115 neurites retained their structural integrity suggesting that factors other than changes in gross microtubule morphology are responsible for cisplatin neurotoxicity. Cisplatin reduces N1E.115 neurite growth after 48 h incubation but this can be prevented by simultaneous use of ACTH4-9. This study demonstrates for the first time that cisplatin and ACTH4-9 affect fast axonal transport by specific mechanisms which appear related to their observed neurotoxic and neuroprotective roles, respectively.

MR imaging of spinal cord and vertebral body infarction.

PURPOSE: To study the usefulness of MR in the evaluation of spinal cord infarctions and associated findings. MATERIALS AND METHODS: MR examinations of 12 patients (10 men and two women) were reviewed retrospectively. Onset of symptoms of spinal cord ischemia was abrupt in all patients; MR was performed 8 hr to 4 months after onset. Contrast-enhanced MR was performed in four of the patients. RESULTS: Abnormal MR findings of the spinal cord included abnormal cord signal (11 of 12), best demonstrated on T2-weighted images, and morphologic changes (cord enlargement during the acute phase in nine patients and cord atrophy during the chronic phase in two), best demonstrated on T1-weighted images. Vascular abnormalities (aortic) were detected by MR in four of the 12 patients. Three of these four patients also had abnormal bone marrow signal, predominantly in the anterior half (one) or in multiple areas near the endplate and/or deep medullary portion of the vertebral body involving several vertebrae (two). T1-weighted images were not sensitive in detecting signal changes in either the bone marrow (two of three) or spinal cord (nine of 12). Enhanced MR imaging was performed in four patients (two in the acute phase and two in the chronic phase) and showed diffuse enhancement of the spinal cord proximal to a relatively unenhancing distal conus in one of the two patients imaged during the acute phase. No abnormal enhancement was noted in the other three patients. CONCLUSION: MR is a useful means of detecting spinal cord infarction and associated vascular and bony changes. The patterns of bone marrow abnormalities reflect the underlying pathophysiology of the blood supply to the spinal cord and bone. The associated vascular and bone marrow abnormalities serve as additional information for the diagnosis of spinal cord infarction.