Paediatric Crohn disease patients with stricturing behaviour exhibit ileal granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody production and reduced neutrophil bacterial killing and GM-CSF bioactivity.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies are associated with stricturing behaviour in Crohn disease (CD). We hypothesized that CD ileal lamina propria mononuclear cells (LPMC) would produce GM-CSF autoantibodies and peripheral blood (PB) samples would contain GM-CSF neutralizing capacity (NC). Paediatric CD and control PBMC and ileal biopsies or LPMC were isolated and cultured and GM-CSF, immunoglobulin (Ig)G and GM-CSF autoantibodies production were measured by enzyme-linked immunosorbent assay (ELISA). Basal and GM-CSF-primed neutrophil bacterial killing and signal transducer and activator of transcription 5 (STAT5) tyrosine phosphorylation (pSTAT5) were measured by flow cytometry. GM-CSF autoantibodies were enriched within total IgG for LPMC isolated from CD ileal strictures and proximal margins compared to control ileum. Neutrophil bacterial killing was reduced in CD patients compared to controls. Within CD, neutrophil GM-CSF-dependent STAT5 activation and bacterial killing were reduced as GM-CSF autoantibodies increased. GM-CSF stimulation of pSTAT5 did not vary between controls and CD patients in washed PB granulocytes in which serum was removed. However, GM-CSF stimulation of pSTAT5 was reduced in whole PB samples from CD patients. These data were used to calculate the GM-CSF NC. CD patients with GM-CSF NC greater than 25% exhibited a fourfold higher rate of stricturing behaviour and surgery. The likelihood ratio (95% confidence interval) for stricturing behaviour for patients with elevation in both GM-CSF autoantibodies and GM-CSF NC was equal to 5 (2, 11). GM-CSF autoantibodies are produced by LPMC isolated from CD ileal resection specimens and are associated with reduced neutrophil bacterial killing. CD peripheral blood contains GM-CSF NC, which is associated with increased rates of stricturing behaviour.

Effect of rumen-protected methionine supplementation to beef cows during the periconception period on performance of cows, calves, and subsequent offspring.

Maternal nutrition affects the development of the fetus and postnatal performance of the calf. Methionine may play a critical role in developmental programming and is likely deficient in beef cows fed low-quality forage. The objective of this study was to determine the effect of metabolizable methionine supply to lactating beef cows during the periconception period on performance of cows, calves, and subsequent offspring. This project involved two consecutive production cycles commencing at calving in which dietary treatments were fed to cows during the periconception period along with measurements on cows and initial calves in Production Cycle 1, and measurements on subsequent calves in Production Cycle 2. Brangus-Angus crossbred lactating beef cows (N = 108; age = 6.4 (2.8) year) were stratified by previous calving date and assigned to one of three supplements: (1) control, molasses plus urea at 2.72 kg/day as fed, (2) fishmeal, 2.27 kg/day molasses plus urea plus 0.33 kg/day as fed of fishmeal, and (3) methionine, 2.72 kg/day of molasses plus urea plus 9.5 g/day of 2-hydroxy-4-(methylthio)-butanoic acid. Cows were fed supplements and low-quality limpograss (Hemarthria altissima) hay while grazing dormant bahiagrass (Paspalum notatum Flüggé) pastures during the 115-day periconception period from December 2014 to April 2015 in Production Cycle 1 only. Body weight change and milk yield of cows were measured during the periconception period in Production Cycle 1. Body weight of calves was measured at birth and weaning in both production cycles. Following weaning in Production Cycle 2, eight subsequent steer calves per treatment were individually housed for a 42-day metabolism experiment. Treatment did not affect (P > 0.10) BW change of cows, but cows fed methionine tended (P = 0.09) to produce more energy-corrected milk than control and fishmeal. Treatment did not affect (P > 0.10) 205-day adjusted weaning weight of calves in either production cycle. During the metabolism experiment, subsequent calves from dams fed fishmeal and methionine gained faster (P < 0.05) and had greater (P < 0.05) gain:feed than control calves. Methionine calves tended (P = 0.06) to have greater apparent total tract NDF and ADF digestibility and lesser (P < 0.05) blood glucose concentration than control and fishmeal calves. These data indicate that maternal methionine supply during the periconception period plays an important role in programming future performance of the offspring.

A pilot study designed to acquaint medical educators with basic pedagogic principles.

BACKGROUND: Faculty development activities in medical schools regularly target teaching behaviours but rarely address basic pedagogic principles underlying those behaviours. Although many teachers have an intuitive or tacit knowledge of basic pedagogic principles, overt knowledge of fundamental educational principles is rare. AIMS: We conducted a short-term pilot study designed to transform teachers' tacit knowledge into explicit knowledge of pedagogic principles. We hypothesized that conscious awareness of these principles will positively influence their teaching effectiveness. METHODS: The intervention included a workshop, provision of a workbook on pedagogic principles and free access to educational consultants. For the intervention, we chose a purposive sample of experienced teachers at our medical school. RESULTS AND CONCLUSIONS: Evaluation of the impact of the intervention using questionnaires and semi-structured interviews revealed three notable findings; 1. Participants were surprised to discover the existence of an extensive body of pedagogic science underlying teaching and learning. 2. They were enthusiastic about the intervention and expressed interest in learning more about basic pedagogic principles. 3. The knowledge acquired had an immediate impact on their teaching.

Aldose reductase inhibitors for the treatment of diabetic polyneuropathy.

BACKGROUND: Polyneuropathy, a common complication of diabetes mellitus, causes pain and sensory and motor deficits in the limbs, and is also an important independent predictor of foot ulceration. Inhibiting the metabolism of glucose by the polyol pathway using aldose reductase inhibitors is a potential mechanism to slow or reverse the neuropathy's progression. OBJECTIVES: To assess the effects of aldose reductase inhibitors on the progression of symptoms, signs or functional disability in diabetic polyneuropathy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (from January 1966 to May 2007), EMBASE (from January 1980 to May 2007) and LILACS (from 1982 to May 2007). We reviewed bibliographies of randomized trials identified, and contacted authors and experts in the field. SELECTION CRITERIA: We included randomized controlled trials comparing an aldose reductase inhibitor with control, and lasting at least six months. The primary outcome measure was change in neurological function, measured in various ways, including strength testing, sensory examination, and composite scores of neurological examination. Secondary outcome measures were nerve conduction studies, neuropathic symptoms, quality of life, occurrence of foot ulcers and adverse effects. DATA COLLECTION AND ANALYSIS: Trials included in the review were selected and assessed independently by at least two of us. Methodological criteria and study results were recorded on data extraction forms. MAIN RESULTS: Thirty-two randomized controlled trials meeting the inclusion criteria were identified. Many had significant methodological flaws. Change in neurological function, our primary outcome measure, was assessed in 29 trials, but sufficient data for meta-analysis were only available in 13 studies, involving 879 treated participants and 909 controls. There was no overall significant difference between the treated and control groups (SMD -0.25, 95% CI -0.56 to 0.05), although one subgroup analysis (four trials using tolrestat) favored treatment. A benefit for neuropathic symptoms was suggested by a group of trials using a dichotomized endpoint (improvement or not), but this was contradicted by another group of trials which measured symptoms on a continuous scale. There was no overall benefit on nerve conduction parameters (27 studies) or foot ulceration (one study). Quality of life was not assessed in any of the studies. While most adverse events were infrequent and minor, three compounds had dose limiting adverse events that lead to their withdrawal from human use: severe hypersensitivity reactions with sorbinil, elevation of creatinine with zenarestat, and alteration of liver function with tolrestat. AUTHORS' CONCLUSIONS: We found no statistically significant difference between aldose reductase inhibitors and placebo in the treatment of diabetic polyneuropathy. Any future clinical trials of aldose reductase inhibitors should be restricted to compounds proven to have substantial biological or preclinical advantages over previously tested agents.

A novel multiply-mutated HSV-1 strain for the treatment of human brain tumors.

A promising approach for the therapeutic treatment of brain tumors utilizes replication-competent, neuroattenuated herpes simplex virus-1 (HSV-1) mutants. This approach requires mutation of HSV-1 to eliminate killing of normal, nondividing cells of the brain (e.g., neurons). We have generated a HSV-1 double-mutant, designated 3616UB, by interrupting the uracil DNA glycosylase (UNG) gene in a previously studied ICP34.5 mutant, R3616. The HSV-1-encoded UNG gene is required for efficient HSV-1 replication in nondividing cells, but is dispensable for replication in rapidly dividing cells. The specific function of the HSV-1 ICP34.5 gene is not completely clear, but it is thought to be necessary for viral replication in cells of the nervous system, because, when mutated, the resultant viral strains are fully neuroattenuated. Strain 3616UB did not replicate in primary neuronal cultures in vitro or in mouse brain, but efficiently killed six of six human tumor cell lines within 6 days in vitro and successfully infected and replicated within brain tumor xenografts. The potential safety of 3616UB for human use is enhanced by an unexpected hypersensitivity to the antiherpetic drug ganciclovir. These data suggest that 3616UB may be effective for the treatment of human brain tumors. Intratumoral injection of 3616UB into human medulloblastoma or angiosarcoma xenografts established in severe combined immunodeficient (SCID) mice produced significant growth arrest and some tumor regressions. Strain 3616UB was as effective as R3616 in this therapy study and did not cause any obvious distress in the treated animals. Together, the data show that 3616UB is a very safe alternative to other HSV-1 mutants because the presence of two mutations reduces the possibility of recombinational events in situ that could lead to the generation of virulent viral progeny during 3616UB therapy.

A syngeneic mouse glioma model for study of glioblastoma therapy.

Animal models of human tumors serve a vital role in the development and testing of new anticancer therapies. Since the immune system is likely to play an essential role in tumor eradication, there is a particular need for modeling human disease in immunocompetent hosts. Few models of glioma have been developed in immunocompetent mice that are commercially available and none of these tumors have histological and antigenic characteristics of human gliomas. We have used a cell line, 4C8, derived from a spontaneous glioma-like tumor that arose in a transgenic mouse to develop a new glioma model. The intracranial injection of 4C8 cells into immunocompetent syngeneic B6D2F1 mice resulted in tumors that were densely cellular, developed a pseudopallisading pattern of necrosis, and expressed GFAP; all important features of human malignant gliomas. The average neurological endpoint was 51 days after intracranial injection. The 4C8 cells also grew rapidly in the flank, retaining histologic features seen in intracranial tumors. Flank tumors reached an average volume of 100 mm3, a volume ideal for therapy testing, by 34 days postinjection. These results suggest that the 4C8 mouse glioma model is an excellent system in which to test new antiglioma therapies for use in humans.

Anti-neutrophil cytoplasmic antibodies in vasculitis peripheral neuropathy.

Anti-neutrophil cytoplasmic antibodies (ANCA) have been reported to be specific serologic markers of systemic necrotizing vasculitis. We looked for ANCA in 166 consecutive patients referred for evaluation of peripheral neuropathy, wondering if ANCA might be helpful in diagnosing vasculitic neuropathy. ANCA were found in four of six patients with vasculitic neuropathy. However, false-positive results limited the diagnostic usefulness of ANCA in peripheral neuropathy.

Familial multiple symmetric lipomatosis with peripheral neuropathy.

We describe coexisting peripheral neuropathy and multiple symmetric lipomatosis in 4 of 7 siblings. The absence of either condition in 3 other generations of this family suggests autosomal recessive inheritance. None of the affected siblings were alcoholic, a factor some have proposed to explain the frequent occurrence of peripheral neuropathy in sporadic multiple symmetric lipomatosis. Serum lipid studies, including apoprotein A levels, were normal. Sural nerve biopsy from 1 patient showed nerve fiber loss, predominantly affecting large myelinated fibers. The relationship between myelin sheath thickness and axon diameter was normal, arguing that this neuropathy is not due to primary axonal atrophy.

Seronegativity for type 1 antineuronal nuclear antibodies ('anti-Hu') in subacute sensory neuronopathy patients without cancer.

We followed 21 patients with sensory neuronopathy without evidence of cancer for up to 23 years. All were seronegative for type 1 antineuronal nuclear antibodies (ANNA-1, also called "anti-Hu"). We additionally studied 67 seropositive patients with sensory neuropathy or a related neurologic syndrome. Ninety-one percent of the seropositive patients had a small-cell lung carcinoma. One, with a normal chest x-ray, had been followed for 7 years for sensory neuronopathy of indeterminate cause before serologic testing for ANNA-1 led to the discovery of the tumor by CT. We conclude that ANNA-1 seropositivity in a patient with sensory neuronopathy is strong evidence for an underlying small-cell lung cancer.

Role of the blink reflex in the evaluation of sensory neuronopathy.

Because of an incidental observation that the blink reflex was normal in paraneoplastic sensory neuronopathy (SN) and frequently abnormal in nonparaneoplastic SN, the authors reviewed the electromyographic records of patients with SN in whom blink reflex studies were performed. The blink reflex was normal in all 17 patients with paraneoplastic SN and abnormal in 20 of 43 patients with nonparaneoplastic SN. Although it does not exclude paraneoplastic SN, an abnormal blink reflex favors a nonparaneoplastic etiology.

Trigeminal nerve hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy.

An unusual clinical manifestation of nerve hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is described. A patient with a 13-year history of CIDP developed diplopia and proptosis. Imaging of the neuraxis showed marked bilateral trigeminal nerve hypertrophy and lumbosacral nerve root hypertrophy. Biopsy of the right infraorbital nerve revealed inflammatory infiltrates and extensive onion bulb formation, consistent with CIDP.

Response of the Lambert-Eaton myasthenic syndrome to treatment of associated small-cell lung carcinoma.

We evaluated the outcome in 16 patients with Lambert-Eaton myasthenic syndrome (LEMS) associated with histologically verified small-cell carcinoma (SCC). Thirteen patients received specific tumor therapy (chemotherapy, radiation therapy, or resection) and most also received pharmacologic and immunologic treatment for LEMS. Seven of 11 patients surviving for more than 2 months after tumor therapy showed substantial neurologic improvement (1 patient being in complete remission at 7 years); in 3 of 11 improvement was transient. An EMG index of disease severity (compound muscle action potential amplitude in abductor digiti minimi) was significantly increased at final follow-up (p less than 0.01; n = 11). A pretreatment amplitude greater than 3.0 mV was a good prognostic sign. We conclude that a combined treatment approach in SCC-LEMS usually results in neurologic improvement.

Varicella-zoster virus DNA in CSF and arteries in delayed contralateral hemiplegia: evidence for viral invasion of cerebral arteries.

A 78-year-old woman presented with a right basal ganglia infarct 6 weeks after a left herpes zoster ophthalmicus. MR angiography showed focal segmental stenosis of the proximal segments of the anterior, middle, and posterior cerebral arteries. Varicella DNA was detected in the CSF by polymerase chain reaction (PCR). Treated with dexamethasone and acyclovir without improvement, she died 1 month later. There was focal endarteritis in the left anterior, middle, and posterior cerebral arteries at autopsy. Varicella DNA was detected by PCR of extracts from these vessels but not from the arteries on the right side. This study provides further evidence that the vasculopathy after herpes zoster ophthalmicus results from direct viral invasion of the vessel wall.

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.

Cryptococcal meningitis manifesting as epilepsia partialis continua of the abdomen.

We report a case of epilepsia partialis continua that primarily involved the abdominal muscles. Thorough assessment ultimately showed that the condition was due to cryptococcal meningitis. Surface electrode electromyography and electroencephalography were helpful in analyzing this unusual epileptic phenomenon. An 8-week treatment regimen of amphotericin B and a 30-day course of 5-fluorocytosine abolished the epilepsia partialis continua and cured the meningitis. This case should alert physicians to the fact that patients with epilepsia partialis continua may have clonic movements of only the trunk and that the spectrum of neurologic manifestations of cryptococcal infection must now include this seizure disorder.

A simple, reproducible technique for establishing leptomeningeal tumors in nude rats.

The incidence of leptomeningeal carcinomatosis is on the rise and current treatment modalities have limited efficacy. The development of new treatment strategies has been hampered by the lack of an appropriate animal model that accurately parallels the clinical condition. We have developed a new surgical technique for the establishment of leptomeningeal tumors in rats. Our technique is simple, reproducible and associated with low morbidity and mortality. Tumor implantation resulted in a defined neurological endpoint and a reproducible time course of disease progression using both human medulloblastoma and breast carcinoma cell lines. This animal model provides an appropriate system for testing conventional and new biologic therapies in both early and late stages of leptomeningeal disease.

Subcortical white matter lesions in osmotic demyelination syndrome.

We describe a case of histologically proved osmotic demyelination syndrome. In addition to abnormal T2 signal within the pons and thalami, MR showed linear enhancing lesions at the cortical medullary junction.

High protein diets are associated with increased bacterial translocation in septic guinea pigs.

During sepsis, body protein stores are decreased due to an increase in protein catabolism. The utilization of nutritional support with high-protein diets has been used as a solution to the problem of sepsis-induced protein loss. Work from our laboratory, however, has shown that diets low in protein (5% of total calories) improve survival in septic animals as compared to high protein (20%) diets. The present study investigated the relationship between low-protein diets and improved survival by determining whether septic animals receiving high-protein diets have increased bacterial translocation. Sepsis was induced in guinea pigs by the implantation of an osmotic minipump into the peritoneal cavity containing an equal mixture of Escherichia coli (10(8)) and Staphylococcus aureus (10(8)) or saline. On Day 3 postlaparotomy, the animals were randomized to one of four groups. The groups consisted of septic and nonseptic animals that received a diet with 5 or 20% of total calories as protein. Following 4 days of diet all animals received an instillation of 14C labeled E. coli (10(10)). Four hours later the animals were sacrificed and blood, mesenteric lymph nodes, spleen, lungs, and liver were removed for determination of radionuclide counts. Results indicated that the septic animals that received the high protein diet had more bacterial translocation, as indexed by higher radionuclide counts in the MLN, liver, lung and blood. These findings suggest that a low protein, enterally fed diet may improve survival in septic patients by decreasing the incidence of bacterial translocation.

Post injury hypermetabolic response and magnitude of translocation: prevention by early enteral nutrition.

The relationship between hypermetabolism and bacterial translocation was investigated in guinea pigs receiving a 40% burn. Animals were infused intragastrically with a complete enteral diet or Ringer's solution for 48 h, given 10(10) 14C-labeled Escherichia coli intragastrically, and killed 4 h later. Resting metabolic expenditure (RME), translocation (dpm of the 14C-labeled E. coli) to the portal blood and ileal mucosa, plasma cortisol, and urinary vanillylmandelic acid (VMA) were determined. Enterally fed animals had significantly lower RME, cortisol, VMA, and dpm, but higher mucosal and body weight than the Ringer's group. Disintegrations per minute (dpm) in the blood were positively correlated with RME (r = 0.856), cortisol (r = 0.872), VMA (r = 0.759), and dpm mucosa (r = 0.836) and inversely correlated with mucosal weight (r = -0.883). We conclude that bacterial translocation is reduced by early feeding and is an important cause of hypermetabolism and stress hormone production after burn injury.