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.

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.

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.

Non-24-hour sleep-wake syndrome following a car accident.

The authors report the case of a 39-year-old sighted woman who displayed non-24-hour sleep-wake cycles following a car accident. The phase relationship between endogenous circadian markers such as plasma melatonin and 6-sulfatoxymelatonin rhythms and self-selected sleep times was abnormal. A laboratory investigation indicated that she was sensitive to bright light as a circadian synchronizer. MRI and brain CT scans were normal, but microscopic brain damage in the vicinity of the suprachiasmatic nucleus or its output pathways is plausible.

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.

Impact of plasma exchange on indices of demyelination in chronic inflammatory demyelinating polyradiculoneuropathy.

We studied the impact of plasma exchange (PE) on indices of primary demyelination in patients of the Canadian multicenter trial of PE in chronic inflammatory demyelinating polyneuropathy (CIDP). Individual motor nerves (median, ulnar, peroneal, tibial) were studied: distal motor latencies (DMLs), proximal and distal compound muscle action potential (M-wave) amplitudes, negative peak areas and durations, and motor conduction velocities (CVs). Proximal M-wave amplitudes in individual motor territories, particularly in the ulnar nerve (from below elbow, above elbow, and axillary stimulating sites) demonstrated significant improvement with PE, but not sham exchange. Proximal ulnar M-wave areas also had significant improvement with PE. Trends toward improvement of individual nerve motor CVs, M-wave durations, and DMLs did not achieve statistical significance. Proximal M-wave amplitudes, particularly in the ulnar motor territory, and proximal M-wave areas (providing a measure of conduction block) were the most sensitive indices of improvement conferred by PE in CIDP. In individual patients, these indices may help judge the efficacy of therapy.

Isolated trigeminal neuropathy due to trigeminal nerve root hemorrhage.

BACKGROUND: Isolated trigeminal neuropathy is uncommon; causes include trauma, inflammation, or neoplasm. METHODS: We report a patient who fell and struck his head during a myocardial infarction, was treated with streptokinase, and developed symptoms and signs of an isolated trigeminal sensory neuropathy. RESULTS: Imaging showed hemorrhage in the trigeminal nerve root; follow-up imaging showed resolution of the hemorrhage, but no underlying structural lesion. CONCLUSION: A combination of head trauma plus thrombolysis resulted in an isolated trigeminal neuropathy.

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.

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.

Classification of teased nerve fibers for multicenter clinical trials.

Teased nerve fibers are used widely in both clinical and experimental neuropathology, but anecdotal evidence indicates that even experienced readers find little agreement on categories for teased fiber classification. To develop a classification scheme that could be used and understood by both experienced and naive readers, specific criteria were developed for normal fibers and those exhibiting Wallerian degeneration, demyelination, hypomyelination, remyelination, and abnormal paranodal myelination. Twenty fibers teased from human sural nerve biopsies were selected as examples of one or more of these categories. Ten readers, including seven having no previous experience with teased fibers, were given a set of instructions and asked to score each fiber for all matching categories. These readers averaged high rates of true positive (56-85%) classifications, while average false positive (3-18%) rates were much lower. Among the three experienced readers, true positive agreements averaged between 75 and 100% across the fiber classifications. False positives were correspondingly low, ranging between 0 and 8%. These results suggest that it is possible to design an easily learned, meaningful scheme for classifying teased nerve fibers.

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.

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.

Acquired peripheral neuropathy.

This article reviews the acquired causes of polyneuropathy other than diabetic and acute-onset neuropathies. The author gives a general method to simplify the diagnosis of chronic polyneuropathy. The acquired polyneuropathies are discussed under four main headings: metabolic disorders, toxic or deficiency states, infections, and immune-mediated. Recent advances in therapy are emphasized, and some illustrative case histories are provided.

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.

Plasma-exchange therapy in chronic inflammatory demyelinating polyneuropathy. A double-blind, sham-controlled, cross-over study.

Eighteen patients with definite, untreated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) of chronic progressive (nine patients) or relapsing course (nine patients) were randomized prospectively to receive 10 plasma-exchange (PE) or sham plasma-exchange (SPE) treatments over 4 weeks in a double-blind trial. After a wash-out period of 5 weeks or when they returned to baseline scores, patients were crossed over to the alternate treatments. Neurological function was assessed serially using a quantitative neurological disability score (NDS), a functional clinical grade (CG) and grip strength (GS) measurements. Electrophysiological studies were done at the beginning and end of each treatment. A primary 'intention to treat' analysis showed significant improvement with PE in all clinical outcome measures: NDS by 38 points, P < 0.001; CG by 1.6 points, P < 0.001; GS by +13 kg, P < 0.003 and in selected electrophysiological measurements, sigma proximal CMAP, P < 0.01; sigma motor conduction velocities, P < 0.006; sigma distal motor latencies, P < 0.01. Fifteen patients completed the trial and of those, 12 patients (80%) improved substantially with PE; i.e. five out of seven patients with chronic progressive course and seven out of eight patients with relapsing CIDP improved. There were three drop-outs; one patient lost venous access; one patient suffered a stroke and one patient left the trial to receive open treatment elsewhere. The improvement in motor functions correlated with the electrophysiological data, i.e. with improved motor conduction velocities and reversal of conduction block. Eight of 12 PE responders (66%) relapsed within 7-14 days after stopping PE. All improved with subsequent open label PE; all but two patients required long-term immunosuppressive drug therapy for stabilization. The PE non-responders improved with prednisone. We conclude that PE is a very effective adjuvant therapy for CIDP of both chronic progressive and relapsing course; concurrent immunosuppressive drug treatment is required. Exchange treatments should be given two to three times per week until improvement is established; the treatment frequency should then be tapered over several months.

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.