Cervical spondylotic myelopathy: Changes of fractional anisotropy in the spinal cord and magnetic resonance spectroscopy of the primary motor cortex in relation to clinical symptoms and their duration.

OBJECTIVE: To determine the changes in fractional anisotropy (FA) at the proximal spinal cord and in magnetic resonance spectroscopy (MRS) of the precentral gyrus in patients with cervical spondylotic myelopathy (CSM) with respect to clinical symptoms and their duration. MATERIAL AND METHODS: 20 patients with CSM (7 female; mean age 64.6 ± 10.5 years) and 18 age/sex matched healthy controls (9 female; mean age 63.5 ± 6.6 years) were prospectively included. Clinical data (modified Japanese Orthopaedic Association Score (mJOA) and Neck Disability Index (NDI)) and 3T MR measurements including DTI at the spinal cord (level C2/3) with FA and MRS of the left and right precentral gyrus were taken. Clinical correlations and regression analyses were performed. RESULTS: Mean clinical scores of patients were significantly different to controls (mJOA; CSM: 10.2 ± 2.9; controls: 18.0 ± 0.0, p < 0.001; NDI; CSM: 41.4±23.5; controls: 4.4±6.6, p<0.001); FA was significantly lower in patients (CSM: 0.645 ± 0.067; controls: 0.699 ± 0.037, p = 0.005). MRS showed significantly lower metabolite concentrations between both groups: creatine (Cr) (CSM: 46.46±7.64; controls: 51.36±5.76, p = 0.03) and N-acetylaspartate (NAA) (CSM: 93.94±19.22; controls: 107.24±20.20, p = 0.05). Duration of symptoms ≤6 months was associated with increased myo-inositol (Ins) (61.58±17.76; 44.44±10.79; p = 0.02) and Ins/Cr ratio (1.36±0.47; 0.96±0.18; p = 0.014) compared to symptoms >6 months. CONCLUSION: Metabolic profiles of the precentral gyrus and FA in the uppermost spinal cord differ significantly between patients and healthy controls. Ins, thought to be a marker of endogenous neuroinflammatory response, is high in the early course of CSM and normalizes over time.

Creep-feeding to stimulate metabolic imprinting in nursing beef heifers: impacts on heifer growth, reproductive and physiological variables.

This experiment compared growth, physiological, and reproductive responses of beef heifers with (MI) or without (CON) access to a creep-feeder, as a manner to stimulate metabolic imprinting while nursing their dams. On day 0, 60 Angus × Hereford heifers were ranked by BW and age (140 ± 3 kg and 68±3 days), and assigned to pairs so all ranking criteria were similar between heifers within each pair. On day 1, pairs were randomly assigned to MI (n=15) or CON (n=15). From day 1 to 51, MI pairs and their dams were allocated to 15 drylot pens where heifers had ad libitum access to a corn-based supplement through a creep-feeder. The CON pairs and their dams were maintained in an adjacent single drylot pen. From day 52 to 111, treatments were managed as a single group on a semiarid range pasture. On day 111, heifers were weaned and allocated to two pastures (one pasture/treatment), receiving hay and a corn-based concentrate until day 326. Heifer BW was recorded before and at the end of the creep-feeding period (day 1 to 51), and on days 112 and 326. On days 0, 51, 111, 187, 261, and 325, jugular blood was collected and real-time ultrasonography for longissimus muscle depth and backfat thickness assessment was performed. Blood was also collected every 10 days from days 113 to 323 for puberty evaluation via plasma progesterone. Liver and subcutaneous fat biopsies were performed on days 51, 111, 261 and 325. Average daily gain was greater (P<0.01) for MI than CON from day 1 to 51, tended (P=0.09) to be greater for CON than MI from day 112 to 326, while BW on day 326 was similar between treatments. On day 51, MI had greater (P ⩽ 0.01) plasma IGF-I and glucose concentrations, as well as mRNA expression of hepatic pyruvate carboxylase and adipose fatty acid synthase than CON. On days 261 and 325, plasma insulin concentrations were greater (P ⩽ 0.03) in CON than MI. Mean mRNA expression of hepatic IGF-I and adipose peroxisome proliferator-activated receptor gamma were greater (P ⩽ 0.05) in MI than CON. No treatment effects were detected for puberty attainment rate. In conclusion, supplementing nursing heifers via creep-feeding for 50 days altered physiological and biochemical variables suggestive of a metabolic imprinting effect, but did not hasten their puberty attainment.

Fatty acid composition of adipose tissue and muscle from Jersey steers was affected by finishing diet and tissue location.

To determine the impacts of finishing diet and tissue type and location on fatty acid composition and palatability of Jersey beef, twenty steers were assigned to a factorial treatment design with initial weight (Light vs. Heavy) and finishing diet (70 vs. 85% concentrate) as treatments. Ribeye steaks were collected for sensory evaluation. Muscle, seam and subcutaneous (s.c.) fat from steaks, kidney fat (KF) and omental fat (OMF) were collected for fatty acid analysis. Initial weight and finishing diet had little impact on beef palatability. The 85% concentrate decreased polyunsaturated fatty acids (PUFA) in muscle and increased trans fatty acids in all tissues (P<0.05). The monounsaturated:saturated fatty acid ratio (MUFA:SFA) was highest in s.c. fat, intermediate in muscle and seam fat, and lowest in KF and OMF. The PUFA:SFA was highest in muscle, intermediate in s.c. and seam fat, and lowest in KF and OMF. Fatty acid composition differed greatly among tissues and the lower concentrate diet increased omega-3 and PUFA percentages in muscle.

Prevention of contrast-induced nephropathy with volume supplementation.

Volume supplementation remains the cornerstone for the prevention of contrast-induced nephropathy (CIN). Current evidence suggests that the combination of intravenous and oral volume supplementation effectively prevents CIN in low- and moderate-risk patients. Normal isotonic (0.9%) saline should be started 12 h before (or at least in the morning of) the contrast procedure with an infusion rate of 1 ml/kg of body weight per hour and be continued for 24 h. In addition, patients should be encouraged to drink plenty of fluids (tea, mineral water). The use of bicarbonate infusion may allow shorter volume supplementation periods. Combined intravenous and oral volume supplementation protocols feasible for outpatients who limit the intravenous infusion to the contrast procedure are under investigation. Future studies are necessary to define further details regarding the optimal use of volume supplementation.

Development of a multi-target screening analysis for 301 drugs using a QTrap liquid chromatography/tandem mass spectrometry system and automated library searching.

A new multi-target screening (MTS) procedure for drugs in blood and urine for toxicological analysis has been developed using a hybrid triple-quadrupole linear ion trap mass spectrometer (QTrap) for the fast detection and identification of 301 forensically important drugs, e.g. tranquilizers (benzodiazepines), hypnotics, drugs of abuse (opiates, cocaine, amphetamines, cannabinoids), antidepressants, neuroleptics, and some cardiac drugs, in one single liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis. Samples were extracted either with liquid-liquid extraction or solid-phase extraction. A multiple reaction monitoring (MRM) as survey scan and an enhanced product ion (EPI) scan as dependent scan were performed in an information-dependent acquisition (IDA) experiment. Finally, drug identification was carried out by library search with a newly developed MS/MS library based on EPI spectra at three different collision energies in positive mode. The advantage of this newly developed method is the possibility to detect and identify 301 drugs in one single LC/MS/MS run.

Prevention of contrast nephropathy in critically ill patients using acetylcysteine and theophylline.

Compared with periprocedural hydration alone, acetylcysteine with hydration significantly reduces the risk of contrast nephropathy in patients with chronic renal insufficiency by 50%. For elective contrast procedures, acetylcysteine should be given in a dose of 600 mg twice daily the day before and on the procedure day. For emergency procedures, a high dose intravenous regimen (150 mg/kg in 500 mL normal saline over 30 minutes immediately before contrast followed by 50 mg/kg in 500 mL normal saline over 4h) is effective. Given the low cost and good side-effect profile of acetylcysteine, it would seem prudent to give this drug with intravenous fluids to all critically ill patients scheduled for intravenous or intraarterial contrast procedures. Theophylline in a dose of 200 mg or 2.5 mg/kg i.v. 30 minutes before contrast may be an effective alternative for emergency procedures. Although its benefit compared with periprocedural hydration alone seems less well established, theophylline is a particularly attractive option for emergency procedures.

Methicillin-resistant Staphylococcus aureus whole-body decolonization among hospitalized patients with variable site colonization by using mupirocin in combination with octenidine dihydrochloride.

The object of this study was to investigate the efficacy of a methicillin-resistant Staphylococcus aureus (MRSA) multisite carriage decolonization in 32 hospitalized carriers--25 from surgical and seven from medical wards. Twenty-four of the patients had wounds (e.g. chronic ulcers, surgical sites) and 17 were spinal cord injury patients. Decolonization was performed by intranasal application of mupirocin, combined with an octenidine dihydrochloride bodywash over a period of five days. Samples from the nose, forehead, neck, axilla and groin were taken 24-48 h before beginning decolonization (sample point I, N=32) and 24-48 h afterwards (sample point II, N=32). Further samples, were taken seven to nine days after the procedure (sample point III, N=25). Contact sheep blood agar plates (24 cm2) were used to quantify MRSA colonies on forehead and neck. MRSA from other sample sites was determined semi-quantitatively. All patients were proven to be MRSA positive at one or more extranasal site(s); 18.8% did not have nasal carriage. The overall decolonization rate for all sites was 53.1% (sample point II) and 64% (sample point III), respectively. The reduction was significant for every site, showing a rate of 88.5% for nose (II, III) and of 56.3% (II) and 68% (III) for all extranasal sites together. Of 32 patients, a median of 6.5 cfu MRSA/24 cm2 was obtained for the forehead before decolonization and 0.5 cfu MRSA/24 cm2 for the neck. A significant reduction (0 cfu MRSA/24 cm2) from both sites was shown after treatment. Before decolonization procedures, median MRSA levels for the nose, groin and axilla were 55, 6 and 0 cfu/swab. After treatment, MRSA from each of these sites was significantly reduced. We conclude that nasal mupirocin combined with octenidine dihydrochloride whole-body wash is effective in eradicating MRSA from patients with variable site colonization.

Recent advances in the diagnosis of malignant hyperthermia susceptibility: how confident can we be of genetic testing?

Malignant hyperthermia (MH) is a condition that manifests in susceptible individuals only on exposure to certain anaesthetic agents. Although genetically heterogeneous, mutations in the RYR1 gene (19q13.1) are associated with the majority of reported MH cases. Guidelines for the genetic diagnosis for MH susceptibility have recently been introduced by the European MH Group (EMHG). These are designed to supplement the muscle biopsy testing procedure, the in vitro contracture test (IVCT), which has been the only means of patient screening for the last 30 years and which remains the method for definitive diagnosis in suspected probands. Discordance observed in some families between IVCT phenotype and susceptibility locus genotype could limit the confidence in genetic diagnosis. We have therefore assessed the prevalence of 15 RYR1 mutations currently used in the genetic diagnosis of MH in a sample of over 500 unrelated European MH susceptible individuals and have recorded the frequency of RYR1 genotype/IVCT phenotype discordance. RYR1 mutations were detected in up to approximately 30% of families investigated. Phenotype/genotype discordance in a single individual was observed in 10 out of 196 mutation-positive families. In five families a mutation-positive/IVCT-negative individual was observed, and in the other five families a mutation-negative/IVCT-positive individual was observed. These data represent the most comprehensive assessment of RYR1 mutation prevalence and genotype/phenotype correlation analysis and highlight the possible limitations of MH screening methods. The implications for genetic diagnosis are discussed.

Host recognition by the tobacco hornworm is mediated by a host plant compound.

It is generally believed that animals make decisions about the selection of mates, kin or food on the basis of pre-constructed recognition templates. These templates can be innate or acquired through experience. An example of an acquired template is the feeding preference exhibited by larvae of the moth, Manduca sexta. Naive hatchlings will feed and grow successfully on many different plants or artificial diets, but once they have fed on a natural host they become specialist feeders. Here we show that the induced feeding preference of M. sexta involves the formation of a template to a steroidal glycoside, indioside D, that is present in solanaceous foliage. This compound is both necessary and sufficient to maintain the induced feeding preference. The induction of host plant specificity is at least partly due to a tuning of taste receptors to indioside D. The taste receptors of larvae fed on host plants show an enhanced response to indioside D as compared with other plant compounds tested.

The non-mevalonate isoprenoid biosynthesis of plants as a test system for drugs against malaria and pathogenic bacteria.

Two plant test systems are presented in the search for new inhibitors of the non-mevalonate isoprenoid pathway. A derivative of clomazone appears to be an inhibitor of the deoxyxylulose 5-phosphate/methylerythritol 4-phosphate (DOXP/MEP) pathway of isoprenoid formation.

Acute and long-term results after transcoronary ablation of septal hypertrophy (TASH). Catheter interventional treatment for hypertrophic obstructive cardiomyopathy.

AIMS: To evaluate acute and long-term symptomatic, haemodynamic (at rest and during exercise) and electrophysiological results of transcoronary ablation of septal hypertrophy (TASH), a catheter interventional treatment for hypertrophic obstructive cardiomyopathy. METHODS AND RESULTS: Sixty-two transcoronary ablations of septal hypertrophy were performed by injection of 4.6+/-2.6 ml 96% ethanol into septal branches in 50 patients with hypertrophic obstructive cardiomyopathy and severe symptoms. Serial left and right heart catheterization, transoesophageal echocardiography and electrophysiological investigations were repeated 2 weeks and 7+/-1 months (n=37) after intervention. Transcoronary ablation of septal hypertrophy led to a reduction in septal thickness, sustained elimination of the outflow obstruction (51+/-41 vs 6+/-10 mmHg at rest, P<0.001; 134+/-48 vs 28+/-32 mmHg, P<0.001, post-extrasystolic), a decrease in left ventricular filling pressures at rest and during exercise and a pronounced clinical improvement. There was no evidence for the creation of an arrhythmogenic substrate as assessed by serial programmed electrical stimulation in 39 patients. However, permanent high-grade atrioventricular block occurred in 17% of the patients. There were two early, but no late deaths during a mean follow-up time of 10. 6+/-5.6 months. CONCLUSION: Transcoronary ablation of septal hypertrophy is a promising new treatment for hypertrophic obstructive cardiomyopathy in patients with severe symptoms. It should now be compared with alternative treatment strategies in prospective randomized studies.

Bulimic adolescents benefit from massage therapy.

Twenty-four female adolescent bulimic inpatients were randomly assigned to a massage therapy or a standard treatment (control) group. Results indicated that the massaged patients showed immediate reductions (both self-report and behavior observation) in anxiety and depression. In addition, by the last day of the therapy, they had lower depression scores, lower cortisol (stress) levels, higher dopamine levels, and showed improvement on several other psychological and behavioral measures. These findings suggest that massage therapy is effective as an adjunct treatment for bulimia.

Polymerase chain reaction selects a novel disintegrin proteinase from CD40-activated germinal center dendritic cells.

To identify genes expressed by a specific subset of dendritic cells found in vivo a polymerase chain reaction-based cDNA subtraction technique was applied to the recently described germinal center dendritic cells. A novel member of the disintegrin metalloproteinase family was cloned which comprises a not typical zinc-chelating catalytic site most similar to a bacterial metalloproteinase. Dendritic cell precursors or immature dendritic cells express no or low levels of the message. It is induced to high levels upon spontaneous or CD40-dependent maturation and in a mixed lymphocyte reaction. In situ hybridization showed distinct expression of this gene in the germinal center. This, together with the findings that certain disintegrin metalloproteinases regulate the activity of tumor necrosis factor alpha and that metalloproteinases have also been implicated in FasL processing, suggest that this novel molecule may play an important role in dendritic cell function and their interactions with germinal center T cells.

Binding of the Ets factor GA-binding protein to an upstream site in the factor IX promoter is a critical event in transactivation.

Factor IX is an essential vitamin K-dependent serine protease that participates in the intrinsic pathway of coagulation. The protein is expressed exclusively in the liver. The rare Leyden form of hemophilia B (inherited factor IX deficiency) results from point mutations in three proximal promoter elements that decrease factor IX expression. Recovery of expression occurs following puberty, with factor IX protein levels rising into the normal range. We have previously implicated the PAR domain D-site-binding protein (DBP) as well as an upstream element, site 5, as playing important roles in the phenotypic recovery of hemophilia B Leyden. Here we demonstrate that site 5 binds both the CCAAT/enhancer-binding protein (C/EBPalpha) and the ubiquitous Ets factor GA-binding protein (GABPalpha/beta). Transactivation of the factor IX promoter by the PAR proteins DBP and hepatic leukemia factor (HLF) is dependent on the binding of GABPalpha/beta to site 5, and coexpression of these two factors is required for optimal activation of this promoter. The binding of C/EBPalpha to site 5 also augments the activity of GABPalpha/beta. Analysis of the developmental regulation of site 5-binding proteins in rat liver has shown that C/EBPalpha and the GABPbeta subunit increase markedly in the 2 weeks after birth. These observations establish a functional association between the Ets factor GABPalpha/beta and C/EBPalpha and indicate that the two PAR proteins, DBP and HLF, may play complementary roles in factor IX activation. Given the developmental changes exhibited by these proteins, it is likely that they play a role in regulation of the normal factor IX promoter as well as promoters carrying hemophilia B Leyden mutations.

NSABP trials of adjuvant chemotherapy for breast cancer. A further look at the evidence.

Two decades ago the National Surgical Adjuvant Breast Project (NSABP) began to test the hypothesis that adjuvant chemotherapy would influence favorably the postsurgical survival rates of women with breast cancer. Although the use of phenylalanine mustard (melphalan or (L-PAM) has been supplemented by other agents, the thrust to recommend adjuvant chemotherapy as standard treatment was created by an L-PAM series of five trials using L-PAM or L-PAM plus fluorouracil. Only the first trial, B-05, contained an untreated group. The main treated groups in these five trials are similar to each other in survival probabilities, and the main untreated group in B-05 is not different in survival than the combined results of these five trials. There were a total of nine comparison in each study-and in B-05 the subgroup of treated women 49 years or younger with one to three positive node was found to be different than the untreated group. Four subsequent subgroups of women who were 49 years or younger with one to three positive nodes are not similar in survival despite the fact that they were developed from similar main groups that had similar treatment. The initial treated subgroup in B-05 had a survival outcome that was never again achieved in the subsequent four studies. The untreated subgroup in B-05 was not different than three of the four subsequently treated subgroups. The NSABP now has evidence that denies the conclusion that adjuvant chemotherapy prolongs survival in premenopausal node-positive women. Recommendations that adjuvant chemotherapy become standard treatment for premenopausal node-positive women should be seriously reconsidered and probably withdrawn.

Phase I-II trial of hyperthermic isolated limb perfusion with cisplatin in the treatment of high risk malignant melanoma of the extremities.

Between 1983 and 1990, 59 patients with malignant melanoma were retrospectively reviewed to assess the safety, efficacy and the maximal tolerated dose of cisplatin used in hyperthermic isolated limb perfusion. The median follow-up was 29 months (range 3-54 months). The local recurrence rate was 12% in Stage I, 33% in Stage II and 30% in Stage III patients. The maximal tolerated dose of cisplatin in hyperthermic isolated limb perfusion was 3.2 mg/kg for forequarter perfusions and 6 mg/kg for hindquarter perfusions based on lean body weight. At these dosages, there is an 8% major complication rate and only one patient experienced long-term sequelae. Hyperthermic isolated limb perfusion using cisplatin in the dosages of 3-6 mg/kg lean body weight is associated with low morbidity and appears to have efficacy comparable to L-phenylalanine mustard for the control of locally recurrent malignant melanoma.

Sequential high-dose methotrexate, 5-fluorouracil, and doxorubicin for treatment of advanced pancreatic cancer.

A phase II trial of sequential high-dose methotrexate, 1500 mg/m2, and 5-fluorouracil, 1500 mg/m2 intravenously on day 1, plus doxorubicin, 30 mg/m2 i.v. on day 14, has been undertaken in patients with locally advanced or metastatic adenocarcinoma of the pancreas. Of 25 evaluable patients there were 1 complete response and 3 partial responses for an overall response rate of 16% (95% confidence interval 5%-36%). The median survival of all patients was 6.7 months (range 1-17 months). There was one treatment-related death due to pancytopenia and sepsis. In all other patients therapy was generally well-tolerated. We conclude that this combination protocol has only modest activity in the treatment of advanced pancreatic cancer.