GLACIER: An open-label, randomized, multicenter study to assess the safety and tolerability of glatiramer acetate 40 mg three-times weekly versus 20 mg daily in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: The efficacy and safety of glatiramer acetate (GA) 20 mg/mL once-daily subcutaneous injections (GA20) in relapsing-remitting multiple sclerosis (RRMS) is well-established. However, injection-related adverse events (IRAEs) may impede treatment adherence and tolerability. GA 40 mg/mL three-times weekly (GA40) also has a favorable efficacy and safety profile. OBJECTIVE: To evaluate the safety, tolerability, and patient experience when converting from GA20 to GA40. METHODS/TRIAL DESIGN: GLACIER was an open-label, randomized, parallel-group trial conducted at 31 sites in the US between June 2013 and December 2013. Stable RRMS patients on GA20 were randomized in a 1:1 ratio to continue with GA20 or convert to GA40. The adjusted mean annualized rate of IRAEs was the primary endpoint for this study. Additionally, the severity of IRAEs, rate of injection-site reactions (ISRs), and patient-reported MS impact and treatment satisfaction were compared for the two treatment groups over the 4-month core study. RESULTS: A total of 209 patients were randomized to convert to GA40 (n=108) or continue with GA20 (n=101). The adjusted mean annualized rate of IRAEs was reduced by 50% with GA40 (35.3 events per year; n=108) versus GA20 (70.4 events per year; n=101) (risk ratio (RR)=0.50; 95% confidence interval [CI]=0.34-0.74; p=0.0006). There was a 60% reduction in the rate of moderate/severe events (GA40 (n=108): 0.9 events per year versus GA20 (n=101): 2.2 events per year; RR=0.40; p=0.0021). Perception of treatment convenience improved for GA40-treated patients soon after converting and was sustained. CONCLUSIONS: The GLACIER study demonstrates a favorable IRAE and convenience profile of GA40 for RRMS patients. TRIAL REGISTRATION: NCT01874145 available at clinicaltrial.gov.

Adaptation of RUSLE in the eastern part of the Mediterranean region.

Empirically based models are used worldwide to estimate soil erosion. The Revised Universal Soil Loss Equation (RUSLE) is one such model that has been intensively tested and validated under conditions in the United States. RUSLE estimates average soil loss as a function of five main factors: rainfall erosivity (R), soil erodibility (K), crop management (C), support practice (P), and topographic (LS) factors. This study investigated the application of RUSLE to Mediterranean conditions. The validation and calibration of RUSLE in the study area utilized field plots' soil erosion measurements. The results found the RUSLE soil loss estimation to be three times the actual soil loss (7.8 and 2.6 Mg/ha, for RUSLE and actual measured soil loss, respectively). The difference between the RUSLE factors and the measured factors were responsible for the differences between the soil loss estimation by RUSLE and the measured soil loss. Specifically, the RUSLE K-factor showed three times the magnitude of the measured K-factor, the RUSLE C-factor underestimated the measured C-factor, and the RUSLE P-factor overestimated the measured P-factor by three times. Adjusting the RUSLE factors according to the measured ones increased the model's predictability, whereas the adjusted-RUSLE soil loss estimation underestimated the measured soil loss by 14%. The adjustment of RUSLE, according to the prevailing conditions of the study area, increased the model efficiency three times (0.26 and 0.86 before and after adjustment of the mode, respectively). For more accurate and reliable validation of the RUSLE under the Mediterranean conditions, it is advisable to conduct long-term soil loss experimentation and measurements.

Anticoagulation in nonvalvular atrial fibrillation.

Atrial fibrillation is a common cardiac arrhythmia. Management of atrial fibrillation should focus on prevention of thromboembolic complications and the treatment of arrhythmia related symptoms. This article will discuss anticoagulant therapy in nonvalvular atrial fibrillation and review results from several controlled trials.

Infratentorial cerebral cryptococcosis.

In a nonimmunocompromised patient with cerebral cryptococcosis, unique magnetic resonance findings included abnormalities limited to the posterior fossa and cerebellar hemispheric edema, gyriform enhancement of the vermis and cerebellar hemispheres, and infratentorial plaquelike enhancement. Magnetic resonance findings in central nervous system cryptococcosis are discussed.

EEG monitoring during carotid surgery: who should do the monitoring?

EEG monitoring was carried out by an EEG technician during 100 consecutive carotid endarterectomies in a community hospital. The technician's rating of the EEGs correlated with an inhouse electroencephalographer's interpretation and with historical published data. We conclude that intraoperative EEG monitoring during carotid endarterectomies can adequately be carried out by a competent EEG technician provided adequate physician backup and supervision are available.

Inhibition of microsomal glucose 6-phosphatase by unsaturated aliphatic aldehydes and ketones.

Aldehydes and ketones with one double bond conjugated to the carbonyl group inhibited the enzyme glucose 6-phosphatase, which is embedded in the microsomal membrane. The Michaelis constant, Km and the maximal rate of reaction, V, were affected in a way dependent on the inhibitor's chain-length: trans-2-pentenal and 1-penten-3-one increased Km linearly with concentration and had almost no effect on V, whereas trans-2-nonenal caused a large increase in V but only a small and non-linear change in Km. The effect of the short-chain aldehydes on the kinetic parameters increased with chain-length, but pentenone increased Km more than did trans-2-heptenal and conjugated dienals did not act as inhibitors. Therefore, sterical effects apparently are of importance. Washing the microsomes after incubation with hexenal or heptenal did not substantially decrease the inhibition, but with nonenal the inhibition was reduced by washing. Inhibition by the SH-group blocking reagent p-hydroxymercuribenzoate was competitive to inhibition by the alkenals. It is concluded that the alpha-beta unsaturated oxo-compounds inhibit glucose 6-phosphatase by binding covalently to an important mercapto group and that perturbation of the enzyme's membrane environment also plays a part in the inhibition.

Purification and characterisation of tyrosine decarboxylase and aromatic-L-amino-acid decarboxylase.

Microbial tyrosine decarboxylase (EC 4.1.1.25) and mammalian aromatic-L-amino-acid decarboxylase (EC 4.1.1.28) catalyse the formation of tyramine from L-tyrosine. These enzymes were characterised after isolation to purity by methods including fast polymer liquid chromatography (FPLC). Tyrosine decarboxylase was isolated from Streptococcus faecalis by FPLC anion exchange chromatography (11-times purification; 72% recovery; 23.2 U/mg protein). FPLC on Phenyl-Superose resulted in purification to 115 U/mg protein. Aromatic-L-amino-acid decarboxylase was isolated from pig kidney by ammonium sulfate fractionation, DEAE chromatography, and FPLC anion exchange chromatography (21-times purification; 22% recovery; 0.71 U/mg protein). By FPLC chromatofocusing, tyrosine decarboxylase eluted at pH 4.3 and aromatic-L-amino-acid decarboxylase at pH 5.0. Isoelectric focusing of tyrosine decarboxylase gave two bands (pI 4.4 and 4.5). With pyridoxal 5'-phosphate removed by ultrafiltration, only one band (pI 4.4) appeared, and SDS polyacrylamide electrophoresis confirmed the purity. FPLC gel filtration resulted in molecular weights 143,000 and 86,000, respectively, for tyrosine decarboxylase and aromatic-L-amino-acid decarboxylase. In SDS electrophoresis, tyrosine decarboxylase had the monomer molecular weight 75,000, showing a dimer structure for the enzyme.

Effect of furosemide on parathyroid hormone stimulated guinea pig renal adenylate cyclase and thyrotrophin and fluoride stimulated human thyroid adenylate cyclase.

The effect of furosemide 8 X 10(-4) mol/l an 8 X 10(-5) mol/l on parathyroid hormone stimulated adenylate cyclase was studied in renal tissue slices from guinea pigs. Furosemide caused a dose-dependent inhibition of the effect of parathyroid hormone on production of cyclic AMP, without having any significant effect on the basal cyclic AMP production. Furosemide in similar concentrations did not inhibit the stimulatory effect of thyrotrophin and fluoride in human thyroid homogenates suggesting that furosemide is not an universal inhibitor of adenylate cyclase and that the inhibition is not caused by a direct action of furosemide on the adenylate cyclase enzyme. Furosemide did not interfere with binding of cyclic AMP to cyclic AMP binding protein kinase from rabbit muscle. The results indicate that furosemide exerts an inhibitory influence either upon binding of parathyroid hormone to renal receptors or upon transmission of impulse from receptor to adenylate cyclase. The inhibitory influence of furosemide on parathyroid hormone action in kidney could explain the value of furosemide in the acute treatment of hypercalcaemia, but also suggest that chronic treatment with furosemide might interfere with normal calcium metabolism.

Appendico-vesical fistula and persistent urachus in a patient with hematuria.

A 35-year-old man had been treated with sulfamethizole on 6 occasions because of recurrent urinary tract infections. Furthermore, he had experienced diffuse monosymptomatic hematuria for 15 years. Cystoscopy and biopsy demonstrated irregular intestinal mucosa. Physical examination and intravenous urography were normal. Preoperative diagnosis was urachus-derived adenoma with the possibility of adenocarcinoma. At operation a typical urachus and--surprisingly--an appendico-vesical fistula was found.

Influence of calcium infusion on urinary cyclic AMP and phosphate in hyperparathyroidism.

Urinary cyclic AMP (cAMP) and phosphate were measured before and after calcium infusion in 12 patients with operatively verified primary hyperparathyroidism (PHP) and in 12 healthy persons. In normal subjects infusion of calcium caused a reduction in urinary cAMP directly correlated to the preinfusion values and inversely correlated to the serum calcium concentration determined as albumin-corrected serum calcium. In normal subjects with high normal albumin-corrected serum calcium the infusion of calcium caused no or only a small depression in the urinary excretion of cAMP. Changes in phosphate excretion were not correlated to the calcium concentration. Four of the 12 hyperparathyroid patients showed normal relative suppression in urinary cAMP after the infusion of calcium, and 5 had normal suppression of phosphate excretion. It is concluded that some patients with PHP retain calcium-sensitive secretion of PTH, and that the classical calcium infusion test is of doubtful value in the diagnosis of PHP.

Decreased norepinephrine concentration in normal tissue neighboring a malignant tumor.

We observed in five adenocarcinomas that norepinephrine as well as nerve fibers were absent from tumor tissue. The number of nerve fibers in normal tissue neighboring the tumor was normal. In contrast, norepinephrine concentration was decreased in normal tissue immediately surrounding tumor and increased in a stepwise fashion with the distance from tumor. Since there is evidence that some catecholamines possess antitumor activity, we suggest that depletion of catecholamines and perhaps other neurotransmitters in normal tissue neighboring a tumor may be of importance for invasion and accelerated malignant growth.