Immunomodulatory and antimetastatic action of propolis and related polyphenolic compounds

The effect of polyphenolic compounds isolated from propolis and propolis itself was investigated on the growth and metastatic potential of a transplantable mammary carcinoma (MCa) of CBA mouse. Metastases in the lung were generated by intravenous injection of tumor cells (2 x 10(5)). A water-soluble derivative of proplis (WSDP), caffeic acid (CA), caffeic acid phenethyl ester (CAPE) and quercetin (QU) were given to mice per os before tumor cells inoculation. Tested compounds significantly decreased the number of tumor nodules in the lung. According to the results obtained the antitumor activity of tested compounds can be related to the immunomodulatory properties of the compounds, their cytotoxicity to tumor cells, and their capacity to induce apoptosis and necrosis. The experimental data support that WSDP, CA, CAPE and QU could be potentially useful in the control of tumor growth in experimental models.     

Mechanisms and targets of deep brain stimulation in movement disorders

Chronic electrical stimulation of the brain, known as deep brain stimulation (DBS), has become a preferred surgical treatment for medication-refractory movement disorders. Despite its remarkable clinical success, the therapeutic mechanisms of DBS are still not completely understood, limiting opportunities to improve treatment efficacy and simplify selection of stimulation parameters. This review addresses three questions essential to understanding the mechanisms of DBS. 1) How does DBS affect neuronal tissue in the vicinity of the active electrode or electrodes? 2) How do these changes translate into therapeutic benefit on motor symptoms? 3) How do these effects depend on the particular site of stimulation? Early hypotheses proposed that stimulation inhibited neuronal activity at the site of stimulation, mimicking the outcome of ablative surgeries. Recent studies have challenged that view, suggesting that although somatic activity near the DBS electrode may exhibit substantial inhibition or complex modulation patterns, the output from the stimulated nucleus follows the DBS pulse train by direct axonal excitation. The intrinsic activity is thus replaced by high-frequency activity that is time-locked to the stimulus and more regular in pattern. These changes in firing pattern are thought to prevent transmission of pathologic bursting and oscillatory activity, resulting in the reduction of disease symptoms through compensatory processing of sensorimotor information. Although promising, this theory does not entirely explain why DBS improves motor symptoms at different latencies. Understanding these processes on a physiological level will be critically important if we are to reach the full potential of this powerful tool.     

Use of aspiration cytology and frozen section examination for management of benign and malignant thyroid nodules

Between January 1980 and December 1988, 161 patients underwent thyroidectomy with intraoperative frozen section consultation after fine-needle aspiration (FNA) of a thyroid nodule. The FNA were insufficient in 15 instances (9%) and in error in 39 (24%). In 15 cases, the incorrect aspiration diagnosis could have led to excessive surgery and in ten cases to delayed therapy if it had been the only guide for therapy. The diagnosis was deferred to permanent section analysis in 30 (19%) frozen sections. Twenty-two errors (14% of cases) were made in the interpretation of frozen section material, and in an additional 15 patients (9%), the diagnosis suggested (but deferred at frozen section) was in error. In one patient, this error could have led to more extensive surgery than necessary; in 21 patients, the frozen section error could have led to undertreatment. When frozen section results were combined with those of FNA, no therapeutically important false-positive diagnoses were made. In five patients, the combination of both FNA and frozen section results would not have identified a carcinoma which, in three cases, was a small occult papillary carcinoma not found in the index nodule.     

Intrathecal synthesis of virus antibodies: a diagnostic test for multiple sclerosis

Intrathecally synthesized antibodies against measles and rubella were determined in 221 patients with multiple sclerosis (MS) and in 476 control cases. A local production was detectable in more than 80% of the MS cases but in none of the control group. These results show that the demonstration of intrathecally synthesized antibodies against neurotropic viruses not related with respective infections may serve as helpful test in the diagnosis of MS.     

Myocardial and ventricular mechanics as influenced by disopyramide

The effects of disopyramide (D) on the mechanics of isolated myocardium as well as on the whole ventricle were examined in the rat model. Moreover bipolar leads of the apex and an area at the base of the left ventricle were set up to get indications for changes in the spread of excitation. D in concentrations of 10(-8) to 10(-4) mol/l did not affect the diastolic elastic properties of isolated myocardium. Isometric contraction amplitude was nearly unaltered, while rate of isometric contraction and relaxation were slightly increased. In the whole ventricle in situ D (2 to 10 mg/kg b.w. administered i.v.) induced a dose-dependent decrease in left ventricular isovolumetric peak pressure (16%), max.pos. dP/dt (40%) and max.neg. dP/dt (30%; for highest doses respectively), while time to peak pressure and relaxation time 90% were prolonged. Therapeutic dose of D (2 mg/kg b.w.i.v.) induced no decrease in essential systolic parameters of the whole ventricle under auxotonic conditions. Left ventricular pressure, dP/dt max.pos. and neg., left ventricular end-diastolic pressure and cardiac output were nearly unaltered. Heart rate showed a tendency to decrease, while total time of contraction and left ventricular ejection time increased. Higher doses of D led to marked cardiac depressant effects. The time interval between the excitation of the apex and an area at the base of the heart was increased. It was concluded that the negative dromotropic effect of D and thereby an altered pattern of left ventricular contraction are essential components in the elimination of the pressure gradient between left ventricle and aorta, observed in patients with muscular subaortic stenosis, and are presumably involved in the cardiac depressant effect of the drug in over-therapeutic doses.     

Rituximab as rescue therapy in anti-neutrophil cytoplasmic antibody-associated vasculitis: a single-centre experience with 15 patients

Background. B-cell depletion with rituximab, a chimeric anti-CD20antibody, is a novel treatment for refractory and relapsingANCA-associated small-vessel vasculitis. Data are limited andmost reports describe single patients or small numbers of patientsfollowed prospectively. Methods. We report a single-centre experience with 15 patientswho received rituximab for refractory or relapsing ANCA-associatedvasculitis. All patients had been treated with corticosteroidsand cyclophosphamide and a variety of other second-line immunosuppressiveagents. None of the patients had evidence of infection and receivedfour infusions of 375 mg/m² of rituximab. Disease activity wasassessed in accordance with the Birmingham Vasculitis ActivityScore (BVAS). BVAS, C-reactive protein and ANCA titres wererecorded at baseline and during follow-up. Results. B-cell depletion was achieved in all patients. Partialor complete remission was seen in 14 of 15 patients with a significantdecline in BVAS compared to baseline (P < 0.007). One patientwith granulomatous ANCA-associated vasculitis did not respondto rituximab. There were no side effects during rituximab infusion.Transient leucopenia was observed in two patients. One patientwith bronchial stenosis died of pneumonia 5.5 months after theinitiation of rituximab treatment. One initially anti-HBc-positive/HBsAg-negativepatient experienced a reactivation of hepatitis B, developedend-stage renal failure and died after refusal of dialysis. Conclusions. We report the largest case series of rituximabuse for ANCA-associated vasculitis so far. Our data supportthat the drug is capable of inducing partial or complete remissionin refractory or relapsing patients. Leucopenia and infectiouscomplications remain a matter of concern.     

Interictal high‐frequency oscillations (HFOs) as predictors of high frequency and conventional seizure onset zones

We investigated the relationship between the interictal high‐frequency oscillations (HFOs) and the seizure onset zones (SOZs) defined by the ictal HFOs or conventional frequency activity (CFA), and evaluated the usefulness of the interictal HFOs as spatial markers of the SOZs. We analysed seizures showing discrete HFOs at onset on intracranial EEGs acquired at ≥1000‐Hz sampling rate in a training cohort of 10 patients with temporal and extratemporal epilepsy. We classified each ictal channel as: HFO+ (HFOs at onset with subsequent evolution), HFO‐ (HFOs at onset without evolution), CFA (1.6–70‐Hz activity at onset with evolution), or non‐ictal. We defined the SOZs as: hSOZ (HFO+ channels only), hfo+&‐SOZ (HFO+ and HFO‐ channels), and cSOZ (CFA channels). Using automated methods, we detected the interictal HFOs and extracted five features: density, connectivity, peak frequency, log power, and amplitude. We created logistic regression models using these features, and tested their performance in a separate replication cohort of three patients. The models containing the five interictal HFO features reliably differentiated the channels located inside the SOZ from those outside in the training cohort (p<0.001), reaching the highest accuracy for the classification of hSOZ. Log power and connectivity had the highest odds ratios, both being higher for the channels inside the SOZ compared with those outside the SOZ. In the replication cohort of novel patients, the same models differentiated the HFO+ from HFO‐ channels, and predicted the extents of the hSOZ and hfo+&‐SOZ (F1 measure >0.5) but not the cSOZ. Our study shows that the interictal HFOs are useful in defining the spatial extent of the SOZ, and predicting whether or not a given channel in a novel patient would be involved in the seizure. The findings support the existence of an abnormal network of tightly‐linked ictal and interictal HFOs in patients with intractable epilepsy.     

Synthesis and evaluation of a C-6 alkylated pyrimidine derivative for the in vivo imaging of HSV1-TK gene expression

IntroductionWe report on the synthesis, radiolabeling, in vitro and in vivo characterization of N-Me-[¹⁸F]FHBT (6-(3-[¹⁸F]fluoro-2-(hydroxymethyl)propyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione), a C-6-substituted N-1-methylated pyrimidine derivative as a reporter probe for imaging herpes simplex virus type 1 thymidine kinase (HSV1-TK) expression.MethodsN-Me-[¹⁸F]FHBT was synthesized via a standard nucleophilic substitution reaction followed by acidic cleavage of the methoxytrityl protecting group. Cell uptake was studied in vitro with control HEK293 (human embryonic kidney cells) and HEK293 cells stably transfected with nonmutant HSV1-tk (HEK293TK+ cells). Positron emission tomography (PET) imaging and biodistribution studies of N-Me-[¹⁸F]FHBT or [¹⁸F]FHBG were performed in nude mice bearing xenografts of HEK293 control and TK+ cells.ResultsN-Me-[¹⁸F]FHBT was obtained in a two-step reaction in an overall maximal radiochemical yield (decay-corrected) of 5% and a radiochemical purity >96%. The tracer uptake in HSV1-TK containing HEK293TK+ cells was 14.5 times (at 30 min) and 55.4 times (at 240 min) higher than in control HEK293 cells. In mice, N-Me-[¹⁸F]FHBT and [¹⁸F]FHBG accumulated significantly and exhibited similar radioactivity levels in the HEK293TK+ xenografts; however, standardized uptake values ratios between HEK293TK+ and HEK293 control xenografts were higher for [¹⁸F]FHBG than for N-Me-[¹⁸F]FHBT. Both tracers showed high gall bladder and abdominal activity.ConclusionThe biological evaluations demonstrated the feasibility of using N-methylated C-6-substituted pyrimidine derivative N-Me-[¹⁸F]FHBT as a PET radiotracer for monitoring HSV1-TK expression in vivo.     

Effects on the offspring of chronic low exposure carbon monoxide during mice pregnancy.

This research is primarily concerned with the effects of chronic low doses of carbon monoxide on fetal development. Carbon monoxide was administered daily by inhalation to female Swiss Webster mice from the beginning of gestation until term. Daily weights were recorded and carbon monoxide blood levels determined every 4 days. The number of offspring in each litter was recorded. At weaning, two males and two females from each litter were randomly picked for maze running studies. When the mice were 6 weeks old, they were tested daily, ten trials per day, in the maze until learning had occurred. The number of days required to learn the maze and the number of incorrect trials were recorded. While there was no significant increase in the number of days needed to learn the maze, there was a significant increase in the number of errors made by the experimental group during this time. This indicated that an increased effort was needed to learn the maze.