Development of a Continuous Segmented Flow Tubular Reactor and the “Scale‐out” Concept – In Search of Perfect Powders

The synthesis of powders with controlled shape and narrow particle size distributions is still a major challenge for many industries. A continuous Segmented Flow Tubular Reactor (SFTR) has been developed to overcome homogeneity and scale‐up problems encountered when using batch reactors. Supersaturation is created by mixing the co‐reactants in a micromixer inducing precipitation; the suspension is then segmented into identical micro‐volumes by a non‐miscible fluid and sent through a tube. These micro‐volumes are more homogeneous when compared to large batch reactors leading to narrower size distributions, better particle morphology, polymorph selectivity and stoichiometry. All these features have been demonstrated on single tube SFTR for different chemical systems. To increase productivity for commercial application the SFTR is being “scaled‐out” by multiplying the number of tubes running in parallel instead of scaling‐up by increasing their size. The versatility of the multi‐tube unit will allow changes in type of precipitate with a minimum of new investment as new chemistry can be researched, developed and optimised in a single tube SFTR and then transferred to the multi‐tube unit for powder production.     

Glutamate metabotropic receptor agonists depress excitatory and inhibitory transmission on rat mesencephalic principal neurons

Intracellular and whole-cell patch-clamp recordings were used to evaluate the actions of different metabotropic glutamate receptor (mGluR) agonists on the synaptic inputs evoked on principal cells of the rat mesencephalon. Bath application of the group III mGluR agonists L-2-amino-4-phosphonobutyric acid (L-AP4) and L-serine-O-phosphonobutanoate (L-SOP) did not change the holding current of the cells held at resting potential (-60 mV) but produced a dose-dependent inhibition of the amplitude of the excitatory and inhibitory events. L-AP4 and L-SOP were more effective at inhibiting the excitatory postsynaptic currents (EPSCs) than the GABA(A) and GABA(B) inhibitory postsynaptic currents (IPSCs). The suppressing effects of L-AP4 and L-SOP were antagonized by (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP-4) but not by +/- -alpha-methyl-4-carboxyphenylglycine (MCPG). Moreover, the group II agonist (2S,1'S,2'S)-(carboxycyclopropyl)glycine (L-CCG1) and the group I agonist (RS)-3,5-dihydrophenylglycine (3,5-DHPG) depressed in a dose-related manner the EPSC, the GABA(A) IPSC and the GABA(B) IPSC. The suppressing effect of the two mGluRs agonists was partially antagonized by MCPG but not by MAP-4. In addition, both L-CCG1 and 3,5-DHPG caused an inward shift of the holding current. To characterize the site of action of the metabotropic receptor agonists, experiments were performed to examine the amplitude and ratio of EPSC and GABA(A) IPSC pairs. The increase of the s2/s1 ratio caused by the agonists suggests that the location of the inhibitory mGluRs was presynaptic. These results indicate that the activation of presynaptic mGluRs controls the release of excitatory and inhibitory transmitters on presumed dopaminergic cells within the ventral mesencephalon.     

Simplified method for the measurement of segmental colonic transit time

Segmental colonic transit has been measured in 101 patients. Two MBq of 111Indium absorbed on resin pellets and encapsulated in an enteric coated capsule was given at 7 00 am. Hourly images during the first day, and three images during each subsequent day were acquired for up to three days. Using all scan and patient data the scans were categorised in one of the five patterns of colonic transit: normal, rapid, right delay, left delay, or generalised delay. The geometric centres and per cent activity at each time point was compared between the five groups of colonic transit patients to find the best time for imaging and so to distinguish the five groups. During the first day, early images did not help in diagnosis of patterns of transit, however, in the later images (six hours onwards after the ingestion of the activity) the rapid transit groups could be identified. Images at 27 and 51 hours were both required to distinguish all five groups of patients from each other. Only in the 'normal' transit patients was there some excretion of the activity during the course of the second day, otherwise there was no difference in the images taken in the course of a day (second or third day). A simplified protocol requires a minimum of three images to distinguish all five patterns of colonic transit. The activity should be ingested in the morning (7 00 am) and the first image taken at the end of the working day (8-10 hours after ingestion), the second image on the morning of the second day, and the third image during the course of the third day. This simple protocol would provide all the clinically relevant information necessary for correct classification of the colonic transit.     

A phase II trial of weekly infusional 5-fluorouracil in combination with low-dose leucovorin in patients with advanced colorectal cancer

We examined 59 breast cancers for p53 and bcl-2 protein expression by immunohistochemistry. The results were correlated with Ki-67 immunostaining. p53-negativity was noted in 40 cases and the remaining 19 tumours were p53-positive. Thirty-six tumours showed strong expression of bcl-2 and in 23 no staining for this protein was observed. We found statistically significant reverse correlation between expression of p53 and bcl-2 in majority of carcinomas: 31 cases were bcl-2 positive and p53-negative, and 14 tumours were bcl-2-negative and p53-positive. Six carcinomas showed no nuclear staining for Ki-67 and in the remaining 53 the percent of cancer cells positive for Ki-67 ranged from 1 to 60 (mean: 14.6). In these 53 cases we found that bcl-2-positive tumours were characterized by lower proliferation than bcl-2-negative tumours, the mean value of Ki-67 immunostaining being 10.7% and 23.0%, respectively. p53-negative tumours showed lower proliferation than p53-positive tumours: mean Ki-67 index was 10.2% and 23.9%, respectively. We conclude that immunohistochemically detected p53 and bcl-2 proteins show a significant inverse relationship in majority of breast carcinomas and their expression correlates with tumour proliferation (Ki-67 immunostaining).     

Ultrastructural and immunocytochemical features of a case of neuroendocrine carcinoma developing in a prior ileostomy site

A patient who developed a mixed neuroendocrine carcinoma and adenocarcinoma at the site of a previous long-standing ileostomy is reported. The neuroendocrine features are documented by both ultrastructural and immunocytochemical findings. Carcinoma arising in an ileostomy site is rare but has been recorded in patients with long-standing ileostomies after colectomy for chronic inflammatory bowel disease, as in this patient. Neuroendocrine carcinoma developing in this setting apparently has not been described before, however.     

Capillarovenous angioma of the maxillary sinus. Apropos of a case with review of the literature

Metabolic side-effects of antihypertensive drugs may increase the risk of coronary heart disease despite an adequate blood pressure reduction. Since combinations of different antihypertensive drugs are often necessary and frequently used, we performed a randomized study comparing the effects of a fixed combination of hydrochlorothiazide and sotalol (group A), or hydrochlorothiazide and captopril (group B) on blood pressure and on lipid and glucose metabolism in 40 men with essential hypertension over 1 year. Significant blood pressure reductions (p < 0.001) were achieved in both treatment groups: from 160/105 to 128/88 mmHg in group A (mean doses: hydrochlorothiazide 33 and sotalol 197 mg) and from 162/106 to 135/89 mmHg in group B (hydrochlorothiazide 33 and captopril 64 mg) after 12 months, respectively. No significant changes in body weight were observed in either treatment group. Triglycerides increased (p < 0.05) in both treatment groups (from 183 to 262 mg/dl in A, and from 160 to 196 mg/dl in B) and HDL cholesterol decreased (p < 0.001 and < 0.05) in both groups (from 45.1 to 35.7 mg/dl in A, and from 49.3 to 46.3 mg/dl in B), whereas LDL cholesterol increased significantly (p < 0.05) only in group A from 153 to 164 mg/dl. No significant changes were observed in total cholesterol nor in lipoprotein(a) concentrations in either treatment group. Fasting plasma glucose and hemoglobin A1 increased significantly (p < 0.05) only in group A after 1 year of treatment (from 91.6 to 98.0 mg/dl, and from 6.3 to 6.9%, respectively). Serum levels of creatinine and potassium decreased, and uric acid increased significantly under either combination. Our data show that the diuretic/beta-blocker combination has adverse effects on lipid and glucose metabolism after long-term therapy. The effects of the diuretic/ACE inhibitor combination on lipid metabolism are less pronounced and there are no adverse effects on glucose metabolism. However, the ACE inhibitor component could not completely counteract the metabolic effects of the diuretic. Both combinations have no effects on Lp(a). We conclude that the combination of hydrochlorothiazide with an ACE inhibitor has a better metabolic profile for the treatment of essential hypertension than the combination with a beta-blocker.     

The synaptic release of dopamine in the striatum of rats during the acquisition of a passive avoidance conditioned reflex

To study the striatal synaptic dopamine release during passive avoidance behaviour the intracranial microdialysis technique combined with radioenzymatic assay method was used in Sprague-Dawley rats. It was shown that the acquisition of passive avoidance conditioning and an unescapable footshock led to delayed increases in striatal synaptic dopamine release.     

Biomimetic engineering of non-adhesive glycocalyx-like surfaces using oligosaccharide surfactant polymers

The external region of a cell membrane, known as the glycocalyx, is dominated by glycosylated molecules, which direct specific interactions such as cell-cell recognition and contribute to the steric repulsion that prevents undesirable non-specific adhesion of other molecules and cells. Mimicking the non-adhesive properties of a glycocalyx provides a potential solution to the clinical problems, such as thrombosis, that are associated with implantable devices owing to non-specific adsorption of plasma proteins. Here we describe a biomimetic surface modification of graphite using oligosaccharide surfactant polymers, which, like a glycocalyx, provides a dense and confluent layer of oligosaccharides. The surfactant polymers consist of a flexible poly(vinyl amine) with dextran and alkanoyl side chains. We show that alkanoyl side chains assemble on graphite through hydrophobic interaction and epitaxial adsorption. This constrains the polymer backbone to lie parallel to the substrate, with solvated dextran side chains protruding into the aqueous phase, creating a glycocalyx-like coating. The resulting biomimetic surface is effective in suppressing protein adsorption from human plasma protein solution.     

Pharmacokinetics and pharmacodynamics of sibrafiban (Ro 48-3657), an orally active IIb/IIIa antagonist, administered alone or in combination with heparin, aspirin, and recombinant tissue-type plasminogen activator in beagles

OBJECTIVE: The study aimed to determine the effectiveness of prophylactic medical intervention in reducing the incidence of cystoid macular edema (CME) and the effectiveness of medical treatment for chronic CME after cataract surgery. DESIGN: The study design was a systematic review and meta-analysis of published reports of randomized clinical trials (RCTs). PARTICIPANTS: Sixteen RCTs involving 2898 eyes examining the effectiveness of medical prophylaxis of CME and 4 RCTs involving 187 eyes testing the effectiveness of medical treatment of chronic CME were used in the study. INTERVENTIONS: Medical prophylaxis of treatment (cyclo-oxygenase inhibitors or corticosteroids) versus control (placebo or active treatment) was performed. MAIN OUTCOME MEASURES: Incidence of angiographically diagnosed CME, incidence of clinically significant CME, and vision were measured. RESULTS: Thirty-six articles reported testing a prophylactic medical intervention for CME after cataract surgery. The incidence of CME varied extensively across studies and was related to the study design used. Summary odds ratios (OR) indicated that prophylactic intervention was effective in reducing the incidence of both angiographic CME (OR = 0.36; 95% confidence interval [CI] = 0.28-0.45) and clinically relevant CME (OR = 0.49; 95% CI = 0.33-0.73). There also was a statistically significant positive effect on improving vision (OR = 1.97; 95% CI = 1.14-3.41). A combination of the results of the four RCTs testing medical therapy for chronic CME indicated a treatment benefit in terms of improving final visual acuity by two or more Snellen lines (OR = 2.67; 95% CI = 1.35-5.30). Assessment of the quality of the 20 RCTs included in the meta-analyses indicated problems in the design, execution, and reporting of a number of trials. CONCLUSION: A combination of the results from RCTs indicates that medical prophylaxis for aphakic and pseudophakic CME and medical treatment for chronic CME are beneficial. Because most of the RCTs performed to date have problems related to quality, a well-designed RCT is needed to confirm this result, using clinical CME and vision as outcomes.     

Gas chromatography in express diagnosis of candidiasis and monitoring of antifungal therapy efficacy by D-arabinitol and mannose levels in pediatric patients]

Methods for preventing and treating Ebola virus hemorrhagic fever are not still available despite the fact that this virus have been studied for 20 years. Methods of immunization of the animals (sheep, goats) non-susceptible to Ebola virus with live virus preparations were developed to obtain the hyperimmune anti-Ebola virus sera required to have highly immune antivirus gamma-globulins. These methods made it possible to obtain the immune sera having high virus-neutralizing antibodies. Caprine immunoglobulins were obtained from sera by fractionation of immune sera by Kohn's method. The neutralization indices of the immunoglobulins obtained were at least Ig. When administered in the first hours of infection, the protective effect of these preparations was shown on guinea pigs infected with LD50 of the strain pathogenic to the animals. Preclinical trials of these immunoglobulins on laboratory animals and clinical trials on volunteers were performed. The preparation was used as a preventive agent when accidents took place at the laboratory working with Ebola virus. The similar preparation from equine sera having high neutralizing and protective properties was elaborated at the Virological Center, Microbiological Institute, Russian Ministry of Defense. Its prophylactic efficiency was also shown in infected gamadrias.