Metronidazole may inhibit intestinal colonization with Clostridium difficile

OBJECTIVE: To evaluate the clinical and microbiological efficacy of minocycline in a subgingival local delivery system as an adjunct to tooth scaling and root planing in dogs with periodontal disease. ANIMALS: Nine 4- to 7-year-old Beagles with periodontitis. PROCEDURE: After scaling of teeth and root planing, 2 treatment and 1 or 2 control sites were selected for each dog: treated sites (n = 18) received minocycline hydrochloride periodontal formulation and control sites (n = 12) received ointment base (no minocycline). Gingival crevicular fluid was collected at a baseline (prior to treatment) and at week 4. Clinical and microbiological effects were evaluated and compared among sites. RESULTS: In minocycline-treated sites, clinical indices were significantly decreased at week 4, compared with those at baseline. Minocycline-treated sites were associated with a significant decrease in gingival crevicular fluid, probing depth, and bleeding on probing values, compared with those for control sites at week 4. Compared with that for control sites, total bacteria count in periodontal pockets of minocycline-treated sites had an obvious tendency to decrease by week 4. Proportions of Porphyromonas and Fusobacterium spp were significantly decreased at week 4, compared with proportions at control sites and with pretreatment (baseline) values. CONCLUSIONS: When used as an adjunct to tooth scaling and root planing, minocycline periodontal formulation stimulated favorable clinical and antimicrobial responses.     

Quantification of intravascular and extravascular contributions to BOLD effects induced by alteration in oxygenation or intravascular contrast agents

A simple model is presented that allows quantitative separation of the contributions of signals from water in blood and extravascular parenchyma due to changes in blood oxygenation, induced either by brain activation or by alteration of inspired oxygen. The separation is based on the progressive attenuation of the signals in the vasculature of different levels when bipolar field gradient pulses are applied. Diffusion-weighted spin-echo echo-planar imaging sequences were used to measure signal changes under various conditions in both animals and human volunteers. Normoxic-hyperoxic episodes were induced in rats before and after injection of a superparamagnetic iron oxide contrast agent. Signal changes produced by visual stimulation were measured in human volunteers, and in volunteers subject to alternating normoxic-hyperoxic episodes, and with administration of Gd-DTPA. Analysis of the results with our simple model suggests that the apparent diffusion coefficient increases and R2 (= 1/T2) decreases upon brain activation, with a large component from extravascular water related to the decrease in the blood deoxyhemoglobin concentration. Furthermore, this study suggests that apparent diffusion coefficient of the extravascular component alone may provide localization of neuronal activation.     

Effect of in vitro incubation on spontaneous acrosome reaction in fresh and cryopreserved human spermatozoa

OBJECTIVES: Capacitation and acrosome reaction are prerequisites for fertilization. However, in vitro capacitation is not necessary for an agonist-induced acrosome reaction. We studied whether in vitro capacitation is important in spontaneous acrosome reaction and analyzed how capacitation before cryopreservation influences the acrosomal status of thawed spermatozoa. METHODS: Semen specimens from normal donors (n = 15) were processed by the swim-up technique and divided into two aliquots. One aliquot was capacitated (capacitation induced) for three hours by incubation in a modified-BWW medium with 3% HSA at 37 degrees C under 5% carbon dioxide. The other aliquot did not receive any treatment. Both aliquots were analyzed by CASA to assess the capacitation status of the spermatozoa and then cryopreserved. Spontaneous acrosome reaction was assessed by FITC-PNA lectin before and after cryopreservation. Sperm viability was measured using Hoechst-33258 stain. RESULTS: Before freezing, the frequency of spontaneous acrosome reaction was higher in the capacitation-induced sperm preparation (median, 20.5% [interquartile range, 17.2-37.8]) than in swim-up-induced specimens (median, 10.6% [range, 4.8-23.2]; P <.001). The percentage of viable cells showing acrosome reaction increased after cryopreservation in both swim-up-induced specimens (median, 241.4% [interquartile range, 37.1-678.6]; P <.001) and capacitation-induced specimens (median, 48.2% [range, 6.1-63.3]; P = 0.002). Although this increase was higher in the swim-up-induced specimens (P = 0.002), frequency of postthaw spontaneous acrosome reaction was similar in both groups (P = 0.18). CONCLUSIONS: We conclude that sperm capacitation significantly optimizes the acrosome reaction. However, a small proportion of normal spermatozoa do not require capacitation to undergo spontaneous acrosome reaction in vitro. After cryopreservation, the percentage of spermatozoa that had intact acrosomes was similar in both groups, despite the fact that one aliquot underwent prefreeze capacitation. These findings suggest that the acrosome reaction may involve complex mechanism(s) rather than a physiological change induced by capacitation.     

Dyspnea resulting from fibromyalgia

Two patients with chronic, severe, episodic dyspnea underwent prolonged, extensive, and invasive evaluations without a diagnosis being made. Both were subsequently diagnosed with fibromyalgia, and therapy directed at this condition resulted in resolution of their symptoms. Fibromyalgia is rarely included in the differential diagnosis of dyspnea, and timely diagnosis and treatment may be delayed. However, this condition must be considered because it can only be established by seeking the appropriate history and physical findings.     

Comparison of single- and two-layer Percoll separation for selection of motile spermatozoa

OBJECTIVE: Sperm recovery using a single-layer Percoll procedure is significantly better than using the swim-up technique for infertile men and patients with normal sperm characteristics; however, in normal men results have been contradictory. Some studies have shown further improvement in semen quality with multiple layers. Therefore, this study compared the effect of single-layer and two-layer Percoll procedures on sperm characteristics of normozoospermic men. METHODS: Semen specimens from 10 normal donors were processed by layering 1 mL of the liquefied ejaculate on a single layer of 80% Percoll or on a two-layer (47% and 90%) Percoll gradient. Computer-assisted semen analysis was done to examine total motile sperm, percentage of recovery of motile cells, percent motility, curvilinear velocity, linearity, and amplitude of lateral head displacement. Each specimen was evaluated by the hypo-osmotic swelling (HOS) test, bovine cervical mucus penetration test, viability (eosin-nigrosin stain), and sperm morphology (World Health Organization and Kruger's strict criteria). RESULTS: Specimens processed with the two-layer Percoll procedure had significantly better recovery of spermatozoa, and significantly better percentage motility, linearity, amplitude of lateral head displacement, percentage tail swelling, and percentage viability than those separated on single-layer Percoll. Results for sperm morphology using WHO and Kruger's criteria were similar between the two methods (P = 0.92 for both sets of criteria). CONCLUSIONS: In normozoospermic men, the two-layer Percoll separation procedure significantly improves semen characteristics compared with separation on a single layer.     

Potent cyano and carboxamido side-chain analogues of 1', 1'-dimethyl-delta8-tetrahydrocannabinol

The synthesis and pharmacological profile of several cyano (1a-e) and carboxamido (2a-h) side-chain-substituted analogues of 1', 1'-dimethyl-Delta8-THC are described. Commercially available cyano compound 3 was transformed to the resorcinol 6 in a three-step sequence. Condensation of 6 with p-menth-2-ene-1,8-diol formed the THC 7a which, with sodium cyanide/DMSO, gave 1b. Protection of the phenol in 7a as the MOM derivative provided the common intermediate 8 for the synthesis of 1a,c,e. Compound 1d was also synthesized from 7a via the aldehyde 9a. Base hydrolysis of 1b gave the acid 10 which, via its acid chloride and subsequent treatment with the appropriate amine, formed the target compounds 2a-h. The pharmacological profile indicated that the cyano analogues 1a-e had very high CB1 binding affinity (0.36-13 nM) and high in vivo potency as agonists. Two analogues (1a,b) had extremely high potency in the mouse tetrad tests. The dimethylcarboxamido analogue 2a showed a similar profile to 1a,b. The high potency was also retained in analogue 2c. In contrast the sulfonamide analogue 2d was unique as it had greater affinity than Delta9-THC, yet it was practically devoid of agonist effects. This study suggests that the incorporation of a cyano or an amide substituent in the side chain of Delta8-THC-DMH can enhance potency and can also lead to compounds with a unique profile which have high binding affinity and are practically devoid of agonist effects.     

Effect of different albuterol dosing regimens in the treatment of acute exacerbation of chronic obstructive pulmonary disease

There is substantial evidence for an activation of the sympathetic nervous system in man as well as in genetic models of hypertension, such as the spontaneously hypertensive rat (SHR), but we are only beginning to understand the central mechanisms that generate changes in sympathetic activity and elevate blood pressure (BP). Significant recent advances have been made in defining the neural pathways involved in BP regulation and in identifying the neurotransmitters these neurones utilise. In this overview, we describe the neural pathways within the medulla oblongata and spinal cord that participate in BP control and examine the role of amino acid neurotransmitters within these pathways. We demonstrate how alterations in these pathways explain the sympathetic activation observed in the SHR and contribute to hypertension in this model. Lastly, we examine the application of modern molecular biological approaches to further our understanding of the neural regulation of the circulation. In these studies, we used the administration of antisense oligonucleotides to interrupt gene expression.     

Chronic electrical stimulation of the auditory nerve at high stimulus rates: a physiological and histopathological study

The ubiquitous distribution of peroxisomes and the identification of a number of inherited diseases associated with peroxisomal dysfunction indicate that peroxisomes play an essential part in cellular metabolism. Some of the most important metabolic functions of peroxisomes include the synthesis of plasmalogens, bile acids, cholesterol and dolichol, and the oxidation of fatty acids (very long chain fatty acids > C22, branched chain fatty acids (e.g. phytanic acid), dicarboxylic acids, unsaturated fatty acids, prostaglandins, pipecolic acid and glutaric acid). Peroxisomes are also responsible for the metabolism of purines, polyamines, amino acids, glyoxylate and reactive oxygen species (e.g. O-2 and H2O2). Peroxisomal diseases result from the dysfunction of one or more peroxisomal metabolic functions, the majority of which manifest as neurological abnormalities. The quantitation of peroxisomal metabolic functions (e.g. levels of specific metabolites and/or enzyme activity) has become the basis of clinical diagnosis of diseases associated with the organelle. The study of peroxisomal diseases has also contributed towards the further elucidation of a number of metabolic functions of peroxisomes.     

Cell interactions with collagen matrices in vivo and in vitro depend on phosphatidylinositol 3-kinase and free cytoplasmic calcium

Itraconazole is a new triazole compound with a broad spectrum of activity against a number of fungal pathogens, including Aspergillus species. The drug is being used increasingly as prophylaxis in patients with immunodepression. Itraconazole is highly lipophilic and only ionised at low pH. The absolute availability of capsules in healthy volunteers under fasting conditions is about 55% and is increased after a meal. Itraconazole is 99.8% bound to human plasma proteins and its apparent volume of distribution is about 11 L/kg. The drug is extensively metabolised by the liver. Among the metabolites, hydroxy-itraconazole is of particular interest because its antifungal activity measured in vitro is similar to that of the parent drug and its plasma concentration is 2 to 3 times higher than that of itraconazole. Mean total itraconazole blood clearance determined in healthy volunteers following a single intravenous infusion was 39.6 L/h. After a single oral dose, the terminal elimination half-life of itraconazole is about 24 hours. The drug exhibits a dose-dependent pharmacokinetic behaviour. Renal failure does not affect the pharmacokinetic properties of itraconazole; however, little is known about the effects of hepatic insufficiency. In immunocompromised patients the absorption of itraconazole is affected by gastrointestinal disorders caused by diseases and cytotoxic chemotherapy. The pharmacokinetics of itraconazole may be significantly altered when the drug is coadministered with certain other agents. Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A4 and, thus, can also considerably change the pharmacokinetics of other drugs. Such changes may have clinically relevant consequences. Itraconazole appears to be well tolerated. Gastrointestinal disturbances and dizziness are the most frequently reported adverse effects. Clinical studies in patients with haemotological malignancies suggest that plasma concentrations [measured by high performance liquid chromatography (HPLC)] > or = 250 micrograms/L itraconazole, or 750 to 1000 micrograms/L for itraconazole plus hydroxy-itraconazole, are required for effective prophylactic antifungal activity. It seems that a curative effect may be enhanced by ensuring that itraconazole plasma concentrations exceed 500 micrograms/L. The marked intra- and inter-patient variability in the pharmacokinetics of the drug, and the fact that it is impossible to predict steady-state plasma concentrations from the initial dosage are major factors obscuring any clear relationship between dose and plasma concentrations and clinical efficacy. Thus, in patients with life-threatening fungal infections treated with itraconazole drug, plasma concentrations should be regularly monitored to ensure sufficient drug exposure for antifungal activity.