Comparison of pharmacodynamics and pharmacokinetics of insulin degludec and insulin glargine 300 U/mL in healthy cats.

Insulin glargine 300 U/mL (IGla-U300) and insulin degludec (IDeg) are synthetic insulin analogs designed as basal insulin formulations. In people, IGla-U300 is more predictable and longer acting compared with glargine 100 U/mL. The duration of action of IDeg in people is > 42 h, allowing flexibility in daily administration. We hypothesized that IDeg would have longer duration of action compared with IGla-U300 in healthy purpose-bred cats. Seven cats received 0.4 U/kg (subcutaneous) of IDeg and IGla-U300 on two different days, >1 wk apart. Exogenous insulin was measured and pharmacodynamic parameters were derived from glucose infusion rates during isoglycemic clamps and suppression of endogenous insulin. The Shapiro-Wilk test was used to assess normality, and normally distributed parameters were compared using paired t-tests. There was no difference between IDeg and IGla-U300 in onset, peak action, or total metabolic effect. On average, time to peak action (TPEAK) of IGla-U300 was 145 ± 114 min (95% confidence interval [CI] = 25-264) longer than TPEAK of IDeg (P = 0.03) and duration of action (TDUR) of IGla-U300 was 250 ± 173 min (95% CI = 68-432) longer than TDUR of IDeg (P = 0.02). The "flatness" of the time-action profile (as represented by the quotient of peak action/TDUR) was significantly greater for IGla-U300 compared with IDeg (P = 0.04). Overall, insulin concentration measurements concurred with findings from isoglycemic clamps. Based on these data, IDeg is not suitable for once-daily administration in cats. The efficacy of once-daily IGla-U300 in diabetic cats should be further investigated.

Seminal plasma biochemical markers and their association with semen analysis findings.

OBJECTIVES: To examine the clinical value of six seminal plasma components in the evaluation of sperm quality and in the differential diagnosis of men with infertility. METHODS: We analyzed 202 seminal plasmas for prostate-specific antigen, glucose, pepsinogen C, insulin-like growth factor binding protein-3, prostaglandin D synthase (PGDS), and BRCA1-like immunoreactive protein (BRCA1-LIP) using quantitative immunofluorometric procedures. The semen donors were categorized in four clinical groups: normal, oligospermic, azoospermic, and vasectomy patients. We then evaluated whether any of these biochemical markers were associated with other parameters of sperm quality, including patient age, total cell concentration, percentage of motility, and percentage of normal morphology. RESULTS: We found that only PGDS concentration was significantly associated with other parameters of sperm quality. PGDS concentration correlated positively with total cell concentration (r = 0.55), percentage of motility (r = 0.31), and percentage of normal morphology (r = 0.31). Median PGDS concentration in seminal plasma decreased progressively from normal to oligospermic to azoospermic to vasectomy patients (P <0.001). There was no overlap between seminal plasma PGDS concentration of normal subjects versus vasectomy patients. The only other parameter that was moderately decreased in vasectomy patients was BRCA1-LIP. The source of PGDS in seminal plasma was determined with various techniques, including immunohistochemistry. This protein is produced and secreted by the Sertoli cells. CONCLUSIONS: Our findings suggest that PGDS concentration in seminal plasma correlates with other known indicators of semen quality and is a new marker of post-testicular obstruction. This biochemical parameter could be used to aid in the differential diagnosis of obstructive and nonobstructive azoospermia in men with infertility.

Characteristics of the intestinal epithelial barrier during dietary manipulation and glucocorticoid stress.

OBJECTIVES: a) To determine the significance of stress-induced alterations in intestinal permeability by measuring the transmucosal flux of formyl-methionyl-leucyl-phenylalanine (f-MLP), a ubiquitous neutrophilic chemoattractant present in the human and rodent colon; and b) to determine whether stress and/or diet influence(s) bacterial adherence-induced changes in epithelial permeability by affecting the production of secretory immunoglobulin A (IgA), the main immune mechanism preventing bacterial adherence. DESIGN: Prospective, randomized, controlled study. SETTING: University animal research laboratory. SUBJECTS: Female Fischer rats. INTERVENTIONS: Rats were randomly assigned to four groups of seven animals each. Groups of animals were assigned to receive saline or dexamethasone (0.8 mg/kg ip) and were either starved (5% dextrose in water ad libitum) or fed (water and rat chow) for 48 hrs. MEASUREMENTS AND MAIN RESULTS: Mucosal barrier function was evaluated by measuring secretory IgA, bacterial adherence to the intestinal mucosa, and transepithelial electrical resistance, a measure of tight junction permeability. The f-MLP permeation across the mucosa was also determined in segments with significant permeability changes. Results indicate that starvation in dexamethasone-treated rats significantly impairs secretory IgA, promotes bacterial adherence to the mucosa, and results in increased intestinal permeability to f-MLP. These effects are significantly attenuated by the feeding of rat chow. CONCLUSIONS: Alterations in intestinal barrier function are characterized by depressed IgA, bacterial adherence to the intestinal mucosa, and permeation of clinically relevant proinflammatory luminal macromolecules (f-MLP). Enteral stimulation with foodstuffs is a necessary protective measure to prevent altered epithelial barrier function during glucocorticoid stress.

Enhanced access to rare brain cDNAs by prescreening libraries: 207 new mouse brain ESTs.

To use single-pass cDNA sequencing to characterize low-frequency cDNA clones from a region of the brain that includes the primary site of neurodegeneration in human Parkinson disease, we have developed a prescreening procedure using single brain region first-strand cDNA probes. Selection of cDNA clones giving low hybridization signals allowed the elimination of clones resulting from abundant messages and enrichment for clones corresponding to low-copy messages. Comparative sequencing of standard and prescreened cDNA libraries (191 and 124 clones, respectively) showed that this procedure raised the frequency of novel sequences encountered from 54 to 81%. The increased proportion of novel ESTs justifies the labor of prescreening. Automation of this procedure will accelerate the molecular description of genes expressed in any brain region, or any tissue, and represents a way to maximize access to cDNA sequences for human and mouse genome characterization. In total, the comparative sequencing experiments generated 207 new mouse and 11 new rat brain ESTs.

Causes and consequences of bacterial adherence to mucosal epithelia during critical illness.

The interaction between host and pathogen during catabolic stress represents a dynamic battlefield, where the microbe's strategy to ensure its survival and multiplication come face to face with the repertoire of the host's immune system. From the microbe's point of view, the ICU offers the least optimal living condition, representing at times an outright holocaust for entire populations of fellow bacteria. This situation is especially true for intestinal bacteria, which can be exposed to all sorts of extreme conditions, such as starvation, turgor pressure, altered temperature, antibiotics, and osmolality changes. These conditions may act as environmental cues and elicit changes in bacterial gene expression that lead to effective coping responses. Starvation countermeasures can be especially strong signals for bacteria to follow chemical trails in search of nutrients. Harming the host is not the microbe's intent; its goal is to prevail. Injury to the host by a microbe struggling to survive is the inadvertent consequence of a threatening environment. This struggle between host and pathogen is particularly apparent at the mucosal surface, especially in the gastrointestinal tract, where microbes have enjoyed the leisurely life of a stable temperature and a constant food supply. The focus of this discussion is on one small aspect of the manner in which microbes ensure their survival during catabolic stress by attaching to host epithelial cells. The conditions and consequences of this process are discussed.

Idiopathic splenomegaly in Iran.

During the past 5 years we have investigated 45 patients with the clinical manifestations suggestive of cirrhosis. We found 40 of them having cirrhosis but 3 patients had idiopathic splenomegaly. They underwent splenctomy and after 1-5 years they have remained free of the disease.