Changes in the physiologic pattern of mitral prosthesis regurgitation in the presence of a prosthetic dysfunction]

AIM OF STUDY: Evaluation by transesophageal echocardiography of the effect on the characteristics of physiological regurgitant jets (JF) resulting from prosthetic disfunction due to pathologic regurgitation (JF). PATIENTS AND METHODS: We studied 69 consecutive patients with the diagnosis of prosthesis in mitral position using transesophageal echocardiography and color doppler codification. The patients were divided in two groups (N and D groups) according to the presence of prosthesis disfunction by pathologic regurgitation. In each patient we determined planimetric areas and atrial peak depth of each JF and also the sum of JF planimetric areas of each mitral prosthesis. When pathological regurgitation was present we calculated the highest planimetric area, severity degree and atrial peak depth in each JP. RESULTS: The planimetric area in each JF of group N was 330 +/- 167 mm2 and in group D 117 +/- 116 mm2 (p less than 0.001). The sum of the areas of JF in group N was 474 +/- 204 mm2 and in group D 254 +/- 176 mm2 (p less than 0.01). The atrial depth of JF in group was 32 +/- 15 mm and in group D 26 +/- 18 mm (p less than 0.01). In group D 29% of the patients had mild pathological regurgitation, 10% moderate and 61% severe. The maximum planimetric area of JP in group D was 1078 +/- 1007 mm2 with atrial depth of 37 +/- 28 mm. CONCLUSION: The pathological regurgitation in disfunction prosthesis in mitral position has a significant reduction effect in the dimension of prosthesis physiologic regurgitation jets. This transesophageal echocardiographic observation makes it possible to characterize and clarify more precisely the different types of mitral prosthesis jets.     

Participation of human epididymal sperm coating antigens in fertilization

A polyclonal antiserum directed against human sperm coating proteins of epididymal origin (anti-KCl) was tested for its ability to alter sperm function. Spermatozoa from normal ejaculates were selected by swim-up separation and capacitated by overnight incubation at room temperature. Exposure of these cells to anti-KCl (0.39 mg protein/ml), prior to their use in the hamster ova penetration test, reduced the penetration of denuded oocytes by 65% (P less than 0.005). Significant inhibitions of lesser magnitude were observed at lower serum concentrations (to 0.098 mg/ml). In an effort to understand the mechanism of this inhibition, other sperm function parameters thought to be related to oocyte penetration were studied. The inhibitory effect was exerted without noticeable changes in sperm motility (determined by the percentage of motile cells and their linear velocity), and in the absence of major sperm agglutination. Anti-KCl did not inhibit the occurrence of spontaneous or induced (by human follicular fluid) acrosome reaction in capacitated spermatozoa. In contrast, exposure to anti-KCl reduced the ability of capacitated spermatozoa to bind tightly to the hamster oolemma. None of these effects were elicited by a control preparation obtained from pre-immune rabbit sera. Exposure of zona-free oocytes to the antiserum did not alter their penetrability by normal sperm. These results suggest that the antigens recognized by anti-KCl participate in some specific step of the sperm-ovum interaction.     

Identification of enterotoxigenic Escherichia coli isolated from swine with diarrhea in Thailand by colony hybridization, using three enterotoxin gene probes.

The DNA colony hybridization assay was used to identify enterotoxigenic Escherichia coli among E. coli isolated from 803 swine with diarrhea at 10 farms in Thailand. Between 5 September and 8 December 1981, enterotoxigenic E. coli were identified in 40% of 58 litters of piglets under 10 days old and 17% of 29 litters between 10 and 21 days old with diarrhea at farms at four different locations in Thailand. All E. coli that hybridized with one or more of the three enterotoxin gene probes produced heat-labile or heat-stable toxin or both, as determined by testing culture supernatants in the Y1 adrenal and suckling mouse assays. The DNA colony hybridization technique is a specific method of identifying enterotoxigenic E. coli from swine and can be used to further characterize these enteric pathogens.     

Etiology of diarrhea among travelers and foreign residents in Nepal

A bacterial pathogen was isolated from 47% of 328 expatriate patients with diarrhea seen at two medical clinics in Nepal in 1986. Enterotoxigenic Escherichia coli (24%), Shigella (14%), and Campylobacter species (9%) were isolated most frequently. Enteroinvasive and adherence factor-positive E coli were isolated from 2% and 1% of patients, respectively. Giardia lamblia was detected in 12% of patients, rotavirus in 8%, and Cryptosporidium and Entamoeba histolytica each in 5%. Blastocystis hominis was present in 33% of patients but in only 9% of those who took trimethoprim-sulfamethoxazole. More than one enteropathogen was detected in 17% of patients. Patients with prolonged symptoms (longer than two weeks) were more likely to have Giardia (27%) and less likely to have Shigella (5%) than were patients with acute symptoms. The isolation rates of bacterial pathogens decreased with length of stay in Nepal. A wide variety of enteropathogens were detected in travelers to Nepal, and Shigella and protozoa were particularly important. Length of time abroad and duration of symptoms were important diagnostic considerations.     

Comparative study of ceftriaxone and trimethoprim-sulfamethoxazole for the treatment of chancroid in Thailand

A single dose of ceftriaxone (250 mg) administered intramuscularly was compared with trimethoprim-sulfamethoxazole (TMP-SMZ; 160/800 mg) administered orally twice daily for seven days or with a single dose of TMP-SMZ (640/3,200 mg) administered orally for the treatment of chancroid in men in Thailand. Haemophilus ducreyi was isolated from 79 (48%) of 164 men with a clinical diagnosis of chancroid. For men with ulcers that were culture positive for H. ducreyi, rates of cure were 100% in 25 men treated with ceftriaxone, 87% in 23 men given TMP-SMZ for seven days, and 55% in 31 men given TMP-SMZ in a single dose. For men with ulcers that were culture negative for H. ducreyi, rates of cure were 100% in 29 men treated with ceftriaxone, 66% in 32 men given TMP-SMZ for seven days, and 63% in 24 men given TMP-SMZ in a single dose. The MIC50 of the three antibiotics for 94 isolates of H. ducreyi were as follows: 0.004 micrograms/ml for ceftriaxone, 16 micrograms/ml for trimethoprim, and greater than 512 micrograms/ml for sulfamethoxazole. Our study indicates that ceftriaxone in a single dose of 250 mg is effective, but that TMP-SMZ, even when given in a standard seven-day regimen, is not effective treatment for chancroid in Thailand.     

Safety and efficacy of olopatadine hydrochloride nasal spray for the treatment of seasonal allergic rhinitis.

BACKGROUND: A nasal spray containing the antiallergy agent olopatadine hydrochloride is being developed for the treatment of seasonal allergic rhinitis (SAR). OBJECTIVE: To evaluate the safety and efficacy of 2 concentrations of olopatadine nasal spray vs placebo in patients with SAR. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. After a 3- to 21-day placebo run-in, 565 patients aged 12 to 80 years were randomized to receive 0.4% or 0.6% olopatadine or placebo, 2 sprays per nostril twice daily for 2 weeks. Patients evaluated morning and evening reflective and instantaneous nasal symptoms (sneezing, stuffy nose, runny nose, and itchy nose, which compose the total nasal symptom score [TNSS]) and ocular symptoms and completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). RESULTS: Olopatadine spray (0.4% and 0.6%) was significantly superior to placebo for percentage change from baseline in overall reflective (P = .004 and P < .001, respectively) and instantaneous (P = .02 and P = .003, respectively) TNSSs. Also, 0.6% olopatadine was significantly superior to placebo for reducing the reflective and instantaneous assessments of sneezing, runny and itchy nose, and itchy eyes; the instantaneous assessments of watery eyes; and the overall and all 7 domain scores of the RQLQ (P < .05). Olopatadine spray exhibited a safety profile comparable with that of placebo. CONCLUSIONS: Olopatadine nasal spray (0.4% and 0.6%) provided statistically significant improvements in allergic rhinitis symptoms compared with placebo regarding TNSSs (reflective and instantaneous) and in quality-of-life variables in patients with SAR. Olopatadine nasal spray administered twice daily was safe and well tolerated in adolescents and adults.     

The Vif and Vpr accessory proteins independently cause HIV-1-induced T cell cytopathicity and cell cycle arrest

HIV type I (HIV-1) can cause G(2) cell cycle arrest and death of CD4(+) T lymphocytes in vitro and inexorable depletion of these cells in vivo. However, the molecular mechanism of viral cytopathicity has not been satisfactorily elucidated. Previously, we showed that HIV-1 kills T cells by a necrotic form of cell death that requires high level expression of an integrated provirus but not the env or nef genes. To determine which viral protein(s) are required for cell death, we systematically mutated, alone and in combination, the ORFs of the NL4-3 strain of HIV-1. We found that the elimination of the viral functions encoded by gag-pol and vpu, tat, and rev did not mitigate cytopathicity. However, elimination of the vif and vpr accessory genes together, but not individually, renders the virus incapable of causing cell death and G(2) cell cycle blockade. We thus identify vif and vpr as necessary for T cell cytopathic effects induced by HIV-1. These findings may provide an important insight into the molecular mechanism of viral pathogenesis in AIDS.     

Efficacy and Safety of Lixisenatide Once-Daily Morning or Evening Injections in Type 2 Diabetes Inadequately Controlled on Metformin (GetGoal-M)

OBJECTIVE

To examine the efficacy and safety of lixisenatide (20 μg once daily, administered before the morning or evening meal) as add-on therapy in patients with type 2 diabetes insufficiently controlled with metformin alone.

RESEARCH DESIGN AND METHODS

This was a 24-week, randomized, double-blind, placebo-controlled study in 680 patients with inadequately controlled type 2 diabetes (HbA_1c 7–10% [53−86 mmol/mol]). Patients were randomized to lixisenatide morning (n = 255), lixisenatide evening (n = 255), placebo morning (n = 85), or placebo evening (n = 85) injections.

RESULTS

Lixisenatide morning injection significantly reduced mean HbA_1c versus combined placebo (mean change −0.9% [9.8 mmol/mol] vs. −0.4% [4.4 mmol/mol]; least squares [LS] mean difference vs. placebo −0.5% [5.5 mmol/mol], P < 0.0001). HbA_1c was significantly reduced by lixisenatide evening injection (mean change –0.8% [8.7 mmol/mol] vs. –0.4% [4.4 mmol/mol]; LS mean difference –0.4% [4.4 mmol/mol], P < 0.0001). Lixisenatide morning injection significantly reduced 2-h postprandial glucose versus morning placebo (mean change −5.9 vs. −1.4 mmol/L; LS mean difference −4.5 mmol/L, P < 0.0001). LS mean difference in fasting plasma glucose was significant in both morning (–0.9 mmol/L, P < 0.0001) and evening (–0.6 mmol/L, P = 0.0046) groups versus placebo. Mean body weight decreased to a similar extent in all groups. Rates of adverse events were 69.4% in both lixisenatide groups and 60.0% in the placebo group. Rates for nausea and vomiting were 22.7 and 9.4% for lixisenatide morning and 21.2 and 13.3% for lixisenatide evening versus 7.6 and 2.9% for placebo, respectively. Symptomatic hypoglycemia occurred in 6, 13, and 1 patient for lixisenatide morning, evening, and placebo, respectively, with no severe episodes.

CONCLUSIONS

In patients with type 2 diabetes inadequately controlled on metformin, lixisenatide 20 μg once daily administered in the morning or evening significantly improved glycemic control, with a pronounced postprandial effect, and was well tolerated.Glucagon-like peptide-1 (GLP-1) receptor agonists are subcutaneously injected glucose-lowering agents that are associated with weight loss and have a low propensity to induce hypoglycemia (1,2). The distinct efficacy and safety profile of this class of drugs provides a novel approach for add-on therapy in the event of failure of other antidiabetic agents. The GLP-1 receptor agonists currently available include twice-daily and once-weekly formulations of exenatide and a once-daily formulation of liraglutide, thus providing a broad scope for tailoring therapy to individual patients (3–5).Lixisenatide is a selective once-daily prandial GLP-1 receptor agonist (6–9) that was approved by the European Medicines Agency in February 2013 for the treatment of type 2 diabetes. The 20-µg once-daily dose was previously shown to provide the best balance of glucose-lowering efficacy and gastrointestinal tolerability in patients with type 2 diabetes inadequately controlled with metformin (7). More recently, lixisenatide 20 μg once daily given as monotherapy was shown to significantly improve HbA_1c and provide a pronounced effect on postprandial plasma glucose (PPG) in patients with type 2 diabetes inadequately controlled with lifestyle intervention alone (6).The efficacy and safety of once-daily morning (prebreakfast) administration of lixisenatide (and twice-daily morning/evening dosing in early studies) have been evaluated in previous clinical studies (6,7,9). If once-daily evening dosing is also effective at reducing HbA_1c with similar tolerability, then this would provide patients with increased flexibility to manage their diabetes according to their lifestyle. In the current study (GLP-1 agonist AVE0010 in paTients with type 2 diabetes mellitus for Glycemic cOntrol and sAfety evaLuation with Metformin treatment [GetGoal-M]), we evaluated the efficacy and tolerability of lixisenatide once daily as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and, in contrast with other studies, included separate treatment arms looking at prebreakfast administration and pre-evening meal administration.