Publications

Gonorrhea remains an important clinical and public health problem throughout the world. Gonococcal infections have historically been diagnosed by Gram stain and culture but are increasingly diagnosed through nucleic acid tests, thereby eliminating the opportunity for antimicrobial susceptibility testing. Gonococcal infections are typically treated with single-dose therapy with an agent found to cure > 95% of cases. Unfortunately, the gonococcus has repeatedly developed resistance to antimicrobials including sulfonamides, penicillin, tetracyclines and fluoroquinolones. This has now left third-generation cephalosporins as the lone class of antimicrobials recommended as first-line therapy for gonorrhea in some regions. However, resistance to oral third-generation cephalosporins has emerged and spread in Asia, Australia and elsewhere. The mechanism of this resistance seems to be associated with a mosaic penicillin binding protein (penA) in addition to other chromosomal mutations previously found to confer resistance to beta-lactam antimicrobials (ponA, mtrR, penB, pilQ). Few good options exist or are in development for treating cephalosporin-resistant isolates, as most have had multidrug resistance. Preventing the spread of resistant isolates will depend on ambitious antimicrobial management programs, strengthening and expanding surveillance networks, and through effective sexually transmitted disease control and prevention.

OBJECTIVE

To determine whether greater frequency and severity of hot flashes are independently associated with insomnia symptoms and objective measures of disrupted sleep among healthy postmenopausal women with hot flashes.

METHODS

A baseline cross-sectional analysis of a multicenter, randomized trial in 217 healthy postmenopausal women aged 40 to 60 years with hot flashes was conducted. Hot flash frequency and severity were recorded in a daily diary; frequency of moderate to severe hot flashes was the primary measure. Insomnia symptoms were assessed with the Insomnia Severity Index (ISI). Hot flash frequency and severity and objective parameters of sleep-wake patterns (using a wrist actigraph) were concurrently measured over an average of seven consecutive 24-hour periods in a subcohort of 112 women.

RESULTS

The mean age of participants was 54 years, and 80% were white; 33% had an ISI score greater than 14, consistent with at least moderate insomnia. In multivariable analysis, the mean ISI score showed a stepwise increase in magnitude with higher frequency of moderate to severe hot flashes (adjusted mean ISI score, 9.5, 11.4, 11.9, and 13.0 for quartiles 1-4, respectively; P for trend = 0.002). Higher frequency of moderate to severe hot flashes was also independently associated in a graded manner with greater nighttime wakefulness (P for trend = 0.028) and a higher number of long wake episodes (P for trend = 0.008) but was not related to sleep efficiency, total sleep time, or sleep latency.

CONCLUSIONS

Among healthy postmenopausal women with hot flashes, frequency of moderate to severe hot flashes was independently associated in a graded manner with severity of insomnia symptoms and objective measures of nighttime wakefulness and sleep fragmentation.

Activation of sphingosine kinase/sphingosine 1-phosphate-mediated signaling has emerged as a critical cardioprotective pathway in response to acute ischemia/reperfusion injury. Application of exogenous sphingosine 1-phosphate (S1P) in cultured cardiac myocytes subjected to hypoxia or treatment of isolated hearts either before ischemia or at the onset of reperfusion (pharmacologic preconditioning or postconditioning) exerts prosurvival effects. Synthetic congeners of S1P mimic these responses. Gene-targeted mice null for the sphingosine kinase 1 isoform whose hearts are subjected to ischemia/reperfusion injury exhibit increased infarct size and respond poorly either to ischemic preconditioning or to ischemic postconditioning. Measurements of cardiac sphingosine kinase activity and S1P parallel these observations. High-density lipoprotein is a major carrier of S1P, and studies of hearts in which selected S1P receptors have been deleted implicate the S1P cargo of high-density lipoprotein in cardioprotection. These observations have considerable relevance for future therapeutic approaches to acute and chronic myocardial injury.

AIM

To compare thromboembolism rates between hospitalized patients with a diagnosis of ulcerative colitis and other hospitalized patients at high risk for thromboembolism. To compare thromboembolism rates between patients with ulcerative colitis undergoing a colorectal operation and other patients undergoing colorectal operations.

METHODS

Data from the National Hospital Discharge Survey was used to compare thromboembolism rates between (1) hospitalized patients with a discharge diagnosis of ulcerative colitis and those with diverticulitis or acute respiratory failure, and (2) hospitalized patients with a discharge diagnosis of ulcerative colitis who underwent colectomy and those with diverticulitis or colorectal cancer who underwent colorectal operations.

RESULTS

Patients diagnosed with ulcerative colitis had similar or higher rates of combined venous thromboembolism (2.03%) than their counterparts with diverticulitis (0.76%) or respiratory failure (1.99%), despite the overall greater prevalence of thromboembolic risk factors in the latter groups. Discharged patients with colitis that were treated surgically did not have significantly different rates of venous or arterial thromboembolism than those with surgery for diverticulitis or colorectal cancer.

CONCLUSION

Patients with ulcerative colitis who do not undergo an operation during their hospitalization have similar or higher rates of thromboembolism than other medical patients who are considered to be high risk for thromboembolism.

The sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P) pathway, known to determine the fate and growth of various cell types, can enhance cardiac myocyte survival in vitro and provide cardioprotection in acute ex vivo heart preparations. However, the relevance of these findings to chronic cardiac pathology has never been demonstrated. We hypothesized that S1P signaling is impaired during chronic remodeling of the uninfarcted ventricle during the evolution of post-myocardial infarction (MI) cardiomyopathy and that a therapeutic enhancement of S1P signaling would ameliorate ventricular dysfunction. SphK expression and activity were measured in the remote, uninfarcted myocardium (RM) of C57Bl/6 mice subjected to coronary artery ligation. The mRNA expression of S1P receptor isoforms was also measured, as was the activation of the downstream S1P receptor mediators. A cardioprotective role for S1P(1) receptor agonism was tested via the administration of the S1P(1)-selective agonist SEW2871 during and after MI. As a result, the expression data suggested that a dramatic reduction in SphK activity in the RM early after MI may reflect a combination of posttranscriptional and posttranslational modulation. SphK activity continued to decline gradually during chronic post-MI remodeling, when S1P(1) receptor mRNA also fell below baseline. The S1P(1)-specific agonism with oral SEW2871 during the first 2-wk after MI reduced apoptosis in the RM and resulted in improved myocardial function, as reflected in the echocardiographic measurement of fractional shortening. In conclusion, these results provide the first documentation of alterations in S1P-mediated signaling during the in situ development of cardiomyopathy and suggest a possible therapeutic role for the pharmacological S1P receptor agonism in the post-MI heart.