Gerry Hobbs

Effects of insufflation on hemodynamics during thoracoscopy

Thoracic procedures once requiring open thoracotomy are now being performed with video-assisted thoracoscopy. To visualize adequately the intrathoracic structures, creation of an artificial pneumothorax by carbon dioxide insufflation under positive pressures has been advocated. We hypothesized that positive-pressure insufflation during thorascopy would cause significant hemodynamic compromise. Eight healthy female pigs underwent general endotracheal anesthesia and placement of monitoring lines. After placement of a thorascope, baseline hemodynamic measurements were obtained at 0 mm Hg (atmospheric pressure). Measurements were taken randomly at 5, 10, and 15 mm Hg using carbon dioxide insufflation after stabilization at each pressure. Data were analyzed using Pages test for noparametric variables. Insufflation pressures of 5 mm Hg or greater resulted in significant decreases in cardiac index, mean arterial pressure, stroke volume, and left ventricular stroke work index, whereas central venous pressure increased (p < 0.001). Changes in heart rate were not significant. We do not recommend routine positive-pressure insufflation during thorascopy because of the significant hemodynamic compromise in our experimental model.

Analysis of the HD-GYP Domain Cyclic Dimeric GMP Phosphodiesterase Reveals a Role in Motility and the Enzootic Life Cycle of Borrelia burgdorferi

ABSTRACT HD-GYP domain cyclic dimeric GMP (c-di-GMP) phosphodiesterases are implicated in motility and virulence in bacteria. Borrelia burgdorferi possesses a single set of c-di-GMP-metabolizing enzymes, including a putative HD-GYP domain protein, BB0374. Recently, we characterized the EAL domain phosphodiesterase PdeA. A mutation in pdeA resulted in cells that were defective in motility and virulence. Here we demonstrate that BB0374/PdeB specifically hydrolyzed c-di-GMP with a Km of 2.9 nM, confirming that it is a functional phosphodiesterase. Furthermore, by measuring phosphodiesterase enzyme activity in extracts from cells containing the pdeA pdeB double mutant, we demonstrate that no additional phosphodiesterases are present in B. burgdorferi. pdeB single mutant cells exhibit significantly increased flexing, indicating a role for c-di-GMP in motility. Constructing and analyzing a pilZ pdeB double mutant suggests that PilZ likely interacts with chemotaxis signaling. While virulence in needle-inoculated C3H/HeN mice did not appear to be altered significantly in pdeB mutant cells, these cells exhibited a reduced ability to survive in Ixodes scapularis ticks. Consequently, those ticks were unable to transmit the infection to naïve mice. All of these phenotypes were restored when the mutant was complemented. Identification of this role of pdeB increases our understanding of the c-di-GMP signaling network in motility regulation and the life cycle of B. burgdorferi.

Analysis of the Borrelia burgdorferi Cyclic-di-GMP-Binding Protein PlzA Reveals a Role in Motility and Virulence

ABSTRACT The cyclic-dimeric-GMP (c-di-GMP)-binding protein PilZ has been implicated in bacterial motility and pathogenesis. Although BB0733 (PlzA), the only PilZ domain-containing protein in Borrelia burgdorferi, was reported to bind c-di-GMP, neither its role in motility or virulence nor its affinity for c-di-GMP has been reported. We determined that PlzA specifically binds c-di-GMP with high affinity (dissociation constant [Kd ], 1.25 μM), consistent with Kd values reported for c-di-GMP-binding proteins from other bacteria. Inactivation of the monocistronically transcribed plzA resulted in an opaque/solid colony morphology, whereas the wild-type colonies were translucent. While the swimming pattern of mutant cells appeared normal, on swarm plates, mutant cells exhibited a significantly reduced swarm diameter, demonstrating a role of plzA in motility. Furthermore, the plzA mutant cells were significantly less infectious in experimental mice (as determined by 50% infectious dose [ID50]) relative to wild-type spirochetes. The mutant also had survival rates in fed ticks lower than those of the wild type. Consequently, plzA mutant cells failed to complete the mouse-tick-mouse infection cycle, indicating plzA is essential for the enzootic life cycle of B. burgdorferi. All of these defects were corrected when the mutant was complemented in cis. We propose that failure of plzA mutant cells to infect mice was due to altered motility; however, the possibility that an unidentified factor(s) contributed to interruption of the B. burgdorferi enzootic life cycle cannot yet be excluded.

The clinical impact of antibacterial prophylaxis and cycling antibiotics for febrile neutropenia in a hematological malignancy and transplantation unit

Febrile neutropenia is an expected complication during treatment of aggressive hematological malignancies and hematopoietic cell transplantation. We conducted a prospective cohort trial to determine the effects and safety of prophylactic fluoroquinolone administration, and rotation of empiric antibiotics for neutropenic fever in this patient population. From March 2002 through 2004, patients were treated with prophylactic levofloxacin during prolonged neutropenia, and a cycling schedule of empiric antibiotic therapy for neutropenic fever was initiated. The rates of bacteremia, resistance and complications were compared to a retrospective cohort of previously treated patients. The rate of gram-negative bacteremia decreased after the initiation of prophylactic levofloxacin (4.7 vs 1.8 episodes/1000 patient days, P<0.05). Gram-positive bacteremia rates remained unchanged, but more isolates of Enterococcus faecium were resistant to vancomycin after the intervention began. Resistance to the antibiotic agents used in the rotation did not emerge. There was no change in mortality during the intervention period. A prophylactic and cycling antibiotic schedule was successfully implemented on a hematological malignancy and hematopoietic cell transplant unit. gram-negative bacteremia was significantly decreased, without emergence of resistance. Concerns with Gram-positive resistance will require further observation.

Suicide and unintentional poisoning mortality trends in the United States, 1987-2006: two unrelated phenomena?

BackgroundTwo counter trends in injury mortality have been separately reported in the US in recent times - a declining suicide rate and a rapidly rising unintentional poisoning mortality rate. Poisoning suicides are especially difficult to detect, and injury of undetermined intent is the underlying cause-of-death category most likely to reflect this difficulty. We compare suicide and poisoning mortality trends over two decades in a preliminary assessment of their independence and implications for suicide misclassification.MethodsDescription of overall and gender- and age-specific trends using national mortality data from WISQARS, the Web-based Injury Statistics Query and Reporting System, maintained by the Centers for Disease Control and Prevention (CDC). Subjects were the 936,633 residents dying in the 50 states and the District of Columbia between 1987 and 2006 whose underlying cause of death was classified as suicide, unintentional poisoning, or injury mortality of undetermined intent.ResultsThe official US suicide rate declined 18% between 1987 and 2000, from 12.71 to 10.43 deaths per 100,000 population. It then increased to 11.15 deaths per 100,000 by 2006, a 7% rise. By contrast to these much smaller rate changes for suicide, the unintentional poisoning mortality rate rose more than fourfold between 1987 and 2006, from 2.19 to 9.22 deaths per 100,000. Only the population aged 65 years and older showed a sustained decline in the suicide rate over the entire observation period. Consistently highest in gender-age comparisons, the elderly male rate declined by 35%. The elderly female rate declined by 43%. Unlike rate trends for the non-elderly, both declines appeared independent of corresponding mortality trends for unintentional poisoning and poisoning of undetermined intent. The elderly also deviated from younger counterparts by having a smaller proportion of their injury deaths of undetermined intent classified as poisoning. Poisoning manifested as a less common method of suicide for this group than other decedents, except for those aged 15-24 years. Although remaining low, the undetermined poisoning mortality rate increased over the observation period.ConclusionsThe official decline in the suicide rate between 1987 and 2000 may have been a partial artifact of misclassification of non-elderly suicides within unintentional poisoning mortality. We recommend in-depth national, regional, and local population-based research investigations of the poisoning-suicide nexus, and endorse calls for widening the scope of the definition of suicide and evaluation of its risk factors.

Effect of High-Dose Vitamin C on the Steady-State Pharmacokinetics of the Protease Inhibitor Indinavir in Healthy Volunteers

Study Objective. To determine whether daily high‐dose vitamin C alters the steady‐state pharmacokinetics of indinavir, a protease inhibitor indicated for treatment of the human immunodeficiency virus type 1.

Increased risk of brain metastases in patients with HER-2/neu-positive breast carcinoma

Preliminary data have indicated that overexpression of HER-2/neu is correlated with more aggressive disease, an increased metastatic potential, and a poorer prognosis in patients with breast carcinoma. Trastuzumab, a humanized anti-HER-2 antibody, reportedly is unable to penetrate the blood– brain-barrier and to our knowledge its efficacy in patients with brain metastases remains unclear. – 6 We conducted a retrospective study to evaluate whether patients with HER-2/neu-positive breast carcinoma have an increased risk of developing brain metastases. After approval from the institutional review board of West Virginia University, the pathology reports of 703 breast carcinoma patients who were diagnosed between April 1998 and January 2003 were reviewed. Based on immunohistochemistry or fluorescence in situ hybridization positivity, all patients who were positive for HER-2/neu were identified and their medical charts reviewed with regard to their course of disease and sites of metastases. Of the 703 patients studied, 164 (23%) were found to be positive for HER-2/neu; a sufficient oncologic history was available for 102 patients. Thirty-one patients (30%) developed distant metastases (95% confidence interval [95% CI], 0.223– 0.399) during follow-up lasting a median of 57 months. Brain metastases were reported to have developed in 15 of these 31 patients (48%)(95% CI, 0.320 – 0.652). A proportional hazards model was fit to the data to explore the association between patient age and time to the development of metastases. A significantly positive association (P 0.01) was found to exist between the two variables. Other models for censored data (Weibul, log-normal, and exponential models) were fitted and were found to produce nearly identical P values (Fig. 1). The results of this small retrospective study demonstrate that younger women with HER-2/neu-positive breast carcinoma may have a higher risk of developing brain metastases than previously reported for the general metastatic breast carcinoma patient population. This 442

5-Hydroxyindoleacetic acid and substance P profiles in patients receiving emetogenic chemotherapy.

Background. Even though direct cause and effect has not been proved, clinical evidence suggests serotonin and substance P (SP) are involved in the emetic response following chemotherapy. Because of several parallels, we hypothesized that SP release, like serotonin, may be propagated by chemotherapy and both substances can be measured in biological fluids, and correlated with a particular phase of emesis. Methods. Urinary 5-hydroxyindoleacetic acid (5-HIAA) was assessed by HPLC; serum and urine SP were measured by immunoassay. In addition to construction of neurotransmitter profiles, all SP data were grouped according to cisplatin dosages, = or>75 mg/m 2 versus <75 mg/m2, and phase of emesis, acute versus delayed. Analyses of these data were performed by repeated measures analysis of variance. Results. Samples were collected over a 72-hour period from 26 adult patients who received cisplatin-(n=13) or non-cisplatin-containing (n=13) chemotherapy. Mean baseline 5-HIAA: creatinine ratios were 5.23 and 5.16 in females and males, respectively; mean baseline SP levels were 392 and 181 pg/mL in females and males, respectively. Comparisons between SP data stratified by cisplatin dosage and emetic phase were significantly different, P <0.0001. Conclusions. Laboratory studies provide additional evidence that serotonin and SP are involved primarily, though not exclusively, in acute and delayed vomiting, respectively.

Efficacy of methylcellulose and loperamide in managing fecal incontinence

Objective. To evaluate the efficacy of methylcellulose (Citrucel®) and loperamide (Imodium®) in managing fecal incontinence by comparing cure rates with expectant management. Design. Prospective controlled study. Setting. Urogynecology clinic in a university hospital. Population. Sixty‐nine women with fecal incontinence. Methods. All incontinent women received one heaping tablespoon of methylcellulose twice a day, which was increased to two heaping tablespoons twice a day as needed. If the incontinence persisted after taking the maximum dose of methylcellulose for two weeks, loperamide, one capsule twice a day was added, which was increased to two capsules three times a day as needed. If both fecal urgency and incontinence resolved, the therapy was continued for a three‐month treatment period. Women, who declined the proposed treatment and did not undergo any other therapy during the subsequent eight weeks, served as controls. A subject or control was considered cured if she stated that her incontinence was cured, had zero Pescatori incontinence point, resolution of fecal urgency, and her incontinence did not affect her emotional, social, occupational, and physical functions during the three‐month treatment or eight‐week observation period. Main outcome measures. Difference in the cure rate between subjects and controls. Results. Fifty‐nine subjects were treated with methylcellulose. Forty (68%) also required loperamide. Ten women served as controls. Women treated with methylcellulose and loperamide had a higher cure rate than those managed expectantly (46% vs. 0%, p<0.01). Conclusion. Methylcellulose and loperamide are an effective treatment for fecal incontinence, at least on a short‐term basis.

Distribution and utilization of home- and community-based long-term care services for the elderly in North Carolina.

ABSTRACT Provision of home- and community-based long-term care is a growing concern at the national, state, and local levels. As more persons grow old, the need for these services is expected to rise. This analysis examines the distribution and utilization of three home- and community-based long-term care programs in North Carolina for each of the states 100 counties. Maps were generated to examine how counties differed in respect to service utilization among the elderly. Great variability was found in number of elderly utilizing the services across the state as well as the percent of Medicaid- and/or age-eligible persons who utilized the programs. Multivariate modeling for associations to service utilization was only possible for one of the long-term care programs. Results indicated that living alone, being non-white, and having a mobility and self-care limitation were all positively related to utilization. Percent of persons 85 years or older and the ratio of institutionalized long-term care beds were negatively associated with utilization. It was concluded that states must engage in concerted efforts to ensure equity in access to home- and community-based long-term care.