NtrBC Selectively Regulates Host-Pathogen Interactions, Virulence, and Ciprofloxacin Susceptibility of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a metabolically versatile opportunistic pathogen capable of infecting distinct niches of the human body, including skin wounds and the lungs of cystic fibrosis patients. Eradication of P. aeruginosa infection is becoming increasingly difficult due to the numerous resistance mechanisms it employs. Adaptive resistance is characterized by a transient state of decreased susceptibility to antibiotic therapy that is distinct from acquired or intrinsic resistance, can be triggered by various environmental stimuli and reverted by removal of the stimulus. Further, adaptive resistance is intrinsically linked to lifestyles such as swarming motility and biofilm formation, both of which are important in infections and lead to multi-drug adaptive resistance. Here, we demonstrated that NtrBC, the master of nitrogen control, had a selective role in host colonization and a substantial role in determining intrinsic resistance to ciprofloxacin. P. aeruginosa mutant strains (ΔntrB, ΔntrC and ΔntrBC) colonized the skin but not the respiratory tract of mice as well as WT and, unlike WT, could be reduced or eradicated from the skin by ciprofloxacin. We hypothesized that nutrient availability contributed to these phenomena and found that susceptibility to ciprofloxacin was impacted by nitrogen source in laboratory media. P. aeruginosa ΔntrB, ΔntrC and ΔntrBC also exhibited distinct host interactions, including modestly increased cytotoxicity toward human bronchial epithelial cells, reduced virulence factor production and 10-fold increased uptake by macrophages. These data might explain why NtrBC mutants were less adept at colonizing the upper respiratory tract of mice. Thus, NtrBC represents a link between nitrogen metabolism, adaptation and virulence of the pathogen P. aeruginosa, and could represent a target for eradication of recalcitrant infections in situ.

Murine Model of Sinusitis Infection for Screening Antimicrobial and Immunomodulatory Therapies.

The very common condition of sinusitis is characterized by persistent inflammation of the nasal cavity, which contributes to chronic rhinosinusitis and morbidity of cystic fibrosis patients. Colonization by opportunistic pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa triggers inflammation that is exacerbated by defects in the innate immune response. Pathophysiological mechanisms underlying initial colonization of the sinuses are not well established. Despite their extensive use, current murine models of acute bacterial rhinosinusitis have not improved the understanding of early disease stages due to analytical limitations. In this study, a model is described that is technically simple, allows non-invasive tracking of bacterial infection, and screening of host-responses to infection and therapies. The model was modified to investigate longer-term infection and disease progression by using a less virulent, epidemic P. aeruginosa cystic fibrosis clinical isolate LESB65. Tracking of luminescent bacteria was possible after intranasal infections, which were sustained for up to 120 h post-infection, without compromising the overall welfare of the host. Production of reactive oxidative species was associated with neutrophil localization to the site of infection in this model. Further, host-defense peptides administered by Respimat® inhaler or intranasal instillation reduced bacterial burden and impacted disease progression as well as cytokine responses associated with rhinosinusitis. Thus, future studies using this model will improve our understanding of rhinosinusitis etiology and early stage pathogenesis, and can be used to screen for the efficacy of emerging therapies pre-clinically.

Dietary weight loss in insulin-resistant non-obese humans: Metabolic benefits and relationship to adipose cell size.

BACKGROUND AND AIMS: Overweight and obesity increase risk for diabetes and cardiovascular disease, largely through development of insulin resistance. Benefits of dietary weight loss are documented for obese individuals with insulin resistance. Similar benefits have not been shown in overweight individuals. We sought to quantify whether dietary weight loss improves metabolic risk profile in overweight insulin-resistant individuals, and evaluated potential mediators between weight loss and metabolic response. METHODS AND RESULTS: Healthy volunteers with BMI 25-29.9 kg/m2 underwent detailed metabolic phenotyping including insulin-mediated-glucose disposal, fasting/daylong glucose, insulin, triglycerides, FFA, and cholesterol. Subcutaneous fat biopsies were performed for measurement of adipose cell size. After 14 weeks of hypocaloric diet and 2 weeks of weight maintenance, cardiometabolic measures and biopsies were repeated. Changes in weight, % body fat, waist circumference, adipose cell size and FFA were evaluated as predictors of change in insulin resistance. Weight loss (4.3 kg) yielded significant improvements in insulin resistance and all cardiovascular risk markers except glucose, HDL-C, and LDL-C. Improvement in insulin sensitivity was greater among those with <2 vs >2 cardiovascular risk factors at baseline. Decrease in adipose cell size and waist circumference, but not weight or body fat, independently predicted improvement in insulin resistance. CONCLUSIONS: Weight loss yields metabolic health benefits in insulin-resistant overweight adults, even in the absence of classic cardiovascular risk factors. Weight loss-related improvement in insulin sensitivity may be mediated through changes in adipose cell size and/or central distribution of body fat. The insulin-resistant subgroup of overweight individuals should be identified and targeted for dietary weight loss. CLINICAL TRIALS IDENTIFIER: NCT00186459.

Lifetime cost for type 2 diabetes mellitus in Singapore.

BACKGROUND: The mean annual direct medical cost of type 2 diabetes mellitus (T2DM) in Singapore has been found to be SGD 2034 using the prevalence-based approach, but the lifetime direct medical cost of T2DM in Singapore remains largely unknown. The aim of the present study was to determine the lifetime direct medical cost attributable to T2DM and provide estimates of potential savings if T2DM can be prevented or delayed. METHODS: The incidence-based approach was used for the cost-of-illness analysis. Yearly medical expenses were obtained from a regional health system database in Singapore to estimate the lifetime medical cost of T2DM patients. Then, the lifetime medical cost of non-T2DM subjects was predicted using a regression model. From the database, gender- and age-specific annual survival rates of T2DM and non-T2DM subjects were obtained and survival-adjusted yearly expenses over the estimated remaining life span were added to obtain lifetime medical costs. The difference between T2DM and non-T2DM subjects was attributed to excess direct medical costs of T2DM. RESULTS: The excess lifetime medical expenses for T2DM patients were SGD 132 506, 108 589, 83 326 and 70 110 when the age of T2DM diagnosis was 40, 50, 60, and 65 years, respectively. CONCLUSIONS: Even though T2DM patients have a lower life expectancy, T2DM is associated with substantially higher lifetime medical costs. Delaying the onset of T2DM, especially in the young, may lead to lower lifetime medical expenses. If prevention costs can be kept sufficiently low, effective T2DM prevention efforts would likely lead to a reduction in long-term medical costs.

Re-examining the sensitivity of HbA1c to screen for diabetes mellitus.

BACKGROUND: One of the laboratory tests recommended by the American Diabetes Association (ADA) to screen for diabetes mellitus (DM) is HbA1c, and it is particularly suitable for segments of the population that cannot or are unwilling to fast for a screening test. The aim of this study was to determine whether HbA1c would be a useful tool to screen for DM in a real-world setting if ADA guidelines for repeat testing to confirm the diagnosis of DM are strictly adhered to. METHODS: A retrospective database study was performed by extracting demographic and laboratory data from a chronic disease registry that collects data on adults from three tertiary hospitals and nine large primary care clinics in Singapore. Data were extracted and analyzed for adults not previously known to have DM whose data was captured in the registry between 2005 and 2016 with HbA1c and at least two diagnostic tests for DM (fasting plasma glucose or 2-h plasma glucose) performed within 4 weeks after HbA1c determination. RESULTS: In all, 3928 adults were included in this study. The sensitivity, specificity, and area under the receiver operating characteristic curve for HbA1c at a threshold of 6.5% were 85.2%, 82.3%, and 0.914, respectively. A higher sensitivity was found in female adults, younger adults, and those of non-Chinese ethnicity. CONCLUSIONS: The sensitivity of HbA1c as a screening test for DM in this study was significantly higher than that reported previously. This work provides additional evidence supporting the inclusion of HbA1c as one of the screening tests for DM.

Current Uses of Botulinum Neurotoxins in Plastic Surgery.

LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Recognize the various types of botulinum toxins and their differences. 2. Identify current indications, both approved and off-label. 3. Inject botulinum toxin to counteract various natural aging processes, including facial descent and rhytides. SUMMARY: Botulinum neurotoxin is a naturally synthesized microbial protein that has been applied in the management of various disorders. In particular, its application within the realm of plastic surgery is addressed in this article. After evaluating the medical literature, the seven indications with the highest quality trials for the use of botulinum neurotoxin in plastic surgery were as follows: rhytides, facial dystonias, facial nerve palsy and aberrant regeneration, hand tremor, palmar hyperhidrosis, neuropathic pain, and upper limb spasticity.

Lower Face: Clinical Anatomy and Regional Approaches with Injectable Fillers.

The use of injectable fillers enables facial sculpting through treatment of volume depletion and modeling of facial contours. Injectable fillers are among the most frequently performed minimally invasive cosmetic procedures.However, treatment of the lower third of the face can be challenging and requires expertise in facial anatomy. In this article, the authors provide a comprehensive review of the anatomy of the lower third of the face, highlighting danger zones. In addition, the authors describe their preferred approach and detailed technique used in the treatment of each specific area, namely the jawline, prejowl sulcus, melomental folds, and lips.

Human cathelicidin LL-37 and its derivative IG-19 regulate interleukin-32-induced inflammation.

Human cathelicidin LL-37 protects against infections and endotoxin-induced inflammation. In a recent study we have shown that IG-19, an LL-37-derived peptide, protects in a murine model of arthritis. Cytokine interleukin-32 (IL-32) is elevated and directly associated with the disease severity of inflammatory arthritis. Therefore, in this study we examined the effects of LL-37 and IG-19 on IL-32-induced responses in human peripheral blood-derived mononuclear cells (PBMC) and macrophages. We showed that CD14(+) monocytes are the primary cells that produce pro-inflammatory tumour necrosis factor-α (TNF-α) following stimulation of PBMC with IL-32. We demonstrated that LL-37 and IG-19 significantly suppress IL-32-induced production of pro-inflammatory cytokines, e.g. TNF-α and IL-1ß, without altering chemokine production. In contrast, LL-37 and IG-19 enhance the production of the anti-inflammatory cytokine IL-1RA. Further mechanistic studies revealed that LL-37 and IG-19 suppress IL-32-mediated phosphorylation of Fyn (Y420) Src kinase. In contrast, IL-32-mediated phosphorylation of AKT-1 (T308) and MKP-1 (S359) is not suppressed by the peptides. LL-37 and IG-19 alone induce the phosphorylation of MKP-1 (S359), which is a known negative regulator of inflammation. Furthermore, the peptides induce the activity of p44/42 mitogen-activated protein kinase, which is known to phosphorylate MKP-1 (S359). This is the first study to demonstrate the regulation of IL-32-induced inflammation by LL-37 and its derivative peptide IG-19. The mechanistic results from this study suggest that regulation of immune-mediated inflammation by these peptides may be controlled by the dual phosphatase MKP-1. We speculate that LL-37 and its derivatives may contribute to the control of immune-mediated inflammatory diseases.

Yersinia enterocolitica infections associated with improperly pasteurized milk products: southwest Pennsylvania, March-August, 2011.

In July 2011, a cluster of Yersinia enterocolitica infections was detected in southwestern Pennsylvania, USA. We investigated the outbreak's source and scope in order to prevent further transmission. Twenty-two persons were diagnosed with yersiniosis; 16 of whom reported consuming pasteurized dairy products from dairy A. Pasteurized milk and food samples were collected from this dairy. Y. enterocolitica was isolated from two products. Isolates from both food samples and available clinical isolates from nine dairy A consumers were indistinguishable by pulsed-field gel electrophoresis. Environmental and microbiological investigations were performed at dairy A and pasteurization deficiencies were noted. Because consumption of pasteurized milk is common and outbreaks have the potential to become large, public health interventions such as consumer advisories or closure of the dairy must be implemented quickly to prevent additional cases if epidemiological or laboratory evidence implicates pasteurized milk as the outbreak source.

Poor histological healing of a femoral fracture following 12 months of oestrogen deficiency in rats.

SUMMARY: Fractures in post-menopausal osteoporosis cause significant morbidity; however, animal models for post-menopausal fracture healing lack the effect of ageing. Therefore, we developed a model using aged animals with chronic oestrogen deficiency, which demonstrates inferior fracture repair (decreased healing histologically, bone mineral density and content and strength). This novel model may help develop molecular strategies for osteoporotic fracture repair. INTRODUCTION: The femur is susceptible to damage by both systemic conditions such as osteoporosis and locally by traumatic injury. The capacity for fracture repair decreases with age, while the risk of fracture increases. As studies of osteoporotic fracture healing in rats traditionally use a period of 3 months or less of oestrogen deficiency prior to fracturing, we aimed to establish a osteoporosis model in rats with chronic oestrogen deficiency by 12 months to better mimic human female osteoporosis. METHODS: Seventy female Sprague-Dawley rats (10 weeks old) were ovariectomised or sham operated and housed for 12 months. The right femur was fractured by way of an open osteotomy and fixed with an intramedullary Kirschner wire. Animals were sacrificed at 1, 3 and 6 weeks for radiography, dual-energy X-ray absorptiometry, tensile testing and histology. RESULTS: Bone mineral density and bone mineral content were lower by 60 and 63 %, respectively, (p < 0.05) in the bilaterally ovariectomized (OVX) groups than those in the sham groups at 6 weeks in the right fractured femurs. Maximum breaking force of the OVX group was lower than that of the sham group, with the greatest difference seen at 6 weeks following osteotomy. Histologically, the OVX groups demonstrated a delay in cellular differentiation within the fracture callus and the presence of bone resorption. The sham animals had a superior histological healing pattern with an Allen score of 4 at 6 weeks compared to a score of 1 for the OVX groups (p < 0.01). CONCLUSIONS: Long-term ovariectomy has a deleterious effect on fracture healing in a rodent model.

Inflammation in subcutaneous adipose tissue: relationship to adipose cell size.

AIMS/HYPOTHESIS: Inflammation is associated with increased body mass and purportedly with increased size of adipose cells. We sought to determine whether increased size of adipose cells is associated with localised inflammation in weight-stable, moderately obese humans. METHODS: We recruited 49 healthy, moderately obese individuals for quantification of insulin resistance (modified insulin suppression test) and subcutaneous abdominal adipose tissue biopsy. Cell size distribution was analysed with a multisizer device and inflammatory gene expression with real-time PCR. Correlations between inflammatory gene expression and cell size variables, with adjustment for sex and insulin resistance, were calculated. RESULTS: Adipose cells were bimodally distributed, with 47% in a 'large' cell population and the remainder in a 'small' cell population. The median diameter of the large adipose cells was not associated with expression of inflammatory genes. Rather, the fraction of small adipose cells was consistently associated with inflammatory gene expression, independently of sex, insulin resistance and BMI. This association was more pronounced in insulin-resistant than insulin-sensitive individuals. Insulin resistance also independently predicted expression of inflammatory genes. CONCLUSIONS/INTERPRETATION: This study demonstrates that among moderately obese, weight-stable individuals an increased proportion of small adipose cells is associated with inflammation in subcutaneous adipose tissue, whereas size of mature adipose cells is not. The observed association between small adipose cells and inflammation may reflect impaired adipogenesis and/or terminal differentiation. However, it is unclear whether this is a cause or consequence of inflammation. This question and whether small vs large adipose cells contribute differently to inflammation in adipose tissue are topics for future research. TRIAL REGISTRATION: ClinicalTrials.gov NCT00285844.

CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice.

Tubular damage following ischemic renal injury is often reversible, and tubular epithelial cell (TEC) proliferation is a hallmark of tubular repair. Macrophages have been implicated in tissue repair, and CSF-1, the principal macrophage growth factor, is expressed by TECs. We therefore tested the hypothesis that CSF-1 is central to tubular repair using an acute renal injury and repair model, ischemia/reperfusion (I/R). Mice injected with CSF-1 following I/R exhibited hastened healing, as evidenced by decreased tubular pathology, reduced fibrosis, and improved renal function. Notably, CSF-1 treatment increased TEC proliferation and reduced TEC apoptosis. Moreover, administration of a CSF-1 receptor-specific (CSF-1R-specific) antibody after I/R increased tubular pathology and fibrosis, suppressed TEC proliferation, and heightened TEC apoptosis. To determine the contribution of macrophages to CSF-1-dependent renal repair, we assessed the effect of CSF-1 on I/R in mice in which CD11b+ cells were genetically ablated and determined that macrophages only partially accounted for CSF-1-dependent tubular repair. We found that TECs expressed the CSF-1R and that this receptor was upregulated and coexpressed with CSF-1 in TECs following renal injury in mice and humans. Furthermore, signaling via the CSF-1R stimulated proliferation and reduced apoptosis in human and mouse TECs. Taken together, these data suggest that CSF-1 mediates renal repair by both a macrophage-dependent mechanism and direct autocrine/paracrine action on TECs.

Tolerability outcomes of a multicenter, observational, open-label, drug-surveillance study in patients with type 2 diabetes mellitus treated with pioglitazone for 2 years.

OBJECTIVE: Pioglitazone (PIO), a thiazolidinedione (TZD), is reported to be highly effective in the treatment of type 2 diabetes mellitus, but is associated with edema, heart failure, and weight gain. This study documented long-term tolerability outcomes of patients taking pioglitazone and assessed how troublesome these adverse events were for the patients. METHODS: This was a prospective, multicenter, observational, open-label, drug-surveillance study that followed patients for 2 years. Patients were already taking or received prescriptions for PIO (PIO group) or a non-TZD (comparator group). Data on glycosylated hemoglobin, fasting plasma glucose, and physician-assessed hypoglycemia were gathered every 4 to 6 months. Patients answered a questionnaire about edema, shortness of breath, and weight gain and were asked to self-assess how troublesome these events were. Peripheral edema and weight gain were selected for post hoc analysis. The Edema Severity scale (ranging from no edema to very deep edema causing gross distortion to amputation) was used to evaluate peripheral edema. Physicians determined the relationship between treatment and serious adverse events. RESULTS: Investigators at 176 sites across Canada enrolled 1871 patients (53 patients in the comparator group were later excluded for receiving PIO). Data from 1527 PIO patients and 291 comparator patients were analyzed (mean age: 59.5 years PIO, 61.6 years comparator; males: 58.0% PIO, 59.8% comparator; white: 77.9% PIO, 81.4% comparator; mean weight: 87.2 kg PIO, 86.1 kg comparator). Median dose of PIO was 30 mg/d. Edema and weight gain were the only adverse events for which statistical models were fitted. Results at 2 years were as follows: peripheral edema-p25.1% (383/1527) of patients in the PIO group, 16.5% (48/291) in the comparator group (adjusted odds ratio [OR]: 1.92 [95% CI, 1.32-2.79]); pulmonary edema-1.3% (20/1527) PIO, 0.7% (2/291) comparator; heart failure-2.4% (37/1527) PIO, 1.4% (4/291) comparator; weight gain-49.6% (757/1527) PIO, 36.8% (107/291) comparator; mean weight gain-2.19 kg PIO (n = 1344), 0.34 kg comparator (n = 251) (adjusted OR: 1.70 [95% CI, 1.29-2.22]). Patient self-assessment at 2 years revealed: edema-rated very or extremely troublesome by 11.2% (29/258) PIO, 13.8% (5/36) comparator; shortness of breath on exertion-15.1% (174/1153) PIO, 16.2% (32/198) comparator (rated very or extremely troublesome by 8.6% [15/174] PIO, 21.9% [7/32] comparator); shortness of breath lying down and at night occurred less frequently (1.8%-4.5% in both groups) than shortness of breath on exertion; and weight gain-rated very or extremely troublesome by 4.8% (22/455) PIO, 2.9% (2/70) comparator. Deaths occurred in approximately 2% of patients in each group (37/1527 PIO, 6/344 comparator); none of the deaths in the PIO group were judged by the investigators to be related to the study drug. CONCLUSIONS: After 2 years of treatment, the incidences of heart failure (2.4%) and pulmonary edema (1.3%) in the patients who received PIO in this observational study were low and consistent with published literature. In this study, patients in the PIO group experienced more peripheral edema (adjusted OR, 1.92) and greater weight gain (adjusted OR, 1.70) than did patients in the non-TZD (comparator) group. The subjective assessment of the troublesome nature of these adverse events on these patients taking PIO was low.

Insulin resistance is associated with a modest increase in inflammation in subcutaneous adipose tissue of moderately obese women.

AIMS/HYPOTHESIS: We have previously described differences in adipose cell size distribution and expression of genes related to adipocyte differentiation in subcutaneous abdominal fat obtained from insulin-sensitive (IS) and -resistant (IR) persons, matched for degree of moderate obesity. To determine whether other biological properties also differ between IR and IS obese individuals, we quantified markers of inflammatory activity in adipose tissue from overweight IR and IS individuals. METHODS: Subcutaneous abdominal tissue was obtained from moderately obese women, divided into IR (n = 14) and IS (n = 19) subgroups by determining their steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Inflammatory activity was assessed by comparing expression of nine relevant genes and by immunohistochemical quantification of CD45- and CD68-containing cells. RESULTS: SSPG concentrations were approximately threefold higher in IR than in IS individuals. Expression levels of CD68, EMR1, IL8, IL6 and MCP/CCL2 mRNAs were modestly but significantly increased (p < 0.05) in IR compared with IS participants. Results of immunohistochemical staining were consistent with gene expression data, demonstrating modest differences between IR and IS individuals. Crown-like structures, in which macrophages surround single adipocytes, were rarely seen in tissue from either subgroup. CONCLUSIONS/INTERPRETATION: A modest increase in inflammatory activity was seen in subcutaneous adipose tissue from IR compared with equally obese IS individuals. Together with previous evidence of impaired adipose cell differentiation in IR vs equally obese individuals, it appears that at least two biological processes in subcutaneous adipose tissue characterize the insulin-resistant state independent of obesity per se.

Enhanced proportion of small adipose cells in insulin-resistant vs insulin-sensitive obese individuals implicates impaired adipogenesis.

AIMS/HYPOTHESIS: The biological mechanism by which obesity predisposes to insulin resistance is unclear. One hypothesis is that larger adipose cells disturb metabolism via increased lipolysis. While studies have demonstrated that cell size increases in proportion to BMI, it has not been clearly shown that adipose cell size, independent of BMI, is associated with insulin resistance. The aim of this study was to test this widely held assumption by comparing adipose cell size distribution in 28 equally obese, otherwise healthy individuals who represented extreme ends of the spectrum of insulin sensitivity, as defined by the modified insulin suppression test. SUBJECTS AND METHODS: Subcutaneous periumbilical adipose tissue biopsy samples were fixed in osmium tetroxide and passed through the Beckman Coulter Multisizer to obtain cell size distributions. Insulin sensitivity was quantified by the modified insulin suppression test. Quantitative real-time PCR for adipose cell differentiation genes was performed for 11 subjects. RESULTS: All individuals exhibited a bimodal cell size distribution. Contrary to expectations, the mean diameter of the larger cells was not significantly different between the insulin-sensitive and insulin-resistant individuals. Moreover, insulin resistance was associated with a higher ratio of small to large cells (1.66 +/- 1.03 vs 0.94 +/- 0.50, p = 0.01). Similar cell size distributions were observed for isolated adipose cells. The real-time PCR results showed two- to threefold lower expression of genes encoding markers of adipose cell differentiation (peroxisome proliferator-activated receptor gamma1 [PPARgamma1], PPARgamma2, GLUT4, adiponectin, sterol receptor element binding protein 1c) in insulin-resistant compared with insulin-sensitive individuals. CONCLUSIONS/INTERPRETATION: These results suggest that after controlling for obesity, insulin resistance is associated with an expanded population of small adipose cells and decreased expression of differentiation markers, suggesting that impairment in adipose cell differentiation may contribute to obesity-associated insulin resistance.

Lopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjects.

Limited data are available about the effect of steady-state lopinavir and ritonavir (LPV/r) on bupropion pharmacokinetics. As patients may benefit by using these two agents in combination, this study determined the extent and direction of this drug-drug interaction. Twelve healthy volunteers received a single 100 mg dose of sustained-release bupropion before and after 2 weeks of treatment with LPV/r 400 mg/100 mg twice daily. Pharmacokinetics profiles were determined on days 1 and 30 for bupropion and hydroxybupropion and days 29 and 30 for LPV/r. LPV/r administration significantly decreased bupropion maximum plasma concentration (C(max)) by 57% (90% confidence interval (CI), 38-76%; P<0.01) and area under the curve (AUC) infinity by 57% (90% CI, 32-83%; P<0.01). Hydroxybupropion C(max) and AUC infinity decreased by 31% (90% CI, 7-55%; P<0.01) and by 50% (90% CI, 34-65%; P<0.01), respectively. No significant changes in the pharmacokinetics of LPV/r were found following administration of a single dose of bupropion. Concurrent use of LPV/r and bupropion resulted in decreased exposure to bupropion and its active metabolite hydroxybupropion that may necessitate as much as a 100% dose increase of bupropion. A probable mechanism for this interaction is the concurrent induction of cytochrome P450 2B6 and UDP-glucuronosyltransferase enzymes. LPV/r exposure is unaffected by a single dose of bupropion.

Intraoperative tissue expansion in rhytidectomy revisited.

Intraoperative tissue expansion is an adjunct that has been used during rhytidectomy to rejuvenate the face and neck. This technique has been thought to allow for additional skin resection and, thus, increased skin tightening during rhytidectomy. The stretch of the skin by expansion should allow for additional skin resection before closure. Also, when the force of the underlying expander is removed, the expanded skin would recoil and the advancement of the flap should become tighter, with improved results. The technique achieved some popularity a few years ago but has received little recent attention. In this study, the authors attempted to compare face-lift results of adjunctive intraoperative tissue expansion during rhytidectomy with similar techniques without intraoperative expansion. The results of 50 female patients who underwent rhytidectomy for midface rejuvenation by a single operating surgeon composed the study group. Twenty-five of the patients had undergone rhytidectomy that addressed the cheek, chin, and neck areas without expansion (nonexpanded rhytidectomy group). The other 25 patients (expanded rhytidectomy group) had adjunctive intraoperative tissue expansion performed with the rhytidectomy. A tissue expander was temporarily placed beneath the rhytidectomy flaps on each side and expanded in a standard manner before final skin resection and closure. Frontal and lateral photographs were evaluated by 54 examiners. Preoperative and postoperative photographs of the 50 patients were viewed side-by-side by the examiners. The patients were presented in blind fashion and random order. The examiners graded the results of each patient on a scale of improvement from 1 to 10, with 10 being the maximum level of improvement. The scores were recorded and statistically evaluated by using the two-sample test. Evaluation of the examiners' scores showed that the mean rating given to patients in the expanded rhytidectomy group was 5.07 (SD = 1.12). The mean rating for the nonexpanded rhytidectomy group was 5.27 (SD = 1.57). When the two groups were compared using the two-sample test, the difference between the two was not statistically significant (p = 0.6127). Intraoperative tissue expansion as an adjunct to rhytidectomy did not result in improved facial rejuvenation in this patient series. The authors' impression is that the benefits of tissue expansion do not justify the added expense, time, and risks associated with using tissue expansion during rhytidectomy.

Topotecan-filgrastim combination is an effective regimen for mobilizing peripheral blood stem cells.

We compared the efficacy, toxicity, and cost of topotecan-filgrastim and filgrastim alone for mobilizing peripheral blood stem cells (PBSCs) in 24 consecutive pediatric patients with newly diagnosed medulloblastoma. PBSCs were mobilized with an upfront window of topotecan-filgrastim for 11 high-risk patients (residual tumor > or =1.5 cm2 after resection; metastases limited to neuraxis) and with filgrastim alone for 13 average-risk patients. All patients subsequently underwent craniospinal irradiation and four courses of high-dose chemotherapy with stem cell rescue. Target yields of CD34+ cells (> or =8 x 10(6)/kg) were obtained with only one apheresis procedure for each of the 11 patients treated with topotecan-filgrastim, but with a mean of 2.3 apheresis procedures for only six (46%) of the 13 patients treated with filgrastim alone (P = 0.0059). The median peak and median total yield of CD34+ cells were six-fold higher for the topotecan-filgrastim group (328/microl and 21.5 x 10(6)/kg, respectively) than for the filgrastim group (54/microl and 3.7 x 10(6)/kg, respectively). Mean times to neutrophil and platelet engraftment were similar. Myelosuppression was the only grade 4 toxicity associated with topotecan-filgrastim mobilization and lasted a median of 5 days. Compared with filgrastim mobilization, topotecan-filgrastim mobilization resulted in a mean cost saving of $3966 per patient. Topotecan-filgrastim is an efficacious, minimally toxic, and cost-saving combination for PBSC mobilization.