Impact of an online reference system on the diagnosis of rare or atypical abdominal tumors and lesions.

The purpose of the present study is to evaluate whether an online reference system (ORS, STATdx Elsevier, Amsterdam, Netherlands) impacts finding the histologically confirmed diagnosis of rare or atypical abdominal tumors and lesions in radiologic imaging. In total, 101 patients with rare tumor entities or lesions and atypical manifestations of common tumors were enrolled retrospectively. Blinded readings were performed by four radiologists with varying levels of experience, who reported on: (a) correct diagnosis (CD), (b) time needed to find the diagnosis, and (c) diagnostic confidence, initially without followed by the assistance of the ORS. The experienced reader (3 years of experience post-residency, CD 49.5%), as well as the advanced reader with 1 year of experience post-residency (CD 43.6%), and a resident with 5 years of experience (CD 46.5%) made the correct diagnosis more frequently compared to the less experienced reader (CD 25.7%). A significant improvement in making the correct diagnosis was only achieved by the advanced reader, the resident with 5 years of experience (CD with ORS 58.4%; p < 0.001). The advanced reader with 1 year of experience post-residency improved slightly (CD ORS 47.5%). The experienced reader (CD ORS 50.5%) and the less experienced reader (CD ORS 27.7%) did not improve significantly. The overall subjective confidence increased significantly when ORS was used (3.2 ± 0.9 vs. 3.8 ± 0.9; p < 0.001). While the ORS had a positive impact on making the correct diagnosis throughout all readers, it favored radiologists with more clinical experience rather than inexperienced residents. Moreover, the ORS increased the diagnostic confidence of all radiologists significantly. In conclusion, the ORS had no significant impact on the diagnosis of rare or atypical abdominal tumors and lesions except for one reader. The greatest benefit is the increase in diagnostic confidence.

Pancreatic cancer in photon-counting CT: Low keV virtual monoenergetic images improve tumor conspicuity.

PURPOSE OF THE STUDY: The aim of the study was to identify differences in the tumor conspicuity of pancreatic adenocarcinomas in different monoenergetic or polyenergetic reconstructions and contrast phases in photon-counting CT (PCCT). MATERIAL AND METHODS: 34 patients were retrospectively enrolled in this study. Quantitative image analysis was performed with region of interest (ROI) measurements in different monoenergetic levels ranging from 40 up to 70 keV (5-point steps) and polyenergetic series. Tumor-parenchyma attenuation differences and contrast-to-noise-ratio (CNR) were calculated. A qualitative image analysis was accomplished by 4 radiologists using a 5-point Likert scale (1 = "not recognizable" up to 5 = "easy recognizable"). Differences between groups were evaluated for statistical significance using the Friedman test and in case of significant differences pair-wise post-hoc testing with Bonferroni correction was applied. RESULTS: Tumor-parenchyma attenuation difference was significantly different between the different image reconstructions for both arterial- and portal-venous-phase-images (p < 0.001). Tumor-parenchyma attenuation difference was significantly higher on arterial-phase-images at mono40keV compared to polyenergetic images (p < 0.001) and mono55keV images or higher (p < 0.001). For portal-venous-phase-images tumor-parenchyma attenuation difference was significantly higher on mono40keV images compared to polyenergetic images (p < 0.001) and mono50keV images (p = 0.03) or higher (p < 0.001). The same trend was seen for CNR. Tumor conspicuity was rated best on mono40keV images with 4.3 ± 0.9 for arterial-phase-images and 4.3 ± 1.1 for portal-venous-phase-images. In contrast, overall image quality was rated best on polyenergetic-images with 4.8 ± 0.5 for arterial-phase-images and 4.7 ± 0.6 for portal-venous-phase-images. CONCLUSION: Low keV virtual monoenergetic images significantly improve the tumor conspicuity of pancreatic adenocarcinomas in PCCT based on quantitative and qualitative results. On the other hand, readers prefer polyenergetic images for overall image quality.

Factors Influencing Quality of Life after Massive Weight Loss-What Makes the Difference?

Although weight reduction in obesity and morbid obesity has been shown to improve associated comorbidities, there is currently no information on what influences quality of life after a large reduction in body weight. The present study looks at differences in patients' quality of life classified by mode and amount of weight loss. MATERIAL AND METHODS: A cross-sectional study was designed using a validated German version of the BODY-Q questionnaire. The internet-based questionnaire was distributed to patients via social media. RESULTS: 460 patients (443 female, 17 male) were interviewed for this study via "Surveymonkey". The comparison of conservative and surgical weight loss showed no significant difference in the patients' quality of life (p > 0.05). A high BMI correlates negatively with body image (p = 0.023 *), as does the specific assessment of most body regions. For example, a negative correlation was found between a high BMI and satisfaction with skin appearance (p < 0.001 *) and satisfaction with the inner thigh (p = 0.011 *). CONCLUSION: Increased weight loss is associated with a greater ability to maximise quality of life. The type of weight loss, whether conservative or surgical, can be neglected based on the present study. Bariatric surgery cannot be considered a universal solution to obesity. Body contouring interventions should also become a focus of therapy.

Measurement of Postoperative Quality of Pain in Abdominoplasty Patients-An Outcome Oriented Prospective Study.

(1) Background: Postoperative pain is a frequently underestimated complication significantly influencing surgical outcome and patient satisfaction. While abdominoplasty is one of the most commonly performed plastic surgery procedures, studies investigating postoperative pain are limited in current literature. (2) Methods: In this prospective study, 55 subjects who underwent horizontal abdominoplasty were included. Pain assessment was performed by using the standardized questionnaire of the Benchmark Quality Assurance in Postoperative Pain Management (QUIPS). Surgical, process and outcome parameters were then used for subgroup analysis. (3) Results: We found a significantly decreased minimal pain level in patients with high resection weight compared to the low resection weight group (p = 0.01 *). Additionally, Spearman correlation shows significant negative correlation between resection weight and the parameter "Minimal pain since surgery" (rs = -0.332; p = 0.013). Furthermore, average mood is impaired in the low weight resection group, indicating a statistical tendency (p = 0.06 and a Χ2 = 3.56). We found statistically significant higher maximum reported pain scores (rs = 0.271; p = 0.045) in elderly patients. Patients with shorter surgery showed a statistically significant (Χ2 = 4.61, p = 0.03) increased claim for painkillers. Moreover, "mood impairment after surgery" shows a dramatic trend to be enhanced in the group with shorter OP duration (Χ2 = 3.56, p = 0.06). (4) Conclusions: While QUIPS has proven to be a useful tool for the evaluation of postoperative pain therapy after abdominoplasty, only continuous re-evaluation of pain therapy is a prerequisite for constant improvement of postoperative pain management and may be the first approach to develop a procedure-specific pain guideline for abdominoplasty. Despite a high satisfaction score, we detected a subpopulation with inadequate pain management in elderly patients, patients with low resection weight and a short duration of surgery.

Complication Rates after Breast Surgery with the Motiva Smooth Silk Surface Silicone Gel Implants-A Systematic Review and Meta-Analysis.

BACKGROUND: In an era where textured devices are being phased out due to concerns about BIA-ALCL, the Motiva SilkSurface breast implants intend to alleviate historical prosthesis-related complications. However, its safety and feasibility remain unelucidated. METHODS: An analysis of Pubmed, Web of Science, Ovid, and Embase databases was performed. A total of 114 studies were identified initially, and 13 of these met the inclusion criteria and were assessed regarding postoperative parameters such as complication rate or follow-up period. RESULTS: In 4784 patients who underwent breast augmentation with Motiva SilkSurface breast implants, a total of 250 (5.2%) complications were observed. Short- and medium-term complication rates ranged from 2.8-14.4% and 0.32-16.67%, respectively. The most common complication was early seroma (n = 52, overall incidence = 1.08%), followed by early hematoma (n = 28, overall incidence = 0.54%). The incidence of capsule contracture was 0.54% and breast implant-associated-anaplastic large cell lymphoma was not observed. DISCUSSION: Although the majority of the studies in the current literature suggest the distinction of the Motiva SilkSurface breast implants in terms of postoperative complications and capsular contracture, its safety and feasibility need to be further elucidated with well-designed, large-scale, multicenter, prospective case-control studies. Other: No funding was received.

Clinical Low-Dose Photon-Counting CT for the Detection of Urolithiasis: Radiation Dose Reduction Is Possible without Compromising Image Quality.

Background: This study evaluated the feasibility of reducing the radiation dose in abdominal imaging of urolithiasis with a clinical photon-counting CT (PCCT) by gradually lowering the image quality level (IQL) without compromising the image quality and diagnostic value. Methods: Ninety-eight PCCT examinations using either IQL70 (n = 31), IQL60 (n = 31) or IQL50 (n = 36) were retrospectively included. Parameters for the radiation dose and the quantitative image quality were analyzed. Qualitative image quality, presence of urolithiasis and diagnostic confidence were rated. Results: Lowering the IQL from 70 to 50 led to a significant decrease (22.8%) in the size-specific dose estimate (SSDE, IQL70 4.57 ± 0.84 mGy, IQL50 3.53 ± 0.70 mGy, p < 0.001). Simultaneously, lowering the IQL led to a minimal deterioration of the quantitative quality, e.g., image noise increased from 9.13 ± 1.99 (IQL70) to 9.91 ± 1.77 (IQL50, p = 0.248). Radiologists did not notice major changes in the image quality throughout the IQLs. Detection rates of urolithiasis (91.3-100%) did not differ markedly. Diagnostic confidence was high and not influenced by the IQL. Conclusions: Adjusting the PCCT scan protocol by lowering the IQL can significantly reduce the radiation dose without significant impairment of the image quality. The detection rate and diagnostic confidence are not impaired by using an ultra-low-dose PCCT scan protocol.

Seasonal Impact on Free Flap Surgery in Terms of Flap Loss and Wound Healing Disorders: A Retrospective Cohort Study of 158 Free Flaps.

(1) Background: Postoperative flap loss and wound healing disorders are severe complications after microsurgical free flap surgery. Despite multiple clinical observations, a possible influence of season and external temperature on outcome are largely missing. (2) Methods: Retrospectively, data were collected from 151 patients receiving microsurgical free flaps from March 2018 to August 2019. Patients were divided into two cohorts. The winter group includes all patients who underwent surgery from October 2018 to March 2019 and the summer group al those who underwent surgery from April 2018 to September 2018. Data included demographic information, pre-existing conditions, flap characteristics, and postoperative complications like flap losses and wound healing problems. External temperatures during the first 14 postoperative days were documented and the predictor of flap loss and wound healing disorders was detected. (3) Results: In the winter group (October-March; Ø 7.24 °C) 72 patients (46 female, 24 males; Ø 57.0 years) and in the summer group (April-September; Ø 18.79 °C) 81 patients (48 female, 33 males; Ø 56.0 years) received free flap surgery. There were no significant differences in demography (age: p = 0.593; gender: p = 0.419; BMI: p = 0.141). We found a significant increase in flap loss during summer (χ2(1) = 6.626; p = 0.010; V = 0.209) strengthened by logistic regression analysis (p = 0.037; Exp(B) = 9.655). Additionally higher average temperatures 14 days postoperatively represents another main driver (p = 0.023, Exp(B) = 1.161) for postoperative flap loss. (4) Conclusions: The data confirm a significantly higher postoperative flap loss in the summer group. This information may potentially contribute to optimization of perioperative management and planning of elective and semi-elective surgeries.

Clinical Low Dose Photon Counting CT for the Detection of Urolithiasis: Evaluation of Image Quality and Radiation Dose.

The purpose of this study was the evaluation of image quality and radiation dose parameters of the novel photon counting CT (PCCT, Naeotom Alpha, Siemens Healthineers) using low-dose scan protocols for the detection of urolithiasis. Standard CT scans were used as a reference (S40, Somatom Sensation 40, Siemens Healthineers). Sixty-three patients, who underwent CT scans between August and December 2021, were retrospectively enrolled. Thirty-one patients were examined with the PCCT and 32 patients were examined with the S40. Radiation dose parameters, as well as quantitative and qualitative image parameters, were analyzed. The presence of urolithiasis, image quality, and diagnostic certainty were rated on a 5-point-scale by 3 blinded readers. Both patient groups (PCCT and S40) did not differ significantly in terms of body mass index. Radiation dose was significantly lower for examinations with the PCCT compared to the S40 (2.4 ± 1.0 mSv vs. 3.4 ± 1.0 mSv; p < 0.001). The SNR was significantly better on images acquired with the PCCT (13.3 ± 3.3 vs. 8.2 ± 1.9; p < 0.001). The image quality of the PCCT was rated significantly better (4.3 ± 0.7 vs. 2.8 ± 0.6; p < 0.001). The detection rate of kidney or ureter calculi was excellent with both CT scanners (PCCT 97.8% and S40 99%, p = 0.611). In high contrast imaging, such as the depiction of stones of the kidney and the ureter, PCCT allows a significant reduction of radiation dose, while maintaining excellent diagnostic confidence and image quality. Given this image quality with our current protocol, further adjustments towards ultra-low-dose CT scans appear feasible.

Low-Dose High-Resolution Photon-Counting CT of the Lung: Radiation Dose and Image Quality in the Clinical Routine.

This study aims to investigate the qualitative and quantitative image quality of low-dose high-resolution (LD-HR) lung CT scans acquired with the first clinical approved photon counting CT (PCCT) scanner. Furthermore, the radiation dose used by the PCCT is compared to a conventional CT scanner with an energy-integrating detector system (EID-CT). Twenty-nine patients who underwent a LD-HR chest CT scan with dual-source PCCT and had previously undergone a LD-HR chest CT with a standard EID-CT scanner were retrospectively included in this study. Images of the whole lung as well as enlarged image sections displaying a specific finding (lesion) were evaluated in terms of overall image quality, image sharpness and image noise by three senior radiologists using a 5-point Likert scale. The PCCT images were reconstructed with and without a quantum iterative reconstruction algorithm (PCCT QIR+/−). Noise and signal-to-noise (SNR) were measured and the effective radiation dose was calculated. Overall, image quality and image sharpness were rated best in PCCT (QIR+) images. A significant difference was seen particularly in image sections of PCCT (QIR+) images compared to EID-CT images (p < 0.005). Image noise of PCCT (QIR+) images was significantly lower compared to EID-CT images in image sections (p = 0.005). In contrast, noise was lowest on EID-CT images (p < 0.001). The PCCT used significantly less radiation dose compared to the EID-CT (p < 0.001). In conclusion, LD-HR PCCT scans of the lung provide better image quality while using significantly less radiation dose compared to EID-CT scans.

Social Media Marketing: What Do Prospective Patients Want to See?

BACKGROUND: Platforms such as Instagram, Facebook, Twitter, and Google+ have created a worldwide audience of almost 3 billion people. Society is dramatically changing, demanding evolution of marketing strategies by plastic surgeons and aesthetic doctors alike. This unknown territory provides excellent opportunities, but creates many pitfalls as well; uncertainty remains as to the most effective manner to promote one's practice/services. OBJECTIVES: The aim of this study was to design a social experiment based on Instagram to give guidance for efficient self-promotion. METHODS: An Instagram account called "doctor.aesthetics" was created. Content was produced, and categorized into 4 groups: Aesthetics, Private Life, Disease, and Science. No bots or other Instagram-based promotion were utilized. Every post was evaluated regarding likes, comments, clicks, new followers, impressions, and savings. RESULTS: After 5 months and 37 posts, 10,500 people followed the account. "Scientific" posts were excluded from the analysis due to a low response rate. A significantly enhanced number of likes for "Private" postings was found. Additionally, "Private" posts led to most clicks and new followers, whereas "Aesthetics" posts were saved by most people. CONCLUSIONS: To benefit the most from social media advertising, it is necessary to offer insights into private life. Although "Aesthetics" and "Disease" postings showed similar response rates, "Scientific" posts failed to attract people.

Mechanical irritation by protruding bone: A possible cause of breast implant rupture.

Although breast implants have been in clinical use for almost 6 decades and have undergone considerable development during this time, implant rupture is still a dreaded long-term complication. Some obvious external factors, such as trauma, can lead to implant rupture, but many studies have reported a high rate of "spontaneous" implant rupture. Herein, we present two cases with the aim of raising awareness of a new possible cause of "spontaneous" implant rupture: mechanical irritation by bony protrusions.

Seasonal Impact on Surgical-Site Infections in Body Contouring Surgery: A Retrospective Cohort Study of 602 Patients over a Period of 6 Years.

BACKGROUND: Postoperative surgical-site infections are severe complications following body contouring surgery. Here, the authors evaluate whether surgical-site infection rates are influenced by higher temperatures during the summer season. METHODS: We enrolled 602 patients who underwent body contouring surgery between 2009 and 2015 in a retrospective cohort study. Data collected included demographics, surgical data, and postoperative outcome. Body contouring surgery procedures included lower and upper body lift, abdominoplasty, breast reduction, mastopexy, brachioplasty, and thigh lift. Infection rates were calculated on a seasonal basis and compared using Fisher's exact test and logistic regression analysis. RESULTS: There were 136 patients (125 women and 11 men) in the warm season [June to August; with an average temperature of 67.622°F (19.79°C)] and 466 patients (438 women and 28 men) in the cold seasons group [September to May, with an average temperature of 45.45 °F (7.47°C)]. The composition of the study cohorts was comparable. The average age was 40 years and the average body mass index was 27 kg/m. From a total of 602 patients, the authors observed 33 surgical-site infections, representing a rate of 5.48 percent. A statistically significant increase of postoperative surgical-site infections could be detected during summer (10.29 percent versus 4.08 percent; p = 0.0071), representing an increase of 150 percent. In addition, a logistic regression analysis determined "season" as the strongest predictor for surgical-site infections, with a risk increase of 2.693 times in the warm season. CONCLUSIONS: Body contouring operations are elective procedures, making careful risk consideration an absolute prerequisite. The authors demonstrate a significantly increased infection risk during summer and establish a causal link between the warm season and surgical-site infection accumulation. Consequently, preoperative patient information and operative planning should be adjusted accordingly. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

[Comparison of the regenerative cytokine profile of adipose-derived stromal cells (ASCs) harvested via abdominoplasty, suction-assisted liposuction (SAL) and ultrasound-assisted liposuction (UAL)]. / Vergleich des Regenerativen Zytokinprofils von Adipose Derived Stromal Cells (ASCs) Gewonnen Mittels Abdominoplastik, Suction Assisted Liposuction (SAL) und Ultrasound Assisted Liposuction (UAL).

INTRODUCTION: Mesenchymal stem cells are already used in numerous areas of medicine. In the field of plastic surgery, the main focus of recent research has been to utilise adipose-derived stromal cells (ASCs), mainly harvested via liposuction. The ability to release regenerative cytokines is supposed to be the key mechanism for the therapeutic efficacy of ASCs. There are currently a variety of methods and devices in clinical use for harvesting lipoaspirate and consequently ASCs. For most of these devices, the effect on the regenerative cytokine profile of ASCs is unknown. The aim of this study is to compare the expression of key regenerative cytokines of ASCs derived by three standard procedures of plastic surgery: abdominoplasty, suction-assisted liposuction (SAL) and ultrasound-assisted liposuction (UAL). PATIENTS AND METHODS: UAL and SAL lipoaspirates were obtained from 3 healthy female volunteers before abdominoplasty was performed in the same patients. ASCs were isolated from UAL and SAL lipoaspirates as well as from abdominoplasty resections and RNA expression of important regenerative cytokines (HGF (hepatocyte growth factor), FGF-2 (basic fibroblast growth factor), MCP-1 (monocyte chemotactic protein 1), SDF-1 (stromal cell-derived factor 1) and VEGF (vascular endothelial growth factor) was compared. RESULTS: There was no difference in the expression of HGF, FGF-2, SDF-1 and VEGF between the individual samples, but we were able to demonstrate significantly increased expression of MCP-1 in ASCs obtained from UAL lipoaspirate. CONCLUSION: UAL and SAL lipoaspirates are suitable for obtaining functional ASCs and are comparable to minimally manipulated cells from abdominoplasty resections.

Effect of myeloid differentiation primary response gene 88 on expression profiles of genes during the development and progression of Helicobacter-induced gastric cancer.

BACKGROUND: Gastric cancer is one of the most common and lethal type of cancer worldwide. Infection with Helicobacter pylori (H. pylori) is recognized as the major cause of gastric cancer. However, it remains unclear the mechanism by which Helicobacter infection leads to gastric cancer. Furthermore, the underlying molecular events involved during the progression of Helicobacter infection to gastric malignancy are not well understood. In previous studies, we demonstrated that that H. felis-infected Myd88 -/- mice exhibited dramatic pathology and an accelerated progression to gastric dysplasia; however, the MyD88 downstream gene targets responsible for this pathology have not been described. This study was designed to identify MyD88-dependent genes involved in the progression towards gastric cancer during the course of Helicobacter infection. METHODS: Wild type (WT) and Myd88 deficient mice (Myd88 -/-) were infected with H. felis for 25 and 47 weeks and global transcriptome analysis performed on gastric tissue using MouseWG-6 v2 expression BeadChips microarrays. Function and pathway enrichment analyses of statistically significant, differential expressed genes (p < 0.05) were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tools. RESULTS: Helicobacter infection affected the transcriptional profile of more genes in Myd88 -/- mice compared to WT mice. Infection of Myd88 -/- mice resulted in the differential expression of 1,989 genes at 25 weeks (1031 up and 958 downregulated). At 47 weeks post-H.felis infection, 2,162 (1140 up and 1022 downregulated) were differentially expressed. The most significant differentially upregulated gene during Helicobacter infection in Myd88 -/- mice was chitinase-like 4 (chil4), which is involved in tissue remodeling and wound healing. Other highly upregulated genes in H. felis-infected Myd88 -/- mice included, Indoleamine 2,3-Dioxygenase 1 (Ido1), Guanylate binding protein 2 (Gbp2), ubiquitin D (Ubd), ß 2 -Microglobulin (B2m), CD74 antigen (Cd74), which have been reported to promote cancer progression by enhancing angiogenesis, proliferation, migration, metastasis, invasion, and tumorigenecity. For downregulated genes, the highly expressed genes included, ATPase H+/K+ transporting, alpha subunit (Atp4a), Atp4b, Mucin 5 AC (Muc5ac), Apolipoprotein A-1 (Apoa1), and gastric intrinsic factor (Gif), whose optimal function is important in maintaining gastric hemostasis and lower expression has been associated with increased risk of gastric carcinogenesis. CONCLUSIONS: These results provide a global transcriptional gene profile during the development and progression of Helicobacter-induced gastric cancer. The data show that our mouse model system is useful for identifying genes involved in gastric cancer progression.

A robust blood gene expression-based prognostic model for castration-resistant prostate cancer.

BACKGROUND: Castration-resistant prostate cancer (CRPC) is associated with wide variations in survival. Recent studies of whole blood mRNA expression-based biomarkers strongly predicted survival but the genes used in these biomarker models were non-overlapping and their relationship was unknown. We developed a biomarker model for CRPC that is robust, but also captures underlying biological processes that drive prostate cancer lethality. METHODS: Using three independent cohorts of CRPC patients, we developed an integrative genomic approach for understanding the biological processes underlying genes associated with cancer progression, constructed a novel four-gene model that captured these changes, and compared the performance of the new model with existing gene models and other clinical parameters. RESULTS: Our analysis revealed striking patterns of myeloid- and lymphoid-specific distribution of genes that were differentially expressed in whole blood mRNA profiles: up-regulated genes in patients with worse survival were overexpressed in myeloid cells, whereas down-regulated genes were noted in lymphocytes. A resulting novel four-gene model showed significant prognostic power independent of known clinical predictors in two independent datasets totaling 90 patients with CRPC, and was superior to the two existing gene models. CONCLUSIONS: Whole blood mRNA profiling provides clinically relevant information in patients with CRPC. Integrative genomic analysis revealed patterns of differential mRNA expression with changes in gene expression in immune cell components which robustly predicted the survival of CRPC patients. The next step would be validation in a cohort of suitable size to quantify the prognostic improvement by the gene score upon the standard set of clinical parameters.

Toll-like receptor 4 protects against lethal Leptospira interrogans serovar icterohaemorrhagiae infection and contributes to in vivo control of leptospiral burden.

The roles of innate immune responses in protection from or pathogenesis of severe leptospirosis remain unclear. We examined the role of Toll-like receptors (TLRs) in mouse infection and macrophage responses to Leptospira. C3H/HeJ mice (TLR4 deficient) and C3H/HeJ-SCID mice, but not C3H/OuJ mice (TLR4 intact), died after intraperitoneal infection with Leptospira interrogans serovar Icterohaemorrhagiae. Death in both C3H/HeJ mouse strains was associated with jaundice and pulmonary hemorrhage, similar to the patient from whom the isolate was obtained. In chronic sublethal infection, TLR4-deficient mice harbored more leptospires in liver, lung, and kidney than control mice. Heat-killed Leptospira stimulated macrophages to secrete proinflammatory cytokines, tumor necrosis factor alpha, interleukin-6, and macrophage inflammatory protein 2 not inhibited by polymyxin B, suggesting that leptospiral lipopolysaccharide (LPS) did not drive these responses. Anti-TLR4 and anti-MD-2 but not anti-CD14 monoclonal antibodies inhibited cytokine production. Peritoneal macrophages from CD14-/- and TLR2-/- mice exhibited no defect in cytokine responses to Leptospira compared to controls. Macrophages from C3H/HeJ, TLR4-/-, and MyD88-/- mice secreted far-lower levels of cytokines than wild-type macrophages in response to Leptospira. TLR4 plays a crucial role in protection from acute lethal infection and control of leptospiral burden during sublethal chronic infection. Cytokine responses in macrophages correlated with leptospiral clearance. These TLR4-dependent but CD14/TLR2-independent responses are likely mediated by a leptospiral ligand(s) other than LPS.

Plasma kinetics of procarbazine and azo-procarbazine in humans.

The plasma kinetics of procarbazine (PCB) and its major metabolite azo-procarbazine (azo-PCB) were systematically investigated in humans for the first time. Eight therapy-refractory tumor patients with normal liver and renal function were given a single oral dose of 300 mg PCB hydrochloride as a drinking solution under fasting conditions. With the exception of the single i.v. administration of 10 mg ondansetron hydrochloride immediately before the administration of PCB, the patients were free of any co-medication 4 weeks before and during the study. PCB and azo-PCB were determined by a specially developed HPLC-UV method. PCB was absorbed very rapidly. Mean maximum plasma concentration was 12.5 min. A high elimination rate of PCB from plasma was found. The mean apparent oral systemic clearance and the plasma elimination half-life were estimated at 35.8 l/min and 9.2 min, respectively. Considerable amounts of azo-PCB are found in the plasma of the eight tumor patients. The mean Cmax and AUC ratios of azo-PCB/PCB were estimated at 5.5 and 45.2. Azo-PCB is formed very rapidly from PCB, but eliminated much more slowly from plasma than PCB. Considerable interindividual differences in the conversion rate of azo-PCB to its further metabolites were observed which should have consequences for the individual tumor therapeutic efficiency of PCB. No toxic side-effects or symptoms such as nausea or vomiting were observed during the entire study.