Current concepts of ectopic nodal inclusions with special emphasis on nodal nevi.

Nodal inclusions of ectopic tissue within lymph nodes are seen comparatively often in dermatopathology and general pathology. Glandular and nonglandular epithelium, as well as melanocytic nevi can be observed within lymph nodes and represent mostly incidental findings without any relevance. The main challenge in reporting these morphologic features is to differentiate such benign inclusions from metastatic settlements of distinct organ tumors. As sentinel node biopsy and lymph node dissection have become standard procedure in clinical oncology and have an immense clinical impact, the correct evaluation of these nodal inclusions is indispensable to avoid undertreatment or overtreatment of patients. In addition, the genesis of these inclusions has not yet been satisfactorily clarified. Two concepts have been laid out: the theory of benign metastases and the migration arrest theory. However, neither theory has so far been able to answer the following questions: Why do we find more nodal nevi in patients with melanoma who had a sentinel node biopsy than in patients without melanoma, and why do we not find nodal nevi in deep visceral lymph nodes? We present a comprehensive review of the current knowledge on nodal inclusions, proposing a concept for the pathogenesis of nodal nevi, to answer these questions.

Calf Resistivity Values in Chronic Kidney Disease in a Caucasian Population.

BACKGROUND: Continuous intradialytic calf bioimpedance spectroscopy (cBIS) allows assessment of changes in calf extracellular fluid volume (ECV) to determine dry weight (DW) in hemodialysis patients. During dialysis, calf ECV decreases until excessive ECV has been removed and normalized resistivity ρN,5 rises to values comparable to those of a normal population (cBIS-DW). It is not clear whether chronic kidney disease (CKD) itself influences ρN,5 and whether normal values depend on race and ethnicity. METHODS: Therefore, we determined ρN,5 in 2 populations consisting of 35 healthy Caucasians and 37 with CKD in KDIGO stages G2-G4. Calf resistivity was determined using a bioimpedance spectrum analyzer (Xitron Technologies, San Diego, CA, USA) and was normalized for body mass index. RESULTS: ρN,5 was significantly higher in healthy subjects than in CKD patients (males: 18.2 ± 2.2 vs. 15.0 ± 2.8 × 10-2·Ωm3kg-1, p < 0.001; females: 19.7 ± 3.2 vs. 16.4 ± 3.3 × 10-2·Ωm3kg-1, p = 0.009). ρN,5 in Caucasians was significantly lower than in previously examined North American healthy subjects with prevailing African American race or Hispanic ethnicity (males: 18.2 ± 2.2 vs. 20.5 ± 2.0 × 10-2·Ωm3kg-1, p < 0.001; females: 19.7 ± 3.2 vs. 21.7 ± 2.6 × 10-2·Ωm3kg-1, p = 0.026). CONCLUSION: We present the first determination of ρN,5 values in a Caucasian healthy as well as a non-dialysis dependent CKD population. Both groups differ significantly. Due to higher amounts of extracellular water, subclinical fluid overload already occurs in pre-dialysis stages of CKD. ρN,5 in Caucasians differs significantly from previously established normal ranges in other races/ethnicities. Population-based reference ranges should be established and used in the future to determine DW by means of cBIS.

Design, synthesis and evaluation of MCH receptor 1 antagonists--Part I: Optimization of HTS hits towards an in vivo efficacious tool compound BI 414.

Despite recent approvals of anti-obesity drugs there is still a high therapeutic need for alternative options with higher efficacy in humans. As part of our MCH-R1 antagonist program for the treatment of obesity, a series of biphenylacetamide HTS hits was evaluated. Several issues of the initial lead structures had to be resolved, such as potency, selectivity over related GPCRs and P-gp efflux limiting brain exposure in this series. We could demonstrate that all parameters can be significantly improved by structural modifications resulting in BI 414 as a potent and orally available MCH-R1 antagonist tool compound with acceptable in vivo efficacy in an animal model of obesity.

Design, synthesis and evaluation of MCH receptor 1 antagonists--Part II: Optimization of pyridazines toward reduced phospholipidosis and hERG inhibition.

Despite recent success there remains a high therapeutic need for the development of drugs targeting diseases associated with the metabolic syndrome. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, a series of 3,6-disubstituted pyridazines was evaluated. During optimization several issues of the initial lead structures had to be resolved, such as selectivity over related GPCRs, inhibition of the hERG channel as well as the potential to induce phospholipidosis. Utilizing property-based design, we could demonstrate that all parameters can significantly be improved by consequently increasing the polarity of the compounds. By this strategy, we succeeded in identifying potent and orally available MCH-R1 antagonists with good selectivity over M1 and 5-HT2A and an improved safety profile with respect to hERG inhibition and phospholipidosis.

Calf bioimpedance spectroscopy for determination of dry weight in hemodialysis patients: effects on hypertension and left ventricular hypertrophy.

BACKGROUND/AIMS: Dry weight estimation in hemodialysis patients is still a substantial problem. Despite meticulous clinical assessment, fluid overload is common, leading to hypertension and left ventricular hypertrophy (LVH). Segmental calf bioimpedance spectroscopy (cBIS) is a novel tool for dry weight assessment. Here we tested the hypothesis, that its clinical routine use reduces arterial hypertension and left ventricular mass. METHODS: Left ventricular mass (determined by magnetic resonance imaging), blood pressure and antihypertensive medication (defined daily doses, ddd) were assessed at baseline (BL). Thereafter post-dialytic target weight was reduced until cBIS-defined dry weight was reached (DW). During a 6-month follow up, DW was re-evaluated monthly by cBIS and end-dialytic weight was adjusted correspondingly. At the end, left ventricular mass, blood pressure and antihypertensive medication were determined a 3rd time (follow-up, FU). RESULTS: Eleven out of 15 patients were available for analysis after 6 months. Left ventricular mass showed a declining trend during the study period (Mean±SD; BL 145±54 g; DW 142±55 g; FU 137±52 g; p=0.61, linear mixed model). Comparable results were obtained for systolic blood pressure (BL 158±18 mmHg; DW 144±19 mmHg; FU 149±21 mmHg; p=0.07), and antihypertensive medication (BL 3.28±2.82ddd; DW 2.86±2.81ddd; FU 3.36±3.05ddd; p=0.37). CONCLUSIONS: We conclude that attainment of dry weight assessed by cBIS tends to reduce left ventricular mass and blood pressure while antihypertensive medication remains unchanged. While the study was underpowered, its results provide an important hypothesis generating data basis for the design of larger studies.