Spectroscopic and biochemical correlations during the course of human lens aging

Background  

With age, the human lens accumulates variety of substances that absorbs and fluorescence, which explains the color of yellow, brunescent and nigrescent cataract in terms of aging. The aim of this study was to assess lens fluorophores with properties comparable to those of advanced glycated end products (AGEs) in relation to age in human lenses. These fluorescent compounds are believed to be involved in the development of cataract.     

Laparoscopic liver resection: experience of 53 procedures at a single center

Background/Purpose The short-term outcome following laparoscopic liver resection at a single center is presented.Methods Fifty-three procedures were carried out in 47 patients, between August 1998 and April 2004 (6 patients were resected on two occasions). A previous laparotomy and/or hepatectomy had been done in 83% and 26% of the procedures, respectively. Colorectal metastasis was the main indication for treatment (42/53). A total laparoscopic approach was applied.Results Three of the 53 (6%) procedures were converted to laparotomy. In one additional procedure, radiofrequency ablation was done instead of resection. Sixty liver resections were done during the 49 procedures completed laparoscopically as planned (9 patients had concomitant resections performed). Nonanatomic (45/60) and anatomic (15/60; left lobectomies) resections were done. Tumor tissue was found in the resection margins of 6% of the specimens. The free margin was very short in 8% of the specimens. The morbidity was 16%. There was no mortality. Blood transfusions were given following 26% of the procedures. The median hospital stay was 3.5 days (range, 1–14 days) and the median number of days on which there was a need for opioids was 1 (range, 0–11 days).Conclusions Laparoscopic liver resection can be performed safely and seems to offer short-term benefits to the patients. Randomized studies are required to further evaluate the potential benefits of this treatment.     

Radiology-Pathology Conference: Bilateral renal oncocytomas

Oncocytoma is an uncommon benign, typically solitary renal tumor first reported in 1942. Renal oncocytomas are rarely multiple and/or bilateral. Accurate preoperative diagnosis and differentiation from renal carcinoma is difficult. We report the radiology and pathology of a patient with bilateral renal oncocytomas and review the literature of this rare presentation.     

Human sympathetic activation by alpha2-adrenergic blockade with yohimbine: Bimodal, epistatic influence of cytochrome P450-mediated drug metabolism

BACKGROUND: alpha2-Adrenergic blockade responses suggest adrenergic dysfunction in hypertension. alpha2-Blockade is also used to treat autonomic dysfunction. However, pharmacokinetic determinants of yohimbine disposition are not understood. METHODS: We evaluated alpha2-blockade with intravenous yohimbine in 172 individuals. Specific cytochrome P450 (CYP) isoform-mediated metabolism was investigated. Results were evaluated by ANOVA and by maximum likelihood analysis for bimodality of response distributions. RESULTS: Yohimbine metabolism to 11-hydroxy-yohimbine displayed greater than 1000-fold variability, with 17 individuals showing no metabolism. Nonmetabolizers differed from others in ethnicity but not in age, sex, body habitus, blood pressure, heart rate, or family history of hypertension. Bimodality of metabolism was suggested by frequency histogram, as well as maximum likelihood and cluster analysis. Among ethnic groups, subjects of European ancestry had the highest frequency of nonmetabolism. In vitro oxidation suggested that the major route of metabolism (lowest Michaelis-Menten constant and greatest intrinsic clearance) was likely via CYP2D6 to 11-hydroxy-yohimbine. In vivo genotypes at both CYP2D6 and CYP3A4 were necessary to predict metabolism (overall F = 3.03, P =.005); an interaction of alleles at these 2 loci (interaction F = 3.05, P =.033) suggested an epistatic effect on drug metabolism in vivo. Nonmetabolizers had greater activation of sympathetic nervous system activity. Yohimbine increased blood pressure, an effect mediated hemodynamically by elevation of cardiac output rather than systemic vascular resistance. Blood pressure and cardiac output responses did not differ by metabolizer group. CONCLUSIONS: We conclude that heterogeneous, bimodally distributed yohimbine metabolism depends on common genetic variation in both CYP2D6 and CYP3A4 and contributes to differences in sympathetic neuronal response to alpha2-blockade. These results have implications for both diagnostic and therapeutic uses of this alpha2-antagonist.     

Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable,locally advanced pancreatic cancer

Background:

To evaluate the efficacy and tolerability of the urokinase plasminogen activator (uPA) inhibitor upamostat in combination with gemcitabine in locally advanced pancreatic adenocarcinoma (LAPC).

Methods:

Within a prospective multicenter study, LAPC patients were randomly assigned to receive 1000 mg m⁻² of gemcitabine IV weekly either alone (arm A) or in combination with 200 mg (arm B) or 400 mg (arm C) oral upamostat daily. Efficacy endpoints of this proof-of-concept study included response rate, time to first metastasis, progression-free and overall survival (OS).

Results:

Of the 95 enroled patients, 85 were evaluable for response and 93 for safety. Median OS was 12.5 months (95% CI 8.2–18.2) in arm C, 9.7 months (95% CI 8.4–17.1) in arm B and 9.9 months (95% CI 7.4–12.1) in arm A; corresponding 1-year survival rates were 50.6%, 40.7% and 33.9%, respectively. More patients achieved a partial remission (confirmed responses by RECIST) with upamostat combination therapy (arm C: 12.9% arm B: 7.1% arm A: 3.8%). Overall, only 12 patients progressed by developing detectable distant metastasis (arm A: 4, arm B: 6, arm C: 2). The most common adverse events considered to be related to upamostat were asthenia, fever and nausea.

Conclusion:

In this proof-of-concept study targeting the uPA system in LAPC, the addition of upamostat to gemcitabine was tolerated well; similar survival results were observed for the three treatment arms.     

Relevance of tenascin-C and matrix metalloproteinases in vascular abnormalities in murine hypoplastic lungs

BACKGROUND: Tenascin-C (TN-C), an extracellular matrix glycoprotein, is crucial to cell-migration, proliferation, apoptosis and remodeling of tissues, with a potential role in pathobiology of pulmonary hypertension. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are crucial to the integrity of the extracellular matrix. TN-C and MMPs are counter-regulatory molecules, which influence the vascular integrity through modulations of elastin. We have a murine model of pulmonary hypoplasia with coexistent diaphragmatic hernia, vascular abnormalities and excessive arterial smooth muscle cell (SMC) proliferation. OBJECTIVES: Our objective was to investigate modulations of TN-C and MMPs in hypoplastic lungs and their possible contribution to the observed pulmonary vascular abnormalities. METHODS: We addressed our objectives by pursing immunoblotting and immunohistochemistry and zymography/reverse zymography to assess the alterations in activities of MMPs and their inhibitors. RESULTS: We observed significant down-regulation of MMP-9 activity in hypoplastic lungs at the later fetal developmental stages, whereas MMP-2 activity assessed by gelatin zymography remained unaltered. Reverse zymography revealed up-regulation of activities of TIMP-1, -2, -3 and -4 in hypoplastic lungs during later fetal development, with pronounced increases in TIMP-3 and -4 activities. Furthermore, immunoblot analyses and immunohistochemistry revealed that TN-C protein was down-regulated in developing hypoplastic lungs, compared to normal lungs. CONCLUSIONS: (1)TN-C is known to inhibit vascular SMC proliferation. But, decrease in TN-C in hypoplastic lungs may support the observed arterial SMC proliferation. (2) Our studies showed that in hypoplastic lungs the SMC apoptosis is not affected, thus suggesting that SMC proliferation and apoptosis may be two separate processes in pulmonary hypoplasia with coexistent diaphragmatic hernia. Together, our data showed an imbalance in the extracellular matrix proteins, which may contribute to the pulmonary vascular abnormalities.