Effect of dietary protein on the renin-angiotensin system in subtotally nephrectomized rats

Effect of dietary protein on the renin-angiotensin system in subtotally nephrectomized rats. Dietary protein restriction improves the course of renal disease in the remnant kidney model. Dietary protein restriction can also reduce plasma renin activity in several circumstances. We examined the interaction between dietary protein and the renin-angiotensin system in subtotally nephrectomized rats (1-2/3 nephrectomy). No difference was seen in tissue renin activity in rats ingesting a high (30%) versus a low (6%) protein diet. To determine the pathophysiological role of angiotensin II in subtotally nephrectomized rats, we examined the acute renal response to an intrarenal infusion of the angiotensin II antagonist Sar1 Gly8-angiotensin II (10 µg/kg/min). Only those subtotally nephrectomized animals ingesting a high protein diet exhibited a consistent improvement in glomerular permselectivity, as manifested by a 24% fall in the fractional clearance of albumin (basal 16.19 ± 3.65 × 10-4 vs. Sar1 Gly8-AII 12.26 ± 3.21 × 10-4; P < 0.02) and a 19% fall in the fractional clearance of IgG (basal 3.75 ± 0.67 × 10-4 vs. Sar1 Gly8-AII 3.03 ± 0.48 × 10-4; P < 0.02). No consistent change occurred in glomerular permselectivity in the rats on the low protein diet or rats infused with vehicle only. No change in mean arterial pressure or whole-kidney hemodynamics were seen with angiotensin II blockade. Decrements in SNGFR and glomerular capillary pressure occurred with angiotensin blockade in the animals ingesting the high protein diet, suggesting hemodynamic factors as a mechanism for the improvement in permselective defects. In conclusion, dietary protein intake determines the glomerular response to angiotensin II blockade, implicating local angiotensin II as an injurious factor with high protein feeding in subtotally nephrectomized rats

A Study of the Vertical Distribution of Periphyton Diatoms in Lake West Okoboji, lowa

A series of five stations, arranged as a bottom transect away from shore between the depths of 15 centimeters and 5 meters, was studied. During the three-month period of study (June, July, and August, 1964) there was an evident seasonal succession of dominant diatom species at all stations. In general, the greatest fluctuations in the dominant elements of the flora were noted in the shallower stations. Besides being more seasonally stable, the floras of the deeper stations were relatively more diverse on all dates sampled

Renal Effects of Aliskiren Compared With and in Combination With Irbesartan in Patients With Type 2 Diabetes, Hypertension, and Albuminuria

Objective: We investigated if the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to irbesartan, and the effect of the combination. Research Design and Methods: Double-blind, randomized, cross-over trial. After a one-month washout period 26 patients with type 2 diabetes, hypertension and albuminuria (>100mg/day) were randomized to four 2-month treatment periods in random order with placebo, aliskiren 300 mg once daily, irbesartan 300 mg once daily or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. Primary endpoint was change in albuminuria. Secondary measures included change in 24h blood pressure (24h BP) and glomerular filtration rate (GFR). Results: Placebo geometric mean albuminuria was 258 mg/day (range 84-2361), mean 24h BP was 140/73 (SD 15/8) mmHg, GFR was 89 (SD 27) ml/min/1.73 m(2). Aliskiren treatment reduced albuminuria by 48% (95% confidence interval 27-62) compared to placebo (p<0.001), not significantly different from irbesartan treatment (58% (42-70) (p<0.001 vs. placebo)). Combination treatment reduced albuminuria by 71% (59-79), more than either monotherapy (p<0.001 and p=0.028). Fractional clearances of albumin were significantly reduced (46, 56 and 67% reduction vs. placebo). 24h BP was reduced 3/4 mmHg by aliskiren (NS/p=0.009), 12/5 mmHg by irbesartan (p<0.001/p=0.002) and 10/6 mmHg by the combination (p=0.001/p<0.001). GFR was significantly reduced 4.6 (0.3, 8.8) ml/min/1.73m(2) by aliskiren, 8.0 (3.6, 12.3) ml/min/1.73m(2) by irbesartan and 11.7 (7.4, 15.9) ml/min/1.73m(2) by the combination. Conclusions: Combining aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria as compared to monotherapy

PET probe-guided surgery: applications and clinical protocol

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Cytokeratin 18 in plasma of patients with gastrointestinal adenocarcinoma as a biomarker of tumour response

BACKGROUND: Plasma biomarkers may be particularly useful as a predictor or early marker of clinical response to treatment in addition to radiological imaging. Cytokeratin 18 (CK18) is an epithelial-specific cytokeratin that undergoes cleavage by caspases during apoptosis. Measurement of caspase-cleaved (CK18-Asp396) or total cytokeratin 18 (CK18) from epithelial-derived tumours could be a simple, non-invasive way to monitor or predict responses to treatment. METHODS: Soluble plasma CK18-Asp396 and CK18 were measured by ELISA from 73 patients with advanced gastrointestinal adenocarcinomas before treatment and during chemotherapy, as well as 100 healthy volunteers. RESULTS: Both CK18-Asp396 and total CK18 plasma levels were significantly higher in patients compared with the healthy volunteers (P = 0.015, P &lt; 0.001). The total CK18 baseline plasma levels before treatment were significantly higher (P = 0.009) in patients who develop progressive disease than those who achieve partial response or stable disease and this correlation was confirmed in an independent validation set. The peak plasma levels of CK18 occurring in any cycle following treatment were also found to be associated with tumour response, but peak levels of CK18-Asp396 did not reach significance (P = 0.01, and P = 0.07, respectively). CONCLUSION: Plasma levels CK18 are a potential marker of tumour response in patients with advanced gastrointestinal malignancy

Involvement of circulating CEA in liver metastases from colorectal cancers re-examined in a new experimental model

Both experimental and clinical data show evidence of a correlation between elevated blood levels of carcinoembryonic antigen (CEA) and the development of liver metastases from colorectal carcinomas. However, a cause-effect relationship between these two observations has not been demonstrated. For this reason, we developed a new experimental model to evaluate the possible role of circulating CEA in the facilitation of liver metastases. A CEA-negative subclone from the human colon carcinoma cell line CO115 was transfected either with CEA-cDNA truncated at its 3' end by the deletion of 78 base pairs leading to the synthesis of a secreted form of CEA or with a full-length CEA-cDNA leading to the synthesis of the entire CEA molecule linked to the cell surface by a GPI anchor. Transfectants were selected either for their high CEA secretion (clone CO115-2C2 secreting up to 13 microg CEA per 10(6) cells within 72 h) or for their high CEA membrane expression (clone CO115-5F12 expressing up to 1 x 10(6) CEA molecules per cell). When grafted subcutaneously, CO115-2C2 cells gave rise to circulating CEA levels that were directly related to the tumour volume (from 100 to 1000 ng ml(-1) for tumours ranging from 100 to 1000 mm3), whereas no circulating CEA was detectable in CO115 and CO115-5F12 tumour-bearing mice. Three series of nude mice bearing a subcutaneous xenograft from either clone CO115-2C2 or the CO115-5F12 transfectant, or an untransfected CO115 xenograft, were further challenged for induction of experimental liver metastases by intrasplenic injection of three different CEA-expressing human colorectal carcinoma cell lines (LoVo, LS174T or CO112). The number and size of the liver metastases were shown to be independent of the circulating CEA levels induced by the subcutaneous CEA secreting clone (CO115-2C2), but they were directly related to the metastatic properties of the intrasplenically injected tumour cells

Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing

Pancreatic adenocarcinoma (PAC) is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, evaluation of separate cases may reveal aberrations, that are less common but may provide relevant information on the disease, or that may represent viable therapeutic targets for the patient. We used next generation sequencing to assess global somatic events across 3 PAC patients to characterize each patient and to identify potential targets. This study is the first to report whole genome sequencing (WGS) findings in paired tumor/normal samples collected from 3 separate PAC patients. We generated on average 132 billion mappable bases across all patients using WGS, and identified 142 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. We did not identify any significant somatic translocation events. We also performed RNA sequencing on 2 of these patients' tumors for which tumor RNA was available to evaluate expression changes that may be associated with somatic events, and generated over 100 million mapped reads for each patient. We further performed pathway analysis of all sequencing data to identify processes that may be the most heavily impacted from somatic and expression alterations. As expected, the KRAS signaling pathway was the most heavily impacted pathway (P<0.05), along with tumor-stroma interactions and tumor suppressive pathways. While sequencing of more patients is needed, the high resolution genomic and transcriptomic information we have acquired here provides valuable information on the molecular composition of PAC and helps to establish a foundation for improved therapeutic selection

Pointing to visible and invisible targets

We investigated how the visibility of targets influenced the type of point used to provide directions. In Study 1 we asked 605 passersby in three localities for directions to well-known local landmarks. When that landmark was in plain view behind the requester, most respondents pointed with their index fingers, and few respondents pointed more than once. In contrast, when the landmark was not in view, respondents pointed initially with their index fingers, but often elaborated with a whole-hand point. In Study 2, we covertly filmed the responses from 157 passersby we approached for directions, capturing both verbal and gestural responses. As in Study 1, few respondents produced more than one gesture when the target was in plain view and initial points were most likely to be index finger points. Thus, in a Western geographical context in which pointing with the index finger is the dominant form of pointing, a slight change in circumstances elicited a preference for pointing with the whole hand when it was the second or third manual gesture in a sequence