Tripeptide aldehyde protease inhibitors may depress in vitro prolactin and growth hormone release

The effects of novel nontoxic tripeptide aldehyde inhibitors of proteolytic enzymes were examined in order to investigate the possibility that serine-thiol protease(s) may be involved in PRL and GH secretion. Rat anterior pituitary cells maintained in culture for 7-8 days or freshly taken pituitary quarters were treated with BOC-DPhe-Pro-Arg-H (BOC-dPPA), DPhe-Pro-Arg-H (dPPA), BOC-DPhe-Leu-Lys-H (BOC-dPLL), or BOC-DPhe-Phe-Lys (BOC-dPPL). Newly synthetized [3H]PRL and [3H]GH as well as immunoreactive (i) hormones (iPRL, iGH) were measured in the incubation media and cell homogenates. Four hours of incubation in the presence of 0.1 mM dPPA resulted in a 30% decrease of [3H]PRL and iPRL release by cell cultures; the inhibition by BOC-dPPA was 60% and 48%, respectively. [3H]PRL biosynthesis was unchanged or slightly decreased. The effect of these tripeptide aldehydes on [3H]GH and iGH release was less pronounced but statistically significant. Pituitary quarters treated with 1.0 or 3.0 mM BOC-dPPA release 20% and 57% less [3H]PRL than the controls. In the same system BOC-dPPA in a 1.0 mM concentration did not effect GH secretion, and 3.0 mM BOC-dPPA inhibited [3H]GH output by 27%. Forty micromolars of BOC-dPPL decreased by 47%, 0.2 mM by 79%, and 1.0 mM by 94% [3H]PRL release from pituitary quarters. GH secretion was not influenced. A similar selectivity was observed when BOC-dPLL was used. It is clear that by serine-thiol protease inhibitors whose effects are sequence and dose dependent, PRL and GH release are decreased. The relative inhibiting potency on PRL release was BOC-dPPL greater than BOC-dPLL greater than BOC-dPPA greater than dPPA. The biosynthesis of [3H]PRL was reduced only in the presence of the highest tripeptide aldehyde concentrations or long (8 h) exposure, and only 1.0 mM Boc-dPPL reduced [3H]GH biosynthesis by 30%. The data suggest that proteolysis may be involved in the process of PRL and GH release and the enzyme(s) in question may be serine-thiol protease(s).     

Mouse DNA polymerase alpha-primase terminates and reinitiates DNA synthesis 2-14 nucleotides upstream of C2A1-2(C2-3/T2) sequences on a minute virus of mice DNA template.

The distribution of termination and initiation sites in a 5081-nucleotide minute virus of mice DNA template being copied by a highly purified mouse DNA polymerase alpha-DNA primase complex in the presence of GTP has been examined. The 3'-hydroxyl termini (17 in all) were clustered at six sites that were located 2-14 nucleotides upstream of C2A2C2, C2AC3, or C2A2T2 sequences. When either [alpha-32P]- or [gamma-32P]GTP was included in the DNA polymerase reaction mixtures, nascent DNA became radiolabeled. Analysis of the 32P-labeled material following treatment of the DNA with tobacco acid pyrophosphatase, bacterial alkaline phosphatase, or ribonuclease T1 revealed the presence of oligoribonucleotide chains averaging 5-7 nucleotides long and beginning with 5' GTP residues. Eight presumptive DNA primase initiation sites were located opposite C4 or C5 sequences 3-9 nucleotides upstream of one of the three closely related hexanucleotides C2A2C2, C2AC3, and C2A2T2. RNA-DNA junctions were found 3-10 nucleotides downstream of DNA primase initiation sites. The results indicate that hexanucleotides having the general formula C2A1-2(C2-3/T2), herein referred to as psi, are involved in promoting termination of DNA synthesis and/or de novo initiation of RNA-primed DNA chains by DNA polymerase alpha-primase.     

Arterialisation of the Portal Vein With an Aortoportal Jump Graft for Portal Vein Thrombosis Following Liver Resection for Malignancy

Fibrolamellar hepatocellular carcinoma (FHCC) is a variant of hepatocellular carcinoma, which mainly affects a young age group and carries a relatively good prognosis. It is widely accepted that aggressive curative resection is still the best option for FHCC. We report here a case of successful arterialisation of the portal vein with an aortoportal jump graft for portal vein thrombosis, which developed postoperatively in an already comprised portal vein with tumour invasion following an extensive liver resection for FHCC.     

Ambulatory blood pressure monitoring and progression in patients with IgA nephropathy.

BACKGROUND: Hypertension is a recognized marker of poor prognosis in IgA nephropathy. METHODS: The present study investigated the prevalence of white-coat hypertension, the diurnal rhythm of blood pressure (BP), the effectiveness of antihypertensive drug therapy, and the effect of the above on the progression of the kidney disease in IgA nephropathy. One hundred twenty-six IgA nephropathy patients were selected consecutively for 24-h ambulatory blood pressure monitoring (ABPM). Fifty-five patients were normotensive and 71 were treated hypertensives. Their antihypertensive drugs were angiotensin-converting enzyme inhibitors (ACEI) alone or in combination with calcium-channel blockers (CCB). RESULTS: The mean night-time BP of normotensives (108+/-9/67+/-6 mmHg) was significantly lower than their day-time BP (125+/-8/82+/-7 mmHg, P<0.05). There was no significant difference between the mean day-time and night-time BP in hypertensive patients (125+/-9/82+/-7 mmHg vs 128+/-10/85+/-9 mmHg). The circadian variation of BP was preserved ('dippers') in 82% of the normotensive and 7% of the hypertensive patients (P<0.001). There were 10 'white-coat hypertensives' among the patients classified as normotensives with ABPM (mean office blood pressure 149+/-7/96+/-8 mmHg, 24-h blood pressure 127+/-6/83+/-5 mmHg, P<0.05) and 14 among treated hypertensives (mean office BP 152+/-8/98+/-6 mmHg, 24-h BP 130+/-4/85+/-8 mmHg, P<0.05). There was no difference in mean day-time BP among normotensive and treated hypertensive patients (125+/-8/81+/-5 mmHg vs 128+/-10/85+/-9 mmHg). Hypertensives had significantly higher night-time BP (125+/-9/85+/-9 mmHg) than normotensives (108+/-9/67+/-6 mmHg, P<0.001). There was no difference in serum creatinine levels among the different groups at the time of the ABPM. However, thirty-six+/-4.1 months after the ABPM, hypertensive patients (n=52) had higher serum creatinine levels (124+/-32 micromol/l) than at the time of the ABPM (101+/-28 micromol/l). The serum creatinine of normotensive patients (n=43) did not change during the follow-up period. 'Non-dipper' normotensives (n=10) had significantly higher serum creatinine levels at the end of the follow-up period than at its beginning (106+/-17 micromol/l vs 89+/-18 micromol/l, P<0.05). There was no increase in serum creatinine of 'dipper' normotensives. The mean serum creatinine of 'white-coat hypertensives' was significantly higher at the end of the study period than at its beginning. CONCLUSIONS: There is no diurnal blood pressure variation in most of the hypertensive IgA nephropathy patients. ACEI and CCB treatment have better effect on day-time than night-time hypertension. The lack of the circadian rhythm and 'white-coat hypertension' seems to accelerate the progression of IgA nephropathy.     

Prevalence and seasonal variation of hypovitaminosis D and its relationship to bone metabolism in healthy Hungarian men over 50 years of age: the HunMen Study

Summary

This study reports a high prevalence of hypovitaminosis D and low bone mineral density (BMD) in a healthy Hungarian male cohort over 50 years of age. Men with 25-hydroxyvitamin D levels of <75 nmol/L had a significantly higher 10-year hip and major osteoporotic fracture probability using the country-specific fracture risk assessment (FRAX) algorithm.

Introduction

The aim of this study is to characterize the prevalence and seasonal variation of hypovitaminosis D and its relationship to bone metabolism in healthy Hungarian men over 50 years of age.

Methods

We determined levels of 25-hydroxyvitamin D (25-OH-D), PTH, osteocalcin (OC), C-terminal telopeptides of type-I collagen (CTX-I), procollagen type 1 amino-terminal propeptide (PINP), BMD at L1–L4 (LS) and femur neck (FN), daily dietary calcium intake, and the 10-year probability of hip fracture and a major osteoporotic fracture using the country-specific FRAX algorithm in 206 randomly selected ambulatory men.

Results

The mean (range) age of the volunteers was 60 (51–81) years. The prevalence of hypovitaminosis D (25-OH-D, <75 nmol/L) was 52.9%. The prevalence of low (T-score?<??1.0) BMD at the FN and LS was 45% and 35.4%, respectively. The mean (range) FRAX hip fracture and FRAX major osteoporotic fracture was 0.8% (0–9.4%) and 3.8% (1.7–16%), respectively. On comparing the vitamin D sufficient to the insufficient group, there was a statistically significant difference between the FRAX hip fracture and FRAX major osteoporotic fracture indexes. There was significant seasonal variation in the vitamin D levels; the lowest levels were measured in winter and the highest in summer.

Conclusions

A high prevalence of hypovitaminosis D and low BMD were observed in the studied Hungarian male population. This is the first study reporting higher 10-year hip and major osteoporotic fracture probability using the country-specific FRAX algorithm in individuals with hypovitaminosis D.     

Reproducibility of proton MR spectroscopic imaging (PEPSI): comparison of dyslexic and normal-reading children and effects of treatment on brain lactate levels during language tasks

BACKGROUND AND PURPOSE: We repeated a proton echo-planar spectroscopic imaging (PEPSI) study to test the hypothesis that children with dyslexia and good readers differ in brain lactate activation during a phonologic judgment task before but not after instructional treatment. METHODS: We measured PEPSI brain lactate activation (TR/TE, 4000/144; 1.5 T) at two points 1-2 months apart during two language tasks (phonologic and lexical) and a control task (passive listening). Dyslexic participants (n = 10) and control participants (n = 8) (boys and girls aged 9-12 years) were matched in age, verbal intelligence quotients, and valid PEPSI voxels. In contrast to patients in past studies who received combined treatment, our patients were randomly assigned to either phonologic or morphologic (meaning-based) intervention between the scanning sessions. RESULTS: Before treatment, the patients showed significantly greater lactate elevation in the left frontal regions (including the inferior frontal gyrus) during the phonologic task. Both patients and control subjects differed significantly in the right parietal and occipital regions during both tasks. After treatment, the two groups did not significantly differ in any brain region during either task, but individuals given morphologic treatment were significantly more likely to have reduced left frontal lactate activation during the phonologic task. CONCLUSION: The previous finding of greater left frontal lactate elevation in children with dyslexia during a phonologic judgment task was replicated, and brain activation changed as a result of treatment. However, the treatment effect was due to the morphologic component rather than the phonologic component.     

The fate of dendritic cells in a mouse model of liver ischemia/reperfusion injury

Ischemia/reperfusion during liver transplantation triggers a complex cascade of inflammatory events that may lead to organ dysfunction. Herein, we investigated the consequences of hepatic ischemia/reperfusion on liver dendritic cells. Liver damage was documented by increased levels of serum alanine aminotransferase and by histopathology showing large areas of hepatocyte cytolysis. MHC class II+ CD45-B220 F4/80 dendritic cells were detected in necrotic areas 20 hours after reperfusion. Dendritic cells freshly isolated from reperfused livers displayed a mature phenotype characterized by upregulated expression of B7 costimulatory molecules; MHC-class II, and CD1d molecules. As shown by real-time PCR, IL-10, and TGF-beta mRNA accumulated in liver dendritic cells isolated after reperfusion, whereas IL-12p40 mRNA levels were decreased and IFN-gamma mRNA levels were unchanged. These results suggest that hepatic ischemia/reperfusion results in maturation of dendritic cells, which preferentially produce inhibitory cytokines.     

Tumor Infiltration in the Medial Resection Margin Predicts Survival After Pancreaticoduodenectomy for Pancreatic Ductal Adenocarcinoma

Background

Microscopic tumor involvement (R1) in different surgical resection margins after pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) has been debated.

Methods

Clinico-pathological data for 258 patients who underwent PD between 2001 and 2010 were retrieved from a prospective database. The rates of R1 resection in the circumferential resection margin (pancreatic transection, medial, posterior, and anterior surfaces) and their prognostic influence on survival were assessed.

Results

For PDAC, the R1 rate was 57.1?% (48/84) for any margin, 31.0?% (26/84) for anterior surface, 42.9?% (36/84) for posterior surface, 29.8?% (25/84) for medial margin, and 7.1?% (3/84) for pancreatic transection margin. Overall and disease-free survival for R1 resections were significantly worse than those for R0 resection (17.2 vs. 28.7?months, P?=?0.007 and 12.3 vs. 21.0?months, P?=?0.019, respectively). For individual margins, only medial positivity had a significant impact on survival (13.8 vs. 28.0?months, P?<?0.001), as opposed to involvement in the anterior (19.7 vs. 23.3?months, P?=?0.187) or posterior margin (17.5 vs. 24.2?months, P?=?0.104). Multivariate analysis demonstrated R0 medial margin was an independent prognostic factor (P?=?0.002, HR?=?0.381; 95?% CI 0.207?C0.701).

Conclusion

The medial surgical resection margin is the most important after PD for PDAC, and an R1 resection here predicts poor survival.