Improved 24-Hour Blood Pressure Control With Sirolimus Versus Calcineurin Inhibitor Based Immunosuppression in Renal Transplant Recipients

Introduction

Calcineurin inhibitors (CNI) have brought dramatic improvements in early renal allograft survival. However, CNI are associated with posttransplant hypertension (PTHTN), a risk factor for mortality from cardiovascular disease and graft failure. Sirolimus (SRL) is emerging as an alternative to CNI. SRL effects on blood pressure (BP) in humans are unclear. We compared the prevalence of PTHTN among patients receiving SRL as maintenance immunosuppression with a group receiving CNI by using 24-hour ambulatory BP (AMBP). AMBP has been shown to predict cardiovascular events and progression of kidney disease better than casual office BP measurements in chronic kidney disease (CKD) patients.

Methods

Renal transplant recipients with office hypertension (defined as BP > 130/80 or on antihypertensive medications), receiving stable immunosuppression and displaying consistent serum creatinine values for ≥6 months were eligible. We enrolled the first 40 patients to consent. Office BP was measured twice using a BP-Tru machine. AMBP was then analyzed for systolic BP (SBP), diastolic BP (DBP), and nocturnal blood pressure fall (NF; “dipping”). Patients were placed in the SRL group (n = 18) and the CNI group (n = 20) based on their maintenance immunosuppressive protocol. Two patients were excluded because of incomplete data. All patients received mycophenolate mofetil, and 14/38, maintenance steroids. We collected, demographics as well as type and date of renal allograft, medications, comorbidities, CKD stage, proteinuria, and plasma creatinine at the time of study enrollment.

Results

Patients in the SRL group displayed lower 24-hour SBP than the CNI group (128.0 ± 10.8 vs 137.7 ± 14; P = .029). Nightime MAP, nightime SBP, and nighttime DBP were all lower in the SRL group. NF did not reach significance between the SRL and CNI groups (44% vs 15%; P = .074). Patient demographics and number of antihypertensive medications did not differ.

Conclusion

The lower 24-hour SBP seen in the SRL group by AMBP may lead to improved cardiovascular and renal outcomes over time. Long-term patient follow-up will be needed to clarify the effect of the lower 24-hour SBP.     

Laminin alpha-1, alpha-3, and alpha-5 chain expression in human prepubertal [correction of prepubetal] benign prostate glands and adult benign and malignant prostate glands

BACKGROUND: Laminins (Lns) are a family of extracellular matrix glycoproteins located in the basement membrane (BM) of epithelial cells. They exist as heterotrimers composed of an alpha, beta, and gamma chain. Presently, five alpha (alpha1-5), three beta (beta1-3), and three gamma (gamma1-3) chains have been identified with different combinations of these chains resulting in 14 laminin heterotrimers thus far identified (1, 3-5). METHODS: In this study, using immunohistochemistry with chain-specific antibodies, we characterized the expression of the alpha1 (Lns-1/3), alpha3 (Lns 5,6,7), and alpha5 (Lns 10/11) chains in fetal, newborn, infant, prepubertal, and adult benign and malignant prostate glands. RESULTS: In general, alpha1 expression was higher in normal fetal prostate glands and declined by full-term birth, whereas the alpha3 and alpha5 chains remained highly expressed in the adult normal glands. In carcinoma alpha1 (Lns 1/3) and alpha5 (Lns 5,6,7) are lost, whereas alpha5 (Lns 10/11) persists. CONCLUSIONS: Alpha 1 (Lns 1/3) is prominent in BM, but is replaced by a laminin matrix rich in alpha3 (Lns 5,6,7) and alpha5 (Lns 10/11) in benign adult prostate glands. In carcinoma, both alpha1 (Lns-1/3) and alpha3 (Lns 5,6,7) are not expressed with persistence of a BM rich in alpha5 (Lns 10/11).     

老年大鼠松质骨骨重建的组织形态计量学研究

目的：研究老年大鼠及在促骨合成药前列腺素E2（PGE2）作用下松质骨骨重建和骨建造的形态计量学改变，探讨动物骨重建形态学新参数测量方法及其意义。方法：50只20月龄雄性Wistar大鼠随机分成5组，年龄对照组（基础组、10d和30d年龄对照组），PGE2给药组（分别10d和30d给予3mg/kg/d处理组）。用体内双荧光标记，不脱钙组织切片，粘合线（cement line）染色，骨组织形态计量学方法，测定骨重建和骨建造参数。结果：20月龄雄性大鼠胫骨近端松质骨的形成表面大多数为骨重建单位（占63．3％），少部分为骨建造单位（占26．7％）；PGE2用药后骨重建单位增加1．5倍，骨建造单位增加4倍，比值倒置，成骨细胞10d时明显增多。说明PGE2通过刺激成骨细胞骨合成而介民导骨建造性骨增加和骨重建性骨量增加，并以前为主。结论：老年雄性大鼠 松质骨以骨重建活动为主，仍有骨建造活动。PGE2主要通过刺激成骨细胞骨建造而增加骨量。     

Concomitant low-dose cisplatin and three-dimensional conformal radiotherapy for locally advanced squamous cell carcinoma of the head and neck: Analysis of survival and toxicity

BACKGROUND: Our center sought to implement a simple chemoradiotherapy schedule for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) with minimal toxicity to achieve rates of overall survival comparable to other schedules. METHODS: The chemoradiotherapy schedule consisted of daily radiation to 70 Gy over 7 weeks with concurrent cisplatin 20 mg/m(2) during days 1 to 4 of weeks 1 and 5. Acute and late toxicities were recorded according to the Radiation Therapy Oncology Group (RTOG) and common toxicity criteria (CTC) grading. The overall, disease-specific, and locoregional recurrence-free survival were calculated using the STATA statistics package. Possible factors influencing these endpoints were analyzed. RESULTS: Fifty-seven patients were treated, and 56 patients were evaluable for follow-up. Median follow-up of alive patients was 16.1 months. There was an 82% complete response rate to chemoradiotherapy. The 2-year Kaplan-Meier overall, disease-specific, and locoregional recurrence-free survival rates were 62%, 67%, and 63%. Acute grade 3 and 4 radiation toxicity was noted in 61% and 2%, respectively. Grade 3 or 4 hematologic toxicity was noted in 7% of patients. Factors influencing overall survival included: Karnofsky performance status, receiving more than 50% of planned chemotherapy, age, and initial hemoglobin level. CONCLUSION: This regimen is tolerable and achieves overall survival and locoregional control rates comparable to other chemoradiotherapy schedules.     

A soluble mouse brain splice variant of type 2alpha corticotropin-releasing factor (CRF) receptor binds ligands and modulates their activity

Peptides of the corticotropin-releasing factor (CRF) family signal through the activation of two receptors, CRF receptor type 1 (CRFR1) and type 2 (CRFR2), both of which exist as multiple splice variants. We have identified a cDNA from mouse brain encoding a splice variant, soluble CRFR2alpha (sCRFR2alpha), in which exon 6 is deleted from the gene encoding CRFR2alpha. Translation of this isoform produces a predicted 143-aa soluble protein. The translated protein includes a majority of the first extracellular domain of the CRFR2alpha followed by a unique 38-aa hydrophilic C terminus resulting from a frame shift produced by deletion of exon 6. By using RT-PCR and Southern hybridization, the relative mRNA expression levels of full-length (seven transmembrane domains) CRFR2alpha and the soluble form (sCRFR2alpha) in the mouse brain were measured with a single reaction. The results demonstrate high levels of expression of sCRFR2alpha in the olfactory bulb, cortex, and midbrain regions. A rabbit antiserum raised against a synthetic peptide fragment encoding the unique C terminus revealed specific sCRFR2alpha immunoreactivity in mouse brain slices by immunohistochemistry and in extracts of brain regions by RIA. Interestingly, the sCRFR2alpha immunoreactivity distribution closely approximated that of CRFR1 expression in rodent brain. A protein corresponding to sCRFR2alpha, expressed and purified from either mammalian or bacterial cell systems, binds several CRF family ligands with low nanomolar affinities. Furthermore, the purified sCRFR2alpha protein inhibits cellular responses to CRF and urocortin 1. These data support a potential role of the sCRFR2alpha protein as a possible biological modulator of CRF family ligands.     

Bedside ultrasonography: Applications in critical care: Part I

There is increasing interest in the use of ultrasound to assess and guide the management of critically ill patients. The ability to carry out quick examinations by the bedside to answer specific clinical queries as well as repeatability are clear advantages in an acute care setting. In addition, delays associated with transfer of patients out of the Intensive Care Unit (ICU) and exposure to ionizing radiation may also be avoided. Ultrasonographic imaging looks set to evolve and complement clinical examination of acutely ill patients, offering quick answers by the bedside. In this two-part narrative review, we describe the applications of ultrasonography with a special focus on the management of the critically ill. Part I explores the utility of echocardiography in the ICU, with emphasis on its usefulness in the management of hemodynamically unstable patients. We also discuss lung ultrasonography - a vastly underutilized technology for several years, until intensivists began to realize its usefulness, and obvious advantages over chest radiography. Ultrasonography is rapidly emerging as an important tool in the hands of intensive care physicians.