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cGMP-dependent protein kinase type I is a major mediator of cGMP signaling in the cardiovascular system. Recent studies on cardiac-specific PRKG1 knockout mice demonstrated that cGMP-dependent protein kinase type I mediates the negative inotropic effect of cGMP in the myocardium. We therefore investigated the association between left ventricular (LV) function and common polymorphisms in the PRKG1 gene in a general population. In 609 randomly selected participants (51.2% women; mean age, 48.8 years; 36.6% hypertensive) who were free from overt cardiac disease, we performed echocardiography and genotyped intronic tag single-nucleotide polymorphisms (SNPs) rs1904694, rs7897633, and rs7905063 in PRKG1. On the basis of color Doppler myocardial motion data, we calculated end-systolic longitudinal and radial deformation (strain) of the LV inferolateral wall. In multivariable-adjusted analyses accounting for confounders and relatedness, systolic radial strain was significantly (P⩽0.005) higher in homozygotes for rs1904694 (GG), rs7897633 (AA), and rs7905063 (U) compared with heterozygotes or noncarriers. Haplotype analysis confirmed that LV radial strain was significantly higher in GAT homozygotes than in noncarriers (62.3% versus 56.0%; P=0.0005). Transmission of the PRKG1 GAT haplotype to informative offspring was associated with higher LV radial strain (effect size, 6.11%; P=0.017). For other LV phenotypes, none of the phenotype-genotype associations reached statistical significance. In conclusion, LV systolic radial function was associated with common polymorphisms in PRKG1. If experimental studies and longitudinal follow-up of LV function confirm the causality of this association, interference with cGMP-dependent protein kinase type I function might be a target for pharmacological intervention. [ABSTRACT FROM AUTHOR]

Defective pressure-natriuresis related to abnormalities in the natriuretic response has been associated with hypertension development. A major signaling pathway mediating pressure natriuresis involves the cGMP-dependent protein kinase 1 (PRKG1) that, once activated by Src kinase, inhibits renal Na+ reabsorption via a direct action on basolateral Na-K ATPase and luminal Na-H exchanger type 3, as shown in renal tubuli of animals. Because a clear implication of PRKG1 in humans is still lacking, here we addressed whether PRKG1 polymorphisms affect pressure-natriuresis in patients. Naive hypertensive patients (n=574), genotyped for PRKG1 rs1904694, rs7897633, and rs7905063 single nucleotide polymorphisms (SNPs), underwent an acute Na+ loading, and the slope of the pressure-natriuresis relationship between blood pressure and Na+ excretion was calculated. The underlying molecular mechanism was investigated by immunoblotting protein quantifications in human kidneys. The results demonstrate that the PRKG1 risk haplotype GAT (rs1904694, rs7897633, rs7905063, respectively) associates with a rightward shift of the pressure- natriuresis curve (0.017±0.004 μEq/mmHg per minute) compared with the ACC (0.0013±0.003 μEq/mmHg per minute; P=0.001). In human kidneys, a positive correlation of protein expression levels between PRKG1 and Src (r=0.83; P<0.001) or al Na-K ATPase (r=0.557; P<0.01) and between al Na-K ATPase and Na-H exchanger type 3 (r=0.584; P<0.0 1) or Src (r=0.691; P<0.001) was observed in patients carrying PRKG1 risk GAT (n=23) but not ACC (n=14) variants. A functional signaling complex among PRKG1, α1 Na-K ATPase, and Src was shown by immunoprecipitation from human renal caveolae. These findings indicate that PRKG1 risk alleles associate with salt-sensitivity related to a loss of the inhibitory control of renal Na+ reabsorption, suggestive of a blunt pressure-natriuresis response. [ABSTRACT FROM AUTHOR]

Abstract: Trastuzumab, in combination with chemotherapy, is the gold standard in the adjuvant treatment of patients with HER2 positive breast cancer. Limited data are available on the role of adjuvant trastuzumab in the elderly population. We performed a systematic review of prospective randomized trials with available data on the use of adjuvant trastuzumab in patients older than 60years, focusing on both the efficacy and the cardiac safety. Data extrapolated from two prospective trials were included for efficacy and cardiac safety. A significant 47% relative risk reduction was observed in elderly patients receiving trastuzumab compared to chemotherapy alone (pooled Hazard Ratio: 0.53; 95% CI, 0.36–0.77). The pooled proportion of cardiac events in elderly patients treated with trastuzumab was 5% (95% CI, 4–7%). The use of trastuzumab should be considered as a standard of care in the adjuvant therapy of elderly patients with HER-2 positive breast cancer. Acute and chronic medical conditions, nutritional status and level of daily activities should be considered. Uncertainty about cardiac safety in the elderly is a major concern. [Copyright &y& Elsevier]

Abstract: Purpose: One method of treating urinary incontinence is to create a catheterizable and continent vesicostomy by the Mitrofanoff principle, based on the use of a conduit, which in the original method is the appendix. The authors present an experimental technique in which a continent vesicostomy is created by the Mitrofanoff principle, using a conduit made of a labial mucosa free graft. Methods: Six 30-day-old pigs underwent surgery to create a continent vesicostomy by the Mitrofanoff principle. A tube, made of labial mucosa free graft from the lower lip, was used. The labial mucosal conduit was anastomosed to the bladder mucosa. The tunnel was then prepared, part of which passed through the fibers of the right rectus muscle. The conduit was taken through the tunnel and anastomosed to the skin in the right iliac fossa. Results: Fifty days after the operation, the vesicostomy was continent, pervious, and easily catheterizable in 5 animals. In the sixth pig, the cystostomic tube did not graft successfully because it was infected. Conclusions: A number of investigators have extrapolated Mitrofanoff method using the ileum, the ureter, or others. The use of a tube made by labial mucosa free graft is an easily performed technique, and as with the Mitrofanoff method, continence and easy catheterization are successfully achieved. [Copyright &y& Elsevier]

The kidney plays an important role in salt and blood pressure (BP) homeostasis. In previous studies, variants in the genes for alpha-adducin (ADD1), WNK1, and NEDD4L, which all regulate renal sodium absorption, have been associated with increased BP. However, findings have been inconsistent. We tested whether this is because of physiological interactions between the effects of variants in these genes. We assessed the single and combined effects of the ADD1 (Gly460Trp), WNK1 (rs880054 A/G), and NEDD4L (rs4149601 G/A) polymorphisms on renal and BP response to an acute Na load (n=344 subjects), BP decrease after 1 month of treatment with 12.5 mg of hydrochlorothiazide (n=193), and ambulatory 24-hour BP (n=690). Individually, the variants showed modest effects on some of the studied phenotypes. We found the ADD1 Trp allele to be permissive for the effects of variants of the other genes. In combination, the same variants (ADD1 Trp/WNK1 GG/Nedd4L GA+AA) showed a consistent effect on renal Na handling (P=0.009) and acute BP response to a saline infusion (P=0.021), BP lowering after thiazide treatment (P=0.008), and nocturnal systolic BP (P=0.044). Physiological interaction between the ADD1 and WNK1-NEDD4L pathways influences the effects of variants in these genes on sodium-related BP regulation. Relatively common alleles in the ADD1, WNK1, and NEDD4L genes when present in combination may have significant effects on renal sodium handling, BP, and antihypertensive response to thiazides. [ABSTRACT FROM AUTHOR]

This article discusses the relationship between the genetic regulation of renal sodium absorption and the prevention of hypertension. Patients with varying genetic polymorphisms are monitored for their ability to absorb sodium at the basal and luminal tubular cell membranes of nephron segments. The study focuses on the connection between a set of alleles that effect sodium transport and blood pressure, as they relate to patient responses to thiazide type drugs.

Summary: Essential hypertension is a heterogeneous multifactorial syndrome associated with a high cardiovascular risk. A multiple choice of antihypertensive drugs is available; however, a high individual variability to the antihypertensive therapy is still responsible for a modest reduction of the CV risk and not satisfactory control of blood pressure levels. The success of future hypertension treatment will depend upon the understanding of the genetic molecular mechanisms operating in subsets of patients, and the ability of new drugs to specifically correct such alterations. Two mechanisms, among others, are involved in determining the abnormalities of tubular Na+ reabsorption observed in essential hypertension: the polymorphism of the cytoskeletal protein α-adducin and the increased circulating levels of endogenous ouabain (EO). Both lead to increased activity and expression of the renal Na–K pump, the driving force for tubular Na transport. Morphological and functional cardiovascular alterations have also been associated with adducin and EO. Rostafuroxin is a new oral antihypertensive agent able to selectively antagonize adducin and EO hypertensive and molecular effects. It is endowed with high potency and efficacy in reducing blood pressure and preventing organ hypertrophy in animal models representative of both adducin and EO mechanisms. At molecular level, in the kidney, Rostafuroxin normalizes the enhanced activity of the Na–K pump induced by adducin mutation and antagonizes the EO triggering of the Src-EGFr-dependent signaling pathway leading to renal Na–K pump, and ERK Tyrosin phosphorylation and activation. In the vasculature, it normalizes the increased myogenic tone caused by ouabain. A very high safety ratio and an absence of interaction with other mechanisms involved in blood pressure regulation, together with initial evidence of high tolerability and efficacy in hypertensive patients, indicate Rostafuroxin as the first example of a new class of antihypertensive agents designed to antagonize adducin and EO-hypertensive mechanisms. Currently, a phase II multicenter European clinical trial is ongoing for providing the proof of concept that such a compound is effective in the subset of patients where these two mechanisms are at work. [Copyright &y& Elsevier]

The angiotensin-converting enzyme (ACE) I/D and the alpha-adducin (ADD1) Gly460Trp polymorphisms are associated with cardiovascular risk factors. In a prospective population study and in cell models, we investigated the combined effects of these 2 polymorphisms. We randomly recruited 1287 white subjects (women: 50.0%; mean age: 55.9 years). We obtained outcomes from registries and repeat examinations (median 3). Over 9.0 years (median), 178 fatal or nonfatal cardiovascular events occurred. In ADD1 Trp allele carriers, the multivariate-adjusted hazard ratios associated with ACE DD versus I were 1.72 (P=0.007) for total mortality, 2.35 (P=0.02) for cardiovascular mortality, 2.02 (P=0.005) for all cardiovascular events, and 2.59 (P=0.03) for heart failure. In contrast, these hazard ratios did not reach significance in ADD1 GlyGly homozygotes (0.08

The article examines the relationship of angiotensin-converting enzyme (ACE) (I/D) and the αadducin (ADDI) Gly460Trp polymorphisms with cardiovascular risk factors. Results show that hazard ratios associated with ACE DD versus I did not reach significance in ADDI GlyGly homozygotes. It concludes that the combination of ACE DD homozygosity and mutated ADDI worsened cardiovascular prognosis, possibly because of increased membrane-bound ACE activity in subjects carrying the ADDI Trp allele.

Purpose: The aim of the present study was to compare the mechanical behavior of some devices used for femoral fixation of doubled hamstring tendon graft in anterior cruciate ligament (ACL) reconstruction when included in a graft fixation complex (GFC). Methods: An ACL reconstruction was performed on 90 porcine knees. The graft used was the doubled lateral extensor of toes (DLET). Nine different femoral fixation devices were tested and classified according to their fixation mechanism: compression (Bioscrew and RCI screw); expansion (Rigidfix); cortical suspension (Ligament Anchor, EndoButton-CL, and Swing Bridge); cancellous suspension (Linx-HT); and cortical-cancellous suspension (Transfix and Bio-Transfix). All GFC were subjected to a cyclic loading test, then to a load-to-failure test. Graft elongation after 1,000 load cycles, failure load, and stiffness were calculated for each device. Results: Regarding graft elongation, Bioscrew and RCI screws showed the highest mean values. All the other GFC showed no significant differences between them when δ elongation (elongation1,000 cycles − elongation20 cycles) was considered. For failure load, the highest mean values were observed for Bio-Transfix, Transfix, and Swing Bridge; a homogeneous subset with the lowest mean values was formed by Ligament Anchor, RCI screw, Bioscrew, and Linx-HT. For stiffness, the greatest values were observed for Bio-Transfix, Transfix, and Swing Bridge; all other groups showed no significant differences between them. Conclusions: Cortical-cancellous suspension fixation seemed to offer the best and most predictable results in terms of elongation, fixation strength, and stiffness. For both compression and suspension, the weakest fixation was attained with cancellous fixation devices. Cortical suspension devices showed a greatly variable mechanical behavior, according to their design. Clinical Relevance: Transcondylar devices offer the best structural properties for femoral fixation of doubled hamstring tendon graft in ACL reconstruction. [Copyright &y& Elsevier]

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

• Deltoid ligament lesion in ankle fracture. • Chronic medial ankle pain and instability. • Surgical reconstruction of the medial ligamentous complex. • Prevention of ankle instability and articular damage. The repair of a deltoid ligament injury, following an ankle fracture with involvement of the syndesmosis, has no univocal consensus. Also the surgical strategies in case of a subsequent chronic instability are still under debate. In this work the result of a double bundle anatomic reconstruction of deltoid ligament with ipsilateral autologous gracilis muscle tendon is presented. A 50 year old active male patient came to our attention with a catastrophic medial ankle instability, a severe pronation of the hindfoot and disabling ankle pain. He reported a Weber type B fracture of the left ankle with a lesion of the syndesmosis treated with anatomic plate and screws and a transyndesmotic screw 8 months before. The imaging showed a complete deltoid ligament lesion. Due to the impossibility of a direct repair of the ligament, we performed the reconstruction of the medial ligamentous complex with an autologous gracilis tendon graft. 10 months after the medial ligamentous complex reconstruction, the patient showed an excellent recovery of walking ability, disappearance of pain under load and resumed an active lifestyle. The deltoid ligament has a key role in ankle joint stability and its integrity promotes the recovery after ankle fractures. However, its lesion is often left untreated in the acute setting. The result of a chronic untreated deltoid ligament injury could be extremely disabling and the ligament reconstruction, when an optimal native deltoid ligament repair is not achievable, is the choice to restore ankle function and stability. In the delayed treatment of a deltoid ligament rupture the described double bundle anatomic reconstruction with autologous tendon graft can be an effective and suitable option. [ABSTRACT FROM AUTHOR]