Medicine by Sfakianakis Alexandros: 01/16/16

Σάββατο 16 Ιανουαρίου 2016

The Association of Resting Heart Rate and Incident Hypertension: The Henry Ford Hospital Exercise Testing (FIT) Project

BACKGROUND

Given that sympathetic tone is associated with hypertension, we sought to determine whether resting heart rate (RHR), as a surrogate for cardiac autonomic function, was associated with incident hypertension.

METHODS

We analyzed 21,873 individuals without a history of hypertension who underwent a clinically indicated exercise stress test. Baseline RHR was assessed prior to testing and was categorized as <70, 70–85, and >85 beats-per-minute (bpm). Incident hypertension was defined by subsequent diagnosis codes for new-onset hypertension from three or more encounters. We tested for effect modification by age (<60 vs. ≥60 years), sex, race, and history of coronary heart disease (CHD).

RESULTS

Mean (±SD) age was 49 (±12) years, 55% were men and 21% were Black. Compared to the lowest RHR (<70 bpm) category, patients in the highest category (>85 bpm) were younger, more likely to be female, heavier, diabetic, and achieve lower metabolic equivalents (METS). Over a median of 4 years follow-up, there were 8,179 cases of incident hypertension. Compared to RHR <70 bpm, persons with RHR >85 bpm had increased risk of hypertension after adjustment for CHD risk factors, baseline blood pressure (BP), and METS (hazard ratio = 1.15 (95% confidence interval 1.08–1.23)). Age was an effect modifier (interaction P = 0.02), whereas sex, race, and CHD were not. In age-stratified analyses the relationship remained significant only in those younger than 60 years.

CONCLUSION

Elevated RHR is an independent risk factor for incident hypertension, particularly in younger persons. Whether lifestyle modification or other strategies to reduce RHR can prevent incident hypertension in high-risk individuals warrants further study.

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Association of Mineralocorticoid Receptor Polymorphism I180V With Left Ventricular Hypertrophy in Resistant Hypertension

OBJECTIVES

Genetic polymorphisms on mineralocorticoid receptor gene (NC3C2) are associated with variability of mineralocorticoid receptor (MR) function and cardiovascular implications. We sought to investigate whether I180V (rs5522) and MRc.-2G_C (rs2070951) polymorphisms in NR3C2 gene are associated with resistance to antihypertensive treatment and target-organ damage in resistant hypertensive (RHTN) patients.

METHODS

One hundred and eighty-one RHTN and 122 mild to moderate hypertensive (HTN) patients were enrolled in this study. Genotypes were obtained by allelic discrimination assay using real-time polymerase chain reaction. We determined pulse wave velocity (PWV), microalbuminuria, and left ventricular mass index to assess target-organ damage. We compared clinical and laboratorial characteristics of AA vs. G carriers for rs5522 and AC vs. GG vs. CG for rs2070951.

RESULTS

We did not found differences in allele, genotype, and haplotype frequencies for both polymorphisms between HTN and RHTN subjects. We found increased levels of aldosterone and ambulatory blood pressure (BP) in G carriers only for rs5522. Left ventricular hypertrophy (LVH) was more prevalent in G carriers than AA homozygous for rs5522 but not for rs2070951 in RHTN. On the other hand, microalbuminuria and PWV were similar among genotypes for both polymorphisms. No differences were observed between the haplotypes, except for higher aldosterone concentration in GG compared to AG and AC haplotypes.

CONCLUSION

Our study suggests that rs5522 polymorphism might affect cardiac remodeling and aldosterone levels in RHTN subjects.

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Cumulative Effects of Several Target Organ Damages in Risk Assessment in Hypertension

BACKGROUND

The prognostic value of screening multiple target organ damages (TODs) in hypertensive subjects has not been extensively studied. We estimated the prognostic value of considering 3 TODs in estimating the 10-year survival in hypertensive subjects.

METHODS

At baseline 1,848 out of a cohort of 1,963 hypertensive patients had a previous cardiovascular disease (CVD) or assessments of 3 TODs: Modification in Diet in Renal Disease (MDRD) <60ml/min or albuminuria >300mg/day, Sokolow index >3.5 mV, and advanced hypertensive retinopathy (grades 3 and 4 of Keith–Wagener–Barker classification). The cohort was divided into 5 groups: 0 TOD (N = 978), 1 TOD (N = 308), 2 TODs (N = 94), 3 TODs (N = 30), and previous CVD (N = 438).

RESULTS

After 10 years of follow-up, we observed 418 deaths of which 254 from cardiovascular cause. The adjusted hazard ratios for the major cardiovascular risk factors showed a progressive risk associated with the number of TODs. For all-cause death, the hazard ratios [95% confidence intervals] vs. 0 TOD of the other 4 groups were 1.91 [1.39–2.63], 1.99 [1.28–3.10], 4.33 [2.42–7.72], and 3.09 [2.35–4.05], respectively. For cardiovascular death, the hazard ratios [95% confidence intervals] were of the same order of magnitude: 2.14 [1.38–3.32], 2.12 [1.15–3.89], 4.22 [1.83–9.72], and 4.24 [2.95–6.11], respectively.

CONCLUSIONS

Our results indicate that hypertensive patients with several TODs had a worst outcome. Thus, it seems important to screen for multiple TODs in hypertension; especially check for severe hypertensive retinopathy in patients with left ventricular hypertrophy (LVH) and renal damage.

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Pesticides Exposure and Cardiovascular Hemodynamic Parameters Among Male Workers Involved in Mosquito Control in East Coast of Malaysia

BACKGROUND

Research findings have linked exposure to pesticides to an increased risk of cardiovascular (CVS) diseases. Therefore, this study aimed to assess the impact of chronic mix-pesticides exposure on CVS hemodynamic parameters.

METHODS

A total of 198 male Malay pesticide-exposed and 195 male Malay nonexposed workers were examined. Data were collected through exposure-matrix assessment, questionnaire, blood analyses, and CVS assessment. Explanatory variables comprised of lipid profiles, paraoxonase 1 (PON1), and oxidized low-density lipoprotein (ox-LDL). Outcome measures comprised of brachial and aortic diastolic blood pressure (DBP) and systolic BP (SBP), heart rate, and pulse wave velocity (PWV). Linear regressions identified the B coefficient showing how many units of CVS parameters are associated with each unit of covariates.

RESULTS

Diazoxonase was significantly lower and ox-LDL was higher among pesticide-exposed workers than the comparison group. The final multivariate linear regression model revealed that age, body mass index (BMI), smoking, and pesticide exposure were independent predictors of brachial and aortic DBP and SBP. Pesticide exposure was also associated with heart rate, but not with PWV. Lipid profiles, PON1 enzymes, and ox-LDL showed no association with any of the CVS parameters.

CONCLUSIONS

Chronic mix-pesticide exposure among workers involved in mosquito control has possible association with depression of diazoxonase and the increase in ox-LDL, brachial and aortic DBP and SBP, and heart rate. This study raises concerns that those using pesticides may be exposed to hitherto unrecognized CVS risks among others. If this is confirmed by further studies, greater efforts will be needed to protect these workers.

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Trends in Elevated Blood Pressure Among US Children and Adolescents: 1999-2012

BACKGROUND

The prevalence of elevated blood pressure (BP) has been reported to increase significantly among the US children and adolescents from 1988–1994 to 1999–2008. We aimed to examine the recent trends in BP levels and prevalence of elevated BP, as well as related influencing factors among US children and adolescents.

METHODS

Data of National Health and Nutrition Examination Survey (NHANES) 1999–2012 were combined into 3 time periods (1999–2002, 2003–2008, and 2009–2012) for the analysis. A total of 14,270 US children and adolescents aged 8–17 years were included in the current analysis. The sex-, age-, and height-BP standards recommended by the US Fourth Report were used to define high BP and elevated BP (including pre-HBP and HBP).

RESULTS

Mean systolic BP (SBP) and diastolic BP (DBP) decreased by 0.7 and 4.2mm Hg from 1999–2002 to 2009–2012, respectively. In 2009–2012, the prevalence of elevated BP and HBP in children and adolescents were 9.6% and 1.6%, with the absolute reduction of 2.8% and 1.3% from 1999–2002 to 2009–2012, respectively. In addition, daily intakes of total energy, carbohydrate, total saturated fatty acids, and caffeine decreased during the period between 1999–2002 and 2009–2012 (all P < 0.05), whereas daily intake of total polyunsaturated fatty acids and dietary fiber increased (P < 0.05).

CONCLUSIONS

Mean BP levels as well as the prevalence of elevated BP and HBP among US children and adolescents have declined during the past decade. In addition, there might be an associated change in dietary factors.

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Racial Disparity in Cognitive and Functional Disability in Hypertension and All-Cause Mortality

BACKGROUND

Subjective cognitive and functional limitations are early markers of future dementia and physical disability. Hypertension may increase the risk of dementia; however, the magnitude and significance of subjective limitations in the hypertensive US population are unknown, particularly in African Americans who bear the greatest burden of hypertension. Our objectives were to assess the prevalence and racial disparity of subjective cognitive and functional limitations and their impact on mortality in the hypertensive US population.

METHODS

We analyzed data from the National Health and Nutrition Examination Survey (NHANES) collected between 1999 and 2010 (N = 28,477; 31% with hypertension; 11% African American), which included blood pressure measurement, self-reported cognitive and functional (physical and non-physical) limitations, and all-cause mortality. Complex survey regression models were used.

RESULTS

In the United States, 8% of the hypertensive population reported cognitive and 25% reported functional limitations (vs. 5.7% and 15% respectively in the non-hypertensive population, P < 0.0001). Hypertensive African Americans carried the highest burden of cognitive (11%, P = 0.01) and functional (27%, P = 0.03) limitations compared to non-hypertensive African Americans and to non-African Americans. All-cause mortality was significantly higher in hypertensive individuals who reported cognitive or functional limitations (P < 0.0001 for both) relative to those without either.

CONCLUSIONS

The prevalence of cognitive and functional disability is larger in the US hypertensive population compared to the non-hypertensive population. African Americans with hypertension carry a disproportionate burden of these limitations. Individuals with hypertension who report cognitive or functional symptoms have higher all-cause mortality and query about these symptoms should be part of hypertension evaluation.

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Evaluating the Hemodynamic Basis of Age-Related Central Blood Pressure Change Using Aortic Flow Triangulation

BACKGROUND

Pulsatile blood pressure rises with age, especially in the aorta. The comparative role of forward and reflected pressure waves (FW and RW, respectively), determined by aortic flow triangulation has not previously been explored in a large clinical cohort. This study aimed to identify the role of FW and RW in the rise in aortic pulse pressure with age.

METHODS

For 879 outpatients, aortic pressure waveforms were generated using a validated generalized transfer function applied to radial pressure waves recorded using applanation tonometry. FW and RW were subsequently determined using aortic flow triangulation. Contributions of FW and RW to rise in aortic pulse pressure with age were determined using multivariate linear regression and product of coefficient mediation analysis, with adjustment for height, weight, heart rate, and mean arterial pressure. Comparisons were made by gender and before and after age 60.

RESULTS

In subjects aged 60 and below, RW was an important contributor to pulsatile pressure elevation with age, but FW was non-contributory in either gender after multivariate correction. In subjects aged above 60, both FW and RW were significant and equal contributors in both genders.

CONCLUSIONS

In a clinical setting, both FW and RW are important to pulsatile aortic blood pressure across the lifespan, but RW appears to have a more pronounced effect across all ages, whereas FW has less effect in younger persons.

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The Effect of Creatine Kinase Inhibition on Contractile Properties of Human Resistance Arteries

BACKGROUND

Creatine kinase (CK) is a main predictor of blood pressure, and this is thought to largely depend on high resistance artery contractility. We previously reported an association between vascular contractility and CK in normotensive pregnancy, but pregnancy is a strong CK inducer, and data on human hypertension are lacking. Therefore, we further explored CK-dependency of vascular contractility outside the context of pregnancy in normotensive and hypertensive women.

METHODS AND RESULTS

Nineteen consecutive women, mean age 42 years (SE 1.3), mean systolic/diastolic blood pressure respectively 142.6 (SE 5.9)/85.6 (3.4) mm Hg (9 hypertensive), donated an omental fat sample during abdominal surgery. We compared vasodilation after the specific CK inhibitor 2,4-dinitro-1-fluorobenzene (DNFB; 10^–6 mol/l) to sodium nitroprusside (10^–6 mol/l) in isolated resistance arteries using a wire myograph. Additionally, we assessed predictors of vasoconstrictive force. DNFB reduced vascular contractility to 24.3% (SE 4.4), P < 0.001, compared to baseline. Sodium nitroprusside reduced contractility to 89.8% (SE 2.3). Maximum contractile force correlated with DNFB effect as a measure of CK (r = 0.8), and with vessel diameter (r = 0.7). The increase in contractile force was 16.5 mN [9.1–23.9] per unit DNFB effect in univariable and 10.35 mN [2.10–18.60] in multivariable regression analysis.

CONCLUSION

This study extends on our previous findings in pregnant normotensive women of CK-dependent microvascular contractility, indicating that CK contributes significantly to resistance artery contractility across human normotension and primary hypertension outside the context of pregnancy. Further studies should explore the effect of CK inhibitors on clinical blood pressure.

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Augmented Blood Pressure Variability in Hypertension Induced by Angiotensin II in Rats

BACKGROUND

Augmented blood pressure (BP) variability is associated with cardiovascular diseases in some clinical conditions including hypertension. Drugs that effectively reduce BP variability need to be identified, while few animal models are currently available to study BP variability. Here, we report that hypertension induced by continuous infusion of angiotensin II (Ang II) was accompanied by increased BP variability in rats.

METHODS

Ang II was subcutaneously infused at a rate of 240 pmol/kg/min into male Wistar rats undergoing intraperitoneal implantation of a transmitter connected to an abdominal aortic catheter. BP was continuously monitored via a telemetry system before and after the Ang II infusion in a conscious, unrestrained condition. BP variability was evaluated by coefficient of variation (CV) of BP levels measured every 15 minutes. In addition, spontaneously hypertensive and Wistar-Kyoto rats (SHR and WKY) were subjected to the BP monitoring experiment at 15 weeks of age.

RESULTS

Both systolic and diastolic BP levels were significantly elevated following the Ang II infusion. Similarly, CVs of systolic and diastolic BP in the Ang II infusion group were significantly higher than in the vehicle group upon 1 and 2 weeks of the infusion. Meanwhile, CVs of systolic and diastolic BP of SHR were in a range similar to those of WKY despite significantly higher BP than in WKY.

CONCLUSIONS

Hypertension induced by the continuous infusion of Ang II was accompanied by augmented BP variability in rats, an effect assumed to be at least in part, independent of BP elevation.

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Effects of Cancer Therapy Targeting Vascular Endothelial Growth Factor Receptor on Central Blood Pressure and Cardiovascular System

BACKGROUND

In the last 2 decades, new drugs that oppose the effects of vascular endothelial growth factor receptor (VEGFR), and thus angiogenesis, have considerably improved treatment of solid tumors. These anti-VEGFR drugs, however, are burdened by several side effects, particularly relevant on heart and vessels. The aim of this study was to analyze the changes in cardiovascular structure and function associated with use of anti-VEGFR drugs.

METHODS

Twenty-nine patients (27 affected by renal and 2 by thyroid cancer), received treatment with anti-VEGFR drugs. Brachial blood pressure (BP), central BP, carotid-femoral pulse wave velocity (cfPWV), augmentation index (Aix), and several echocardiographic markers of systolic and diastolic left ventricular functions including global longitudinal strain were measured before starting treatment (T0), after 2 (T1), and 6 weeks (T2) of treatment.

RESULTS

Anti-VEGFR treatment was accompanied by a significant increase of both peripheral (systolic BP +13±15.5mm Hg, diastolic BP +7.1±9.3mm Hg, P < 0.001) and central BP (systolic BP +14±14.2mm Hg, diastolic BP +7.3±10.4mm Hg, P < 0.001) and a significant raise of cfPWV (+1.3±1.8 m/sec, P = 0.003). There was also a significant alteration of markers of diastolic and subclinical left ventricular systolic function, including global longitudinal strain (–19.9±3.8% at T0, –17.8±2.6% at T2, P < 0.05). All the changes were already evident at T1, worsened at T2 in patients who maintained oncological treatment, but disappeared at T2 in patients in whom treatment was stopped.

CONCLUSIONS

All the changes regarding BP and cfPWV appear early after treatment initiation and seem to be reversible if treatment is stopped, instead diastolic and systolic left ventricular function are persistently altered by anti-VEGFR drugs.

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Pharmacological thromboprophylaxis and total hip or knee replacement

British Journal of Nursing, Volume 25, Issue 1, Page 45-53, January 2016.

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Shared decision making for patients living with inflammatory arthritis

British Journal of Nursing, Volume 25, Issue 1, Page 31-35, January 2016.

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No health without a workforce, no workforce without nurses

British Journal of Nursing, Volume 25, Issue 1, Page 54-55, January 2016.

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A question of accountability

British Journal of Nursing, Volume 25, Issue 1, Page 75-75, January 2016.

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Management of the behavioural manifestations of Hunter syndrome

British Journal of Nursing, Volume 25, Issue 1, Page 22-30, January 2016.

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From staff nurse to nurse consultant

British Journal of Nursing, Volume 25, Issue 1, Page 66-66, January 2016.

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Calling into question the current NHS approach to patient safety: continued

British Journal of Nursing, Volume 25, Issue 1, Page 68-69, January 2016.

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Efficacy of the nurse ethicist in reducing moral distress: what can the NHS learn from the USA?

British Journal of Nursing, Volume 25, Issue 1, Page 36-39, January 2016.

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Screening mammography: There is a golden mammoth in the room!

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Bmp signaling in colonic mesenchyme regulates stromal microenvironment and protects from polyposis initiation

Abstract

In the colon, myofibroblasts are primary contributors in the establishment of the microenvironment involved in tissue homeostasis. Alterations in myofibroblast functions lead to changes resulting in a toxic microenvironment nurturing tumorigenesis. Bone morphogenetic proteins (Bmps) are morphogens known to play key roles in adult gut homeostasis. Studies in genetically-modified mice have shown that Bmp disruption in all cell layers leads to the development of gut polyposis. In contrast, our studies showed that loss of Bmp exclusively in the gastrointestinal epithelium resulted in increased epithelial proliferation without polyposis initiation, thus suggesting a key role for mesenchymal Bmp signaling in polyposis initiation. In order to identify the role of mesenchymal Bmp signaling on the microenvironment and its impact on colonic mucosa, a mouse model was generated with suppression of Bmp signaling exclusively in myofibroblasts (Bmpr1a ^ΔMES). Bmpr1a ^ΔMES mice exhibited increased subepithelial proliferation with changes in cellular composition leading to the development of a primed stroma with modulation of extracellular matrix proteins, immune cells and cytokines as early as 90 days of age. This microenvironmental deregulation was associated with increased polyposis initiation at one year of age. These results are the first to demonstrate that mesenchymal Bmpr1a inactivation alone is sufficient to prompt an expansion of myofibroblasts leading to the development of a reactive mesenchyme that contributes to polyposis initiation in the colon. These findings support the novel concept that inhibition of Bmp signaling in mesenchymal cells surrounding the normal epithelium leads to important changes instructing a toxic microenvironment sufficient to induce colonic polyposis. This article is protected by copyright. All rights reserved.

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β-Glucan restores tumor-educated dendritic cell maturation to enhance antitumor immune responses

Abstract

Tumors can induce the generation and accumulation of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) in a tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell-based cancer vaccines can initiate antitumor immune responses, tumor-educated dendritic cells (TEDCs) involved in the tolerance induction have attracted much attention recently. In this study, we investigated the effect of β-glucan on TEDCs and found that β-glucan treatment could promote the maturation and migration of TEDCs and that the suppressive function of TEDCs was signiﬁcantly decreased. Treatment with β-glucan drastically decreased the levels of regulatory T (Treg) cells but increased the infiltration of macrophages, granulocytes and DCs in tumor masses, thus elicited Th1 differentiation and cytotoxic T-lymphocyte responses and led to a delay in tumor progression. These findings reveal that β-glucan can inhibit the regulatory function of TEDCs, therefore revealing a novel function for β-glucan in immunotherapy and suggesting its potential clinical benefit. β-Glucan directly abrogated tumor-educated dendritic cells-associated immune suppression, promoted Th1 differentiation and cytotoxic T-lymphocyte priming and improved antitumor responses. This article is protected by copyright. All rights reserved.

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A pilot study of the utility of a laboratory-based spinal fixation training program for neurosurgical residents

Journal of Neurosurgery: Spine, Ahead of Print.
OBJECTIVE Pedicle and lateral mass screw placement is technically demanding due to complex 3D spinal anatomy that is not easily visualized. Neurosurgical and orthopedic surgery residents must be properly trained in such procedures, which can be associated with significant complications and associated morbidity. Current training in pedicle and lateral mass screw placement involves didactic teaching and supervised placement in the operating room. The objective of this study was to assess whether teaching residents to place pedicle and lateral mass screws using navigation software, combined with practice using cadaveric specimens and Sawbones models, would improve screw placement accuracy. METHODS This was a single-blinded, prospective, randomized pilot study with 8 junior neurosurgical residents and 2 senior medical students with prior neurosurgery exposure. Both the study group and the level of training-matched control group (each group with 4 level of training-matched residents and 1 senior medical student) were exposed to a standardized didactic education regarding spinal anatomy and screw placement techniques. The study group was exposed to an additional pilot program that included a training session using navigation software combined with cadaveric specimens and accessibility to Sawbones models. RESULTS A statistically significant reduction in overall surgical error was observed in the study group compared with the control group (p = 0.04). Analysis by spinal region demonstrated a significant reduction in surgical error in the thoracic and lumbar regions in the study group compared with controls (p = 0.02 and p = 0.04, respectively). The study group also was observed to place screws more optimally in the cervical, thoracic, and lumbar regions (p = 0.02, p = 0.04, and p = 0.04, respectively). CONCLUSIONS Surgical resident education in pedicle and lateral mass screw placement is a priority for training programs. This study demonstrated that compared with a didactic-only training model, using navigation simulation with cadavers and Sawbones models significantly reduced the number of screw placement errors in a laboratory setting.

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The 100 most-cited articles in spinal oncology

Journal of Neurosurgery: Spine, Ahead of Print.
OBJECTIVE The authors' objective was to identify the 100 most-cited research articles in the field of spinal oncology. METHODS The Thomson Reuters Web of Science service was queried for the years 1864–2015 without language restrictions. Articles were sorted in descending order of the number of times they were cited by other studies, and all titles and abstracts were screened to identify the research areas of the top 100 articles. Levels of evidence were assigned on the basis of the North American Spine Society criteria. RESULTS The authors identified the 100 most-cited articles in spinal oncology, which collectively had been cited 20,771 times at the time of this writing. The oldest article on this top 100 list had been published in 1931, and the most recent in 2008; the most prolific decade was the 1990s, with 34 articles on this list having been published during that period. There were 4 studies with Level I evidence, 3 with Level II evidence, 9 with Level III evidence, 70 with Level IV evidence, and 2 with Level V evidence; levels of evidence were not assigned to 12 studies because they were not on therapeutic, prognostic, or diagnostic topics. Thirty-one unique journals contributed to the 100 articles, with the Journal of Neurosurgery contributing most of the articles (n = 25). The specialties covered included neurosurgery, orthopedic surgery, neurology, radiation oncology, and pathology. Sixty-seven articles reported clinical outcomes. The most common country of article origin was the United States (n = 62), followed by Canada (n = 8) and France (n = 7). The most common topics were spinal metastases (n = 35), intramedullary tumors (n = 18), chordoma (n = 17), intradural tumors (n = 7), vertebroplasty/kyphoplasty (n = 7), primary bone tumors (n = 6), and others (n = 10). One researcher had authored 6 studies on the top 100 list, and 7 authors had 3 studies each on this list. CONCLUSIONS This study identified the 100 most-cited research articles in the area of spinal oncology. The studies highlighted the multidisciplinary and multimodal nature of spinal tumor management. Recognition of historical articles may guide future spinal oncology research.

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Lumbar paraspinal muscle morphometry and its correlations with demographic and radiological factors in adult isthmic spondylolisthesis: a retrospective review of 120 surgically managed cases

Journal of Neurosurgery: Spine, Ahead of Print.
OBJECTIVE The objective of this study was to assess the cross-sectional areas (CSAs) of lumbar paraspinal muscles in adults with isthmic spondylolisthesis (IS), to compare them with those in the normative population, and to evaluate their correlations with demographic factors and MRI changes in various spinal elements. METHODS The authors conducted a retrospective study of patients who had undergone posterior lumbar interbody fusion for IS, and 2 of the authors acting as independent observers calculated the CSAs of various lumbar paraspinal muscles (psoas, erector spinae [ES], multifidus [MF]) on preoperative axial T2-weighted MR images from the L-3 to L-5 vertebral levels and computed the CSAs as ratios with respect to the corresponding vertebral body areas. These values were then compared with those in an age- and sex-matched normative population and were analyzed with respect to age, sex, duration of symptoms, grade of listhesis, and various MRI changes at the level of the listhesis (pedicle signal change, disc degeneration, and facetal arthropathy). RESULTS Compared with values in normative controls, the mean CSA value for the ES muscle was significantly higher in the study cohort of 120 patients (p = 0.002), whereas that for the MF muscle was significantly lower (p = 0.009), and more so in the patients with PSC (p = 0.002). Magnetic resonance imaging signal change in the pedicle was seen in half of the patients, all of whom demonstrated a Type 2 change. Of the variables tested in a multivariate analysis, age independently predicted lower area values for all 3 muscles (p ≤ 0.001), whereas female sex predicted a lower mean psoas area value (p < 0.001). None of the other variables significantly predicted any of the muscle area values. A decrease in the mean MF muscle area value alone was associated with a significantly increased likelihood of a PSC (p = 0.039). CONCLUSIONS Compared with normative controls, patients with IS suffer selective atrophy of their MF muscle, whereas their ES muscle undergoes a compensatory hypertrophy. Advancing age has a detrimental effect on the areas of the lumbar PSMs, whereas female sex predisposes to a decreased psoas muscle area. Multifidus muscle atrophy correlates with PSC, indicating the role of this deep stabilizer in the biomechanical stability of spondylolisthetic spines. This may be of clinical significance in targeted physiotherapy programs during the conservative management of IS.

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Percutaneous pedicle screw placement into a spinal segment previously treated with vertebroplasty: technical note

Journal of Neurosurgery: Spine, Ahead of Print.
Vertebral augmentation with cement has become a common procedure for the treatment of compression fractures, leading to a growing population who have had this procedure and are now in need of another spinal surgery. This technical note reports an undescribed method for placing pedicle screws through a previously cemented level.

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Disc nucleus fortification for lumbar degenerative disc disease: a biomechanical study

Journal of Neurosurgery: Spine, Ahead of Print.
OBJECTIVE Spinal stability is attributed in part to osteoligamentous structures, including the vertebral body, facets, intervertebral discs, and posterior elements. The materials in this study provide an opportunity to augment the degenerated nucleus without removing native disc material, a procedure introduced here as "fortification." The objective of this study was to determine the effect of nucleus fortification on lumbar disc biomechanics. METHODS The authors performed in vitro analysis of human cadaveric functional spinal units (FSUs), along with characterization and quantification of movement of the units using biomechanical data in intact, disc-only, and fortified specimens. The units underwent removal of all posterior elements and annulus and were fortified by injecting a biogel into the nucleus pulposus. Each specimen was subjected to load testing, range of motion (ROM) quantification, and disc bulge measurements. Optoelectric tracking was used to quantify disc bulge. These criteria were assessed in the intact, disc-only, and fortified treatments. RESULTS Disc-only FSUs resulted in increased ROM when compared with intact and fortified conditions. Fortification of the FSU resulted in partial restoration of normal ROM in the treatment groups. Analysis of hysteresis loops showed more linear response in the fortified groups when compared with the intact and disc-only groups. CONCLUSIONS Disc nucleus fortification increases linearity and decreases ROM.

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The long-term recurrence of Rathke's cleft cysts as predicted by histology but not by surgical procedure

Journal of Neurosurgery, Ahead of Print.
OBJECTIVE Patients with symptomatic Rathke's cleft cysts (RCCs) managed by surgical treatment often experience recurrence. The authors attempted to clarify the outcome of surgically treated RCCs over a long-term follow-up period. METHODS Ninety-one consecutive RCC patients with a follow-up period of more than 12 months (mean 80.2 months, range 12–297 months) were retrospectively studied. The authors examined the clinical features and postoperative course of patients who experienced a reaccumulation of cyst contents visible on MRI after the initial surgery, and they investigated data from the patients who underwent reoperation for symptomatic recurrent RCCs. RESULTS Reaccumulation of cyst contents occurred in 36 patients (39.6%). In 34 of these patients, a reaccumulation occurred in the first 5 years after surgery. The initial cysts in these patients were most often large, with squamous metaplasia in the cyst walls. Thirteen patients (14.3%) with recurrent symptoms underwent a reoperation, and 10 of the 13 patients had a reaccumulation of RCCs within the 1st year after surgery. The reoperations were performed in the 1st year (61.5%) or several years later (23.1%). Patients were likely to initially have had a visual disturbance and the cyst walls likely included squamous metaplasia. However, no association was observed between the incidence of reaccumulation/reoperation of RCCs and the surgical procedure for RCCs. CONCLUSIONS The reaccumulation rate of RCC is high in the long-term period, and it is associated with the histological findings but not with the surgical procedure. Long-term monitoring, for a period of at least 5 years, should therefore be conducted to identify and assess any RCC reaccumulation.

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Genomic landscape of intracranial meningiomas

Journal of Neurosurgery, Ahead of Print.
Meningiomas are the most common primary intracranial neoplasms in adults. Current histopathological grading schemes do not consistently predict their natural history. Classic cytogenetic studies have disclosed a progressive course of chromosomal aberrations, especially in high-grade meningiomas. Furthermore, the recent application of unbiased next-generation sequencing approaches has implicated several novel genes whose mutations underlie a substantial percentage of meningiomas. These insights may serve to craft a molecular taxonomy for meningiomas and highlight putative therapeutic targets in a new era of rational biology-informed precision medicine.

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Eliminating unnecessary routine head CT scanning in neurologically intact mild traumatic brain injury patients: implementation and evaluation of a new protocol

Journal of Neurosurgery, Ahead of Print.
OBJECTIVE The utility of routine repeat head CT (HCT) scans in the management of minimal head injury (MHI) patients with an intracranial hemorrhage (ICH) has been questioned in multiple studies. All these studies analyzed this by obtaining a repeat HCT study, and none examined the effects of eliminating these routine HCT studies in neurologically intact patients. The authors' institution implemented a new "Neurologic Observation without Repeat HCT" (NORH) protocol with no repeat HCT scanning for patients admitted for MHI and ICH whose neurological status was maintained or improved to a Glasgow Coma Scale score of 15 at 24 hours after admission. This purpose of this study was to assess the outcomes and safety of this novel protocol. METHODS Records of patients who sustained blunt trauma MHI and an ICH and/or skull fracture on initial HCT between January 1, 2009, and December 31, 2012, were retrieved from the trauma registry of a Level I trauma center. The authors analyzed 95 patients in whom the NORH protocol was followed. Outcome measures included death, emergency department readmission, neurosurgical intervention, delayed repeat HCT, and length of stay. RESULTS The NORH protocol was followed for 95 patients; 83% of the patients were male, the average age was 38 ± 16.0 years old, and the most common cause of trauma was assault (35%). Of the 95 patients in whom the NORH protocol was followed, 8 (8%) had a delayed repeat HCT study (> 24 hours) after admission, but none resulted in neurosurgical intervention because of progression of ICH. The average length of stay was 4 ± 7.2 days. None of the patients were readmitted to the hospital. CONCLUSIONS Implementation of the NORH protocol (eliminating routine follow-up HCT) resulted in very low rates of delayed neurological deterioration, no late neurosurgical interventions resulting from ICH progression, very few emergency department revisits, and no readmissions. For a select group of MHI patients with ICH, the NORH protocol is safe and effective, and can reduce radiation exposure and costs.

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Endovascular management of internal carotid artery injuries secondary to endonasal surgery: case series and review of the literature

Journal of Neurosurgery, Ahead of Print.
OBJECTIVE Internal carotid artery (ICA) injury is a rare but severe complication of endonasal surgery. The authors describe their endovascular experience managing ICA injuries after transsphenoidal surgery; they review and summarize the current literature regarding endovascular techniques; and they propose a treatment algorithm based on the available evidence. METHODS A retrospective review of 576 transsphenoidal pituitary adenoma resections was performed. Cases of ICA injury occurring at our institution and transfers from other hospitals were evaluated. Endovascular treatments for ICA injury reported in the literature were also reviewed and summarized. RESULTS Seven cases were identified from the institutional cohort (mean age 46.3 years, mean follow-up 43.4 months [1–107 months]) that received endovascular treatment for ICA injury. Five injuries occurred at our institution (5 [0.9%] of 576), and 2 injuries occurred at outside hospitals. Three patients underwent ICA sacrifice by coil placement, 2 underwent lesion embolization (coil or stent-assisted coil placement), and 2 underwent endoluminal reconstruction (both with flow diversion devices). Review of the literature identified 98 cases of ICA injury treated with endovascular methods. Of the 105 total cases, 46 patients underwent ICA sacrifice, 28 underwent lesion embolization, and 31 underwent endoluminal reconstruction. Sacrifice of the ICA proved a durable solution in all cases; however, the rate of persistent neurological complications was relatively high (10 [21.7%] of 46). Lesion embolization was primarily performed by coil embolization without stenting (16 cases) and stent-assisted coiling (9 cases). Both techniques had a relatively high rate of at least some technical complication (6 [37.5%] of 16 and 5 [55.6%] of 9, respectively) and major technical complications (i.e., injury, new neurological deficit, or ICA sacrifice) (5 [31.3%] of 16 and 2 [22.2%] of 9, respectively). Endoluminal reconstruction was performed by covered stent (24 cases) and flow diverter (5 cases) placement. Covered stents showed a reasonably high rate of technical complications (10 [41.7%] of 24); however, 8 of these problems were resolved, leaving a small percentage with major technical complications (2 [8.3%] of 24). Flow diverter placement was also well tolerated, with only 1 minor technical complication. CONCLUSIONS Endovascular treatments including vessel sacrifice, coil embolization (with or without stent assistance), and endoluminal reconstruction offer a tailored approach to ICA injury management after endonasal surgery. Vessel sacrifice remains the definitive treatment for acute, uncontrolled bleeding; however, vessel preservation techniques should be considered carefully in select patients. Multiple factors including vascular anatomy, injury characteristics, and risk of dual antiplatelet therapy should guide best treatment, but more study is needed (particularly with flow diverters) to refine this decision-making process. Ideally, all endovascular treatment options should be available at institutions performing endonasal surgery.

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Patterns and Frequencies of Acquired and Constitutional Uniparental Isodisomies in Pediatric and Adult B-Cell Precursor Acute Lymphoblastic Leukemia

Abstract

Single nucleotide polymorphism (SNP) arrays are increasingly being used in clinical routine for genetic analysis of pediatric B-cell precursor acute lymphoblastic leukemias (BCP ALL). Because constitutional DNA is not readily available as a control at the time of diagnosis, it is important to be able to distinguish between acquired and constitutional aberrations in a diagnostic setting. In the present study we focused on uniparental isodisomies (UPIDs). SNP array analyses of 143 pediatric and 38 adult B-cell precursor acute lymphoblastic leukemias and matched remission samples revealed acquired whole chromosome or segmental UPIDs (wUPIDs, sUPIDs) in 32 cases (18%), without any age- or gender-related frequency differences. Acquired sUPIDs were larger than the constitutional ones (mean 35.3 Mb vs. 10.7 Mb; P<0.0001) and were more often terminally located in the chromosomes (69% vs. 4.5%; P<0.0001). Chromosomes 3, 5, and 9 were most often involved in acquired wUPIDs, whilst recurrent acquired sUPIDs targeted 6p, 9p, 9q, and 14q. The majority (56%) of sUPID9p was associated with homozygous CDKN2A deletions. In pediatric ALL, all wUPIDs were found in high hyperdiploid (51-67 chromosomes) cases and an extended analysis, also including unmatched diagnostic samples, revealed a higher frequency of wUPID-positivity in higher modal number (56-67 chromosomes) than in lower modal number (51-55 chromosomes) high hyperdiploid cases (34% versus 11%; P=0.04), suggesting different underlying mechanisms of formation of these subtypes of high hyperdiploidy. This article is protected by copyright. All rights reserved.

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ALK-Rearranged Renal Cell Carcinomas in Children

ABSTRACT

Knowledge of the clinicopathological and molecular spectrum of pediatric renal cell carcinomas (RCCs) remains limited, and approximately 16-24% of these neoplasms cannot be classified into specific subtypes. In our review of 168 pediatric RCC prospectively registered on Children's Oncology Group AREN03B2 protocol, we identified six RCC (3.5%) that demonstrated a unique epithelioid morphology and a peculiar immunophenotypic profile that includes expression of ALK, TFE3 and retention of INI1. Further investigation revealed ALK rearrangements in all cases, manifested molecularly by fusion transcripts of either VCL-ALK (3 patients all with sickle cell trait which had been previously reported) or TPM3-ALK (3 patients, none with sickle cell trait). Based on the shared unique morphologic, immunophenotypic and genetic features, we propose that these neoplasms belong to a distinct subgroup of RCC frequently occurring in pediatric patients, which we have termed ALK-rearranged RCC. Importantly, additional therapeutic options may be available for these patients. This article is protected by copyright. All rights reserved.

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HRAS mutation prevalence and associated expression patterns in pheochromocytoma

ABSTRACT

Pheochromocytomas (PCC) and abdominal paragangliomas (PGL) display a highly diverse genetic background and recent gene expression profiling studies have shown that PCC and PGL (together PPGL) alter either kinase signaling pathways or the pseudo-hypoxia response pathway dependent of the genetic composition. Recurrent mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been verified in sporadic PPGLs. In order to further establish the HRAS mutation frequency and to characterize the associated expression profiles of HRAS mutated tumors, we screened 156 PPGLs for exon 2 and 3 hotspot mutations in the HRAS gene, and compared with microarray-based gene expression profiles for 93 of the cases. The activating HRAS mutations G13R, Q61R and Q61K were found in 10/142 PCC (7.0%) and a Q61L mutation was revealed in 1/14 PGL (7.1%). All HRAS mutated cases included in the mRNA expression profiling grouped in Cluster 2, and 21 transcripts were identified as altered when comparing the mutated tumors with 91 HRAS wild-type PPGL. Somatic HRAS mutations were not revealed in cases with known PPGL susceptibility gene mutations and all HRAS mutated cases were benign. The HRAS mutation prevalence of all PPGL published up to date is 5.2% (49/950), and 8.8% (48/548) among cases without a known PPGL susceptibility gene mutation. The findings support a role of HRAS mutations as a somatic driver event in benign PPGL without other known susceptibility gene mutations. HRAS mutated PPGL cluster together with NF1- and RET-mutated tumors associated with activation of kinase-signaling pathways. This article is protected by copyright. All rights reserved.

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Guidelines for Genomic Array Analysis in Acquired Haematological Neoplastic Disorders

Abstract

Genetic profiling is important for disease evaluation and prediction of prognosis or responsiveness to therapy in neoplasia. Microarray technologies, including array comparative genomic hybridization and single-nucleotide polymorphism-detecting arrays have in recent years been introduced into the diagnostic setting for specific types of haematological malignancies and solid tumours. It can be used as a complementary test or depending on the neoplasia investigated, also as a standalone test. However, comprehensive and readable presentation of frequently identified complex genomic profiles remains challenging. To assist diagnostic laboratories, standardization and minimum criteria for clinical interpretation and reporting of acquired genomic abnormalities detected through arrays in neoplastic disorders are presented. This article is protected by copyright. All rights reserved.

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Frequent BCOR Aberrations in Extranodal NK/T-Cell Lymphoma, Nasal Type

Abstract

Extranodal natural killer/T cell lymphoma (ENKTL) is a rare subtype of lymphoma. Recurrent mutations in the JAK-STAT pathway, recently reported in ENKTL cases, are interesting in terms of both pathogenesis and inhibitor therapy. However, the frequencies of these mutations are low and variable among reports, and other pathognomonic mutations in ENKTL remain to be elucidated. In the present study, we performed targeted capture sequencing of 602 cancer-related genes from 25 frozen ENKTL samples, 11 of which were matched to normal samples. We identified several recurrent somatic mutations involving BCOR (32%), TP53 (16%), DDX3X (12%), FAT4 (8%), NRAS (8%), MLL3 (12%) and MIR17HG (8%). The pattern of BCOR aberrations (1 nonsense and 5 frame-shift mutations, a mutation leading to a splicing error, and gene loss) suggested that loss of function of BCOR was the functionally important outcome of such changes. We reviewed the literature and reanalyzed the public data on BCOR aberrations and found that the aberrations were frequently found in myeloid neoplasms, but, interestingly, were highly specific to ENKTL among lymphoid malignancies. Given the high frequency and pattern of aberration, BCOR is likely to play an important role in ENKTL pathogenesis as a tumor suppressor gene. This article is protected by copyright. All rights reserved.

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Work-Related Lung Diseases

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American Journal of Respiratory and Critical Care Medicine, Volume 193, Issue 2, Page P3-P4, January 15, 2016.

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Is the Road to Precision Medicine in Chronic Lung Disease Paved with Degraded Chitin?

American Journal of Respiratory and Critical Care Medicine, Volume 193, Issue 2, Page 107-108, January 15, 2016.

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Evaluating Risk Factors for Pediatric Post-extubation Upper Airway Obstruction Using a Physiology-based Tool

American Journal of Respiratory and Critical Care Medicine, Volume 193, Issue 2, Page 198-209, January 15, 2016.

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Written Action Asthma Plans: Not Such a Simple Issue in Subspecialist Care?

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American Journal of Respiratory and Critical Care Medicine, Volume 193, Issue 2, Page 221-222, January 15, 2016.

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Diagnosis of Post-extubation Stridor: Easier with Technology Support?

American Journal of Respiratory and Critical Care Medicine, Volume 193, Issue 2, Page 113-115, January 15, 2016.

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Macrophages, Inflammation, and Lung Cancer

American Journal of Respiratory and Critical Care Medicine, Volume 193, Issue 2, Page 116-130, January 15, 2016.

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Inhibition of Neutrophil Extracellular Trap Formation after Stem Cell Transplant by Prostaglandin E2

American Journal of Respiratory and Critical Care Medicine, Volume 193, Issue 2, Page 186-197, January 15, 2016.

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Reply: “Written Asthma Action Plans: The Devil’s in the Details” and “Written Action Asthma Plans: Not Such a Simple Issue in Subspecialist Care?”

American Journal of Respiratory and Critical Care Medicine, Volume 193, Issue 2, Page 222-223, January 15, 2016.

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Σάββατο 16 Ιανουαρίου 2016

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